Progressive reduction of synaptophysin message in single neurons in Alzheimer disease.
The data presented here examine 2 hypotheses: 1) that viable but vulnerable single neurons remaining in the Alzheimer brain lose synaptic markers, and 2) that the extent of this loss is related to the disease state of these single neurons when disease state is defined by immunoreactivity. We used double immunohistochemistry (IHC) to define neurofibrillary tangle (NFT) and phosphorylation status of tau at selected defined epitopes. This double IHC was combined with quantitative in situ hybridization for message for the synaptic marker, synaptophysin, in 1,127 single hippocampal CA1 pyramidal neurons from 15 Alzheimer disease (AD) and 4 control cases. We found that there is a graded, progressive, decrease of synaptophysin message expressed by single neurons related to immunohistochemical markers of tau status, and that neurons in similar immunohistochemically defined classes show similar losses of synaptophysin message regardless of whether they were sampled from clinical control brains or advanced AD. The resulting conclusions are consistent with a suggestion that differences among clinically defined AD and control status are defined by the numbers of neurons in various disease states.


Coping with Racial Discrimination: Assessing the Vulnerability of African Americans and the Mediated Moderation of Psychosocial Resources.
Research demonstrates that the mental health of African Americans is negatively affected by discrimination, but few studies have investigated the effects of racial discrimination specifically and whether these effects vary by poverty and education levels. Using a sample of 3,372 African Americans from the National Survey of American Life (NSAL), we find a positive relationship between racial discrimination and depressive symptoms, with both lifetime and daily racial discrimination being more salient for depressive symptoms among impoverished African Americans than those living above 200% of the poverty line. Evaluating mediated moderation models, we also find that the conditional effects of socioeconomic status are mediated by poor African Americans' having fewer psychosocial resources. Namely, lower levels of mastery are influential in accounting for poor African Americans' greater vulnerability to both daily and lifetime discrimination. The findings highlight the importance of examining specific reasons for discrimination as well as mediated moderation in future research.


A Phylogeographic Assessment of the Malagasy Giant Chameleons (Furcifer verrucosus and Furcifer oustaleti).
The Malagasy giant chameleons (Furcifer oustaleti and Furcifer verrucosus) are sister species that are both broadly distributed in Madagascar, and also endemic to the island. These species are also morphologically similar and, because of this, have been frequently misidentified in the field. Previous studies have suggested that cryptic species are nested within this chameleon group, and two subspecies have been described in F. verrucosus. In this study, we utilized a phylogeographic approach to assess genetic diversification within these chameleons. This was accomplished by (1) identifying clades within each species supported by both mitochondrial and nuclear DNA, (2) assessing divergence times between clades, and (3) testing for niche divergence or conservatism. We found that both F. oustaleti and F. verrucosus could be readily identified based on genetic data, and within each species, there are two well-supported clades. However, divergence times are not contemporary and spatial patterns are not congruent. Diversification within F. verrucosus occurred during the Plio-Pleistocene, and there is evidence for niche divergence between a southwestern and southeastern clade, in a region of Madagascar that shows no obvious landscape barriers to dispersal. Diversification in F. oustaleti occurred earlier in the Pliocene or Miocene, and niche conservatism is supported with two genetically distinct clades separated at the Sofia River in northwestern Madagascar. Divergence within F. verrucosus is most consistent with patterns expected from ecologically mediated speciation, whereas divergence in F. oustaleti most strongly matches the patterns expected from the riverine barrier hypothesis.


Electrophysiology and biochemical analysis of cyclocreatine uptake and effect in hippocampal slices.
In in vitro mouse hippocampal slices we investigated whether cyclocreatine is capable of entering brain cells independently of the creatine transporter and if it reproduces the neuroprotective effect of creatine. Our study shows that cyclocreatine does not increase the creatine content, but is taken up as such and then phosphorylated to phosphocyclocreatine. This uptake is largely blocked by inactivation of the creatine transporter, however some cyclocreatine is taken up and posphorylated even after such inactivation. Thus, cyclocreatine sets up a cyclocreatine/phosphocyclocreatine system in the brain independently of the creatine transporter. Cyclocreatine did not delay the disappearance of the evoked synaptic potentials during anoxia in hippocampal slices, unlike creatine which exerts a neuroprotective effect.


Herpetic meibomianitis: an unusual case report.
Herpes simplex virus (HSV) infection of the eye can vary from mild blepharitis to sight threatening choreoretinitis. Primary infection of the eye is usually sub-clinical but reactivation of a latent infection can lead to recurrent disease. Although, herpetic blepharitis is a well documented entity, this virus has so far not been incriminated in the causation of meibomianitis, an inflammatory condition of the meibomian gland. This paper reports a case of meibomianitis due to Herpes simplex virus.


Expression and clinical significance of serum MMP-7 and PTEN levels in patients with acute myeloid leukemia.
The aim of this study was to examine the changes of serum matrix metalloproteinase-7 (MMP-7) and phosphatase and tension homolog (PTEN) in patients with acute myeloid leukemia (AML) at different time points following treatment. The levels of serum MMP-7 and PTEN were measured from 80 AML patients with a diagnosis of peripheral blood, immune cell phenotype, and bone marrow puncture cytology examination. Among these, there were 20 cases of complete remission, 20 cases of primary untreated patients, 21 cases of incomplete remission, and 19 cases of relapse after remission. In addition, 20 healthy adults with normal physical examination results were enrolled as the control group. Patients were divided into different groups according to the treatment period. Serum MMP-7 and PTEN levels in patients and the healthy control group were measured using an ELISA. Compared with the control group, the levels of MMP-7 of 20 primary untreated patients were significantly increased (P<0.05), while there was no significant difference for the levels of PTEN in the incomplete remission group. A comparison between the control and complete remission groups revealed that the levels of MMP-7 and PTEN in the serum samples of 21 cases of patients with incomplete remission were significantly increased (P<0.05). In addition, the content of MMP-7 in 19 patients in relapse after remission group was significantly higher (P<0.05) than that of the complete remission and healthy control groups, while the levels of serum PTEN did not show significant changes. In conclusion, the level of serum MMP-7 and PTEN in AML patients was closely related to the clinical stage and the degree of disease. The combination of MMP-7 and PTEN may provide theoretical support for the accurate diagnosis, understanding of efficacy, prognosis and improvement of survival rate of AML.


Pediatric facial fractures: recent advances in prevention, diagnosis and management.
During the last 25 years, there have been considerable advances in the prevention, diagnosis and management of craniomaxillofacial injuries in children. When compared to adults, the pattern of fractures and frequency of associated injuries are similar but the overall incidence is much lower. Diagnosis is more difficult than in adults and fractures are easily overlooked. Clinical diagnosis is best confirmed by computed tomographic (CT) scans. Treatment is usually performed without delay and can be limited to observation or closed reduction in non-displaced or minimally displaced fractures. Operative management should involve minimal manipulation and may be modified by the stage of skeletal and dental development. Open reduction and rigid internal fixation is indicated for severely displaced fractures. Primary bone grafting is preferred over secondary reconstruction and alloplastic materials should be avoided when possible. Children require long-term follow-up to monitor potential growth abnormalities. This article is a review of the epidemiology, diagnosis and management of facial fractures in children.


Perceived need to take medication is associated with medication non-adherence in patients with rheumatoid arthritis.
This is the first cross-sectional study that aims to examine associations between beliefs about medication and non-adherence in patients with rheumatoid arthritis (RA) using disease-modifying antirheumatic drugs, taking potential psychological confounders into account. Eligible patients (diagnosed with RA for ≥1 year or ≥18 years, using greater than or equal to one disease-modifying antirheumatic drug) were included by their rheumatologist during regular outpatient visits between September 2009 and September 2010. Included patients received questionnaires. The Beliefs about Medicines Questionnaire was used to measure the perceived need to take medication (necessity beliefs), the concerns about taking medication (concern beliefs), general medication beliefs, and attitudes toward taking medication. Medication non-adherence (no/yes) was measured using the Compliance Questionnaire Rheumatology (CQR). Associations between beliefs and non-adherence, and the influence of demographical, clinical, and psychological factors (symptoms of anxiety/depression, illness cognitions, self-efficacy) were assessed using logistic regression. A total of 580 of the 820 eligible patients willing to participate were included in the analyses (68% female, mean age 63 years, 30% non-adherent to their medication). Weaker necessity beliefs (OR [odds ratio]: 0.8, 95% CI [confidence interval]: 0.8-0.9) and an unfavorable balance between necessity and concern beliefs (OR: 0.9, 95% CI: 0.9-1.0) were associated with CQR non-adherence. Also, having an indifferent attitude toward medication (no/yes) was associated with CQR non-adherence (OR: 5.3, 95% CI: 1.1-25.8), but the prevalence of patients with an indifferent attitude toward medication was low. The associations were barely confounded by demographical, clinical, and psychological factors. Increasing necessity beliefs about medication in clinical practice might be worthwhile in improving medication adherence in RA patients.


Optimized Extraction Method To Remove Humic Acid Interferences from Soil Samples Prior to Microbial Proteome Measurements.
The microbial composition and their activities in soil environments play a critical role in organic matter transformation and nutrient cycling. Liquid chromatography coupled to high-performance mass spectrometry provides a powerful approach to characterize soil microbiomes; however, the limited microbial biomass and the presence of abundant interferences in soil samples present major challenges to proteome extraction and subsequent MS measurement. To this end, we have designed an experimental method to improve microbial proteome measurement by removing the soil-borne humic substances coextraction from soils. Our approach employs an in situ detergent-based microbial lysis/TCA precipitation coupled to an additional cleanup step involving acidified precipitation and filtering at the peptide level to remove most of the humic acid interferences prior to proteolytic peptide measurement. The novelty of this approach is an integration to exploit two different characteristics of humic acids: (1) Humic acids are insoluble in acidic solution but should not be removed at the protein level, as undesirable protein removal may also occur. Rather it is better to leave the humics acids in the samples until the peptide level, at which point the significant differential solubility of humic acids versus peptides at low pH can be exploited very efficiently. (2) Most of the humic acids have larger molecule weights than the peptides. Therefore, filtering a pH 2 to 3 peptide solution with a 10 kDa filter will remove most of the humic acids. This method is easily interfaced with normal proteolytic processing approaches and provides a reliable and straightforward protein extraction method that efficiently removes soil-borne humic substances without inducing proteome sample loss or biasing protein identification in mass spectrometry. In general, this humic acid removal step is universal and can be adopted by any workflow to effectively remove humic acids to avoid them negatively competing with peptides for binding with reversed-phase resin or ionization in the electrospray.


Multilocus analysis of the catfish family Trichomycteridae (Teleostei: Ostariophysi: Siluriformes) supporting a monophyletic Trichomycterinae.
Trichomycteridae is the second most diverse family of the order Siluriformes, its members are widely distributed through the freshwaters of Central and South America, exhibiting an exceptional ecological and phenotypic disparity. The most diverse subfamily, Trichomycterinae, represented mainly by the genus Trichomycterus, historically has been recognized as non-monophyletic and various characters used to unite or divide its constituents are repeatedly called into question. No comprehensive molecular phylogenetic hypothesis regarding relationships of trichomycterids has been produced, and the present study is the first extensive phylogeny for the family Trichomycteridae, based on a multilocus dataset of three mitochondrial loci and two nuclear markers (3284bp total). Our analysis has the most comprehensive taxon-sampling of the Trichomycteridae published so far, including members of all subfamilies and a vast representation of Trichomycterus diversity. Analysis of these data showed a phylogenetic hypothesis with broad agreement between the Bayesian (BI) and maximum-likelihood (ML) trees. The results provided overwhelming support for the monophyletic status of Copionodontinae, Stegophilinae, Trichomycterinae, and Vandelliinae, but not Sarcoglanidinae and Glanapteryginae. A major feature of our results is the support to the current conceptualization of Trichomycterinae, which includes Ituglanis and Scleronema and excludes the "Trichomycterus" hasemani group. Divergence time analysis based on DNA substitution rates suggested a Lower Cretaceous origin of the family and the divergence events at subfamilial level shaped by Paleogene events in the geohistory of South America. This hypothesis lays a foundation for an array of future studies of evolution and biogeography of the family.


Structure of the fetal brain: what we are learning from diffusion tensor imaging.
Human brain anatomy is extraordinarily complex, and yet, its origin is a simple tubular structure. It is characterized by dramatic structural changes during fetal development. Revealing detailed anatomy at different stages of human fetal brain development not only aids in understanding this highly ordered process but also provides clues to detect abnormalities caused by genetic or environmental factors. However, anatomical studies of human brain development during this period are surprisingly scarce, and histology-based atlases have become available only recently. Diffusion tensor imaging (DTI), a recently developed technology of magnetic resonance imaging (MRI), is capable of noninvasively delineating macroscopic anatomical components with high contrast and revealing structures at the microscopic level. In this article, the fetal brain white matter is explored using contrasts from DTI-derived images and axonal reconstruction from DTI tractography. The highly organized structures in the cerebral layer have been revealed with primary direction of diffusion tensors. Complementary to the histology, the DTI of the fetal brain provides a valuable resource to understand the structural development of the entire brain. The resultant database will provide reference standards for diagnostic radiology of premature newborns.


Three RNA binding proteins form a complex to promote differentiation of germline stem cell lineage in Drosophila.
In regenerative tissues, one of the strategies to protect stem cells from genetic aberrations, potentially caused by frequent cell division, is to transiently expand the stem cell daughters before further differentiation. However, failure to exit the transit amplification may lead to overgrowth, and the molecular mechanism governing this regulation remains vague. In a Drosophila mutagenesis screen for factors involved in the regulation of germline stem cell (GSC) lineage, we isolated a mutation in the gene CG32364, which encodes a putative RNA-binding protein (RBP) and is designated as tumorous testis (tut). In tut mutant, spermatogonia fail to differentiate and over-amplify, a phenotype similar to that in mei-P26 mutant. Mei-P26 is a TRIM-NHL tumor suppressor homolog required for the differentiation of GSC lineage. We found that Tut binds preferentially a long isoform of mei-P26 3'UTR, and is essential for the translational repression of mei-P26 reporter. Bam and Bgcn are both RBPs that have also been shown to repress mei-P26 expression. Our genetic analyses indicate that tut, bam, or bgcn is required to repress mei-P26 and to promote the differentiation of GSCs. Biochemically, we demonstrate that Tut, Bam, and Bgcn can form a physical complex in which Bam holds Tut on its N-terminus and Bgcn on its C-terminus. Our in vivo and in vitro evidence illustrate that Tut acts with Bam, Bgcn to accurately coordinate proliferation and differentiation in Drosophila germline stem cell lineage.


Endoscopic variceal ligation caused massive bleeding due to laceration of an esophageal varicose vein with tissue glue emboli.
Endoscopic variceal obturation of gastric varices with tissue glue is considered the first choice for management of gastric varices, and is usually safe and effective. However, there is still a low incidence of complications and some are even fatal. Here, we present a case in which endoscopic variceal ligation caused laceration of the esophageal varicose vein with tissue glue emboli and massive bleeding after 3 mo. Cessation of bleeding was achieved via variceal sclerotherapy using a cap-fitted gastroscope. Methods of recognizing an esophageal varicose vein with tissue glue plug are discussed.


Preferential Lineage-Specific Differentiation of Osteoblast-Derived Induced Pluripotent Stem Cells into Osteoprogenitors.
While induced pluripotent stem cells (iPSCs) hold great clinical promise, one hurdle that remains is the existence of a parental germ-layer memory in reprogrammed cells leading to preferential differentiation fates. While it is problematic for generating cells vastly different from the reprogrammed cells' origins, it could be advantageous for the reliable generation of germ-layer specific cell types for future therapeutic use. Here we use human osteoblast-derived iPSCs (hOB-iPSCs) to generate induced osteoprogenitors (iOPs). Osteoblasts were successfully reprogrammed and demonstrated by endogenous upregulation of Oct4, Sox2, Nanog, TRA-1-81, TRA-16-1, SSEA3, and confirmatory hPSC Scorecard Algorithmic Assessment. The hOB-iPSCs formed embryoid bodies with cells of ectoderm and mesoderm but have low capacity to form endodermal cells. Differentiation into osteoprogenitors occurred within only 2-6 days, with a population doubling rate of less than 24 hrs; however, hOB-iPSC derived osteoprogenitors were only able to form osteogenic and chondrogenic cells but not adipogenic cells. Consistent with this, hOB-iOPs were found to have higher methylation of PPARγ but similar levels of methylation on the RUNX2 promoter. These data demonstrate that iPSCs can be generated from human osteoblasts, but variant methylation patterns affect their differentiation capacities. Therefore, epigenetic memory can be exploited for efficient generation of clinically relevant quantities of osteoprogenitor cells.


Multiple genetic analyses for Chinese Hunan Han population via 46 A-STRs.
Short tandem repeats (STRs) are important as common genetic markers in forensic identification and population genetics due to their highly polymorphic nature. To explore genetic polymorphisms of the Chinese Hunan Han population and further dissect genetic relationships among the Hunan Han and other populations from China. In this study, samples of 394 unrelated healthy individuals from the Chinese Hunan Han population were analysed using 46 autosomal-STRs (A-STRs). Thirteen previously reported populations (6378 individuals) from China were subsequently collected for population genetic analyses based on 23 shared A-STRs. In the Hunan Han population, a total of 452 alleles were detected in 46 A-STRs with allelic frequencies spanning from 0.0013 to 0.5571. Except for the Penta D locus in linkage disequilibrium, the combined power of discrimination and the combined power of exclusion for 45 A-STRs in the Hunan Han population were 0.999999999999999999999999999999999999999999999999510314 and 0.999999999999999726596, respectively. Results of interpopulation differentiation, principal component analysis, and phylogenetic relationship analyses uniformly showed that the Hunan Han have closer genetic affinities with Han populations from different Chinese regions and a geographically close ethnic minority group, namely the Hubei Tujia. To summarise, these 46 A-STRs showed high polymorphism in the Chinese Hunan Han population for forensic practice.


Asthma nurse practice improves outcomes and reduces costs in primary health care.
The aim of this study was to elucidate the care of patients with asthma in primary health care from medical, patient self-management, health, quality of life, and health economic perspectives. Asthma nurse practice (ANP), an alternative asthma self-management strategy, was compared with traditional asthma care in primary health care in southern Sweden regarding medical history, lifestyle, self-management, symptoms caused by asthma, effects on sick leave, state of health, quality of life and health care costs. The first part of the investigation comprised a retrospective study of a randomly selected sample of patient records of asthmatics (n=152). The second part, lasting 3 months, was prospective and included consecutive patients visits (n=347). The ANP approach showed better results in most of the evaluated outcomes such as asthma quality documentation and self-management and the number of asthma symptoms was significantly lower. From a health economic perspective the results were encouraging with respect to ANP. This alternative asthma strategy, ANP, improved asthma care in primary health care and resulted in economic advantages in the health care sector. However the result may only be generalized to other practices working with asthma nurses in the same way.


Construction and Validation of a Diagnostic Scoring System for Predicting Active Pulmonary Tuberculosis in Patients with Positive T-SPOT Based on Indicators Associated with Coagulation and Inflammation: A Retrospective Cross-Sectional Study.
Tuberculosis (TB) is a life-threatening single infectious disease, which remains a major global public health concern. This study was to establish and validate a clinically practical diagnostic scoring system for predicting active pulmonary tuberculosis (APTB) in patients with positive tuberculosis T cell spot test [T-SPOT] using indicators associated with coagulation and inflammation. A single-center retrospective cross-sectional study was performed to include patients with positive T-SOPT registered and hospitalized at Wuhan Jinyintan Hospital between January 2017 and December 2019. All patients were separated into the active pulmonary tuberculosis (APTB) group and the inactive pulmonary tuberculosis (IPTB) group, according to the diagnostic criteria from China's Expert Consensus for APTB and IPTB. Subsequently, the patients were randomized into a training set and a validation set at a ratio of 2:1. Indicators associated with coagulation and inflammation, including prothrombin time activity (PTA), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen concentration (Fbg-C), C-reactive protein/albumin ratio (CAR), C-reactive protein/prealbumin ratio (CPR), neutrophils count/lymphocyte count ratio (NLR), platelet count/lymphocyte count ratio (PLR), monocyte count/lymphocyte count ratio (MLR), and erythrocyte sedimentation rate (ESR) were obtained from electronic medical record system (EMRS). Stepwise logistic regression was performed in the training set to build a diagnostic model for predicting APTB, which was transformed into an easily applicable scoring system via nomogram. Receiver operating characteristic (ROC) analysis, calibration curve (CC), and decision curve analysis (DCA) were conducted to evaluate the predictive performance of the established diagnostic scoring system. A total of 508 patients [training set (211 cases of APTB and 116 cases of IPTB) and validation set (103 cases of APTB and 78 cases of IPTB)] with positive T-SPOT were recruited in the study. Stepwise logistic regression showed that CPR, MLR, ESR, APTT and Fbg-C were independent predictors for APTB. The scoring system was subsequently formulated based on the abovementioned predictors, which correspond to scores of 10, 6, 7, 5, and 5, respectively. In addition, patients are more likely to be diagnosed as APTB when the cut-off score was ≥16 scores, while patients with <16 scores are more likely to be diagnosed as IPTB. The scoring system showed good predictive efficacy in both the training set [area under the curve (AUC): 0.887] and the validation set (AUC: 0.898). Furthermore, both CC and DCA confirmed the clinical utility of the scoring system. The data suggest that the combination of indicators associated with coagulation and inflammation could serve as biomarkers to identify APTB in patients with positive T-SPOT. In addition, patients with positive T-SPOT were more prone to be diagnosed with APTB when having a combined total of scores ≥16 in the scoring system.


Tumor-induced osteomalacia in association with PTEN-negative Cowden syndrome.
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic condition in which phosphaturic mesenchymal tumors (PMTs) secrete high levels of fibroblast growth factor 23 (FGF23) into the circulation. This results in renal phosphate wasting, hypophosphatemia, muscle weakness, bone pain, and pathological fractures. Recent studies suggest that fibronectin-fibroblast growth factor receptor 1 (FN1-FGFR1) translocations may be a driver of tumorigenesis. We present a patient with TIO who also exhibited clinical findings suggestive of Cowden syndrome (CS), a rare autosomal dominant disorder characterized by numerous benign hamartomas, as well as an increased risk for multiple malignancies, such as thyroid cancer. While CS is a clinical diagnosis, most, but not all, harbor a mutation in the tumor suppressor gene PTEN. Genetic testing revealed a somatic FN1-FGFR1 translocation in the FGF23-producing tumor causing TIO; however, a germline PTEN mutation was not identified. To our knowledge, this is the first reported case of concurrent TIO and CS.


Prognostic significance of long-period heart rate rhythms in chronic heart failure.
Abnormalities in autonomic control are a feature of neuroendocrine activation in HF and are responsible for dysregulation of biological rhythms. The purpose was to investigate the presence and the prognostic significance of long-period heart rate (HR) rhythms in heart failure (HF) patients. In the study, 92 HF patients were enrolled (age 53 ± 14 years and left ventricular ejection fraction [LVEF] 37 ± 10%). A rhythmometric analysis was used to assess the HR rhythms in 7-days (7D) Holter recordings. Rhythms properties were quantified by mesor and amplitude, in beats/min and by acrophase, in hours. Cardiac death or HF decompensation were registered. All patients had 24-h rhythm, 61 patients (77%) had 8-h rhythm, and 66 patients (83%) had 7D rhythm. Twelve patients (15%) experienced events. Among rhythm parameters only 7D median amplitude was different between patients with or without events: 1.1 beats/min [0.5-1.5] vs. 2.0 beats/min [0.0-3.9], P=0.049 respectively. After multivariate adjustment, LVEF (per 1%, hazard ratio 0.92, 95% confidence interval (CI) 0.87 to 0.98, P=0.01), N-terminal portion of pro-natriuretic hormone type B (per 100 pg/ml, hazard ratio 1.036, 95% CI 1.005-1.069, P=0.022), and 7D amplitude of the HR ≤1.71 beats/min (hazard ratio 5.4, 95% CI 1.2-34.4, P=0.047) were independent predictors of events. A 7D HR rhythm is present in most patients with HF, and has prognostic significance.


Control of Bull's-Eye Rot of Apple Caused by Neofabraea perennans and Neofabraea kienholzii Using Pre- and Postharvest Fungicides.
Bull's-eye rot is a major postharvest disease of apple caused by several fungi belonging to the Neofabraea and Phlyctema genera. Chemical control of these fungi is a crucial component of disease management for apples that are conventionally grown. The efficacy of several preharvest and postharvest applied fungicides were evaluated to identify effective chemistries that can control bull's-eye rot incited by Neofabraea perennans and N. kienholzii on apples. In general, the preharvest fungicide thiophanate-methyl was found to be effective at reducing disease caused by N. perennans and N. kienholzii. Two postharvest fungicides, thiabendazole and pyrimethanil, also provided disease control that was far superior to other chemical compounds evaluated in this study. The efficacy of thiabendazole and pyrimethanil was unaffected by application method (fungicide dip compared with thermofog). Despite providing satisfactory control of bull's-eye rot, integration of these three chemicals into disease management programs should proceed judiciously with consideration of their impact on the development of fungicide resistance and influence on diversity in populations of apple postharvest pathogens.


Goitrin--a nitrosatable constitutent of plant foodstuffs.
N-nitrosamides are known as direct-acting carcinogens at the site of their formation; they do not need any metabolic activation in vivo. The conditions leading to their formation in the stomach, and also their genotoxicity, have been thoroughly studied with some model compounds. Several reports link this type of compound to the induction of gastric cancer in human. However, only limited data are presently available about possible precursors of N-nitrosamides in foods. In the present study we found that goitrin --a naturally occurring compound in cruciferous vegetables and rape--could be easily nitrosated by treatment with nitrite under stomach conditions, yielding with loss of sulfur the N-nitroso- oxazolidone 4 (fig.). This product has a mutagenicity pattern and potency similar to that of N-nitroso-N-methyl-N'- nitroguanidine (MNNG) in the Ames Salmonella/mammalian microsome test.


Ikaros inhibits megakaryopoiesis through functional interaction with GATA-1 and NOTCH signaling.
The transcription factor Ikaros regulates the development of hematopoietic cells. Ikaros-deficient animals fail to develop B cells and display a T-cell malignancy, which is correlated with altered Notch signaling. Recently, loss of Ikaros was associated with progression of myeloproliferative neoplasms to acute myeloid leukemia and increasing evidence shows that Ikaros is also critical for the regulation of myeloid development. Previous studies showed that Ikaros-deficient mice have increased megakaryopoiesis, but the molecular mechanism of this phenomenon remains unknown. Here, we show that Ikaros overexpression decreases NOTCH-induced megakaryocytic specification, and represses expression of several megakaryocytic genes including GATA-1 to block differentiation and terminal maturation. We also demonstrate that Ikaros expression is differentially regulated by GATA-2 and GATA-1 during megakaryocytic differentiation and reveal that the combined loss of Ikzf1 and Gata1 leads to synthetic lethality in vivo associated with prominent defects in erythroid cells and an expansion of megakaryocyte progenitors. Taken together, our observations demonstrate an important functional interplay between Ikaros, GATA factors, and the NOTCH signaling pathway in specification and homeostasis of the megakaryocyte lineage.


An overview on systemic lupus erythematosus pregnancy.
Abstract A systemic lupus erythematosus (SLE) pregnancy is no longer regarded as unacceptable, with an early diagnosis, a mild disease condition, and good interdisciplinary collaboration ensuring intense surveillance of pregnant SLE patients. The key point is a sufficiently long period of disease quiescence before conception. A low dose of prednisone is preferable during pregnancy. Nevertheless, 20% of disease flare-up still happens interpartum or postpartum, even in such well-planned pregnancies, although usually with only mild severity. Pregnancy during an active disease stage, especially active nephritis, should always be avoided. Substantial renal function damage may occur, and there is a relatively high prevalence of preeclampsia, which may further compromise the mother as well as the fetus. It is well documented that antiphospholipid syndrome and antiphospholipid antibodies are strongly associated with fetal wastage. Low-dose aspirin or heparin is indicated for a favorable fetal outcome. Women with positive anti-SSA and/or anti-SSB should be aware of the danger of congenital heart block in their infants. Cytotoxic drugs applied in the early stage of pregnancy are dangerous to the fetus. A rather long-term follow-up is required to make a precise evaluation of the maternal SLE influence on the offspring.


Utilization of Carbon Dioxide and Fluidized Bed Fly Ash in Post-Industrial Land Remediation.
The utilization of carbon dioxide and combustion products in cost- and energy-efficient technologies is an important element of creating sustainable energy systems, particularly in the transition period towards carbon neutrality and in light of the latest political developments, when solid fuels are still competing for a dominant role in securing energy supplies. Within the study presented, bituminous coal-derived fluidized bed fly ash samples of high calcium content, treated using a dry carbonation method under ambient conditions, were tested in terms of their specific properties to determine their usability in the preparation of injection mixtures for the filling of voids after shallow mining activities and other selected geo-engineering techniques. The study goes beyond the existing literature in terms of the carbonation method used, alkaline earth metal source, scale of the experiment, process conditions employed and product application studied. The results showed that the bituminous coal-derived fluidized bed fly ash, carbonated using the direct method adopted, may be successfully employed as the main solid component (over 82% w/w) of the injection mixtures for filling voids after shallow mining activities. The achievable compressive strength of a few MPa makes these materials applicable also in terms of ground strengthening in case it is required in light of the expected land development options to be employed. All principal materials used in the injection mixtures developed (carbonated fluidized bed fly ash, carbon dioxide, bottom ash) are industrial waste, and the carbonation method employed is simple and performed under ambient conditions, which reduces the required energy and cost input of filling mixture production, avoids the surface waste storage requirements, and contributes to the development of low energy-intensive carbon dioxide utilization and solid waste valorization methods.


A proteinase-free DNA replication machinery for in vitro and in vivo amplified MicroRNA imaging.
The construction of robust, modular and compact DNA machinery facilitates us to build more intelligent and ingenious sensing strategies in complex biological systems. However, the performance of conventional DNA amplifiers is always impeded by their limited in-depth amplifications and miscellaneously enzymatic requirements. Here, a proteinase-free reciprocal DNA replication machinery is developed by exploiting the synergistic cross-activation between hybridization chain reaction (HCR) and DNAzyme. The DNAzyme provides an efficient way to simplify the sophisticated design of HCR machinery and simultaneously to promote the amplification capacity. And the HCR-assembled tandem DNAzyme nanowires produce numerous new triggers for reversely stimulating HCR amplifier as systematically explored by experiments and computer-aided simulations. The reciprocal amplifier can be executed as a versatile and powerful sensing platform for analyzing miRNA in living cells and even in mice, originating from the inherent reaction accelerations and multiple-guaranteed recognitions. The reciprocal catalytic DNA machine holds great potential in clinical diagnosis and assessment.


A case report of Linguatula serrata infestation from rural area of Isfahan city, Iran.
Linguatulosis occurs accidentally in human by ingestion of raw or undercooked visceral tissues of sheep, goat, camel, and other herbivores. In this case report, 2 patients from an Afghan family infested with this parasite in rural area of Isfahan, Iran are presented. Clinical signs and symptoms including pricking sensation in throat, coughing, sneezing, yellow nasal and ears discharges, which started 2-3 hours after eating raw goat liver. Nymphs of Linguatula serrata were isolated from their tongues and later, several more parasites were discharged by coughing and sneezing. An ancient belief about nutritional benefits of eating raw liver may causes more Halzoun syndrome in future.


Expression of Numb and Numb-like in the development of mammalian auditory sensory epithelium.
The Numb and Numb-like are evolutionarily conserved cell fate-determining factors in mammals. For the first time, we investigate the involvement of the Numb and Numb-like in the developing auditory sensory epithelium. We show that both of them are expressed in the rat auditory sensory epithelium, and the four isoforms of the Numb have dynamic expression patterns during cochlear development. At the early stage of the auditory epithelium development, they occur in all progenitor cells. At the late stage of cell differentiation, they are expressed mainly in the cytoplasm of apical cells and their locations are different. Furthermore, we find overexpression of the Numb or Numb-like, in cochlear whole mount cultures, can upregulate mRNA level of Rath1, which is important in the hair-cell development.


Tissue Expression of Programmed Cell Death 1 Ligand1 (PD-L1) in Biopsies of Transplant Livers of Pediatric Patients as a Possible Marker of Acute Cellular Rejection.
Preclinical models have demonstrated that PD-1 and its ligand programmed death ligand1 (PD-L1) play significant roles in both graft induction and the maintenance of immune tolerance. It has also been suggested that PD-L1 tissue expression may predict graft rejection; however, the available data are sparse and inconclusive. Some studies were conducted on patients with cancer; most of them do not concern the liver, especially within the context of the use of immunohistochemical tests. Therefore, the aim of our study was to assess the relationship between tissue expression of PD-L1 in a unique material, i.e., in the liver biopsies of pediatric patients after transplantation with the presence of acute cellular rejection (ACR). This retrospective study enrolled 55 biopsies from 55 patients who underwent protocol liver biopsies. The control group consisted of 19 biopsies from 13 patients diagnosed with acute cellular rejection (rejection activity index/RAI/ from 2 to 8). An immunohistochemical (IHC) staining for PD-L1 was performed in all of the liver specimens; its expression was analyzed in different regions of liver tissue (in inflammatory infiltrates and within the endothelium and hepatocytes). The following changes were re-evaluated in each specimen: features of any kind of rejection (acute cellular, antibody-mediated, chronic); the presence and severity of fibrosis (Ishak scale); and the presence of cholestasis and steatosis. Clinical parameters were also evaluated, including tests of liver function (AST, ALT, GGT, bilirubin). The age of patients in the study group ranged from 2.37 to 18.9 years (median 13.87 years), with the time after transplantation being 1-17 years (median 8.36 years). The age of patients in the control group ranged from 1.48 to 17.51 years (median 7.93 years), with their biopsies being taken 0.62-14.39 years (median 1.33 years) after transplantation. We found a statistically significant relationship between PD-L1 expression on inflammatory infiltrates and ACR; however, there was no statistically significant relationship between PD-L1 endothelial expression and ACR. PD-L1 was not positive in the hepatocytes regardless of if it was the study or control group that was under observation. PD-L1 appears to be a promising marker to predict graft rejection.


The Effect of In-School Saccadic Training on Reading Fluency and Comprehension in First and Second Grade Students.
Efficient eye movements provide a physical foundation for proficient reading skills. We investigated the effect of in-school saccadic training on reading performance. In this cross-over design, study participants (n = 327, 165 males; mean age [SD]: 7 y 6 mo [1y 1 mo]) were randomized into treatment and control groups, who then underwent eighteen 20-minute training sessions over 5 weeks using King-Devick Reading Acceleration Program Software. Pre- and posttreatment reading assessments included fluency, comprehension, and rapid number naming performance. The treatment group had significantly greater improvement than the control group in fluency (6.2% vs 3.6%, P = .0277) and comprehension (7.5% vs 1.5%, P = .0002). The high-needs student group significantly improved in fluency ( P < .001) and comprehension ( P < .001). We hypothesize these improvements to be attributed to the repetitive practice of reading-related eye movements, shifting visuospatial attention, and visual processing. Consideration should be given to teaching the physical act of reading within the early education curriculum.


Secondary relaxation behavior in a strong glass.
In the present paper we study the enthalpy relaxation behavior of the hyperquenched GeO(2) (HQGeO(2)) glass, one of the strongest glass systems. By applying the hyperquenching-annealing-calorimetry approach, we have found that unlike fragile glasses the strong HQGeO(2) glass relaxes in a manner that all the secondary relaxation units contribute to the primary relaxation. By analyzing dynamic properties of the secondary relaxation, we have identified two typical features of the Johari-Goldstein relaxation in the HQGeO(2) glass. First, the quantitative relationship observed here between E(beta) and T(g) agrees well with the empirical relation of the JG relaxation. Second, the characteristic relaxation time of the GeO(2) glass at T(g) is found to be about 10 s, larger than that of relatively fragile glasses. These results verify that the JG peak in strong glasses is hidden by the alpha peak in the dielectric loss curves.


Oxidase catalysis via aerobically generated hypervalent iodine intermediates.
The development of sustainable oxidation chemistry demands strategies to harness O2 as a terminal oxidant. Oxidase catalysis, in which O2 serves as a chemical oxidant without necessitating incorporation of oxygen into reaction products, would allow diverse substrate functionalization chemistry to be coupled to O2 reduction. Direct O2 utilization suffers from intrinsic challenges imposed by the triplet ground state of O2 and the disparate electron inventories of four-electron O2 reduction and two-electron substrate oxidation. Here, we generate hypervalent iodine reagents-a broadly useful class of selective two-electron oxidants-from O2. This is achieved by intercepting reactive intermediates of aldehyde autoxidation to aerobically generate hypervalent iodine reagents for a broad array of substrate oxidation reactions. The use of aryl iodides as mediators of aerobic oxidation underpins an oxidase catalysis platform that couples substrate oxidation directly to O2 reduction. We anticipate that aerobically generated hypervalent iodine reagents will expand the scope of aerobic oxidation chemistry in chemical synthesis.


An efficient method to estimate the optimum regularization parameter in RLDA.
The biomarker discovery process in high-throughput genomic profiles has presented the statistical learning community with a challenging problem, namely learning when the number of variables is comparable or exceeding the sample size. In these settings, many classical techniques including linear discriminant analysis (LDA) falter. Poor performance of LDA is attributed to the ill-conditioned nature of sample covariance matrix when the dimension and sample size are comparable. To alleviate this problem, regularized LDA (RLDA) has been classically proposed in which the sample covariance matrix is replaced by its ridge estimate. However, the performance of RLDA depends heavily on the regularization parameter used in the ridge estimate of sample covariance matrix. We propose a range-search technique for efficient estimation of the optimum regularization parameter. Using an extensive set of simulations based on synthetic and gene expression microarray data, we demonstrate the robustness of the proposed technique to Gaussianity, an assumption used in developing the core estimator. We compare the performance of the technique in terms of accuracy and efficiency with classical techniques for estimating the regularization parameter. In terms of accuracy, the results indicate that the proposed method vastly improves on similar techniques that use classical plug-in estimator. In that respect, it is better or comparable to cross-validation-based search strategies while, depending on the sample size and dimensionality, being tens to hundreds of times faster to compute. The source code is available at https://github.com/danik0411/optimum-rlda CONTACT: firstname.lastname@example.com information: Supplementary materials are available at Bioinformatics online.


Mussel-Inspired Polydopamine-Coated Lanthanide Nanoparticles for NIR-II/CT Dual Imaging and Photothermal Therapy.
Nanomedicine has attracted substantial attention for the accurate diagnosis or treatment of carcinoma in recent years. Nd3+-doped lanthanide nanophosphor-based near-infrared-II (NIR-II) optical imaging is widely used for deep penetration tissue imaging while X-ray computed tomography (CT) is well-suited for in vivo imaging. Polymer-coated lanthanide nanophosphors are increasingly used in both diagnostics and therapies for tumor in vivo. However, the biocompatibility of nanocomposites and the efficiency of tumor ablation should be taken into consideration when constructing a nanotheranostic probe. In this article, we have fabricated polydopamine (PDA)-coated NaYF4:Nd3+@NaLuF4 nanocomposites using the reverse microemulsion approach. The thickness of the PDA shell can be precisely modulated from ∼1.5 to ∼18 nm, endowing the obtained NaYF4:Nd3+@NaLuF4@PDA with an excellent colloidal stability and considerable biocompatibility. The photothermal conversion efficiency of the resultant nanocomposites was optimized and maximized by the increase of the PDA shell thickness. Because of the remarkable photothermal conversion efficiency, the mice xenograft tumors were completely eradicated after NIR irradiation. Given the considerable photoluminescence and X-ray attenuation efficiency, the performance of NaYF4:Nd3+@NaLuF4@PDA for NIR-II optical imaging and X-ray CT dual imaging of the tumor in vivo was evaluated. All of the results above highlight the great potential of PDA-based NaYF4:Nd3+@NaLuF4 nanocomposites as a novel multifunctional nanotheranostic agent.


Effect of smoking cessation on airway inflammation of rats with chronic bronchitis.
Smoking is the major cause of airway inflammation in chronic obstructive pulmonary disease (COPD), and smoking cessation is regarded as one of the important strategies for prevention and treatment of the inflammation. The inflammation of the chronic airway may be present and deteriorated even if the COPD patients stop smoking. Whether and how early smoking cessation affects the progress of inflammation is still obscure. This study was conducted to find the appropriate time for smoking cessation to terminate the airway inflammation in rats with smoke-induced chronic bronchitis. A rat model of COPD was established by passively inhaling smoke mixture. Fifty-four young male Sprague-Dawley rats were randomly divided into 9 groups with different periods of smoke exposure and different time points of cessation. The inflammation markers to be detected included inflammatory cells in the bronchoalveolar lavage fluid (BALF), the myeloperoxidose (MPO) activity, the morphologic changes and the expression of ICAM-1 on the airway epithelium. When smoking was terminated at early stage, the inflammatory markers and related indexes were different from those of the typical chronic bronchitis group (group M7) (P < 0.01). The pathologic score of group SC7 (2 weeks of smoking cessation after occurrence of typical chronic bronchitis) was not different from that of group M7, and the level of ICAM-1 was still up-regulated (compared to group M7, P > 0.05). Meanwhile, most of inflammatory cells in BALF were neutrophils compared to other groups (P < 0.01). When smoking was terminated, the MPO activity was significantly lower than that of group M7 (P < 0.01). Smoking cessation at early stage can effectively inhibit the inflammatory reaction of COPD. Once chronic bronchitis occurs, little could be improved by smoking cessation.


Improvement of human embryonic stem cell-derived retinal pigment epithelium cell adhesion, maturation, and function through coating with truncated recombinant human vitronectin.
To explore an xeno-free and defined coating substrate suitable for the culture of H9 human embryonic stem cell-derived retinal pigment epithelial (hES-RPE) cells in vitro, and compare the behaviors and functions of hES-RPE cells on two culture substrates, laminin521 (LN-521) and truncated recombinant human vitronectin (VTN-N). hES-RPE cells were used in the experiment. The abilities of LN-521 and VTN-N at different concentrations to adhere to hES-RPE cells were compared with a high-content imaging system. Quantitative real-time polymerase chain reaction was used to evaluate RPE-specific gene expression levels midway (day 10) and at the end (day 20) of the time course. Cell polarity was observed by immunofluorescent staining for apical and basal markers of the RPE. The phagocytic ability of hES-RPE cells was identified by flow cytometry and immunofluorescence. The cell adhesion assay showed that the ability of LN-521 to adhere to hES-RPE cells was dose-dependent. With increasing coating concentration, an increasing number of cells attached to the surface of LN-521-coated wells. In contrast, VTN-N presented a strong adhesive ability even at a low concentration. The optimal concentration of LN-521 and VTN-N required to coat and adhesion to hES-RPE cells were 2 and 0.25 µg/cm2, respectively. Furthermore, both LN-521 and VTN-N could facilitate adoption of the desired cobblestone cellular morphology with tight junction and showed polarity by the hES-RPE cells. However, hES-RPE cells cultivated in VTN-N had a greater phagocytic ability, and it took less time for these hES-RPE cells to mature. VTN-N is a more suitable coating substrate for cultivating hES-RPE cells.


The prevalence of growth hormone deficiency and celiac disease in short children.
To assess the occurrence of growth hormone deficiency (GHD) in patients with celiac disease (CD) referred for short stature. A retrospective, multi-center study. A total of 7066 children with short stature were referred to a number of centers for second-line evaluation over a 5-year period. All patients were screened for CD by antiendomysial antibodies (EMA) and antitissue transglutaminase IgA. Those with positive sera underwent intestinal biopsy. The EMA-negative patients and the EMA-positive ones who did not grow after 1 year of gluten-free diet underwent endocrinological investigation. Among the 7066 short children (age 2-14 years) evaluated, 650 (9.2%) had GHD and 44 (0.63%) had CD. An association of both CD and GHD was found in 16 short children (0.23%); these children did not grow after 1 year of gluten-free diet and therefore GH treatment was started. GH secretion should be evaluated in celiac patients showing no catch-up growth after an appropriate period on a gluten-free diet in spite of reversion to seronegativity for EMA.


Practical Guidance of the GTH Haemophilia Board on the Use of Emicizumab in Patients with Haemophilia A.
Emicizumab has been approved for bleeding prophylaxis in patients with haemophilia A (PWHAs) with or without inhibitors. Because of substantial differences between factor VIII (FVIII) and Emicizumab, the 'Ständige Kommission Hämophilie' of the German, Austrian, Swiss Society for Thrombosis and Haemostasis Research (GTH) established a practical guidance for the use of Emicizumab in PWHAs. A systematic literature research was conducted in PubMed. Based on this and on personal experience, this practical guidance has been developed. Each single statement has been discussed among members of the 'Ständige Kommission Hämophilie' and revised accordingly. The final set of recommendations has been approved by all authors analogous to the Delphi method. This practical guidance is provided for physicians treating PWHAs with regard to general aspects, patient education, bleeding treatment, surgery, use of Emicizumab in previously untreated patients (PUPs), patients with newly diagnosed inhibitors and elderly patients. Patients should be treated in expert centres and adequate laboratory tests to monitor Emicizumab levels, FVIII replacement and inhibitors should be available. Early experience of immune tolerance induction protocols integrating Emicizumab is reviewed, and the limited experience in PUPs and very young children is described. So far, no thromboembolic complications have been reported with the concomitant use of FVIII or recombinant activated FVII for bleeding treatment or surgery. Activated prothrombin complex concentrate doses of >100 U/kg for >24 hours should be avoided whenever possible because of the high risk of thrombosis and/or thrombotic microangiopathy. In conclusion, this study is designed to support haemophilia physicians using Emicizumab in physicians treating hemophilia and using (PWHAs). With further post-marketing experience and trials, regular updates are necessary.


Vestibular evoked myogenic potential (VEMP) in patients with auditory neuropathy: Auditory neuropathy or audiovestibular neuropathy?
Our results suggest that isolated auditory or vestibular involvement is unlikely and in fact audiovestibular neuropathy can better explain auditory neuropathy. The purpose of this study was to investigate saccule and related neural pathways in auditory neuropathy patients. Three males and five females diagnosed with auditory neuropathy were included in this prospective study. Patients' ages ranged from 21 to 45 years with a mean age of 28.6 ± 8.1 years and the history of disease was between 4 and 19 years. A group of 30 normal subjects served as the control group. The main outcome measures were the mean peak latency (in ms) of the two early waves (p13 and n23) of the vestibular evoked myogenic potential (VEMP) test in patients and controls. Of the 8 patients (16 ears), normal response was detected in 3 ears (1 in right and 2 in left ears). There were unrepeatable waves in four ears and absent VEMPs in nine ears.


Pseudolymphomatous folliculitis.
Pseudolymphomatous folliculitis is a benign entity that is included within pseudolymphomas. Because of its rapid clinical growth and suspicious histology it has to be differentiated from malignant entities. Given its low frequency, the dermatoscopic characteristics of this entity are not well-characterized and have been described only once previously. We present a middle-aged woman with a facial erythematous plaque of 6 months' evolution, with dermatoscopy in which follicular plugs on an erythematous base were appreciated. The histology showed a dense lymphocytic infiltrate with folliculotropism and follicular alteration, with numerous peripheral histiocytes positive for S100 and CD1a. The lesion partially disappeared after the biopsy, and completely after topical treatment.


Spatial and temporal integration of signals in foveal line orientation.
The discrimination of the orientation of a line improves with line length, reaching an optimum when a foveal line is approximately 0.5 degrees long. We studied the effect of eliminating sections of the line, of displacing them out of alignment, and of delaying them. Orientation discrimination thresholds are only a little elevated when a 25-arcmin line is replaced by three equally spaced collinear 5-arcmin segments. Two collinear 5-arcmin segments show better thresholds than a single one when they are separated by as much as 20 arcmin. But thresholds are impaired by bringing line segments out of collinearity by as little as 1 arcmin. Asynchrony of up to 50 ms can be tolerated, but when the middle segment of a three-line pattern is delayed by approximately 100 ms there is active inhibition, thresholds being now higher than when the middle segment is absent. It is concluded that for signals to address the orientation discrimination mechanism optimally, they have to be contained inside a narrow spatial corridor and be presented within a time window of approximatley 50 ms, but that some spatial summation can take place over a length of > or = 0.5 degrees in the fovea. Because short lines made of black and white collinear segments do not have good orientation thresholds, whereas longer and interrupted lines do, it is concluded that what is involved is potentiating interaction between collinearly arranged neurons with identical orientation selectivity rather than summation of signals within the receptive fields of single neurons.


Structure of the Ockelbo virus genome and its relationship to other Sindbis viruses.
Ockelbo virus was first isolated in 1982 in Sweden. It is the causal agent of disease in humans characterized by arthritis, rash, and fever and is antigenically very closely related to Sindbis virus. We have determined the nucleotide and translated amino acid sequences of the prototype Ockelbo virus isolate (82-5) to determine the relatedness of Ockelbo virus to Sindbis virus at the genomic level and clarify the taxonomic position of Ockelbo virus within the alphavirus genus. The numbers of nucleotides and of translated amino acids in each region of the Ockelbo virus genome were exactly the same as those for the prototype AR339 strain of Sindbis virus except for three small deletions and insertions in the C-terminal half of nsP3 and for three single nucleotide insertions and deletions in the 3' untranslated region. Overall there were 672 nucleotide differences (5.7% divergence), resulting in 97 amino acid changes (2.6% divergence), between the two viruses: more than 85% of the nucleotide changes were silent. Only the C-terminal domain of nsP3 and the E2 glycoprotein showed a higher degree of amino acid substitution than the overall average. The former domain is not conserved among alphaviruses, and the latter is primarily responsible for antigenic variation. Sequence analysis of 420 nucleotides at the 3' end of a number of other Sindbis-like alphaviruses, including Karelian fever virus and South African, Indian, and Australian isolates of Sindbis virus, demonstrated that Ockelbo virus is more closely related to South African strains of Sindbis virus than it is to the prototypic Egyptian AR339 strain. Thus the South African strains, which have caused epidemic disease in humans, may have been introduced into Northern Europe by man or by migratory birds to establish Ockelbo disease there. The Indian and Australian strains form a distinct branch of the evolutionary tree and differ from prototypic AR339 Sindbis virus in 17% of the nucleotides sequenced.


Genome communication in plants mediated by organelle-n-ucleus-located proteins.
An increasing number of eukaryotic proteins have been shown to have a dual localization in the DNA-containing organelles, mitochondria and plastids, and/or the nucleus. Regulation of dual targeting and relocation of proteins from organelles to the nucleus offer the most direct means for communication between organelles as well as organelles and nucleus. Most of the mitochondrial proteins of animals have functions in DNA repair and gene expression by modelling of nucleoid architecture and/or chromatin. In plants, such proteins can affect replication and early development. Most plastid proteins with a confirmed or predicted second location in the nucleus are associated with the prokaryotic core RNA polymerase and are required for chloroplast development and light responses. Few plastid-nucleus-located proteins are involved in pathogen defence and cell cycle control. For three proteins, it has been clearly shown that they are first targeted to the organelle and then relocated to the nucleus, i.e. the nucleoid-associated proteins HEMERA and Whirly1 and the stroma-located defence protein NRIP1. Relocation to the nucleus can be experimentally demonstrated by plastid transformation leading to the synthesis of proteins with a tag that enables their detection in the nucleus or by fusions with fluoroproteins in different experimental set-ups. This article is part of the theme issue 'Retrograde signalling from endosymbiotic organelles'.


A Systematic Review and Meta-Analysis of Personality Disorder Prevalence and Patient Outcomes in Emergency Departments.
The objectives of this study were to perform a systematic review and meta-analysis of studies reporting prevalence of personality disorders (PDs) in emergency departments (EDs) and evaluate the effect of comorbid PDs on clinical outcomes. A systematic search of five databases along with manual searching and expert consultation was performed. A quality appraisal was conducted. A total of 29 articles were included. Prevalence of PDs in ED attendees varied depending on presenting complaint, Q(4) = 577.5, p < .01, with meta-analytic prevalence rates of suicide and self-harm at 35% and 22%, respectively. The assessment method had a significant effect on prevalence rates, Q(3) = 17.36, p < .01. Comorbid PD was a risk factor for repeating presenting complaint, subsequent ED return, and hospitalization. Better identification of PDs using screening tools in EDs could improve patient management and clinical outcomes. Future research should focus on PD prevalence in unselected ED populations using validated diagnostic interviews.


Successful treatment of post-transplant Kaposi's sarcoma by reduction of immunosuppression.
The aim of this study was to investigate retrospectively the clinical presentation, the efficacy of reducing immunosuppression and the consequences of this therapeutic approach in Kaposi's sarcoma (KS) developing after renal transplantation. We reviewed the records of 502 patients who had been followed up at our transplantation unit between October 1, 1987 and December 30, 1998. Twelve patients (2.4%) with KS were included in the study. The mean age of KS patients was 38+/-11 years (one female, 11 males). All were on prednisone, azathioprine (AZT) and cylcosporin treatment. KS was encountered at a mean of 18+/-10 months post-renal transplantation. Typical Kaposi's lesions were present in the skin of 11 out of l2 patients. In the only patient without skin involvement, who died from haemophagocytic histiocytic syndrome caused by septicaemia, KS was diagnosed post-mortem in a lymph node. In five patients only skin involvement was present, while the others also had visceral involvement (oropharynx in two patients, trachea and lung in three, lymph node in two, stomach and duodenum in two). Cyclosporin was stopped within 1 month after KS diagnosis, and AZT was stopped in three patients. Both cutaneous and visceral KS manifestations disappeared and no patient was lost due to KS. During a follow-up period 46+/-19 months, KS recurred in the lungs in one patient together with lung tuberculosis, while he was on prednisone and AZT. Two patients lost their graft due to chronic rejection. The remaining eight patients currently have a functioning graft with a mean creatinine level of 1.4+/-0.5 mg/dl. KS is the most frequent post-transplant neoplasia (80%) in our country. In the present study cohort, half of the patients had visceral involvement. Reduction or discontinuation of immunosuppression caused complete remission in all patients without surgical intervention, chemotherapy or radiotherapy.


Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection.
Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year). Minor cervical traumas, infection, migraine and hypertension are putative risk factors, and inverse associations with obesity and hypercholesterolemia are described. No confirmed genetic susceptibility factors have been identified using candidate gene approaches. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69-0.82; P = 4.46 × 10(-10)), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 × 10(-3); combined P = 1.00 × 10(-11)). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions.


Lymphokine-induced cytotoxicity: characterization of effectors, precursors, and regulatory ancillary cells.
In the present study, we have characterized the effectors, precursors, and regulatory ancillary cells involved in the in vitro generation of lymphokine-induced cytotoxicity. It was first shown that at least two lymphokines are needed for the generation of lymphokine-induced cytotoxicity. They are interleukin 2 and a novel lymphokine, the cytotoxic cell differentiation factor (CCDF). CCDF was produced primarily by the macrophages. The effectors of the lymphokine-induced cytotoxic cells thus generated selectively killed tumor targets of different etiological origins. The serological phenotype of lymphokine-induced cytotoxic cell effectors were found to be Thy 1+, Lyt 2-, and AGM1-; therefore, they were neither classic natural killer (NK) cells nor cytotoxic T-lymphocytes. Extensive characterization of the precursors by sequential column separation and antibody lysis and also by limiting dilution analysis showed that they were AGM1+ and Lyt 2-; thus they were NK-like cells. In addition to NK-like cells being identified as the precursors, two other cell compartments were identified as ancillary cells which regulate the lymphokine-induced cytotoxicity. They were the macrophages and T-cells. Macrophages were needed to produce CCDF and to activate the Lyt 1+ helper T-cells to produce interleukin 2. The Lyt 2+ T-cells play a negative role in the regulation of the lymphokine-induced cytotoxic cell response. The process of lymphokine-induced cytotoxicity thus involves a complex interaction between at least two lymphokines (interleukin 2 and CCDF) and three cell compartments, namely, NK-like cells, macrophages, and T-cells of Lyt 1+ and Lyt 2+ phenotypes.


Finetuning Hole-Extracting Monolayers for Efficient Organic Solar Cells.
Interface layers used for electron transport (ETL) and hole transport (HTL) often significantly enhance the performance of organic solar cells (OSCs). Surprisingly, interface engineering for hole extraction has received little attention thus far. By finetuning the chemical structure of carbazole-based self-assembled monolayers with phosphonic acid anchoring groups, varying the length of the alkane linker (2PACz, 3PACz, and 4PACz), these HTLs were found to perform favorably in OSCs. Compared to archetypal PEDOT:PSS, the PACz monolayers exhibit higher optical transmittance and lower resistance and deliver a higher short-circuit current density and fill factor. Power conversion efficiencies of 17.4% have been obtained with PM6:BTP-eC9 as the active layer, which was distinctively higher than the 16.2% obtained with PEDOT:PSS. Of the three PACz derivatives, the new 3PACz consistently outperforms the other two monolayer HTLs in OSCs with different state-of-the-art nonfullerene acceptors. Considering its facile synthesis, convenient processing, and improved performance, we consider that 3PACz is a promising interface layer for widespread use in OSCs.


[Transforming growth factor of beta-type].
Recent data about the structure and properties of the beta-type transforming growth factor as well as evidence about its influence on different target cells are presented. The regulatory action of the factor is shown to depend mainly on the type of tested cells, conditions of their culturing and the presence of other bioregulators of cell proliferation in the medium. The prospects of the beta-type transforming growth factor use in practice are considered.


Case report: A novel CACNA1S mutation associated with hypokalemic periodic paralysis.
Hypokalemic periodic paralysis (HypoKPP) is a rare neuromuscular genetic disorder causing recurrent episodes of flaccid paralysis. Most cases are associated with CACNA1S mutation, causing defect of calcium channel and subsequent impairment of muscle functions. Due to defined management approaches early diagnosis is crucial for promptly treatment and prevention new attacks. We report a case of HypoKPP associated with previously unreported mutation in CACNA1S gene (p.R900M). Molecular modeling of CaV1.1 was applied to evaluate its pathogenicity. As a patient referred between attacks neurological status, laboratory and neurophysiological examination were unremarkable. Molecular modeling predicted that the p.R900M mutation affects the process of calcium channels activation. Novel CACNA1S mutation, associated with HypoKPP was identified. Monte-Carlo energy minimization of the CaV1.1 model supported the association of this mutation with this disease.


miR-144 inhibits growth and metastasis of cervical cancer cells by targeting VEGFA and VEGFC.
MicroRNAs (miRs) are aberrantly expressed in various cancer types and have critical roles in their genesis and progression. miR-144 has been identified to be involved in the development of hepatocellular carcinoma and rectal cancer. However, the roles of miR-144 in cervical cancer and the underlying molecular mechanisms have remained elusive. The present study identified that miR-144 was significantly decreased in cervical cancer tissues compared with that in matched normal cervical tissues as well as in metastatic vs. non-metastatic cervical cancer tissues. miR-144 downregulation was significantly associated with the International Federation of Gynecology and Obstetrics stage and lymph node metastasis. In a gain-of function study, miR-144 mimics were transfected into the Hela and C33A cervical cancer cell lines, which led to suppression of cell growth. In addition, overexpression of miR-144 inhibited the migration and invasion of Hela and C33A cells. Furthermore, a bioinformatics analysis identified vascular endothelial growth factor A (VEGFA) VEGFC as two novel target genes of miR-144. Of note, a dual luciferase reporter assay, reverse-transcription quantitative polymerase chain reaction analysis and western blot analysis demonstrated that miR-144 repressed the expression of VEGFA and VEGFC by directly targeting to their 3'-untranslated region. Taken together, the results suggested that miR-144 acts as a tumor suppressor in the proliferation and metastasis of cervical cancer cells by directly targeting VEGFA and VEGFC, suggesting that miR-144 may be a novel promising diagnostic and therapeutic biomarker for cervical cancer.


Clinical and biological features in PIEZO1-hereditary xerocytosis and Gardos channelopathy: a retrospective series of 126 patients.
We describe the clinical, hematologic and genetic characteristics of a retrospective series of 126 subjects from 64 families with hereditary xerocytosis. Twelve patients from six families carried a KCNN4 mutation, five had the recurrent p.Arg352His mutation and one had a new deletion at the exon 7-intron 7 junction. Forty-nine families carried a PIEZO1 mutation, which was a known recurrent mutation in only one-third of the cases and private sequence variation in others; 12 new probably pathogenic missense mutations were identified. The two dominant features leading to diagnosis were hemolysis that persisted after splenectomy and hyperferritinemia, with an inconstant correlation with liver iron content assessed by magnetic resonance imaging. PIEZO1-hereditary xerocytosis was characterized by compensated hemolysis in most cases, perinatal edema of heterogeneous severity in more than 20% of families and a major risk of post-splenectomy thrombotic events, including a high frequency of portal thrombosis. In KCNN4-related disease, the main symptoms were more severe anemia, hemolysis and iron overload, with no clear sign of red cell dehydration; therefore, this disorder would be better described as a 'Gardos channelopathy'. These data on the largest series to date indicate that PIEZO1-hereditary xerocytosis and Gardos channelopathy are not the same disease although they share hemolysis, a high rate of iron overload and inefficient splenectomy. They demonstrate the high variability in clinical expression as well as genetic bases of PIEZO1-hereditary xerocytosis. These results will help to improve the diagnosis of hereditary xerocytosis and to provide recommendations on the clinical management in terms of splenectomy, iron overload and pregnancy follow-up.


Amplification of the human putative oncogene INT1 in primary retinoblastoma tumors.
We report the amplification of the putative oncogene INT1 in two of four retinoblastomas. In one case, the INT1 signal was amplified 10 to 15-fold, in the other 100-fold. In both cases there were signs of increased tumor aggressiveness with invasion of the choroid and development of metastases. The two cases without INT1 amplification had neither metastases nor locally invasive growth. Our findings indicate that INT1 amplification may be a feature of increased malignant potential in retinoblastomas.


Outside fibroblasts play a key role in the development of inner neointima after the implantation of polytetrafluoroethylene grafts.
The neointima formation inside of polytetrafluoroethylene (PTFE) grafts may be associated with the migration of outside fibroblasts to the luminal surfaces. This study aimed to verify whether blockade of fibroblast migration can prevent neointima formation by testing two types of prosthetic vessels, the porous PTFE graft and the impermeable Grasil graft, respectively. After implantation of the PTFE graft in dogs, a time-dependent migration of outside fibroblasts to the luminal side occurred. Compared with the PTFE grafts, the total neointima formation in the Grasil grafts was significantly less. Although the neointima formation at the arterial or venous anastomotic regions did not significantly differ between the two grafts, the neointima at the middle region of the PTFE grafts was significantly evident than the Grasil grafts. The components of the renin–angiotensin system (RAS), such as angiotensin II and its receptor AT1, as well as the forming enzymes of the RAS (angiotensin-converting enzyme and chymase), were all detectable in the grafts' surrounding tissues. Neointima formation at the middle region of the prosthetic vessels could be suppressed almost completely by the blockade of outside fibroblast migration, indicating that outside fibroblasts play a key role in the formation of neointima in this region.


Proteomic serum biomarkers and their potential application in cancer screening programs.
Early diagnosis of cancer is of pivotal importance to reduce disease-related mortality. There is great need for non-invasive screening methods, yet current screening protocols have limited sensitivity and specificity. The use of serum biomarkers to discriminate cancer patients from healthy persons might be a tool to improve screening programs. Mass spectrometry based proteomics is widely applied as a technology for mapping and identifying peptides and proteins in body fluids. One commonly used approach in proteomics is peptide and protein profiling. Here, we present an overview of profiling methods that have the potential for implementation in a clinical setting and in national screening programs.


Purification and characterization of the inducible a agglutinin of Saccharomyces cerevisiae.
A cell surface glycoprotein induced by the mating pheromone alpha factor in Saccharomyces cerevisiae a cells has been purified to homogeneity. At 4 x 10(-9) M it strongly inhibits mating-type-specific agglutination between a and alpha cells. The protein is solely O-glycosylated. It consists of 29% carbohydrate and its apparent molecular mass is 22 kd on SDS gels. After HF treatment it behaves like a protein of 13 kd; therefore its true molecular mass probably is close to 18 kd. Mild periodate treatment destroys the biological activity of the purified protein. The protein contains one cysteine, no arginine, and 27% of the amino acids are serine and threonine residues, two thirds of which are glycosylated. With a polyclonal antibody the glycoprotein can already be detected at the cell surface 15 min after pheromone addition. The inducible antigen is not expressed in a specific phase of the cell cycle; it first appears exclusively on the growing bud. Mother cells express the antigen on their surface only after the daughter cells have separated; it is then localized at the tip of the pear-shaped 'shmoo'. Using the secretory ts-mutant sec 18 is shown that a mannosylated precursor of a agglutinin accumulates at the endoplasmic reticulum.


Safety for the user of the feed additive consisting of ferric citrate chelate (CI-FER™) for suckling and weaned piglets and minor porcine species (Akeso Biomedical, Inc.).
Following a request from the European Commission (EC), the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP Panel) was asked to deliver a scientific opinion on the safety for the users of the feed additive consisting of ferric citrate chelate (CI-FER™) when used as a zootechnical additive for suckling and weaned piglets and minor porcine species. The EC request follows a previous opinion of the FEEDAP Panel. In that opinion, the Panel identified several risks for the users of the additive; it was listed that it posed a risk to users by inhalation, should be considered as an irritant to skin, eyes and mucous membranes, and also that, due to its nickel content, should be considered as a dermal and respiratory sensitiser. The applicant provided additional data including information on the manufacturing process of the additive and data supporting the safety of the additive for the users to address those concerns. Some changes have been applied to the original manufacturing process which led to a dust-free additive, with the following specifications: total iron ≤ 23%, iron (III) ≥ 16.5% and moisture ≤ 10.0%. The FEEDAP Panel concluded that CI-FER™ does not pose a risk by inhalation and is classified as non-irritant to the skin. The additive should be classified as a skin sensitiser. In the absence of new data, the FEEDAP Panel reiterates its previous conclusion that the additive should be considered irritant to eyes.


Radiological findings in pulmonary paragonimiasis heterotremus.
The routine chest roentgenogram of pulmonary paragonimiasis heterotremus were evaluated in 93 Thai and Laotian patients. They were 44 males and 49 females; the ages ranged from 12 to 79 years; the history of illness ranged from 4 months to 14 years and the egg output per day was 400 to 300,000. Twelve patients, 12.9% had normal roentgenologic films and 81 patients (87.1%) had abnormalities with 316 lesions; 22.2% had one lesion and 77.7% had multiple lesions. The common lesions were cystic formation, multiple or single and linear infiltration. Both lower lobes of the lungs and the left upper lobe were the common sites but any part of the lung may be affected. There were correlation between the duration of illness, number of eggs output per day and the extent of the lesions. The longer the duration of illness or the higher number of eggs output per day the more extensive lesions in the X-ray films have been observed.


The effects of normobaric and hyperbaric oxygenation on MRI signal intensities in T1 -weighted, T2 -weighted and FLAIR images in human brain.
Dissolved oxygen has known paramagnetic effects in magnetic resonance imaging (MRI). The aim of this study was to compare the effects of normobaric oxygenation (NBO) and hyperbaric oxygenation (HBO) on human brain MRI signal intensities. Baseline brain MRI was performed in 17 healthy subjects (mean age 27.8 ± 3.2). MRI was repeated after exposure to the NBO and HBO at different time points (0 min, 25 min, 50 min). Signal intensities in T 1-weighted, T 2-weighted images and fluid attenuated inversion recovery (FLAIR) signal intensities of several intracranial structures were compared between NBO and HBO. Increased T 1-weighted signal intensities were observed in white and deep grey brain matter, cerebrospinal fluid (CSF), venous blood and vitreous body after exposure to NBO as well as to HBO compared to baseline (Dunnett's test, p < 0.05) without significant differences between both protocols. There was also no significant difference in T 2-weighted signal intensities between NBO and HBO. FLAIR signal intensities were increased only in the vitreous body after NBO and HBO and FLAIR signal of caudate nucleus was decreased after NBO (Dunnett's test, p < 0.05). The statistically significant differences in FLAIR signal intensities were found between NBO and HBO (paired t-test, p < 0.05) in most observed brain structures (paired t-test, p < 0.05). Our results show that NBO and HBO alters signal intensities T 1-weighted and FLAIR images of human brain. The differences between NBO and HBO are most pronounced in FLAIR imaging.


[Single center experience with Siemens Lithostar Modularis for treatment of 1500 solitiary urinary stones].
the aim of the study was to evaluate the results of extracorporeal shock wave lithotripsy (ESWL) treatment with Siemens Lithostar Modularis in urinary stones. from May 2000 until September 2006, 1500 patients, 62% men and 38% women, ages 15 to 89 years (mean age 53), underwent ESWL as treatment of urinary stones at the Lithotripsy Unit of León. Data were analized retrospectively. More than half (56%) had left urinary stones. The most frequent ureteral localization (55%) was proximal (420 patients), and the most frecuent renal was renal pelvis (345 patients). The mean stone diameter was 1.3 cm. (1.01 ureteral and 1.7 renal). All patients received ESWL-session under i.v. analgesia with alfentanil and midazolam. Mean number of sessions per lithiasis was 1.5 (ureteral stones 1.4 and renal stones 1.7). The retreatment rate was 33%, 28% for ureteral stones and 39% for renal stones with a cumulative success of 86% with two sessions. 22% of the patients required auxiliary manouvers, 24% of the patients with ureteral stones and 18% of the renal stones patients. Stone free rate was 91%, 97% in ureteral stones and 82% in renal stones. treatment of urinary stones with Siemens Lithostar Modularis showed good results, with a stone free patient rate of more than 90%, although 33% of the patients need multiple ESWL treatment sessions and 20% of the patient required auxiliary procedures.


Chemoproteomic Approaches for Unraveling Prokaryotic Biology.
Bacteria are ubiquitous lifeforms with important roles in the environment, biotechnology, and human health. Many of the functions that bacteria perform are mediated by proteins and enzymes, which catalyze metabolic transformations of small molecules and modifications of proteins. To better understand these biological processes, chemical proteomic approaches, including activity-based protein profiling, have been developed to interrogate protein function and enzymatic activity in physiologically relevant contexts. Here, chemoproteomic strategies and technological advances for studying bacterial physiology, pathogenesis, and metabolism are discussed. The development of chemoproteomic approaches for characterizing protein function and enzymatic activity within bacteria remains an active area of research, and continued innovations are expected to provide breakthroughs in understanding bacterial biology.


Elevated plasma tricyclic levels with therapeutic doses of imipramine.
Nine (15%) of 59 patients treated with imipramine at doses of 150 to 300 mg/day had steady-state plasma levels greater than 500 ng/ml. Low capacity for hydroxylation was found in all six patients for whom hydroxy metabolites were measured. Maximum tricyclic levels in the nine study patients were comparable to levels found in tricyclic antidepressant overdoses (651-2439 ng/ml). No study patient experienced any adverse effects: QRS durations were all less than 100 msec, and a mildly dry mouth was the most commonly reported side effect (five of nine patients). Depressive symptoms recurred in three patients when their imipramine dose was decreased.


Interactions of the human calcitonin fragment 9-32 with phospholipids: a monolayer study.
Human calcitonin and its C-terminal fragment 9-32 (hCT(9-32)) administered in a spray translocate into respiratory nasal epithelium with an effect similar to intravenous injection. hCT(9-32) is an efficient carrier to transfer the green fluorescent protein into excised bovine nasal mucosa. To understand the translocation of hCT(9-32) across plasma membranes, we investigated its interactions with phospholipids and its interfacial structure using model lipid monolayers. A combination of physicochemical methods was applied including surface tension measurements on adsorbed and spread monolayers at the air-water interface, Fourier transform infrared, circular dichroism, and atomic force microscopy on Langmuir-Blodgett monolayers. The results disclose that hCT(9-32) preferentially interacts with negatively charged phospholipids and does not insert spontaneously into lipid monolayers. This supports a nonreceptor-mediated endocytic internalization pathway as previously suggested. Structural studies revealed a random coil conformation of hCT(9-32) in solution, transforming to alpha-helices when the peptide is localized at lipid-free or lipid-containing air-water interfaces. Atomic force microscopy studies of monolayers of the peptide alone or mixed with dioleoylphosphatidylcholine revealed that hCT(9-32) forms filaments rolled into spirals. In contrast, when interacting with dioleoylphosphatidylglycerol, hCT(9-32) does not adopt filamentous structures. A molecular model and packing is proposed for the spiral-forming hCT(9-32).


Usability of bacteriological milk analyses for genetic improvement of udder health in Austrian Fleckvieh cows.
In addition to somatic cell count records and clinical mastitis diagnoses, results of bacteriological milk analyses provide valuable information regarding udder health. The pathogen causing an udder infection is currently not considered in Austria as part of the information used for estimation of routine breeding values for mastitis resistance. Therefore the objective of this study was to estimate heritabilities for, and genetic correlations between, udder traits of bacterial infection (bacterial infection, gram-positive and gram-negative bacterial infection) and routinely recorded udder health traits [acute mastitis, chronic mastitis, culling due to udder health problems, and somatic cell score (SCS)] in Austrian Fleckvieh cows. The basis for the genetic analyses was a data set with results from bacteriological milk analyses collected from 237 dairy farms and 6,822 cows over a period of 1 yr. Traits were defined as binary, apart from SCS, for which measures were available continuously. Multivariate analyses using a linear animal model were applied for estimating genetic parameters. The heritabilities for the occurrence of bacterial udder infection traits were 0.01. Heritabilities were 0.04 for acute mastitis, 0.02 for chronic mastitis, 0.02 for culling due to udder health problems, and 0.20 for SCS. Genetic correlations between bacteriological infection and the routinely recorded udder health traits were positive and ranged from 0.62 to 0.96. The genetic correlation between gram-positive and gram-negative bacterial infection was -0.20. The genetic correlation between acute and chronic mastitis was also close to zero. These results show that mastitis caused by different pathogens may be seen as different traits. As analyses were based on a relatively small data set and results were associated with rather high standard errors, further research with a larger data set should be carried out to confirm these results.


Effectiveness of a telemedicine programme for patients with metabolic syndrome.
There is a high prevalence of metabolic syndrome in Western societies, and it is therefore an example of chronic disease whose follow-up could be enhanced by telemedicine. The objective of this study was to assess the effectiveness of a telemedicine programme for the follow-up and control of patients with metabolic syndrome in a primary-care setting. Semi-experimental study in which 82 patients with metabolic syndrome were included in a telemedicine programme and compared to 82 patients routinely followed up at health-care facilities. The programme consisted of the teletransmission of analytical parameters via the PITES technological platform for chronic and dependent patients. Other study variables were lifestyle, treatment compliance, perceived health status and satisfaction with the programme. Follow-up showed that 68 patients (82.9%) continued in the programme after 6 months and 45 (54.9%) after one year, with a mean stay of 39.7 weeks. Comparison of the parameters obtained for the telemedicine and control-group patients indicated that the former registered significantly lower mean values for systolic blood pressure (125.5 ± 10.6 SD vs. 136.7 ± 12.0 SD), diastolic blood pressure (81.0 ± 6.3 SD vs. 84.0 ± 6.8 SD), total cholesterol (177.4 ± 34.5 SD vs. 202.4 ± 31.7 SD) and cLDL (106.0 ± 28.1 SD vs. 121.3 ± 30.6 SD). By the end of follow-up, the health status scores of the patients monitored by telemedicine had risen significantly (69.2 vs. 64.2; p=0.04), and 86.6% stated that they were satisfied. Telemedicine allows for better control of some of the defining parameters of metabolic syndrome than is achieved by routine clinical practice. Teletransmission is viable and satisfactory, and constitutes a novel contribution to the clinical management of these patients.


A Versatile Near Infrared Light Triggered Dual-Photosensitizer for Synchronous Bioimaging and Photodynamic Therapy.
Photodynamic therapy (PDT) based on Tm3+-activated up-conversion nanoparticles (UCNPs) can effectively eliminate tumor cells by triggering inorganic photosensitizers to generate cytotoxic reactive oxygen species (ROS) upon tissue penetrating near-infrared (NIR) light irradiation. However, the partial use of the emitted lights from UCNPs greatly hinders their application. Here we develop a novel dual-photosensitizer nanoplatform by coating mesoporous graphitic-phase carbon nitride (g-C3N4) layer on UCNPs core, followed by attaching ultrasmall Au25 nanoclusters and PEG molecules (named as UCNPs@g-C3N4-Au25-PEG). The ultraviolet-visible (UV-vis) light and the intensive near infrared (NIR) emission from UCNPs can activate g-C3N4 and excite Au25 nanoclusters to produce ROS, respectively, and thus realize the simultaneous activation of two kinds of photosensitizers for enhanced the efficiency of PDT mediated by a single NIR light excitation. A markedly higher PDT efficacy for the dual-photosensitizer system than any single modality has been verified by the enhanced ROS production and in vitro and in vivo results. By combining the inherent multi-imaging properties (up-conversion, CT, and MRI) of UCNPs, an imaging guided therapeutic platform has been built. As the first report of dual-inorganic-photosensitizer PDT agent, our developed system may be of high potential in future NIR light induced PDT application.


A temperature-controlled glove with non-invasive arterial pulse sensing for active neuro-vascular assessment.
A non-invasive, active neuro-vascular assessment system was developed using a modified temperature-controlled glove and feedback techniques. The glove incorporates local heating and cooling of the hand using multi-point skin temperature measurements as feedback, and thereby induces local and central mechanisms involved in thermoregulation. Electrocardiogram (ECG), photoplethysmogram (PPG) and non-invasive finger-cuff based blood pressure (BP) measurements were used to monitor electrophysiology and hemodynamic changes in response to temperature modulation. Then, the triggered neuro-vascular mechanisms associated with thermoregulation were quantified by extracting parameters from the measured waveforms, specifically heart rate variability (HRV), vascular tone, and BP. The system was tested on six young, healthy individuals with no history of microvascular diseases. During heating, vasodilation, decrease in systolic BP, and a decrease in parasympathetic tone were observed, while during cooling, vasoconstriction and increased BP were observed. While such changes are expected physiologically using passive experiments, the ability to modulate the physiology non-invasively with a controlled, quantitative, and inexpensive instrument can potentially enable serial assessments of neuro-vascular control outside of clinical settings.


A giant left renal cyst presenting as obesity: a unique presentation.
Benign renal cysts are commonly found in adult patients. However, giant renal cysts measuring more than 15 cm in greatest diameter or containing more than 1500 cc of fluid are rarely seen. A giant renal cyst presenting as obesity, a unique form of presentation, is described herein. We report the unique case of 78-year-old male who was diagnosed with a 25 cm left renal cyst after presenting solely with diffuse progressive abdominal distention. He had no other signs or symptoms and had been followed at our institution for seven years with a diagnosis of obesity. The patient was effectively treated by open renal cyst decortication. Giant renal cyst measuring > or = 15 cm or containing more than 1500 cc of fluid rarely occur. This case is unique in that unlike other adult patients, this patient presented with no sign or symptom other than diffuse, nonlateralizing, abdominal distension.


Ryanodine receptor dysfunction and triggered activity in the heart.
Arrhythmogenesis has been increasingly linked to cardiac ryanodine receptor (RyR) dysfunction. However, the mechanistic relationship between abnormal RyR function and arrhythmogenesis in the heart is not clear. We hypothesize that, under abnormal RyR conditions, triggered activity will be caused by spontaneous calcium release (SCR) events that depend on transmural heterogeneities of calcium handling. We performed high-resolution optical mapping of intracellular calcium and transmembrane potential in the canine left ventricular wedge preparation (n = 28). Rapid pacing was used to initiate triggered activity under normal and abnormal RyR conditions induced by FKBP12.6 dissociation and beta-adrenergic stimulation (20-150 microM rapamycin, 0.2 microM isoproterenol). Under abnormal RyR conditions, almost all preparations experienced SCRs and triggered activity, in contrast to control, rapamycin, or isoproterenol conditions alone. Furthermore, under abnormal RyR conditions, complex arrhythmias (monomorphic and polymorphic tachycardia) were commonly observed. After washout of rapamycin and isoproterenol, no triggered activity was observed. Surprisingly, triggered activity and SCRs occurred preferentially near the epicardium but not the endocardium (P < 0.01). Interestingly, the occurrence of triggered activity and SCR events could not be explained by cytoplasmic calcium levels, but rather by fast calcium reuptake kinetics. These data suggest that, under abnormal RyR conditions, triggered activity is caused by multiple SCR events that depend on the faster calcium reuptake kinetics near the epicardium. Furthermore, multiple regions of SCR may be a mechanism for multifocal arrhythmias associated with RyR dysfunction.


Adult Cardiac Surgery and the COVID-19 Pandemic: Aggressive Infection Mitigation Strategies Are Necessary in the Operating Room and Surgical Recovery.
The COVID-19 pandemic necessitates aggressive infection mitigation strategies to reduce the risk to patients and healthcare providers. This document is intended to provide a framework for the adult cardiac surgeon to consider in this rapidly changing environment. Preoperative, intraoperative, and postoperative detailed protective measures are outlined. These are guidance recommendations during a pandemic surge to be used for all patients while local COVID-19 disease burden remains elevated.