Gastrointestinal Toxicity, Systemic Inflammation, and Liver Biochemistry in Allogeneic Hematopoietic Stem Cell Transplantation.
Liver toxicity is frequently seen in relation to allogeneic hematopoietic stem cell transplantation (HSCT), but pathogenesis and the risk factors are poorly understood. The purpose of this study was to investigate associations between liver toxicity, gastrointestinal toxicity, and levels of immune-regulating cytokines during the early post-transplantation period. We prospectively included 81 children and adults undergoing HSCT after myeloablative conditioning. Alanine aminotransferase (ALT), total bilirubin levels, and international normalized ratio were measured longitudinally until 3 months after the transplantation and related to levels of inflammatory markers (C-reactive protein [CRP], IL-6, and IL-10) and to plasma citrulline as a marker of intestinal toxicity during the first 3 weeks after HSCT. The majority of patients experienced ALT levels above the normal range (45 U/L) with significant increases at 3 months after HSCT. Increased levels of total bilirubin were observed in 26% during the 3-month period. Citrulline levels decreased significantly to a nadir at day 7 (B = .23; 95% confidence interval [CI], .12 to .35; P < .0001), but citrulline levels at nadir were not associated with parameters of liver toxicity. However, a faster reconstitution of mucosa with higher citrulline levels at day +21 correlated with lower bilirubin levels 3 months after HSCT (r = -.26, P = .034) and increased overall survival (hazard ratio, .88; 95% CI, .79 to .97; P = .008) . Increased levels of CRP and IL-6 at day 7 after HSCT correlated positively with ALT and bilirubin, and in the multivariate analysis, IL-6 at day 7 appeared to be the only predicting risk factor for increased mean bilirubin during the early post-transplantation phase (B = .01; 95% CI, .01 to .02; P = .001) as well as maximum levels of bilirubin (B = .3; 95% CI, .12 to .48; P= .001) and occurrence of sinusoidal obstruction syndrome during the first 3 months after HSCT (odds ratio, 1.003; 95% CI, 1.001 to 1.005; P = .002). The results of this study indicate that liver toxicity after HSCT is associated with an increased inflammatory response mounted during the phase of maximal gastrointestinal toxicity in the early phase after transplantation.


Revised simulation model does not predict rebound in gonorrhoea prevalence where core groups are treated in the presence of antimicrobial resistance.
To determine the effects of using discrete versus continuous quantities of people in a compartmental model examining the contribution of antimicrobial resistance (AMR) to rebound in the prevalence of gonorrhoea. A previously published transmission model was reconfigured to represent the occurrence of gonorrhoea in discrete persons, rather than allowing fractions of infected individuals during simulations. In the revised model, prevalence only rebounded under scenarios reproduced from the original paper when AMR occurrence was increased by 10(5) times. In such situations, treatment of high-risk individuals yielded outcomes very similar to those resulting from treatment of low-risk and intermediate-risk individuals. Otherwise, in contrast with the original model, prevalence was the lowest when the high-risk group was treated, supporting the current policy of targeting treatment to high-risk groups. Simulation models can be highly sensitive to structural features. Small differences in structure and parameters can substantially influence predicted outcomes and policy prescriptions, and must be carefully considered.


Development and validation of an online emotional intelligence training program.
Emotional intelligence (EI) is associated with a range of positive health, wellbeing, and behavioral outcomes. The present article describes the development and validation of an online training program for increasing EI abilities in adults. The training program was based on theoretical models of emotional functioning and empirical literature on successful approaches for training socioemotional skills and resilience. After an initial design, programming, and refinement process, the completed online program was tested for efficacy in a sample of 326 participants (72% female) from the general population. Participants were randomly assigned to complete either the EI training program (n = 168) or a matched placebo control training program (n = 158). Each program involved 10-12 hours of engaging online content and was completed during either a 1-week (n = 175) or 3-week (n = 151) period. Participants who completed the EI training program showed increased scores from pre- to post-training on standard self-report (i.e., trait) measures of EI (relative to placebo), indicating self-perceived improvements in recognizing emotions, understanding emotions, and managing the emotions of others. Moreover, those in the EI training also showed increased scores in standard performance-based (i.e., ability) EI measures, demonstrating an increased ability to strategically use and manage emotions relative to placebo. Improvements to performance measures also remained significantly higher than baseline when measured six months after completing the training. The training was also well-received and described as helpful and engaging. Following a rigorous iterative development process, we created a comprehensive and empirically based online training program that is well-received and engaging. The program reliably improves both trait and ability EI outcomes and gains are sustained up to six months post-training. This program could provide an easy and scalable method for building emotional intelligence in a variety of settings.


Determinants of Corneal Endothelial Cell Loss After Trabeculectomy With Mitomycin C.
To investigate factors associated with decreased corneal endothelial cell density (ECD) after trabeculectomy with mitomycin C (MMC). Retrospective review of consecutive glaucoma cases who underwent trabeculectomy with MMC. The types of glaucoma included were primary open-angle glaucoma, exfoliation glaucoma (XFG), neovascular glaucoma, and uveitic glaucoma (UG). The postoperative ECD changes compared with the preoperative ECD and risk factors for ECD decrease were analyzed using mixed-effects models. In total, 162 eyes of 136 patients were included in this study. Postoperative ECD measurements were performed 3.7±1.8 times (mean±SD) during a median follow-up period of 34 months. The mean intraocular pressure decreased from 25.3±9.6 to 9.2±2.3 mm Hg postoperatively. The marginal mean (SE) ECD decrease at 24 months was 9.3% (1.3%) in all cases. The marginal mean ECD decrease at 24 months was 18.2% (3.1%) and 20.6% (4.7%) in eyes with XFG and UG, respectively, which was significantly greater than 4.8% (1.8%) in eyes with primary open-angle glaucoma (P<0.001, each), after accounting for the variability in the number and timepoint of ECD measurements. Multivariate mixed-effects model analyses showed that type of glaucoma (XFG and UG) and older age were significantly associated with larger ECD decrease, and preoperative factors (oral carbonic anhydrase inhibitor and vitrectomy) and postoperative choroidal detachment were significantly associated with a declining trend of ECD over time. The type of glaucoma (XFG, UG) and older age were risk factors for larger ECD decrease after trabeculectomy with MMC.


Integrated analysis of genome‑wide gene expression and DNA methylation microarray of diffuse large B‑cell lymphoma with TET mutations.
Diffuse large B-cell lymphoma (DLBCL), the most frequently occurring type of lymphoid malignancy, has been demonstrated to be associated with mutations of Ten‑Eleven Translocation (TET). In order to explore the association between DLBCL and TET mutations, the present study analyzed the gene expression and methylation profiles in human DLBCL biopsy tissues with wildtype and mutated TET2. The microarray dataset GSE37365, containing two subseries: the genome‑wide gene expression dataset GSE37362 and the DNA methylation microarray dataset GSE37363, was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified using the limma package of R. Furthermore, differentially methylated sites and differentially methylated regions were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed via GO stats and GSEABase packages respectively. Finally, the Pathview package was used to construct the network of enriched pathways. A total of 198 DEGs (106 up‑ and 92 downregulated) were obtained. A total of 602 shared differentially methylated genes (DMGs) were identified according to differentially methylated levels. A total of 12 overlapping genes were identified in DEGs and DMGs. It was observed that 9 of the 12 overlapped genes were downregulated and hypermethylated, with 24 GO terms and one KEGG pathway significantly enriched. The results of the present study demonstrated that the genes cryptochrome circadian clock 1, zinc finger protein (ZNF) interacting with K protein 1, ZNF134, ZNF256 and ZNF615, which were hypermethylated and downregulated in DLBCL patients with TET2 mutations, were the key genes in the association between DLBCL and TET mutations. These genes may act as potential biomarkers for the diagnosis of DLBCL in the future.


L-VTP: Long-Term Vessel Trajectory Prediction Based on Multi-Source Data Analysis.
With the rapid development of marine IoT (Internet of Things), ocean MDTN (Mobile Delay Tolerant Network) has become a research hot spot. Long-term trajectory prediction is a key issue in MDTN. There are no long-term fine-grained trajectory prediction methods proposed for ocean vessels because a vessel's mobility pattern lacks map topology support and can be easily influenced by the fish moratorium, sunshine duration, etc. A traditional on-land trajectory prediction algorithm cannot be directly utilized in this field because trajectory characteristics of ocean vessels are far different from that on land. To address the problem above, we propose a novel long-term trajectory prediction algorithm for ocean vessels, called L-VTP, by utilizing multiple sailing related parameters and K-order multivariate Markov Chain. L-VTP utilizes multiple sailing related parameters to build multiple state-transition matrices for trajectory prediction based on quantitative uncertainty analysis of trajectories. Trajectories' sparsity of ocean vessels results in a critical state missing problem of a high-order state-transition matrix. L-VTP automatically traverses other matrices in a specific sequence in terms of quantitative uncertainty results to overcome this problem. Furthermore, the different mobility models of the same vessel during the day and the night are also exploited to improve the prediction accuracy. Privacy issues have been taken into consideration in this paper. A quantitative model considering Markov order, training metadata and privacy leak degree is proposed to help the participant make the trade-off based on their customized requirements. We have performed extensive experiments on two years of real-world trajectory data that include more than two thousand vessels. The experiment results demonstrate that L-VTP can realize fine-grained long-term trajectory prediction with the consideration of privacy issues. The average error of 4.5-hour fine-grained prediction is less than 500 m. In addition, the proposed method can be extended to 10-hour prediction with an average error of 2.16 km, which is also far less than the communication range of ocean vessel communication devices.


Adult Pacific Oyster (Crassostrea gigas) May Have Light Sensitivity.
Light-sensitivity is an important aspect of mollusk survival as it plays a vital role in reproduction and predator avoidance. In the Pacific oyster Crassostrea gigas light sensitivity has been demonstrated in the larval stage but has not yet been conclusively demonstrated in adult oysters. In this paper we describe an experiment which was undertaken to determine if adult Pacific oysters were sensitive to light. One LED flashlight was used to shine light onto adult oysters while they were filtering seawater through their shell openings. We found that the degree of opening increased gradually during the light period but rapidly decreased when the flashlight was turned off in the treated group but not in the control group. These results suggest that adult Pacific oyster may be sensitive to light.


Changes in Ia expression in mouse kidney during acute graft-vs-host disease.
We induced graft-vs-host disease (GVHD) in mice to determine whether immunologic stimuli could alter renal Ia expression. Two strain combinations were used: B6.C-H-2bm12 into C57BL/6, an I-A mutation difference, and A.SW into A.TL, differing in the I and D regions of H-2. By day 10 after allogeneic reconstitution of lethally irradiated recipients with bone marrow and spleen cells, the recipients had developed acute GVHD, as measured by their spleen to body weight ratio. Histologic examination revealed focal interstitial infiltrates of mononuclear cells in the kidneys. The expression of host Ia in these kidneys was increased up to 10-fold, as measured by absorption, and indirect immunofluorescence indicated that certain renal tubule cells had become strongly positive, suggesting that these were the principal sites of the increase in Ia expression. Similar increases were not observed in donor Ia. Tubule cells may have become Ia positive by passive uptake, or more probably, by the increase of Ia biosynthesis in cells that usually synthesize little or no Ia. Lethal irradiation without reconstitution tended to decrease renal Ia expression, as assessed by absorption and immunofluorescence. The results indicate that renal Ia expression, particularly in renal tubules, can be altered by changes in the immune system, raising the possibility of a role for such altered Ia expression in autoimmune or alloimmune responses involving the kidney.


Alendronate soluble solution: a higher adherence rate in the treatment of osteoporosis.
Since low adherence to a long-term therapy results in a poor clinical outcome and significantly increases healthcare costs, adherence to the treatment of chronic disorders is an issue of great interest. This is particularly true of the treatment of osteoporosis (OP). Adherence to the osteoporosis therapy in patients treated with bisphosphonates in tablet form has been evaluated in comparison with the adherence of those taking alendronate in soluble solution. Here we present a retrospective study of 245 patients treated with alendronate, risedronate and ibandronate tablets and a prospective study of 118 patients treated with soluble alendronate. In both studies, patients have been observed for a period of 12 months. The analysis of patients' persistence with the treatment plan, assessed at three, six and 12 months, revealed a significantly higher adherence (p < 0.005) in the cohort of patients treated with soluble alendronate (92.37% at 12 months) compared with those who followed the course of treatment with tablets (65.4 %, 12 months). The investigation showed higher adherence to the oral therapy with soluble alendronate, demonstrating that a formulation obtained by this method can contribute to a higher level of persistence with the treatment of a disease such as osteoporosis, which requires a long-term therapeutic plan.


Identification of two novel ACTH-responsive genes encoding manganese-dependent superoxide dismutase (SOD2) and the zinc finger protein TIS11b [tetradecanoyl phorbol acetate (TPA)-inducible sequence 11b].
ACTH is the major trophic factor regulating and maintaining adrenocortical function, affecting such diverse processes as steroidogenesis, cell proliferation, cell migration, and cell survival. We used differential display RT-PCR to identify genes that are rapidly induced by ACTH in the bovine adrenal cortex. Of 42 PCR products differentially amplified from primary cultures of bovine adrenocortical cells treated with 10 nM ACTH, six identified mRNAs that were confirmed by Northern blot analysis to be induced by ACTH. Four of these amplicons encoded noninformative repetitive sequences. Of the other two sequenced amplicons, one encoded a partial sequence for mitochondrial manganese-dependent superoxide dismutase (SOD2), an enzyme that is likely to protect adrenocortical cells from the cytotoxic effects of radical oxygen species generated during steroid biosynthesis. The second was identified as TIS11b (phorbol-12-myristate-13-acetate-inducible sequence 11b)/ERF-1/cMG, a member of the CCCH double-zinc finger protein family. SOD2 induction by ACTH was independent of extracellular steroid concentration or oxidative stress. SOD2 and TIS11b mRNA expressions were rapidly induced by ACTH, reaching a maximal level after 8 h and 3 h of treatment, respectively. These ACTH effects were mimicked by forskolin but appeared independent of cortisol secretion. Upon ACTH treatment, induction of TIS11b expression closely followed the previously characterized peak of vascular endothelial growth factor (VEGF) expression. Transfection of a TIS11b expression plasmid into 3T3 fibroblasts induced a decrease in the expression of a reporter gene placed upstream of the VEGF 3'-untranslated region, indicating that TIS11b may be an important regulator of VEGF expression through interaction with its 3'-untranslated region.


[Somatosensory Evoked Potential during Cardiac Surgery].
Neurologic complications are common in cardiac surgery. The rate of complication can range from 1.6% to 23% for permanent neurologic deficits and from 7% to 61% for transient neurologic deficits. Although several studies have suggested the effectiveness of brain monitoring in reducing postoperative adverse neurologic outcomes, brain monitoring during cardiac surgery has not yet been adopted for routine use. Somatosensory evoked potential (SEP) can provide direct information on the integrity of somatosensory pathway such as SEP elicited by median nerve stimulation in cardiac surgery. An electrode is placed over primary sensory cortex, C3' C4', so called Shagss point. The N20/P25 waveform can be recorded. N20/P25 evoked potentials reflect the perfusion of medial brain circulation. When cerebral blood flow decreases or when brachial plexus is obstructed, N20/P25 amplitude decreases with latency delay. SEP can quickly detect brain ischemia and brachial plexus dysfunction, and it is useful for nervous system monitoring in cardiac surgery.


Using Cramer-Rao theory as spectrometer design tool aimed at quantitative complex-spectrum analysis.
In this paper the use of the Cramer-Rao lower bound (CRLB) to aid in the design of diagnostic systems dealing with complex spectra is discussed. Specifically it is discussed how a priori knowledge, used to improve the estimation, can be included in the CRLB analysis. This provides improved predictions for the spectrometer characteristics that will lead to an optimal system.


Targeting CREB for cancer therapy: friend or foe.
The cyclic-AMP response element-binding protein (CREB) is a nuclear transcription factor activated by phosphorylation at Ser133 by multiple serine/threonine (Ser/Thr) kinases. Upon phosphorylation, CREB binds the transcriptional co-activator, CBP (CREB-binding protein), to initiate CREB-dependent gene transcription. CREB is a critical regulator of cell differentiation, proliferation and survival in the nervous system. Recent studies have shown that CREB is involved tumor initiation, progression and metastasis, supporting its role as a proto-oncogene. Overexpression and over-activation of CREB were observed in cancer tissues from patients with prostate cancer, breast cancer, non-small-cell lung cancer and acute leukemia while down-regulation of CREB in several distinct cancer cell lines resulted in inhibition of cell proliferation and induction of apoptosis, suggesting that CREB may be a promising target for cancer therapy. Although CREB, as a transcription factor, is a challenging target for small molecules, various small molecules have been discovered to inhibit CREB phosphorylation, CREB-DNA, or CREB-CBP interaction. These results suggest that CREB is a suitable transcription factor for drug targeting and therefore targeting CREB could represent a novel strategy for cancer therapy.


Scoring Systems for Estimating the Risk of Anticoagulant-Associated Bleeding.
Anticoagulant medications are frequently used to prevent and treat thromboembolic disease. However, the benefits of anticoagulants must be balanced with a careful assessment of the risk of bleeding complications that can ensue from their use. Several bleeding risk scores are available, including the Outpatient Bleeding Risk Index, HAS-BLED, ATRIA, and HEMORR2HAGES risk assessment tools, and can be used to help estimate patients' risk for bleeding on anticoagulants. These tools vary by their individual risk components and in how they define and weigh clinical factors. However, it is not yet clear how best to integrate bleeding risk tools into clinical practice. Current bleeding risk scores generally have modest predictive ability and limited ability to predict the most devastating complication of anticoagulation, intracranial hemorrhage. In clinical practice, bleeding risk tools should be paired with a formal determination of thrombosis risk, as their results may be most influential for patients at the lower end of thrombosis risk, as well as for highlighting potentially modifiable risk factors for bleeding. Use of bleeding risk scores may assist clinicians and patients in making informed and individualized anticoagulation decisions.


Instrumented ligamentotaxis and stabilization of compression and burst fractures of dorsolumbar and mid-lumbar spines.
Controversy continues regarding the best treatment for compression and burst fractures. The axial distraction reduction utilizing the technique employing the long straight rod or curved short rod without derotation to reduce fracture are practised together with short segment posterolateral fusion (PLF). Effects of the early postoperative mobilization without posterolateral fusion on reduction maintenance and fracture consolidation were not evaluated so far. The present prospective study is designed to assess the effectiveness of i) reduction and restoration of sagittal alignment, ii) no posterolateral fusion on the reduced, fractured vertebral body and injured disc, iii) fracture consolidation and iv) the fate of the unfused cephalad and caudal injured motion segments of the fractured vertebra. The study includes 15 Denis burst and two Denis type D compression fractures between T(12) and L(3). The lordotic distraction technique was used for ligamentotaxis utilizing the contoured short rods and pedicle screw fixator. Three vertebrae including the fractured one were fixed. The patients after surgery were braced for ten weeks with activity restriction for 2-4 weeks. The patients were evaluated for change in vertebral body height, sagittal curve, reduction of retropulsion, improvement in neural deficit. The unfused motion segments, residual postoperative pain and bone and metal failure were also evaluated. The preoperative and postreduction percentile vertebral heights at, zero (immediate postoperative), at three, six and 12 months followup were 62.4, 94.8, 94.6, 94.5 and 94.5%, respectively. The percentages of the intracanal fragment retropulsion at preoperative, and postoperative at zero, 3, 6 and 12 months followup were 59.0, 36.2,, 36.0, 32.3, and 13.6% respectively. The preoperative and postreduction percentile loss of the canal dimension and at zero, three, six and 12 months were 52.1, 45.0, 44.0, 41.0 and 29% respectively suggesting that the under-reduced fragment was being resorbed gradually by a remodeling process. The mean initial kyphosis of 33° became mean 2° immediately after reduction and mean 3° at the final followup. The fractured vertebral bodies consolidated in an average period of ten weeks (range 8-14 weeks). The restored disc heights were relatively well maintained throughout the observation period. All paraparetic patients recovered neurologically. There were no postoperative complications. Instrument-aided ligamentotaxis for compression and burst fractures utilizing the short contoured rod derotation technique and the instrumented stabilization of the fractured spine are found to be effective procedures which contribute to the fractured vertebral body consolidation without recollapse and maintain the motion segment function.


Purification and characterization of an inhibitor of plasminogen activator released by rat mammary adenocarcinoma cells.
An inhibitor of plasminogen activator (PA) secreted by a tumorigenic, but non-metastatic, rat mammary adenocarcinoma cell line has been purified to apparent homogeneity and characterized. It strongly inhibited human urokinase, but was 100 times less potent in inhibiting bovine trypsin and had no effect on plasmin or thrombin. A secreted, urokinase-type PA (Mr 48 000) and a cell-associated PA from a metastatic rat adenocarcinoma cell line were also strongly inhibited. In contrast, a tissue-type PA (Mr 66 000), secreted by human melanoma cells, was only slightly inhibited. Purified inhibitor showed a band of Mr 66 000 in sodium dodecyl sulphate/polyacrylamide gel electrophoresis and an isoelectric point of 4.5 after chromatofocusing. The inhibition of human urokinase was non-competitive.


Genome-wide analysis of LTR-retrotransposons in oil palm.
The oil palm (Elaeis guineensis Jacq.) is a major cultivated crop and the world's largest source of edible vegetable oil. The genus Elaeis comprises two species E. guineensis, the commercial African oil palm and E. oleifera, which is used in oil palm genetic breeding. The recent publication of both the African oil palm genome assembly and the first draft sequence of its Latin American relative now allows us to tackle the challenge of understanding the genome composition, structure and evolution of these palm genomes through the annotation of their repeated sequences. In this study, we identified, annotated and compared Transposable Elements (TE) from the African and Latin American oil palms. In a first step, Transposable Element databases were built through de novo detection in both genome sequences then the TE content of both genomes was estimated. Then putative full-length retrotransposons with Long Terminal Repeats (LTRs) were further identified in the E. guineensis genome for characterization of their structural diversity, copy number and chromosomal distribution. Finally, their relative expression in several tissues was determined through in silico analysis of publicly available transcriptome data. Our results reveal a congruence in the transpositional history of LTR retrotransposons between E. oleifera and E. guineensis, especially the Sto-4 family. Also, we have identified and described 583 full-length LTR-retrotransposons in the Elaeis guineensis genome. Our work shows that these elements are most likely no longer mobile and that no recent insertion event has occurred. Moreover, the analysis of chromosomal distribution suggests a preferential insertion of Copia elements in gene-rich regions, whereas Gypsy elements appear to be evenly distributed throughout the genome. Considering the high proportion of LTR retrotransposon in the oil palm genome, our work will contribute to a greater understanding of their impact on genome organization and evolution. Moreover, the knowledge gained from this study constitutes a valuable resource for both the improvement of genome annotation and the investigation of the evolutionary history of palms.


Formation and reactions of metal-metal bonded heterobimetallic (C5H4PR2)-bridged (Zr-Ir) and (Zr-Rh) complexes: evidence for the participation of metal hydride intermediates.
Treatment of the complexes [(C(5)H(4)PR(2))(2)Zr(CH(3))(2)](b: R = isopropyl; c: R = cyclohexyl) with the reagent HIr(CO)(PPh(3))(3) (2b) yield the heterobimetallic complexes [mu-C(5)H(4)PR(2))(2)(H(3)C-Zr-Ir(CO)(PPh(3)))] (4b, 4c) with evolution of methane. The reaction of the -PPh(2) substituted analogue with initially yields an intermediate [(H(3)C)(2)Zr(mu-C(5)H(4)PPh(2))(2)Ir(H)(CO)(PPh(3))] 5a, that still contains both methyl groups at zirconium and does not contain a metal-metal bond. At room temperature, the intermediate reacts further with methane formation to eventually yield the (Zr-Ir) complex 4a. The corresponding [mu-C(5)H(4)PR(2))(2)(H(3)C-Zr-Rh(CO)(PPh(3)))] complexes 3a (R = Ph) and 3b (R = isopropyl) react cleanly with isopropyl alcohol to liberate methane and yield the corresponding [mu-C(5)H(4)PR(2))(2)(Me(2)CHO-Zr-Rh(CO)(PPh(3)))] products (7a, 7b). Carefully monitoring the reaction of with Me(2)CHOH by NMR revealed that the Zr-Rh functionality is attacked first to give the intermediate [Me(Me(2)CHO)Zr([micro sign]-C(5)H(4)PR(2))(2)Rh(H)(CO)(PPh(3))] (6b). This intermediate then reacts further to cleave off methane and re-form the (Zr-Rh) metal-metal bond to yield the product 7b. The tetrametallic mu-oxo-(Zr-Rh) metallocene derivate 11a was obtained starting from the (Zr-Rh) complex 3a and it was characterized by X-ray diffraction. It may be that this reaction is also initiated by H-OH addition to the [Zr-Rh] metal-metal bond.


Cyclic erythropoiesis in the S1/S1d mouse.
Previously we reported that when young adult female W/Wv mice are given 0.5 microCi strontium-89 per gram body weight IV, their hematocrit values oscillate from nadirs of 26% to zeniths of 42% with a periodicity of 16 days. We now report that a second strain of congenitally anemic female mice, the S1/ S1d , also exhibit large fluctuations in their hematocrit values following a dose of 0.5 microCi 89Sr/g body weight. The zeniths through which these mice cycled averaged 37% (range 35%-38%) and the nadirs averaged 13% (range 12%-14%). Reticulocytes fluctuated from highs averaging 40% (range 35%-45%) to lows that averaged 3% (range 1%-5%). The periodicity of cycling in these eight mice ranged from 16 to 19 days. The hematocrits of three out of five non-strontium-treated mice were found to cycle spontaneously in the absence of 89Sr-mediated hematopoietic insult, with nadirs averaging 22% and zeniths averaging 39%. Similarly, doses as small as 0.1 microCi 89Sr/g body weight coupled with antecedent phlebotomy induced cyclic erythropoiesis of substantial amplitude (average nadir 16% and average zenith of 39%). Splenectomy in the S1/ S1d mouse eliminates both spontaneous and 89Sr-induced cyclic erythropoiesis. If the spleen is removed prior to radiostrontium treatment, then cyclic erythropoiesis is not observed following a dose of 0.5 microCi 89Sr/g body weight.


Standardized evidence-based approach for assessment of oncogenic and clinical significance of NTRK fusions.
Gene fusions involving the neurotrophic receptor tyrosine kinase genes NTRK1, NTRK2, and NTRK3, are well established oncogenic drivers in a broad range of pediatric and adult tumors. These fusions are also important actionable markers, predicting often dramatic response to FDA approved kinase inhibitors. Accurate interpretation of the clinical significance of NTRK fusions is a high priority for diagnostic laboratories, but remains challenging and time consuming given the rapid pace of new data accumulation, the diversity of fusion partners and tumor types, and heterogeneous and incomplete information in variant databases and knowledgebases. The ClinGen NTRK Fusions Somatic Cancer Variant Curation Expert Panel (SC-VCEP) was formed to systematically address these challenges and create an expert-curated resource to support clinicians, researchers, patients and their families in making accurate interpretations and informed treatment decisions for NTRK fusion-driven tumors. We describe a system for NTRK fusion interpretation (including compilation of key elements and annotations) developed by the NTRK fusions SC-VCEP. We illustrate this stepwise process on examples of LMNA::NTRK1 and KANK1::NTRK2 fusions. Finally, we provide detailed analysis of current representation of NTRK fusions in public fusion databases and the CIViC knowledgebase, performed by the NTRK fusions SC-VCEP to determine existing gaps and prioritize future curation activities.


The identification of incident cancers in UK primary care databases: a systematic review.
UK primary care databases are frequently used in observational studies with cancer outcomes. We aimed to systematically review methods used by such studies to identify and validate incident cancers of the breast, colorectum, and prostate. Medline and Embase (1980-2013) were searched for UK primary care database studies with incident breast, colorectal, or prostate cancer outcomes. Data on the methods used for case ascertainment were extracted and summarised. Questionnaires were sent to corresponding authors to obtain details about case ascertainment. Eighty-four studies of breast (n = 51), colorectal (n = 54), and prostate cancer (n = 31) were identified; 30 examined >1 cancer type. Among the 84 studies, 57 defined cancers using only diagnosis codes, while 27 required further evidence such as chemotherapy. Few studies described methods used to create cancer code lists (n = 5); or made lists available directly (n = 5). Twenty-eight code lists were received on request from study authors. All included malignant neoplasm diagnosis codes, but there was considerable variation in the specific codes included which was not explained by coding dictionary changes. Code lists also varied in terms of other types of codes included, such as in-situ, cancer morphology, history of cancer, and secondary/suspected/borderline cancer codes. In UK primary care database studies, methods for identifying breast, colorectal, and prostate cancers were often unclear. Code lists were often unavailable, and where provided, we observed variation in the individual codes and types of codes included. Clearer reporting of methods and publication of code lists would improve transparency and reproducibility of studies.


Dietary iron overload inhibits carbon tetrachloride-induced promotion in chemical hepatocarcinogenesis: effects on cell proliferation, apoptosis, and antioxidation.
The aim of this study was to investigate if feeding with carbonyl iron would facilitate the development of preneoplastic lesions initiated by diethylnitrosamine (DEN) and promoted by CCl4-induced liver cirrhosis. Male Wistar rats were fed a diet with 1.25%-2.5% carbonyl iron for 23 weeks and received intragastric injections of CCl4 (1.0 or 2.0 ml/kg per week) for 13 weeks, followed by one i.p. injection of DEN (200 mg/kg), after which CCl4 was administered for 8 additional weeks. Animals were killed 48 h after the first CCl4 injection to evaluate liver necrosis, 8 weeks later to evaluate fibrosis, and 9 weeks after DEN to determine formation of glutathione S-transferase 7,7 (GST-7,7) positive foci. Treatment with iron counteracted the increased serum alanine aminotransferase levels and liver necrosis following CCl4 administration. Hepatic levels of reduced Q9 and alpha-tocopherol were elevated in rats treated with CCl4 and decreased in rats treated with iron compared to the controls. Fibrogenesis was not altered by iron treatment. Nine weeks after DEN initiation, the number and volume density of GST-7,7-positive foci in rats treated with CCl4 were significantly increased as compared with controls, but co-treatment with iron inhibited this increase. Apoptotic index was increased in iron-loaded livers, and labelling index (the fraction of S-phase hepatocytes) was decreased by co-treatment with iron in livers exposed to CCl4. Carbonyl iron depleted hepatic levels of antioxidants, it decreased CCl4-induced necrosis and cell proliferation, it enhanced apoptosis and did not facilitate fibrogenesis. These effects together may explain the suppression of CCl4-induced promotion after DEN initiation exerted by carbonyl iron in the present study.


Interaction of magnetic nanoparticles with phospholipid films adsorbed at a liquid/liquid interface.
The interaction of Co hexagonal magnetic nanoparticles (MNPs) with distearoyl phosphatidyl glycerol (DSPG) and distearoyl phosphatidic acid (DSPA) films adsorbed at a water/1,2-dichloroethane interface is studied employing cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), capacity curves and interfacial pressure-area isotherms. DSPA and DSPG adsorb at the interface forming homogenous films and producing a blocking effect on the transfer process of tetraethyl ammonium (TEA(+)), used as a probe cation. In the presence of Co NPs this effect is reversed and the reversible transfer process for TEA(+) is reestablished, to a greater or lesser extent depending on the structuration of the film. Co-DSPA hybrid films have a homogeneous structure while Co-DSPG films present different domains. Moreover, the presence of Co on DSPA film modifies the partition coefficient of the organic electrolyte into the hydrocarbon layer.


Translocation of spin-labelled radioactive lipids from isolated guinea pig liver microsomal to mitochondrial membranes.
Translocation of membrane-bound labelled lipids from guinea pig liver microsomal to mitochondrial membranes was studied. When microsomal membranes containing known amounts and composition of spin-labelled radioactive lipids were incubated with unlabelled mitochondrial membranes, reisolated mitochondria contained spin- and radioactive-lipids in an amount which could not be accounted for by the microsomal contamination of reisolated mitochondria, establishing therefore the translocation of labelled lipids from microsomal to mitochondrial membranes. The effect of addition of crude 105000 X g supernatant on the translocation was studied. The translocation of labelled lipids in aged membranes was also described. The rate of loss of paramagnetism in microsomal and reisolated mitochondrial membranes was measured and found to be different, supporting the conclusion that the translocation of labelled lipids between membranes took place. Data from these studies suggested that the translocatndrial membranes probably occurred. Furthermore, our results suggest that the mechanism by which lipid translocation takes place does not necessarily involve soluble cytosol proteins. In view of experimental data, possible mechanisms for the translocation of lipids between biological membranes were discussed.


Smart Fuzzy Petri Net-Based Temperature Control Framework for Reducing Building Energy Consumption.
This study addresses the pressing issue of energy consumption and efficiency in the Kingdom of Saudi Arabia (KSA), a region experiencing growing demand for energy resources. Temperature control plays a vital role in achieving energy efficiency; however, traditional control systems may struggle to adapt to the non-linear and time-varying characteristics of the problem. To tackle this challenge, a fuzzy petri net (FPN) controller is proposed as a more suitable solution that combines fuzzy logic (FL) and petri nets (PN) to model and simulate complex systems. The main objective of this research is to develop an intelligent energy-saving framework that integrates advanced methodologies and air conditioning (AC) systems to optimize energy utilization and create a comfortable indoor environment. The proposed system incorporates user identification to authorize individuals who can set the temperature, and FL combined with PN is utilized to monitor and transmit their preferred temperature settings to a PID controller for adjustment. The experimental findings demonstrate the effectiveness of integrating the FPN controller with a convertible frequency AC compressor in significantly reducing energy consumption by 94% compared to using the PN controller alone. The utilization of the PN controller alone resulted in a 25% reduction in energy consumption. Conversely, employing a fixed-frequency compressor led to a 40% increase in energy consumption. These results emphasize the advantages of integrating FL into the PN model, as it effectively reduces energy consumption by half, highlighting the potential of the proposed approach for enhancing energy efficiency in AC systems.


Analysis of pursuit tracking eye movements in pilots and nonfliers.
Pursuit tracking eye movements were recorded and analyzed from a group of Air Force pilots and a group of nonflying Air Force members. The tracking performance of the pilots was compared to the performance of the nonfliers. Subjects tracked a small spot of light moving sinusoidally in the horizontal plane at frequencies ranging from 0.2 to 1.0 Hz at a peak-to-peak amplitude of 40 degrees. Maximum target velocities ranged from 25 to 126 degrees/s. An adaptive nonlinear digital filter was used to separate the total tracking response (TTR) into smooth pursuit (SP) and saccadic (SA) components. Frequency domain analysis was used to relate the tracking components to the target movement. There were no statistically significant differences in tracking performance between the pilots and nonfliers. When tracking the 0.2 and 0.4 Hz targets, the TTR consisted principally of SP tracking with SA tracking representing less than 11% of the TTR. As the target velocity increased, the TTR remained adequate but the proportion of SP tracking decreased while the SA tracking increased. Over one-half of the TTR is contributed by the SA system when tracking the 1.0 Hz targets for both the pilot and nonpilot groups.


Mammalian target of rapamycin and caspase inhibitors in polycystic kidney disease.
One of the most important abnormalities of the tubular epithelial cells lining the cysts as well as noncystic tubular epithelium is a disturbance in the balance between tubular cell proliferation and apoptosis. Activation of the mammalian target of rapamycin signaling pathway results in increased cell proliferation. Recent studies suggested abnormalities of the mammalian target of rapamycin signaling pathway in polycystic kidney disease. Mammalian target of rapamycin inhibition with sirolimus or everolimus results in attenuation of cyst formation in rat and mouse models of polycystic kidney disease. Apoptosis is a pathologic feature of most models of polycystic kidney disease, including human polycystic kidneys. Caspases, the major mediators of apoptosis, are increased in polycystic kidney disease kidneys. Both in vitro and in vivo studies suggest that caspase or apoptosis inhibition attenuates cyst formation. This review focuses on mammalian target of rapamycin and apoptosis signaling pathways in polycystic kidney disease and the role of mammalian target of rapamycin inhibitors and apoptosis inhibitors as potential therapies to reduce cyst formation.


Basic studies on 5-(7-hydroxy-3-O-phosphonocholyl)aminosalicylic acid for the evaluation of microbial overgrowth.
A newly synthesized conjugate of 7-hydroxy-3-O-phosphonocholic acid (ursodeoxycholic acid monophosphate) with 5-aminosalicylic acid (5-ASA-UDCA monophosphate) was investigated to determine its suitability for the evaluation of enteric bacteria. This compound, 5-ASA-UDCA monophosphate, was efficiently deconjugated by cholylglycine hydrolase to release 5-ASA, whereas it was completely resistant to deconjugation by pancreatic and intestinal mucosal enzymes. In everted gut sac experiments, 5-ASA-UDCA monophosphate was not actively absorbed from any part of the small intestine. In animal experiments, urinary excretions of N-acetyl-5-ASA (Ac-5ASA) were measured for 24 h following the oral administration of 20 mg of 5-ASA-UDCA monophosphate. Control rats excreted 276.3 +/- 89.0 micrograms (mean +/- S.E.) of Ac-5ASA, whereas the rats with intestinal bacterial overgrowth excreted more (1224.1 +/- 231.5 micrograms; p < 0.01). These basic studies indicate that this compound is likely to offer a simple method for the evaluation of microbial overgrowth without the use of radioisotopes or expensive, special apparatus.


Assessment of aortic valve disease - a clinician oriented review.
Aortic valve disease [aortic stenosis (AS) and aortic regurgitation (AR)] represents an important global health problem; when severe, aortic valve disease carries poor prognosis. For AS, aortic valve replacement, either surgical or interventional, may provide definite treatment in carefully selected patients. For AR, valve surgery (either replacement or - in selected cases - aortic valve repair) remains the gold standard of care. To properly identify those patients who are candidates for surgery, the clinician has to carefully assess the severity of valve disease with an understanding of the potential pitfalls involved in these assessments. This review focuses on the practical issues concerning the evaluation of patients with AS and AR from a general cardiologist's perspective. The most important issues regarding the documentation of the severity of AS and AR are summarized. More specific issues, such as the role of stress echocardiography, other imaging techniques and details regarding the treatment options (medical, surgical, or interventional), are mentioned briefly.


Fas/Fas ligand signaling during gestational T cell development.
Most thymocytes express high levels of Fas Ag (Apo-1/CD95); however, the role of Fas/Fas ligand-mediated apoptosis in thymocyte development remains unclear. During gestational development of thymocytes in C57BL/6(B6) +/+ mice, the highest levels of Fas ligand mRNA and Fas ligand protein expression were detected at gestational day (GD) 15, and there was a ninefold decrease in Fas ligand mRNA expression between GD 15 and 17 accompanied by a sixfold increase in Fas mRNA. Apoptotic thymocytes were first detected in the medulla at GD 15, and increasing numbers of cortical clusters and scattered, single apoptotic cells were present on GD 16 and 17. Thus, early apoptosis correlated with high expression of Fas ligand. High levels of Fas ligand mRNA were maintained throughout gestational development in thymocytes of Fas-deficient B6-lpr/lpr mice, but cortical clusters and scattered apoptotic cells were decreased relative to B6 +/+ mice before GD 17. Kinetic analysis of fetal thymic organ cultures treated with anti-Fas Ab demonstrated that thymocytes become sensitive to Fas-mediated apoptosis during the transition from the CD4-CD8- to the CD4+CD8+ phenotype. More mature CD4+CD8+ thymocytes and CD4+ and CD8+ thymocytes became resistant to Fas-mediated apoptosis after GD 17, despite high expression of Fas. However, low avidity engagement of the TCR on Fas-sensitive CD4+CD8+ thymocytes before GD 17 induced resistance to Fas-mediated apoptosis. The present results indicate that Fas plays a critical role in mediating apoptosis during early gestational thymocyte development and that thymocytes that receive a survival signal through TCR/CD3 become resistant to Fas-mediated apoptosis.


[Clinical trials of flomoxef in patients with chronic respiratory tract infections].
Flomoxef (FMOX, 6315-S), a newly developed oxacephem drug, was administered to 6 patients with chronic respiratory tract infections. Bacteriological examination of these infections using quantitative sputum cultures revealed that 2 patients had Haemophilus influenzae, 2 had Branhamella catarrhalis and 2 had mixed pathogens (one was with H. influenzae + B. catarrhalis and the other with Streptococcus pneumoniae + B. catarrhalis). The administration of the drug was done by drip infusion, twice daily, with a daily dose of 1 to 2 g. As results, all the above mentioned pathogenic organisms were eradicated in 5 to 10 days after the initiation of the drug therapy. No undesirable symptoms were observed in these patients during the course of the chemotherapy. Serum drug concentrations after an intravenous administration of the drug reached their peak values averaging 134.32 +/- 40.32 micrograms/ml immediately after a single dose of 2 g of FMOX in 5 patients with chronic respiratory tract infections. Drug concentration in the sputum was at highest 1.86 micrograms/ml. Susceptibilities to FMOX of clinically isolated 49 strains of H. influenzae and 35 strains of B. catarrhalis from our clinic in the year of 1986 were compared to those to ampicillin and to latamoxef (LMOX). The study revealed that MICs of FMOX against H. influenzae were 0.10 to 1.56 micrograms/ml, hence H. influenzae strains seemed to be sensitive to FMOX regardless of beta-lactamase activities. LMOX had higher activities against H. influenzae than FMOX, however. Activities of FMOX against B. catarrhalis, on the other hand, were distributed from less than 0.05 to 0.39 microgram/ml which were also not as good as LMOX activities.


Biochemical and immunological characterization of Toxoplasma gondii macrophage migration inhibitory factor.
Macrophage migration inhibitory factor (MIF) is a proinflammatory molecule in mammals that, unusually for a cytokine, exhibits tautomerase and oxidoreductase enzymatic activities. Homologues of this well conserved protein are found within diverse phyla including a number of parasitic organisms. Herein, we produced recombinant histidine-tagged Toxoplasma gondii MIF (TgMIF), a 12-kDa protein that lacks oxidoreductase activity but exhibits tautomerase activity with a specific activity of 19.3 μmol/min/mg that cannot be inhibited by the human MIF inhibitor ISO-1. The crystal structure of the TgMIF homotrimer has been determined to 1.82 Å, and although it has close structural homology with mammalian MIFs, it has critical differences in the tautomerase active site that account for the different inhibitor sensitivity. We also demonstrate that TgMIF can elicit IL-8 production from human peripheral blood mononuclear cells while also activating ERK MAPK pathways in murine bone marrow-derived macrophages. TgMIF may therefore play an immunomodulatory role during T. gondii infection in mammals.


A mathematical analysis of microbial inactivation at linearly rising temperatures: calculation of the temperature rise needed to kill Listeria monocytogenes in different foods and methods for dynamic measurements of D and z values.
From a theoretical analysis of the inactivation of microbes heated at linearly rising temperatures an equation was derived for predicting the linear temperature rise needed to reduce viable numbers of microbes by any chosen factor. This equation is used to predict the temperatures needed to inactivate Listeria monocytogenes in different foods based on published D and z values. Two novel mathematical methods for deriving D and z values from viable counts obtained at linearly rising temperatures are also presented.


Obese, fat, or just overweight?
Discussing obesity with the patient without this being perceived as offensive may represent a challenge. Prevention of lifestyle diseases requires that this topic be addressed with those concerned. In this study, we investigate the patients' sensitivity to expressions, i.e. their notions of appropriateness or inappropriateness regarding various terms for obesity, and what patient characteristics are associated with such sensitivity to expressions. The investigation is part of a five-year study of patients in Central Norway who were treated for morbid obesity. The terms used in the study had been suggested by the Overweight Patients' Association. Data on sensitivity to expressions were collected with the aid of a questionnaire one year after completion of the treatment. Altogether 157 out of 206 participants completed the questionnaire. Their average body mass index (BMI) (SD) amounted to 37.6 kg/m² (7.3 kg/m²). Their sensitivity to 14 different designations varied. «Weight», «overweight» and «weight problem» returned the best scores, whereas «obesitas», «obese» and «fat» were deemed least appropriate. The highest sensitivity to expressions was found among women, those who developed overweight early in life, those who had higher education and those who were dissatisfied with their weight. The perceptions of various expressions for overweight and obesity varied considerably. Knowledge about this topic may be relevant for doctors and other health personnel in prevention and treatment of obesity.


Capturing membrane structure and function in lattice Boltzmann models.
We develop a mesoscopic approach to model the nonequilibrium behavior of membranes at the cellular scale. Relying on lattice Boltzmann methods, we develop a solution procedure to recover the Nernst-Planck equations and Gauss's law. A general closure rule is developed to describe mass transport across the membrane, which is able to account for protein-mediated diffusion based on a coarse-grained representation. We demonstrate that our model is able to recover the Goldman equation from first principles and show that hyperpolarization occurs when membrane charging dynamics are controlled by multiple relaxation timescales. The approach provides a promising way to characterize non-equilibrium behaviors that arise due to the role of membranes in mediating transport based on realistic three-dimensional cell geometries.


Maspin Enhances the Anticancer Activity of Curcumin in Hormone-refractory Prostate Cancer Cells.
Androgen deprivation therapy remains the principal treatment for patients with advanced prostate cancer, though, most patients will eventually develop hormone-refractory prostate cancer (HRPC). Androgen ablation mediated maspin-induction has been identified in cancer patients. However, the role of maspin on the anticancer activity of curcumin derived from turmeric (Curcuma longa) in HRPC cells has not been elucidated. The anticancer action of curcumin in hormone-independent prostate cancer cells (DU145, and PC-3) was determined by measures of cell survival rate. The cause of maspin silencing on the anti-tumor abilities of curcumin in PC-3 cells was evaluated by measures of cell survival rate, cell-cycle distribution, and apoptosis signaling analysis. Our present study showed that PC-3 cells (with higher maspin expression) were more sensitive than DU145 cells to curcumin treatment (with lower maspin expression). RNA interference-mediated maspin silencing reduced curcumin sensitivity of PC-3 cells, as evidenced by reduced apoptotic cell death. After exposure to curcumin, maspin-knockdown cells showed lower expression levels of pro-apoptotic proteins, Bad and Bax, as compared with control cells. Maspin can enhance the sensitivity of HRPC cells to curcumin treatment.


Enduring emotions: James L. Halliday and the invention of the psychosocial.
Emotions maintain an ambivalent position in the economy of science. In contemporary debates they are variously seen as hardwired biological responses, cultural artifacts, or uneasy mixtures of the two. At the same time, there is a tension between the approaches to emotion developed in modern psychotherapies and in the history of science. While historians see the successful ascription of affective states to individuals and populations as a social and technical achievement, the psychodynamic practitioner treats these enduring associations as pathological accidents that need to be overcome. This short essay uses the career of the Glaswegian public health investigator James L. Halliday to examine how debates over the ontological status of the emotions and their durability allow them to travel between individual identity and political economy, making possible new kinds of psychological intervention.


Detection of serum IgA to HSV1 and its diagnostic role in sudden hearing loss.
A viral etiology of sudden hearing loss has been hypothesized by many authors. HSV1 neurotropism and its involvement in sudden hearing loss has implicated HSV1 as one of the most accredited etiological agents. A non-invasive method such as the titration of HSV1-specific IgA was evaluated to determine the role of HSV1 as a possible cause sudden hearing loss. A prospective study was carried out by titration of serum IgA to HSV1 in 93 patients and in a control group of 50 healthy subjects and 35 subjects suffering from recent herpes labialis reactivation. Statistical analysis of the results disclosed that IgA titers to HSV1 higher than 1:80 are suggestive for the association of HSV1 infection and sudden hearing loss. Moreover, acyclovir therapy was effective in 81% of patients who showed high specific IgA titers. Overall, the titration of specific serum IgA to HSV1 can be a useful tool to determine the viral etiology of certain cases of sudden hearing loss. This method is simple to perform and minimally invasive. It can lead to a rapid presumptive diagnosis and to prompt specific therapy, reducing the need for corticosteroids.


Glomeruloid Hemangioma as a Late Manifestation of POEMS Syndrome.
Glomeruloid hemangiomas were first described by Chan in 1990 as a cutaneous marker of POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal proteinemia, and Skin changes). POEMS syndrome is a multisystem disease with a significant cutaneous involvement. Among its manifestations, hemangiomas are common, observed in up to one third of the patients, and, although specific, the glomeruloid subtype is very rare. The vascular endothelium growth factor (VEGF) is an angiogenic stimulation factor, which also induces increased systemic vascular permeability. Thus, a scenario of overexpression of VEGF can credibly lead to the assumption of an association between cutaneous hemangiomas and systemic manifestations, implying prognostic and therapeutic considerations and reinforcing the importance of dermatological periodical consultations for these patients. We report the case of a patient in whom glomeruloid hemangiomas marked the recurrence of POEMS syndrome, occurring before the systemic symptoms.


Immediate Effects of Traditional Thai Massage on Psychological Stress as Indicated by Salivary Alpha-Amylase Levels in Healthy Persons.
BACKGROUND Stress can cause psychological and physiological changes. Many studies revealed that massage can decrease stress. However, traditional Thai massage has not been well researched in this regard. The purpose of this study was to investigate the immediate effects of traditional Thai massage (TTM) on salivary alpha-amylase levels (sAA), heart rate variability (HRV), autonomic nervous system (ANS) function, and plasma renin activity (PRA). MATERIAL AND METHODS Twenty-nine healthy participants were randomly allocated into either a traditional Thai massage (TTM) group or Control (C) group, after which they were switched to the other group with a 2-week wash-out period. Each of them was given a 10-minute mental arithmetic test to induce psychological stress before a 1-hour session of TTM or rest. RESULTS Within-groups comparison revealed that sAA was significantly decreased (p<0.05) in the TTM group but not in the C group. HRV and ANS function were significantly increased (p<0.05) and PRA was significantly decreased (p<0.05) in both groups. However, low frequency per high frequency ratio (LF/HF ratio) and ANS balance status were not changed. Only sAA was found to be significantly different between groups (p<0.05). CONCLUSIONS We conclude that both TTM and rest can reduce psychological stress, as indicated by decreased sAA levels, increased parasympathetic activity, decreased sympathetic activity, and decreased PRA. However, TTM may have a modest effect on stress reduction as indicated by a reduced sAA.


PI3K Signaling in Chronic Obstructive Pulmonary Disease: Mechanisms, Targets, and Therapy.
Chronic Obstructive Pulmonary Disease (COPD) is a progressive respiratory disorder characterized by irreversible chronic inflammation and airflow obstruction. It affects more than 64 million patients worldwide and it is predicted to become the third cause of death in the industrialized world by 2030. Currently available therapies are not able to block disease progression and to reduce mortality, underlying the need for a better understanding of COPD pathophysiological mechanisms to identify new molecular therapeutic targets. Recent studies demonstrated that phosphoinositide 3-kinase (PI3K) signaling is prominently activated in COPD and correlates with an increased susceptibility of patients to lung infections. PI3Ks have thus emerged as promising alternative drug targets for COPD and a wide array of pan-isoform and isoform-selective inhibitors have been tested in preclinical models and are currently being evaluated in clinical studies. Here, we summarize the recent knowledge on the involvement of PI3K enzymes in the pathophysiology of COPD, and we discuss the most recent results arising from the preclinical as well as the clinical testing of PI3K inhibitors as novel therapeutics for COPD.


[Effect of exogenous gonadotropin dosage on embryo aneuploidy rate and pregnancy outcome in patients of preimplantation genetic test].
Objective: To investigate the effect of gonadotropin (Gn) on embryo aneuploidy rate and pregnancy outcome during preimplanptation genetic testing for aneuploidy (PGT-A) cycles. Methods: The clinical data of patients undergoing PGT-A cycle at the First Medical Center of the PLA General Hospital from January 1, 2013 to May 31, 2019 were retrospectively analyzed. Patients were divided into younger patient group (<35 years old) and elder patient group (≥35 years old) by maternal age, then divided into two groups in line with Gn dosage (≤2 250 U, >2 250 U), and into four groups by number of oocytes retrieved (1-5, 6-10, 11-15 and ≥16 oocytes). The embryo aneuploidy rate and pregnancy outcome between the groups were compared. Logistic regression was used to analyze the relationship between the cumulative amount of Gn, embryo aneuploidy rate and live-birth rate. Results: A total of 402 cycles (338 patients) and 1 883 embryos were included in the study. (1) In the younger patients, the aneuploidy rate was 52.5% (304/579) in the group of Gn≤2 250 U and 48.6% (188/387) in the group of Gn>2 250 U, with no significant difference between them (P=0.232). In the elderly patients, the difference in embryo aneuploidy rate between the two Gn group [57.9% (208/359) versus 60.6% (319/526)] was not statistically significant (P=0.420). (2) The embryonic aneuploidy rate in different protocol of ovary stimulation was analyzed,in the younger group, the embryonic aneuploidy rate in patients using antagonist long protocol was 50.3% (158/314), it was 50.0% (121/242) in agonist long protocol, 52.1% (207/397) in agonist short protocol and 6/13 in luteal phase protocol, no statistical difference was found in above groups (P=0.923); in the elder group, embryonic aneuploidy rate was 60.8% (191/314) in antagonist protocol, 58.4% (132/226) in agonist long protocol, 59.2%(199/336) in agonist short protocol, 5/9 in luteal phase protocol, respectively,no significant difference was found (P=0.938). (3) In the younger patients, the aneuploidy rate in 1-5 oocytes group, 6-10 oocytes group, 11-15 oocytes group and ≥16 oocytes group was 37.9% (11/29), 54.0% (94/174), 52.5% (104/198) and 50.1% (283/565) respectively, no significant difference was found between the groups (P=0.652); while in the elder patients, the difference between aneuploidy rate in each retrieved oocytes group [73.6% (89/121), 57.5% (119/207), 56.3% (108/192), 57.8% (211/365)] was statistically significant (P=0.046). (4) Logistic regression analysis of age, cumulative dosage of Gn, number of oocytes obtained, and embryo aneuploidy rate showed that there was no association between the amount of Gn and embryo aneuploidy rate (P>0.05); the increase in maternal age would increase the risk of aneuploidy rate of embryos, which was statistically significant (OR=1.031, 95%CI: 1.010-1.054, P=0.004); the increase in oocytes retrived would significantly decrease the risk of aneuploidy (OR=0.981, 95%CI: 0.971-0.991, P<0.01). (5) There was no significant difference in biochemical pregnancy rate [55.6% (80/144) versus 52.1% (63/121)], clinical pregnancy rate [50.0% (72/144) versus 47.9% (58/121)] and live-birth rate [46.5% (67/144) versus 40.5% (49/121)] between different Gn dosage groups (P=0.613, P=0.738, P=0.324). The logistic regression analysis showed that the maternal age, the cumulative dosage of Gn, the number of oocytes obtained, and the ovarian stimulation protocol had no effect on the live-birth rate (all P>0.05). Conclusions: In PGT-A cycle, the dosage of Gn has no association with the embryo aneuploidy rate and pregnancy outcome. In the patients ≥35 years old, the increase in number of oocytes obtained may decrease the risk of aneuploidy. Age is an important factor affecting the embryo aneuploidy in PGT-A cycle.


Establishing mental health priorities.
Mental health policy has evolved haphazardly, reflecting fragmentation of authority, competing ideologies, limitations of current knowledge and technologies, and changes in entitlements and insurance associated with health and welfare programs. While seeking parity with general health services, the mental health sector requires as well a range of health and social services that extends well beyond acute care, particularly for those with severe and persistent illness. Despite recent advances in articulating health, disability, and social services programs, much remains undone. The stigma of mental illness affects both intergovernmental cooperation and public response. Health reform provides an opportunity to address neglected areas and to build a closer connection with general health services. New coalitions of advocates for the mentally ill, the elderly, and persons with disabilities could construct a coherent long-term-treatment orientation that would benefit all.


Awareness and Knowledge of Human Papillomavirus (HPV) Infection and Vaccine Among Women: A Cross-Sectional Study in Jeddah, Saudi Arabia.
Background This study evaluated the comprehension and awareness of human papillomavirus (HPV) infection and vaccination among women in Jeddah, Saudi Arabia. Methods A cross-sectional study included 696 female respondents from Jeddah between the ages of 18 and 60. Ethical approval and informed consent were obtained before administering the questionnaire through social media. The data collected included social demographic information and information about HPV and vaccination. Results According to the results, only 332 respondents (47.70%) demonstrated good knowledge about HPV. Less than half (47.84%) were aware of the HPV vaccine. However, a slightly higher percentage (53.02%) would be willing to receive the vaccination if it were free. Individuals who were not willing to accept the vaccine believed it had side effects (25.70%), was unsafe (19.92%), or was unnecessary as HPV was a rare infection (17.55%). Demographic variables, such as educational level and occupation, were found to be predictors of HPV knowledge since their corresponding p-values were statistically significant. Conclusion It is crucial to raise awareness about HPV and its vaccine among adult women in Jeddah due to the alarmingly low levels of knowledge and awareness. The importance of HPV vaccination must be emphasized repeatedly to ensure that this critical information is understood and acted upon. Overall, there is low knowledge and awareness about HPV and its vaccine among adult women in Jeddah. Therefore, it is imperative to increase awareness while reiterating the importance of HPV vaccination.


A prospective cohort study of ALI/ARDS in the Tohoku district of Japan (second report).
We previously reported a study of systemic inflammatory response syndrome (SIRS) cases in the Tohoku district of Japan in which the patients showed a 30-day mortality from acute lung injury/acute respiratory distress syndrome (ALI/ARDS) of about 20%. Cases in which chest X-ray findings did not meet ALI/ARDS criteria were diagnosed as acute hypoxemic respiratory failure (AHRF), but about 50% of these patients progressed to ALI/ARDS. The objective of this study was to verify the findings obtained in the earlier study and to gain further insights into the pathognomonic symptoms of AHRF associated with SIRS. A prospective cohort study was performed in SIRS patients admitted to the intensive care unit (ICU) with PaO(2)/fractional inspired oxygen (FIO(2)) < or = 300 mmHg. Patients were assigned to ALI or ARDS groups based on symptoms at ICU entry. Cases in which chest X-ray showed no infiltration shadows in bilateral lung fields were classified as AHRF. A total of 240 patients were enrolled in the study. The 30-day mortalities were 21.6% and 20.0% in the ALI and ARDS groups, respectively. Of the 88 AHRF patients, 49 progressed to ALI/ARDS, with progression occurring within 3 days after ICU entry in most cases; 39 patients recovered with no progression. Chest X-ray and computed tomography (CT) showed no findings indicating ALI/ARDS in 20 AHRF patients at ICU entry, but 7 of these patients progressed to ALI/ARDS. The mortality rates of ALI and ARDS were 21.6% and 20.5%, respectively. More than half of the AHRF patients progressed to ALI or ARDS. Some AHRF patients had normal findings on chest CT, but subsequently showed a bilateral shadow on a chest X-ray. This indicates that mild pathologic lesions may not show imaging abnormalities.


Distinct patterns of expression and evolution of intronless and intron-containing mammalian genes.
Comparison of expression levels and breadth and evolutionary rates of intronless and intron-containing mammalian genes shows that intronless genes are expressed at lower levels, tend to be tissue specific, and evolve significantly faster than spliced genes. By contrast, monomorphic spliced genes that are not subject to detectable alternative splicing and polymorphic alternatively spliced genes show similar statistically indistinguishable patterns of expression and evolution. Alternative splicing is most common in ancient genes, whereas intronless genes appear to have relatively recent origins. These results imply tight coupling between different stages of gene expression, in particular, transcription, splicing, and nucleocytosolic transport of transcripts, and suggest that formation of intronless genes is an important route of evolution of novel tissue-specific functions in animals.


Creating physicians of the 21st century: assessment of the clinical years.
Medical education has been under a constant state of revision for the past several years. The overarching theme of the curriculum revisions for medical schools across the USA has been creating better physicians for the 21st century, with the same end result: graduating medical students at the optimal performance level when entering residency. We propose a robust, thorough assessment process that will address the needs of clerkships, residents, students, and, most importantly, medical schools to best measure and improve clinical reasoning skills that are required for the learning outcomes of our future physicians. The Accreditation Council for Graduate Medical Education (ACGME) evaluates and accredits medical school graduates based on competency-based outcomes and the assessment of specialty-specific milestones; however, there is some evidence that medical school graduates do not consistently meet the Level 1 milestones prior to entering/beginning residency, thus starting their internship year underprepared and overwhelmed. Medical schools should take on the responsibility to provide competency-based assessments for their students during the clinical years. These assessments should be geared toward preparing them with the cognitive competencies and skills needed to successfully transition to residency. Then, medical schools can produce students who will ultimately be prepared for transition to their residency programs to provide quality care.


Effect of purified staphylococal alpha toxin on active sodium transport and aerobic respiration in the isolated toad bladder.
Purified staphylococcal alpha toxin was found to inhibit the active transport of sodium across the isolated toad bladder when applied to the serosal but not to mucosal surface. Heating or the addition of specific antitoxin abolished this effect. Low temperatures reduced this activity significantly. Application of vasopressin to the bladder serosa shortly after toxin resulted in only weak and transient stimulation of sodium transport; once maximal toxin activity had been established, exposure to the hormone was without effect. Transport in bladders previously stimulated by vasopressin was rapidly inhibited by alpha toxin. Concentrations that suppressed active sodium transport completely within 30-45 min produced a significant increase in oxygen consumption by minced bladder tissue within the same period; antitoxin neutralized this activity. 2,4-dinitrophenol also inhibited sodium transport and stimulated oxygen consumption by the toad bladder. The addition of 2,4 dinitrophenol to bladder tissue in which respiration was maximally stimulated by alpha toxin resulted in a further increase in respiratory rate. The addition of toxin to bladder tissue after its exposure to a concentration of 2,4 dinitrophenol known to uncouple oxidative phosphorylation produced a significant stabilization but no increment in respiratory rate. The data are consistent with the previously suggested action of staphylococcal alpha toxin on cell membranes and suggest that energy-dependent transport processes are inhibited. The stimulation of oxygen consumption may be due to an additional effect on oxidative phosphorylation.


[A representative case of joint contracture as a main feature of AL amyloid deposits identified in the skeletal muscles].
A 68-year-old man, with a history of type 2 diabetes mellitus and chronic kidney impairment, had been suffering from progressive knee joint contracture and dysesthesia of the lower extremities for 4 years. When he walked, his knees remained bent owing to contracture of the knee joints. There was no evidence of muscle pseudohypertrophy, intramuscular nodules, or muscle weakness. Clinical examination revealed IgA λ M-protein, reticular high-signal intensity lesions demonstrated by magnetic resonance T2-short TI IR(STIR) imaging of the lower extremity muscles, and a mixture of neurogenic and myogenic changes demonstrated by needle electromyography. A biopsy specimen from the vastus lateralis muscle identified Aλ amyloid deposits around the vessels, establishing a diagnosis of amyloid myopathy based on systemic AL amyloidosis. This case demonstrated that joint contracture and reticular lesions shown by magnetic resonance STIR imaging of the muscles can alert the physician to consider muscle biopsy to investigate deposition of amyloid in the skeletal muscles even in the absence of muscle pseudohypertrophy or weakness, both of which are characteristic of amyloid myopathy.


Mental health of help-seeking outpatients pre and post COVID-19: A real-world data, multicentre study.
A great deal of research addresses the mental health implications of the COVID-19 pandemic for the general population. Little is known about the implications for mental health of help-seeking outpatients and for the effectiveness of mental health services. The present study investigated the mental health and treatment response of help-seeking outpatients before and during the COVID-19 pandemic. Routine outcome monitoring data from 3706 clients in the United States and Northern Europe was analysed using multilevel modelling with global subjective well-being as the dependent variable. As opposed to before the pandemic, during the pandemic, well-being scores were significantly higher at intake and improvement throughout treatment was significantly smaller in the US sample, while both were comparable in the EU sample. Although there is also evidence of less effective treatments since the pandemic, no conclusive picture emerges that portrays the impact of the pandemic on mental health as uniform. More research is needed to elucidate the impact of the pandemic on the help-seeking population.


Imported fire ant allergy. Perspectives on diagnosis and treatment.
As the imported fire ant relentlessly expands its territory, more and more people are at risk of the insects' discomforting and sometimes dangerous stings. Thus, all primary care physicians in fire ant-infested areas should be familiar with diagnosis and treatment of fire ant stings and of allergic reactions to the stings. Fire ant venom is unique when compared with other Hymenoptera venoms, as it consists mainly of nonallergenic alkaloids that are of small molecular weight with only a small percentage of allergenic proteins. Fire ant wholebody extract, unlike other Hymenoptera wholebody extracts, retains its allergenic activity and is an adequate material for use in diagnostic testing and immunotherapy. Diagnosis of fire ant allergy can be readily made by the radioallergosorbent test (RAST) or by skin testing using fire ant wholebody extract. Immunotherapy with fire ant whole-body extract in allergic individuals can prevent serious recurrent systemic reactions.


Elder Self-neglect and Suicidal Ideation in an U.S. Chinese Aging Population: Findings From the PINE Study.
Self-neglect and suicidal ideations are important public health issues among the aging population. This study aims to examine the association between self-neglect, its phenotypes, and suicidal ideation among U.S. Chinese older adults. Guided by a community-based participatory research approach, the Population Study of Chinese Elderly in Chicago (PINE) study is a population-based epidemiological study conducted from 2011 to 2013 among 3,159 Chinese older adults aged 60 years and older in the Greater Chicago area. Self-neglect was assessed by a 27-item instrument, describing five phenotypes with hoarding, poor personal hygiene, unsanitary condition, lack of utilities, and need of home repair. Suicidal ideation was assessed by the ninth item of the Patient Health Questionnaire-9 (PHQ-9) and the Geriatric Mental State Examination-Version A (GMS-A). Logistic regression is utilized to analyze the association. Higher level of self-neglect was found significantly associated with increased risk of self-reported suicidal ideation within 2 weeks (odds ratio 2.97 [1.54-5.72]); 12 months (odds ratio 2.82 [1.77-4.51]); and lifetime (odds ratio 2.74 [1.89-3.95]). For phenotypes, the study found that poorer personal hygiene and severer level of unsanitary conditions were associated with increased risk of suicidal ideation at all three time periods. This study suggests that self-neglect and its phenotypes are significantly associated with suicidal ideation among Chinese older adults. Longitudinal studies are needed to explore the mechanisms through which self-neglect links with suicidal ideation.


Regional properties of the superior head of human lateral pterygoid muscle.
The aim of this study was to investigate functional heterogeneity within the superior head of the human lateral pterygoid (SHLP) muscle by comparing the functional properties (e.g. firing rates) of single motor units (SMUs) between different arbitrarily defined regions of the SHLP, namely, medial, middle or lateral; origin or insertion; and superior or inferior regions. Jaw movement and electromyographic (EMG) activity was recorded from computed tomography-verified locations within the SHLP of 27 asymptomatic human subjects during goal-directed contralateral, ipsilateral, and protrusive jaw movements. The SMU firing rates for protrusion in the medial, origin, and inferior regions were significantly lower than, respectively, the firing rates in the middle, insertion, and superior regions. For contralateral movement, the firing rates were significantly greater in the medial and middle regions than those in the lateral region. The data provide additional evidence that the SHLP is functionally heterogeneous and, together with previous evidence for functional heterogeneity within the inferior head of the lateral pterygoid, support the proposition that both heads should be regarded as functionally heterogeneous.


Distributed Humidity Sensing in PMMA Optical Fibers at 500 nm and 650 nm Wavelengths.
Distributed measurement of humidity is a sought-after capability for various fields of application, especially in the civil engineering and structural health monitoring sectors. This article presents a method for distributed humidity sensing along polymethyl methacrylate (PMMA) polymer optical fibers (POFs) by analyzing wavelength-dependent Rayleigh backscattering and attenuation characteristics at 500 nm and 650 nm wavelengths. Spatially resolved humidity sensing is obtained from backscatter traces of a dual-wavelength optical time domain reflectometer (OTDR). Backscatter dependence, attenuation dependence as well as the fiber length change are characterized as functions of relative humidity. Cross-sensitivity effects are discussed and quantified. The evaluation of the humidity-dependent backscatter effects at the two wavelength measurements allows for distributed and unambiguous measurement of relative humidity. The technique can be readily employed with low-cost standard polymer optical fibers and commercial OTDR devices.


The peopling of Madeira Archipelago (Portugal) according to HLA genes.
The Madeira-Porto Santo Archipelago was officially colonized in 1420 by Portuguese settlers. Its importance in Columbus' information for the American discovery and for slave traffic across the Atlantic is unquestionable. Thus, a complex peopling may have given rise to a present-day high admixture of ethnicities according to HLA genes. A sample of 173 healthy unrelated Madeirans was analysed and compared with 6986 HLA chromosomes from other worldwide populations. Genetic distances, neighbour-joining dendrograms and correspondence analyses were used for comparisons. Southern European, North African (including Canary Islands), Jewish and Mediterranean typical HLA alleles were found and genetic distances from Madeirans to these populations were the closest ones. In addition A*24-B*65-DRB1*0102-DQB1*0501 and A*68-B*08-DRB1*0301-DQB1*0201 haplotypes were newly found in Madeira and not found in any other population. Jewish-Armenian-Middle East haplotype (A*33-B*65-DRB1*0102-DQB1*0501) is one of the most common haplotypes; this haplotype is also present in Spaniards and North Africans. Quantitatively, Portuguese, North Africans (Algerians), Spaniards and Canary Islanders (in this order) are the most important parental populations to Madeirans. Results are discussed on the basis of the recorded historical peopling which does not show a noticeable African gene input in present-day Madeiran population according to our data; one of the closest related populations found is the Canary Islanders, suggesting that Guanche (Canary Islands first inhabitants) slaves gene flow is still noticed at present, both in Madeira and in Canary Islands populations.


Ergonomics of bronchoscopy: good advice or a pain in the neck?
Interventional pulmonologists require a unique set of skills including precise motor abilities and physical endurance, but surprisingly the application of ergonomic principles in the field of bronchoscopy remains limited. This is particularly intriguing when considering the significant impact that poor ergonomics can have on diagnostic aptitude, income potential and overall health. It is therefore imperative to provide comprehensive education to physicians regarding the significance of ergonomics in their work, especially considering the introduction of advanced diagnostic and therapeutic procedures. By implementing simple yet effective measures (e.g. maintaining neutral positions of the wrist, neck and shoulder; adjusting the height of tables and monitors; incorporating scheduled breaks; and engaging in regular exercises), the risk of injuries can be substantially reduced. Moreover, objective tools are readily available to assess ergonomic postures and estimate the likelihood of work-related musculoskeletal injuries. This review aims to evaluate the current literature on the impact of procedure-related musculoskeletal pain on practising pulmonologists and identify modifiable factors for future research.


Early relapse in a case of primary bone marrow diffuse large B-cell lymphoma treated with rituximab-CHOP.
As an uncommon disease, primary bone marrow diffuse large B-cell lymphoma (PBM DLBCL) is rarely reported in recent years. In this paper, we discuss a case of a 58-year-old man who presented with fever and fatigue, and was diagnosed with PBM DLBCL. Although the initial diagnosis reflected a positive expression of CD20 by lymphoma cells, the course of disease appeared as a rapid remission but a quick recurrence, after eight cycles of rituximab-based immunochemotherapy (R-CHOP). With the positive expression of CD20 in recurrent lesions, he received another four cycles of rituximab-based immunochemotherapy (R-GDP). However, an earlier relapse still occurred, and he died of CNS involvement. PBM DLBCL has been classified as an aggressive type of DLBCL, which should be heavily treated since the initial diagnosis. MYC-BCL2 gene rearrangement and P53 gene mutation cannot be ignored. Of note, rituximab resistance has become a severe and urgent problem in the rituximab era.


Spatial genetic structure across a hybrid zone between European rabbit subspecies.
The Iberian Peninsula is the only region in the world where the two existing subspecies of the European rabbit (Oryctolagus cuniculus) naturally occur and hybridize. In this study we explore the relative roles of historical and contemporary processes in shaping the spatial genetic structure of the rabbit across its native distribution range, and how they differently affect each subspecies and the hybrid zone. For that purpose we obtained multilocus genotypes and mitochondrial DNA data from 771 rabbits across most of the distribution range of the European rabbit in Spain. Based on the nuclear markers we observed a hierarchical genetic structure firstly comprised by two genetic groups, largely congruent with the mitochondrial lineages and subspecies distributions (O. c. algirus and O. c. cuniculus), which were subsequently subdivided into seven genetic groups. Geographic distance alone emerged as an important factor explaining genetic differentiation across the whole range, without the need to invoke for the effect for geographical barriers. Additionally, the significantly positive spatial correlation up to a distance of only 100 km supported the idea that differentiation at a local level is of greater importance when considering the species overall genetic structure. When looking at the subspecies, northern populations of O. c. cuniculus showed more spatial genetic structure and differentiation than O. c. algirus. This could be due to local geographic barriers, limited resources, soil type and/or social behavior limiting dispersal. The hybrid zone showed similar genetic structure to the southern populations but a larger introgression from the northern lineage genome. These differences have been attributed to selection against the hybrids rather than to behavioral differences between subspecies. Ultimately, the genetic structure of the rabbit in its native distribution range is the result of an ensemble of factors, from geographical and ecological, to behavioral and molecular, that hierarchically interact through time and space.


Mutation analysis provides additional proof that mottled is the mouse homologue of Menkes' disease.
Menkes' disease (MD) and occipital horn syndrome (OHS) are allelic X-linked disorders caused by mutations in the copper ion transporting ATPase, ATP7A. Genetic, phenotypic and biochemical data suggest that mottled mutants in the mouse, which range in severity and phenotype, are caused by mutations in Atp7a, the mouse homologue of ATP7A. As the only causal mutation in Atp7a has been reported in one very mild allele thought to be a model for OHS, Atp7aMo-blo (mottled blotchy), we sequenced the entire 4.5 kb coding region of three other mottled mutants, two of which are thought to be models for classical MD (AtpaMo-br, AtpaMo-13H) and one with a slightly milder phenotype (Atp7aMo-vbr). Although no causal mutation was found in Atp7aMo-13H, mutations which can be predicted to affect Atp7a function were identified in Atp7aMo-br and Atp7aMo-vbr. A 6 bp deletion of nucleotides 2478-2483, which can be predicted to affect the correct processing of the protein, was found in Atp7aMo-br and an A3189-->C nucleotide change, which results in lysine-->threonine amino acid substitution in the phosphorylation domain, was found in Atp7aMo-vbr. Thus we provide further proof that mottled mutants will provide excellent models for MD as well as OHS.


Hyperosmotic tolerance of human spermatozoa: separate effects of glycerol, sodium chloride, and sucrose on spermolysis.
Hyperosmotic stress, which cells experience during the freezing process, and its release during the warming process are both related to cryoinjury. To define optimal cooling or warming rates and prevent osmotic injury to human sperm, information is required regarding the osmotic tolerance of the cells as a function of 1) time, 2) temperature, 3) type of solute, and 4) solute concentration. Human sperm samples were divided into three aliquots. The aliquots were equilibrated at 0, 8, and 22 degrees C, respectively. Different hyperosmotic solutions were prepared by addition of either a permeating cryoprotective agent (glycerol) or nonpermeating solutes (sucrose, non-ionic; or NaCl, ionic) to isotonic Mann's Ringer solution. Aliquots of the prepared solutions were equilibrated at 0, 8, and 22 degrees C, respectively. A small volume (2.5 microliters) of each sperm aliquot was quickly mixed with 50 microliters of each hyperosmotic solution at the corresponding temperature. After times ranging from 5 s to 5 min, 10 microliters of each hyperosmotic cell suspension was abruptly returned to an isosmotic environment by mixing with 500 microliters of Mann's Ringer solution at the corresponding temperature. The plasma membrane integrity of cells after exposure to hyperosmotic stress and after return to isosmotic conditions was measured by a dual staining (carboxyfluoroscein diacetate and propidium iodide) technique and flow cytometry. The morphology of the treated cells was observed by scanning electron microscopy of freeze-substituted sperm. The results indicate that human spermatozoa exhibited a significant posthypertonic lysis/injury, i.e., loss of membrane integrity, when returned to isosmotic conditions after exposure to hyperosmotic solutions of NaCl or sucrose. The higher the hyperosmolality, the more serious the cell injury. The majority of the cells (> 50%) lost membrane integrity when the osmolality was > or = 2000 mOsm. In contrast, if the sperm were not returned to isosmotic conditions, the majority of the sperm in the hyperosmotic solutions appeared to maintain membrane integrity. For a given higher hyperosmolality (> 1000 mOsm), posthypertonic spermolysis was reduced with a decrease of temperature. Cell survival was also affected by time of cell exposure to hyperosmotic environments before cells were returned to the isotonic condition. The shorter the time, the higher the cell survival. When exposed to hyperosmotic glycerol solutions that were isotonic with respect to electrolytes, few cells lost their membrane integrity if the osmolality of glycerol was < 3000 mOsm. For a fixed high osmolality (> 3000 mOsm), the lower the temperature, the higher the percentage spermolysis.(ABSTRACT TRUNCATED AT 400 WORDS)


Seizure-induced hilar ectopic granule cells in the adult dentate gyrus.
Epilepsy is a chronic neurological disorder characterized by hypersynchronous spontaneous recurrent seizures, and affects approximately 50 million people worldwide. Cumulative evidence has revealed that epileptogenic insult temporarily increases neurogenesis in the hippocampus; however, a fraction of the newly generated neurons are integrated abnormally into the existing neural circuits. The abnormal neurogenesis, including ectopic localization of newborn neurons in the hilus, formation of abnormal basal dendrites, and disorganization of the apical dendrites, rewires hippocampal neural networks and leads to the development of spontaneous seizures. The central roles of hilar ectopic granule cells in regulating hippocampal excitability have been suggested. In this review, we introduce recent findings about the migration of newborn granule cells to the dentate hilus after seizures and the roles of seizure-induced ectopic granule cells in the epileptic brain. In addition, we delineate possible intrinsic and extrinsic mechanisms underlying this abnormality. Finally, we suggest that the regulation of seizure-induced ectopic cells can be a promising target for epilepsy therapy and provide perspectives on future research directions.


Prevalence and resistance of Pseudomonas aeruginosa in severely burned patients: a 10-year retrospective study.
Infection complications caused by gram-negative bacteria nowadays constitute the dominant mortality cause in severely burned patients. Pseudomonas aeruginosa is the most feared nosocomial pathogen among burn centers worldwide, with the highest mortality. The study involved adult patients hospitalized at the Intensive Care Unit at the Department of Burns and Reconstructive Surgery, University Hospital Brno, between the years 2000 and 2009. These patients were hospitalized for thermal injuries. Retrospectively we have evaluated the extent of the burned areas, ages, depth of injury at admission and at discharge or in dissection (histology) and length of hospitalization on the Intensive Care Unit. By completing regular swabs we monitored and evaluated the microbiological situation not only at the burned areas but also in the lower respiratory system, in the urinary tract and in the blood stream. The study involved a total of 640 adults hospitalized at the Intensive Care Unit at the Department of Burns and Reconstructive Surgery, University Hospital Brno, for burn trauma between the years 2000 and 2009. The average extent of the burned area in patients was 36.2% TBSA (2-97% TBSA), average age was 36.7% years (18-92 years), average length of hospitalization at the Intensive Care Unit was 27.1 days (1-151 days). We isolated a total of 2,958 strains of Pseudomonas aeruginosa (including repeated isolation of pseudomonas strains in the same patients) in these patients. The most frequently found of these was Pseudomonas aeruginosa isolated from the burned area (1,301 strains), from the lower respiratory system (651) and from the urinary tract (592 strains). During the monitored period the number of strains isolated in our patients increased (146 strains in 2000, 521 strains in 2009). Furthermore, we noticed increased resistance to all available antibiotics except Polymyxins. All of the Pseudomonas aeruginosa strains in the monitored years maintained 100% sensitivity to Colistin. Of the routinely used antibiotics Meropenem showed the greatest increase of resistance (in 2000 this comprised a total of 18% of the resistant Pseudomonas aeruginosa strains, and in 2009 58% of the strains). Ceftazidime shows similar results (in 2000 12%, in 2009 39% of resistant strains). Amikacin displayed a relatively good effect against pseudomonas infections; in 2009 we registered total of 34% of the resistant strains of Pseudomonas aeruginosa to this aminoglycoside. In 2000 there were 13 multiresistant strains (i.e. 8.9%) of Pseudomonas aeruginosa, in 2009 the figure was 171 strains (i.e. 32.82%). In our study we point to the increasing trend not only in the prevalence but also in the resistance of Pseudomonas aeruginosa strains. This limits our choices for suitable antibiotic therapy. This is why infection complications play such a significant role in morbidity and mortality in severely burned patients.


Simultaneous acquisition of functional magnetic resonance images and impedance cardiography.
While simultaneous acquisition of electrocardiography (ECG) data during MRI is a widely used clinical technique, the effects of the MRI environment on impedance cardiography (ICG) data have not been characterized. We collected echo planar MRI scans while simultaneously recording ECG and thoracic impedance using carbon fiber electrodes and customized amplifiers. Here, we show that the key changes in impedance (dZ/dt) and features of the ECG waveforms are not obstructed during MRI. We present a method for ensemble averaging ICG/ECG signals collected during MRI and show that it performs comparably with signals collected outside the MRI environment. These results indicate that ICG can be used during MRI to measure stroke volume, cardiac output, preejection period, and left ventricular ejection time.


An Unusual Presentation of Sarcoidosis.
Bilateral pleural effusions are a rare manifestation of sarcoidosis. We describe here the case of a 30 year old Vietnamese man living in Ireland who presented with a 4 month history of cough, dyspnoea on exertion and fatigue. On chest CT, he was found to have bilateral pleural effusions, bihilar lymphadenopathy and multiple pulmonary nodules. Pleural biopsy confirmed the presence of non caseating granulomas. He was commenced on steroids with excellent clinical response.


Chronic oral supplementation with sepiapterin prevents endothelial dysfunction and oxidative stress in small mesenteric arteries from diabetic (db/db) mice.
We previously reported that acute incubation with tetrahydrobiopterin (BH4) or sepiapterin, a cofactor for endothelial nitric oxide synthase and a stable precursor of BH4, respectively, enhanced the acetylcholine (Ach)-induced relaxation of isolated small mesenteric arteries (SMA) from diabetic (db/db) mice. In this study, we investigated the effect of chronic oral supplementation of sepiapterin (10 mg x kg-1 x day-1) to db/db mice on endothelium function, biopterin levels and lipid peroxidation in SMA. Oral dietary supplementation with sepiapterin had no effect on glucose, triglyceride, cholesterol levels and body weight. SMA from db/db mice showed enhanced vascular reactivity to phenylephrine, which was corrected with sepiapterin supplementation. Furthermore, Ach, but not sodium nitroprusside-induced relaxation, was improved with sepiapterin supplementation in db/db mice. BH4 levels and guanosine triphosphate cyclohydrolase I activity in SMA were similar in db/+ and db/db mice. Sepiapterin treatment had no effects on BH4 or guanosine triphosphate cyclohydrolase I activity. However, the level of dihydrobiopterin+biopterin was higher in SMA from db/db mice, which was corrected following sepiapterin treatment. Thiobarbituric acid reactive substance, malondialdehyde, a marker of lipid peroxidation, was higher in SMA from db/db mice, and was normalized by sepiapterin treatment. These results indicate that sepiapterin improves endothelial dysfunction in SMA from db/db mice by reducing oxidative stress. Furthermore, these results suggest that decreased biosynthesis of BH4 may not be the basis for endothelial dysfunction in SMA from db/db mice.