Association Between Impairment of DNA Double Strand Break Repair and Decreased Ovarian Reserve in Patients With Endometriosis.
Background: Repair of DNA double strand break (DSB) is an important mechanism for maintaining genetic stability during a DNA damage event. Although, a growing body of recent evidence suggests that DNA DSBs and related repair mechanisms may be important in ovarian aging and in various cancers, there are few reports in endometriosis. We, therefore, examined expression levels of genes pertaining to DNA DSB repair in patients with endometriosis to assess the potential effects on ovarian reserves. Materials and methods: A total of 69 women undergoing laparoscopic surgery for endometriosis and other benign conditions was included; endometriosis group (n = 38) vs. controls (n = 31). DNA DSBs in endometrial and ovarian tissues of both groups were compared via immunohistochemistry, aimed at γ-H2AX expression. To gauge genotoxin-induced DNA DSBs in endometrial stromal cells, γ-H2AX expression was determined by western blot after H2O2 treatment of cultured endometrial stromal cells (endometriosis group and controls) and Ishikawa cell-line cultures. Endometrial and ovarian tissue levels of BRCA1, BRCA2, Rad51, and ATM (ataxia-telangiectasia mutated) mRNA expression were also compared. Correlations between expression levels of genes of interest and serum anti-müllerian hormone (AMH) levels were assessed as well. Results: Expression of γ-H2AX in immunostained endometrial and ovarian tissue preparations was greater in the endometriosis group, compared with controls. After H2O2 treatment, γ-H2AX expression levels were also significantly greater in cultured stromal cells of the endometriosis group and in the Ishikawa cell line than in controls. Endometrial expression of BRCA1 and Rad51 mRNA proved significantly lower in the endometriosis group (vs. controls), as did ovarian expression of BRCA1 and BRCA2 mRNA. Serum AMH concentration showed a significant correlation with ovarian BRCA1 mRNA expression in women with endometriosis (p = 0.03). Conclusions: In women with endometriosis, expression levels of various genes implicated in DSB repair are decreased and ovarian BRCA1 expression correlates with.


High quit ratio among Asian immigrants in California: implications for population tobacco cessation.
Asian immigrants to the U.S. are participants in a natural experiment on the effects of social norms on tobacco cessation. Smoking is socially acceptable in most Asian countries. When Asian smokers move to U.S. states such as California, they experience a radically different social norm toward smoking. This study examines ever smokers among two groups of Asian immigrants in California, Chinese and Koreans, and finds that most have quit smoking. The quit ratios (percent of ever smokers who have quit) for Chinese (52.5%) and Korean immigrants (51.1%) have quit ratios for ever smokers in California in general (53.3%), which is among the highest in the U.S. These high quit ratios contrast sharply with much lower quit ratios for Chinese in China (11.5%) and for Koreans in Korea (22.3%). Such large differences in quit ratios are the results of accumulated differences over the years, because of dramatic differences in annual cessation rates: Chinese in California quit at roughly seven times the rate of Chinese in China, and Koreans in California three times that of Koreans in Korea. Analyses further show that these large differences in annual cessation rates come mainly from the fact that these immigrants in California made quit attempts at a much higher rate than their counterparts in their home countries. These results suggest that creating an impetus to drive up quit attempts, which often results from a significant change in social norms toward smoking, is the most important strategy to improve cessation on the population level.


In-Vitro Anti-Proliferative, Apoptotic and Antioxidative Activities of Medicinal Herb Kalonji (Nigella sativa).
Natural product with apoptotic activity could serve as a potential new source for anti-cancer medicine. Numerous phytochemicals from plants have shown to exert antineoplastic effects via programmed cell death (apoptosis). Cancer is one of the leading causes of death in prosperous countries. The subject study was intended to evaluate the anticancer properties of Kalonji extracts against cancer cell lines HeLa and HepG2 and normal cell lines BHK and VERO were used as normal controls. For the evaluation of anti-proliferative effects, cell viability and cell death in all groups of cells were evaluated via MTT, crystal violet and trypan blue assays. For the evaluation of angiogenesis, Immunocytochemistry and ELISA of VEGF were done. Immunocytochemistry and ELISA of Annexin-V and p53 were performed for the estimation of apoptosis in all groups of cells. Furthermore, LDH assay, antioxidant enzymes activity (GSH, APOX, CAT and SOD) and RT-PCR with proliferative and apoptotic markers along with internal control were also performed. Cancer cells of both cell lines HepG2 and HeLa cells showed reduced viability, angiogenesis and proliferation with increased apoptosis when treated with Kalonji extracts. Whereas anti-oxidative enzymes show enhanced levels in treated cancer cells as compared to untreated ones. It was observed that Kalonji extracts have the ability to induce apoptosis and improve the antioxidant status of HeLa and HepG2 cells. They can also inhibit the proliferation and angiogenesis in both these cancer cell lines.


Effects of kernel and window setting combinations on assessments of small and complicated vasculature in computed tomography angiographic images of dogs with and without tumors.
To evaluate the effect of kernel and window settings on the assessment of small and complicated vasculature in CT angiographic (CTA) images of kidneys, jejunum with mesentery, and tumors in dogs. 20 healthy dogs and 20 dogs with tumors. Images from CTA performed previously in dogs were reconstructed with 3 different combinations of kernel and window settings (soft kernel with soft tissue window, soft kernel with bone window, and sharp kernel with bone window), and reconstructed images of the left kidney and the jejunum with the mesentery in healthy dogs and tumors in affected dogs were evaluated by reviewers blinded to the settings. For images of kidney and jejunum with mesentery, reviewers' scores for the conspicuity of vascularity in the arterial phase and the differentiation of the organs from the adjacent structures were significantly higher when viewed in bone window (vs soft tissue window) regardless of kernel setting. For images of head and gastrointestinal tumors, reviewers' scores for differentiation of intratumoral vasculature were higher when viewed in sharp kernel with bone window versus other setting combinations. However, the conspicuity of gastrointestinal, hepatic, or splenic tumoral vessels from the adjacent structures had higher reviewer scores for images in soft kernel with soft tissue window, compared with other setting combinations. Results indicated that reconstruction of CTA images with sharp kernel combined with bone window settings might have clinical utility in evaluating and planning treatments for dogs with various tumors; however, additional research is warranted to further identify effects of various kernel and window setting combinations on assessments of small and complicated vasculature in larger and more diverse populations of dogs with and without tumors.


Non-equilibrium estimates of gene flow inferred from nuclear genealogies suggest that Iberian and North African wall lizards (Podarcis spp.) are an assemblage of incipient species.
The study of recently-diverged species offers significant challenges both in the definition of evolutionary entities and in the estimation of gene flow among them. Iberian and North African wall lizards (Podarcis) constitute a cryptic species complex for which previous assessments of mitochondrial DNA (mtDNA) and allozyme variation are concordant in describing the existence of several highly differentiated evolutionary units. However, these studies report important differences suggesting the occurrence of gene flow among forms. Here we study sequence variation in two nuclear introns, beta-fibint7 and 6-Pgdint7, to further investigate overall evolutionary dynamics and test hypotheses related to species delimitation within this complex. Both nuclear gene genealogies fail to define species as monophyletic. To discriminate between the effects of incomplete lineage sorting and gene flow in setting this pattern, we estimated migration rates among species using both FST-based estimators of gene flow, which assume migration-drift equilibrium, and a coalescent approach based on a model of divergence with gene flow. Equilibrium estimates of gene flow suggest widespread introgression between species, but coalescent estimates describe virtually zero admixture between most (but not all) species pairs. This suggests that although gene flow among forms may have occurred the main cause for species polyphyly is incomplete lineage sorting, implying that most forms have been isolated since their divergence. This observation is therefore in accordance with previous reports of strong differentiation based on mtDNA and allozyme data. These results corroborate most forms of Iberian and North African Podarcis as differentiated, although incipient, species, supporting a gradual view of speciation, according to which species may persist as distinct despite some permeability to genetic exchange and without having clearly definable genetic boundaries. Additionally, this study constitutes a warning against the misuse of equilibrium estimates of migration among recently-diverged groups.


Transduction of signals in the activation of T lymphocytes: relation to leukemia.
The biochemical events initiated by mitogen in T lymphocytes are the subject of this paper. Following interaction of the mitogen with its receptors, a transmembrane 'trigger-type' signal is propagated which has both positive and negative correlates. The negative signal occurs with high mitogen concentrations and is associated with membrane freezing, microtubular aggregation, receptor capping, adenylate cyclase activation, and cellular cyclic AMP increases. The positive signal occurs with optimal mitogen concentrations and is associated with changes in membrane permeability and transport with influx of calcium and potassium ion and efflux of sodium, in transport processes for glucose, amino acids, and nucleosides, and in a collected series of early membrane lipid changes which can be considered essential for the positive signal. These lipid changes include the uptake of arachidonic acid and other fatty acids, choline, phosphate and other molecules, their incorporation into membrane phospholipids, particularly phosphatidylinositol (PI), and a turnover of PI with the production of inositol triphosphate, which can be related to calcium mobilization and diacylglycerol which activates a cytoplasmic protein kinase C. A key event associated with mitogen action is arachidonic acid release. Arachidonic acid may give rise to prostaglandins and thromboxanes as part of negative components of the signal through effects on the adenylate cyclase/cyclic AMP system. Arachidonic acid gives rise to eicosanoids like 5-, 11-, possibly 12- and 15-hydroxyperoxy and hydroxy eicosatetraenoic acids and leukotrienes B4 and C4. The activation of the 5-lipoxygenase, a critical calcium-dependent step, leads via the production of 5-HPETE and 5-HETE to the activation of membrane and soluble guanylate cyclase and the production of cyclic GMP. Cyclic GMP appears to be essential for mitogen activation and is associated with cyclic GMP-dependent protein kinase activation and the phosphorylation of a number of substrates. Calcium ion influx is clearly central to mitogen action. Calcium through its influx and mobilization from cellular stores is thought to contribute directly and indirectly through the action of calmodulin and protein kinase C to the activation of a number of enzymatic processes involved in the positive signal including phospholipase C, diglyceride kinase and lipase, 5-lipoxygenase, and guanylate cyclase. Cyclic GMP and calcium ion both participate in nuclear processes leading to RNA and protein synthesis. Interleukin 2 is associated with midcycle increases in cyclic GMP and entry into DNA synthesis.(ABSTRACT TRUNCATED AT 400 WORDS)


Effect of iodoacetate on the bone marrow immunocompetence of AKR mice.
Studies were conducted to determine whether the sulfhydryl inhibitor, sodium iodoacetate, administered to preleukemic AKR mice and to mature C3H mice altered the immunocompetence of their bone marrow. Parameters investigated included the splenic plaque-forming capacity directed to sheep erythrocytes of bone marrow transferred from iodoacetate-treated aanimals to irradiated syngeneic recipients and the mitogenic responsiveness of bone marrow cells from untreated and iodoacetate-treated preleukemic AKR mice to phytohemagglutinin and concanavalin A. The administration of two 0.5-ml doses of 10 mM iodoacetate to preleukemic AKR mice and to C3H mice resulted in a significant increase in bone marrow immunocompetence. Irradiated mice given marrow transplants from iodoacetate-treated syngeneic donors exhibited greater numbers of plaque-forming cells directed against sheep erythrocytes than did recipients of marrow from control animals. This effect was abrogated when the donor marrow was previously treated in vitro with rabbit antimouse brain serum and the complement to remove thymus-derived lymphocytes. The mitogenic responsiveness of marrow cultures from iodoacetate-treated AKR mice to phytohemagglutinin was similar to that observed for control mice, while the response to concanavalin A was decreased. These findings suggest that the administration of iodoacetate potentiated the immunocompetence of bone marrow by affecting thymus-derived cells.


Clinical application of ventricular end-systolic elastance and the ventricular pressure-volume diagram.
The ability to clinically assess myocardial contractility in a load-independent fashion facilitates the selection of appropriate inotropes, when needed, during shock resuscitation. Within the framework of the ventricular pressure-volume diagram, the slope of the ventricular end-systolic pressure-volume relationship (expressed as ventricular end-systolic elastance, Ees), has been shown to accurately reflect ventricular inotropic state, and to be insensitive to loading conditions. It has not, however, been widely used at the bedside. Our goal was to evaluate the clinical utility of Ees and the ventricular pressure-volume diagram as bedside methods of hemodynamic assessment. We performed a prospective study of 123 hemodynamic interventions in 100 trauma patients during shock resuscitation in which contractility (Ees), preload (left ventricular end-diastolic volume index), and afterload (effective arterial elastance) were calculated before and after addition of inotropes, fluid bolus, and afterload reduction. Mean values of each variable were compared before and after each type intervention using the paired t test. The ventricular pressure-volume diagram was used to predict changes in the studied variables, and the experimental results were compared with predicted changes. Ees (mmHg/mL/m2) increased significantly with inotropes (4.7 +/- 3.2 to 10 +/- 8.7, p < .0001), but was not affected by clinically significant fluid administration (7.0 +/- 4.7 to 8.3 +/- 8.0, p = .10) or afterload reduction (9.6 +/- 5.2 to 9.2 +/- 4.7, p = .72). Left ventricular end-diastolic volume index (mL/m2) improved with fluid administration (54 +/- 8.9 to 62 +/- 9.8, p < .0001) and effective arterial elastance (mmHg/mL/m2) decreased with afterload reduction (3.3 +/- .9 to 2.6 +/- .7, p < .0001). We conclude that Ees is a load-independent measure of contractility, which is measurable at the bedside. The pressure-volume diagram is a useful method of monitoring hemodynamic changes associated with interventions during shock resuscitation.


Genomic landscape of cutaneous follicular lymphomas reveals 2 subgroups with clinically predictive molecular features.
Primary cutaneous follicle center lymphomas (PCFCLs) are indolent B-cell lymphomas that predominantly remain skin restricted and manageable with skin-directed therapy. Conversely, secondary cutaneous involvement by usual systemic follicular lymphoma (secondary cutaneous follicular lymphoma [SCFL]) has a worse prognosis and often necessitates systemic therapy. Unfortunately, no histopathologic or genetic features reliably differentiate PCFCL from SCFL at diagnosis. Imaging may miss low-burden internal disease in some cases of SCFLs, leading to misclassification as PCFCL. Whereas usual systemic FL is well characterized genetically, the genomic landscapes of PCFCL and SCFL are unknown. Herein, we analyzed clinicopathologic and immunophenotypic data from 30 cases of PCFCL and 10 of SCFL and performed whole-exome sequencing on 18 specimens of PCFCL and 6 of SCFL. During a median follow-up of 7 years, 26 (87%) of the PCFCLs remained skin restricted. In the remaining 4 cases, systemic disease developed within 3 years of diagnosis. Although the SCFLs universally expressed BCL2 and had BCL2 rearrangements, 73% of the PCFCLs lacked BCL2 expression, and only 8% of skin-restricted PCFCLs had BCL2 rearrangements. SCFLs showed low proliferation fractions, whereas 75% of PCFCLs had proliferation fractions >30%. Of the SCFLs, 67% had characteristic loss-of-function CREBBP or KMT2D mutations vs none in skin-restricted PCFCL. Both SCFL and skin-restricted PCFCL showed frequent TNFRSF14 loss-of-function mutations and copy number loss at chromosome 1p36. These data together establish PCFCL as a unique entity with biological features distinct from usual systemic FL and SCFL. We propose 3 criteria based on BCL2 rearrangement, chromatin-modifying gene mutations (CREBBP, KMT2D, EZH2, and EP300), and proliferation index to classify cutaneous FL specimens based on the likelihood of concurrent or future systemic spread.


A case of unilateral adrenal medullary hyperplasia.
We report a case of unilateral hyperplasia of the adrenal medulla. The patient showed clinical features suggestive of pheochromocytoma. Removal of the hyperplastic adrenal gland resulted in complete disappearance of all prior symptoms, decrease of the plasma and urinary catecolamine levels and no high uptake in [133I] metaiodobenzylguanidine scintigraphy. A histological study revealed diffuse hyperplasia of the adrenal medulla. Up to now, there are relatively few reports of adrenal medullary hyperplasia in English literatures.


Postlactational involution biomarkers plasminogen and phospho-STAT3 are linked with active age-related lobular involution.
Breast terminal duct lobular units undergo two distinctive physiological processes of involution: age-related lobular involution (LI), which is gradual and associated with decreased breast cancer risk, and postlactational involution, which is relatively precipitous, occurs with weaning, and has been associated with potentiation of tumor aggressiveness in animal models. Here we assessed whether markers of postlactational involution are associated with ongoing LI in a retrospective tissue cohort. We selected 57 women from the Mayo Clinic Benign Breast Disease Cohort who underwent multiple biopsies and who were average age 48 at initial biopsy. Women were classified as having progressive or non-progressive LI between initial and subsequent biopsy. Serial tissue sections were immunostained for plasminogen, matrix metalloproteinase 9 (MMP-9), phospho-STAT3 (pSTAT3), tenascin C, Ki67, CD44, cytokeratin 14 (CK14), cytokeratin 19 (CK19), and c-myc. All but Ki67 were digitally quantified. Associations between maximal marker expression per sample and progressive versus non-progressive LI were assessed using logistic regression and adjusted for potential confounders. While no biomarker showed statistically significant association with LI progression when evaluated individually, lower expression of pSTAT3 (OR 0.35, 95% CI 0.13-0.82, p = 0.01) and higher expression of plasminogen (OR 2.89, 95% CI 1.14-8.81, p = 0.02) were associated with progressive LI in models simultaneously adjusted for all biomarkers. Sensitivity analyses indicated that the strengthening in association for pSTAT3 and plasminogen with progressive LI was due to collinearity between these two markers. This is the first study to identify biomarkers of active LI. Our findings that plasminogen and pSTAT3 are significantly associated with LI suggest that they may represent signaling nodes or biomarkers of pathways common to the processes of postlactational involution and LI.


Generalized correlation measure using count statistics for gene expression data with ordered samples.
Capturing association patterns in gene expression levels under different conditions or time points is important for inferring gene regulatory interactions. In practice, temporal changes in gene expression may result in complex association patterns that require more sophisticated detection methods than simple correlation measures. For instance, the effect of regulation may lead to time-lagged associations and interactions local to a subset of samples. Furthermore, expression profiles of interest may not be aligned or directly comparable (e.g. gene expression profiles from two species). We propose a count statistic for measuring association between pairs of gene expression profiles consisting of ordered samples (e.g. time-course), where correlation may only exist locally in subsequences separated by a position shift. The statistic is simple and fast to compute, and we illustrate its use in two applications. In a cross-species comparison of developmental gene expression levels, we show our method not only measures association of gene expressions between the two species, but also provides alignment between different developmental stages. In the second application, we applied our statistic to expression profiles from two distinct phenotypic conditions, where the samples in each profile are ordered by the associated phenotypic values. The detected associations can be useful in building correspondence between gene association networks under different phenotypes. On the theoretical side, we provide asymptotic distributions of the statistic for different regions of the parameter space and test its power on simulated data. The code used to perform the analysis is available as part of the Supplementary Material. email@example.com or firstname.lastname@example.com. Supplementary data are available at Bioinformatics online.


Synthesis of Zwitterionic Polymers Containing a Tertiary Sulfonium Group for Protein Stabilization.
The present study demonstrates the controlled synthesis and biological potential of poly( N-acryloyl-l-methionine methyl sulfonium salt)s (poly(A-Met(S+)-OH)s), which mimic dimethylsulfoniopropionate (DMSP), a compound produced by marine algae to protect their proteins. The novel sulfonium-containing zwitterionic polymers were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization of the amino acid-based monomer N-acryloyl-l-methionine (A-Met-OH) followed by a postmodification process in which the sulfide groups were reacted with iodomethane. The DMSP-mimic zwitterionic macromolecules were shown for the first time to exhibit low cytotoxicity and the ability to stabilize proteins. By adding the resulting poly(A-Met(S+)-OH)s to horse radish peroxidase (HRP) solution, the activity of HRP was maintained even after storage at 4 °C for several days. In addition, the protein activities were tested using peroxidase-labeled antibody to mouse immunoglobulin G (IgG-HRP) and alkaline phosphatase (ALP) after storage and for HRP after freeze-thaw cycles. Amphiphilic random copolymers, poly(A-Met(S+)-OH- co-BA)s, also exhibited excellent properties for protein stabilization.


Long noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers.
The functional impact of recently discovered long noncoding RNAs (ncRNAs) in human cancer remains to be clarified. One long ncRNA which has attracted attention is the Hox transcript antisense intergenic RNA termed HOTAIR, a long ncRNA expressed from the developmental HOXC locus located on chromosome 12q13.13. In cooperation with Polycomb complex PRC2, the HOTAIR long ncRNA is reported to reprogram chromatin organization and promote breast cancer metastasis. In this study, we examined the status and function of HOTAIR in patients with stage IV colorectal cancer (CRC) who have liver metastases and a poor prognosis. HOTAIR expression levels were higher in cancerous tissues than in corresponding noncancerous tissues and high HOTAIR expression correlated tightly with the presence of liver metastasis. Moreover, patients with high HOTAIR expression had a relatively poorer prognosis. In a subset of 32 CRC specimens, gene set enrichment analysis using cDNA array data revealed a close correlation between expression of HOTAIR and members of the PRC2 complex (SUZ12, EZH2, and H3K27me3). Our findings suggest that HOTAIR expression is associated with a genome-wide reprogramming of PRC2 function not only in breast cancer but also in CRC, where upregulation of this long ncRNA may be a critical element in metastatic progression.


The hydrological context determines the beta-diversity of aerobic anoxygenic phototrophic bacteria in European Arctic seas but does not favor endemism.
Despite an increasing number of studies over the last 15 years, aerobic anoxygenic photoheterotrophic (AAP) bacteria remain a puzzling functional group in terms of physiology, metabolism, and ecology. To contribute to a better knowledge of their environmental distribution, the present study aims at analyzing their diversity and structure at the boundary between the Norwegian, Greenland, and Barents Seas. The polymorphism of a marker gene encoding a sub-unit of the photosynthetic apparatus (pufM gene) was analyzed and attempted to be related to environmental parameters. The Atlantic or Arctic origin of water masses had a strong impact on the AAP bacterial community structure whose populations mostly belonged to the Alpha- and Gammaproteobacteria. A majority (>60%) of pufM sequences were affiliated to the Gammaproteobacteria reasserting that this class often represents the major component of the AAP bacterial community in oceanic regions. Two alphaproteobacterial groups dominate locally suggesting that they can constitute key players in this marine system transiently. We found that temperature is a major determinant of alpha diversity of AAP bacteria in this marine biome with specific clades emerging locally according to the partitioning of water masses. Whereas we expected specific AAP bacterial populations in this peculiar and newly explored ecosystem, most pufM sequences were highly related to sequences retrieved elsewhere. This observation highlights that the studied area does not favor AAP bacteria endemism but also opens new questions about the truthfulness of biogeographical patterns and on the extent of AAP bacterial diversity.


Subjective or objective binge: is the distinction valid?
The aim of this study was to examine the validity of the distinction between objective and subjective binge episodes. Data were analyzed from 101 women who received 12 weeks of cognitive-behavioral therapy (CBT) for binge eating in a previous treatment study. Binges recorded by participants on daily food records were rated as either subjective or objective according to the Eating Disorder Examination rating guidelines. Unpaired t tests were performed to determine the relationship between type of binge, psychopathology, and other descriptive measures, including response to treatment. These analyses revealed no significant differences between types of binge episodes. Of note is the observation that objective binge episodes appeared to decrease more rapidly than subjective episodes during treatment. Future research should continue to investigate whether "large amount of food" is an appropriate criterion for the diagnosis of binge eating.


Anaphylactic shock associated with intravenous thrombolytics.
Adverse events including intracerebral hemorrhage and reperfusion arrhythmias are well known to occur with thrombolytic therapy. We report a case report of anaphylactic reaction directly attributable to intravenous (IV) recombinant tissue plasminogen activator and identify additional cases through review of the Food and Drug Administration Adverse Event Reporting System. A systematic review of Adverse Event Reporting System was performed for allergic adverse events occurring in conjunction with IV thrombolytics. We reviewed 924 adverse events which occurred between 2004 and 2012 that were associated with thrombolytics. We subsequently acquired detailed individual safety reports of 33 cases in which allergic events were documented. Out of the 33 reports, there were 12 cases (age range, 57-93 years) of adverse allergic reaction directly attributable to IV thrombolytics. Allergic reactions included angioedema, facial swelling, urticaria, skin rash, cutaneous hypesthesia, hypotension, anaphylactic shock, and death. Of the patients who were reported to suffer from allergic adverse events, 11 received IV alteplase and 1 received IV reteplase. Most reactions associated with IV alteplase resolved with withdrawal of medication and treatment with diphenhydramine and steroids ± epinephrine. There was 1 death directly attributable to allergic reaction in a patient who received IV reteplase for MI.Although IV alteplase is identical to endogenous tissue plasminogen activator, it appears to be the most common cause of allergic reaction among currently used thrombolytics, with or without concomitant administration of angiotensin-converting enzyme inhibitors. A greater awareness among physicians may result in prompt recognition and treatment.


Engineering a potent boron-10-enriched polymeric nanoparticle for boron neutron capture therapy.
Background: Boron neutron capture therapy (BNCT) is a promising cancer treatment that eliminates tumor cells by triggering high-energy radiation within cancer cells. Aim: In vivo evaluation of poly(vinyl alcohol)/boric acid crosslinked nanoparticles (PVA/BA NPs) for BNCT. Materials & methods: PVA/BA NPs were synthesized and intravenously injected into tumor-bearing mice for BNCT. Results: The in vitro boron uptake of PVA/BA NPs in tumor cells was 70-fold higher than the required boron uptake for successful BNCT. In an in vivo study, PVA/BA NPs showed a 44.29% reduction in tumor size compared with clinically used boronophenylalanine for oral cancer in a murine model. Conclusion: PVA/BA NPs exhibited effective therapeutic results for oral cancer treatments in BNCT.


Large-scale and automated DNA sequence determination.
DNA sequence analysis is a multistage process that includes the preparation of DNA, its fragmentation and base analysis, and the interpretation of the resulting sequence information. New technological advances have led to the automation of certain steps in this process and have raised the possibility of large-scale DNA sequencing efforts in the near future [for example, 1 million base pairs (Mb) per year]. New sequencing methodologies, fully automated instrumentation, and improvements in sequencing-related computational resources may render genome-size sequencing projects (100 Mb or larger) feasible during the next 5 to 10 years.


In Vivo Visualization of Spontaneous Activity in Neonatal Mouse Sensory Cortex at a Single-neuron Resolution.
The mammalian brain undergoes dynamic developmental changes at both the cellular and circuit levels throughout prenatal and postnatal periods. Following the discovery of numerous genes contributing to these developmental changes, it is now known that neuronal activity also substantially modulates these processes. In the developing cerebral cortex, neurons exhibit synchronized activity patterns that are specialized to each primary sensory area. These patterns markedly differ from those observed in the mature cortex, emphasizing their role in regulating area-specific developmental processes. Deficiencies in neuronal activity during development can lead to various brain diseases. These findings highlight the need to examine the regulatory mechanisms underlying activity patterns in neuronal development. This paper summarizes a series of protocols to visualize primary sensory areas and neuronal activity in neonatal mice, to image the activity of individual neurons within the cortical subfields using two-photon microscopy in vivo, and to analyze subfield-related activity correlations. We show representative results of patchwork-like synchronous activity within individual barrels in the somatosensory cortex. We also discuss various potential applications and some limitations of this protocol.


[Disorders of smell and taste. Standard and recent methods in diagnosis and therapy].
Compared to disorders of the ears and eyes, diseases of smell and taste seem to be far less outstanding: however, the unimpaired perception of odours and flavours comprises an important part of our well-being, as can be seen in the perfume industry or in drinking and eating habits. The ENT-specialist covers organic causes of these senses, as he has the tools to explore and treat in the depth of the nasal and oral cavities. The "Arbeitsgemeinchaft Olfaktologie/Gustologie der Deutschen Gesellschaft für Hals-Nasen-Ohrenheilkunde, Kopf- und Halschirurgie" therefore is in process of establishing a new set for a standardised smell and taste test, which is based in part on the sniffin'sticks, which were developed by Prof. Kobal, Erlangen. The examination procedure of nasal and oral chemosensory performance requires a high test-retest reliability and an efficiency comparable to internationally established measurements in order to render valid results in diagnostic and therapeutic procedures. The new test kit with the sniffin'sticks is presented in this paper, followed by an overview on some disorders of smell and taste perception and proposals for actual therapeutic procedures.


A cluster randomised trial to evaluate a nutrition training programme.
The need for training to equip primary care staff with the knowledge and skills to provide dietary advice to the public has been acknowledged. Little is known about the effectiveness of such training at improving the dietary counselling skills of multidisciplinary practice teams. To evaluate the effectiveness of a nutrition training programme, delivered to primary care teams by a dietitian. A paired-cluster randomised trial. Twelve general practices in Sunderland, in the United Kingdom. A nutrition training programme, aimed at improving the quality of dietary consultations, was developed and delivered to six primary care teams by a dietitian. Main outcome measures were patients' recall of seven key consulting behaviours. Data were collected from patients in intervention and control practices, pre- and post-intervention. Change in knowledge and attitude of practitioners was also measured. All 12 practices completed the trial. Data were collected from 251 patients pre-intervention and 228 patients post-intervention. Of the seven consulting behaviours targeted in the training, only the proportion of consultations where written information (diet sheets) was provided to patients was significantly higher (13% higher, 95% confidence interval [CI = 4 to 21, P = 0.004) in the intervention practices post-training. Some evidence of improved practitioner knowledge and attitude was detected. This evaluation of a nutrition training intervention detected only a limited impact on the behaviour, knowledge, and attitudes of primary care practitioners in dietary consultations.


FUS Recognizes G Quadruplex Structures Within Neuronal mRNAs.
Fused in sarcoma (FUS), identified as the heterogeneous nuclear ribonuclear protein P2, is expressed in neuronal and non-neuronal tissue, and among other functions, has been implicated in messenger RNA (mRNA) transport and possibly local translation regulation. Although FUS is mainly localized to the nucleus, in the neurons FUS has also been shown to localize to the post-synaptic density, as well as to the pre-synapse. Additionally, the FUS deletion in cultured hippocampal cells results in abnormal spine and dendrite morphology. Thus, FUS may play a role in synaptic function regulation, mRNA localization, and local translation. Many dendritic mRNAs have been shown to form G quadruplex structures in their 3'-untranslated region (3'-UTR). Since FUS contains three arginine-glycine-glycine (RGG) boxes, an RNA binding domain shown to bind with high affinity and specificity to RNA G quadruplex structures, in this study we hypothesized that FUS recognizes these structural elements in its neuronal mRNA targets. Two neuronal mRNAs found in the pre- and post-synapse are the post-synaptic density protein 95 (PSD-95) and Shank1 mRNAs, which encode for proteins involved in synaptic plasticity, maintenance, and function. These mRNAs have been shown to form 3'-UTR G quadruplex structures and were also enriched in FUS hydrogels. In this study, we used native gel electrophoresis and steady-state fluorescence spectroscopy to demonstrate specific nanomolar binding of the FUS C-terminal RGG box and of full-length FUS to the RNA G quadruplex structures formed in the 3'-UTR of PSD-95 and Shank1a mRNAs. These results point toward a novel mechanism by which FUS targets neuronal mRNA and given that these PSD-95 and Shank1 3'-UTR G quadruplex structures are also targeted by the fragile X mental retardation protein (FMRP), they raise the possibility that FUS and FMRP might work together to regulate the translation of these neuronal mRNA targets.


[Presence of conjugative transposon Tn1545 in strains of Streptococcus pneumoniae with mef(A), erm(B), tet(M), catpC194 and aph3'-III genes].
We studied the association of MLS resistance genes (erm(B) and mef(A) with others non-MLS resistance genes: tet(M) (tetracycline and minocycline), catpC194 (chloramphenicol) and aph3'-III (kanamycin) in order to know how is selected the multiresistant in Streptococcus pneumoniae. The tet(M) and catpC194 genes were present very often in the pneumococci with the erm(B) gene but the aph3'-III was found only in four strains. Tn1545 was nearly always the responsible for the dissemination of these genes. In contrast, mef(A) was not associated with tet(M) and and catpC194 and is disseminated in a different conjugative transposon. The linkage of multiple antibiotic resistance genes on the same mobile element is of importance for public health, because the use of one antibiotic selects for the transposon which carries multidrug resistance genes.


Group 3 innate lymphoid cells mediate early protective immunity against tuberculosis.
Tuberculosis is the leading cause of death by an infectious disease worldwide1. However, the involvement of innate lymphoid cells (ILCs) in immune responses to infection with Mycobacterium tuberculosis (Mtb) is unknown. Here we show that circulating subsets of ILCs are depleted from the blood of participants with pulmonary tuberculosis and restored upon treatment. Tuberculosis increased accumulation of ILC subsets in the human lung, coinciding with a robust transcriptional response to infection, including a role in orchestrating the recruitment of immune subsets. Using mouse models, we show that group 3 ILCs (ILC3s) accumulated rapidly in Mtb-infected lungs and coincided with the accumulation of alveolar macrophages. Notably, mice that lacked ILC3s exhibited a reduction in the accumulation of early alveolar macrophages and decreased Mtb control. We show that the C-X-C motif chemokine receptor 5 (CXCR5)-C-X-C motif chemokine ligand 13 (CXCL13) axis is involved in Mtb control, as infection upregulates CXCR5 on circulating ILC3s and increases plasma levels of its ligand, CXCL13, in humans. Moreover, interleukin-23-dependent expansion of ILC3s in mice and production of interleukin-17 and interleukin-22 were found to be critical inducers of lung CXCL13, early innate immunity and the formation of protective lymphoid follicles within granulomas. Thus, we demonstrate an early protective role for ILC3s in immunity to Mtb infection.


Isotope effects reveal that para-substituted benzylamines are poor reactivity probes of the quinoprotein mechanism for aromatic amine dehydrogenase.
Structure-activity correlations have been employed previously in the mechanistic interpretation of TTQ-dependent amine dehydrogenases using a series of para-substituted benzylamines. However, by combining the use of kinetic isotope effects (KIEs) and crystallographic analysis, in conjunction with structure-reactivity correlation studies, we show that para-substituted benzylamines are poor reactivity probes for TTQ-dependent aromatic amine dehydrogenase (AADH). Stopped-flow kinetic studies of the reductive half-reaction, with para-substituted benzylamines and their dideuterated counterparts, demonstrate that C-H or C-D bond breakage is not fully rate limiting (KIEs approximately unity). Contrary to previous reports, Hammett plots exhibit a poor correlation of structure-reactivity data with electronic substituent effects for para-substituted benzylamines and phenylethylamines. Crystallographic studies of enzyme-substrate complexes reveal that the observed structure-reactivity correlations are not attributed to distinct binding modes for para-substituted benzylamines in the active site, although two binding sites for p-nitrobenzylamine are identified. We identify structural rearrangements, prior to the H-transfer step, which are likely to limit the rate of TTQ reduction by benzylamines. This work emphasizes (i) the need for caution when applying structure-activity correlations to enzyme-catalyzed reactions and (ii) the added benefit of using both isotope effects and structural analysis, in conjunction with structure-reactivity relationships, to study chemical steps in enzyme reaction cycles.


Influenza Viruses in Mice: Deep Sequencing Analysis of Serial Passage and Effects of Sialic Acid Structural Variation.
Influenza A viruses have regularly jumped to new host species to cause epidemics or pandemics, an evolutionary process that involves variation in the viral traits necessary to overcome host barriers and facilitate transmission. Mice are not a natural host for influenza virus but are frequently used as models in studies of pathogenesis, often after multiple passages to achieve higher viral titers that result in clinical disease such as weight loss or death. Here, we examine the processes of influenza A virus infection and evolution in mice by comparing single nucleotide variations of a human H1N1 pandemic virus, a seasonal H3N2 virus, and an H3N2 canine influenza virus during experimental passage. We also compared replication and sequence variation in wild-type mice expressing N-glycolylneuraminic acid (Neu5Gc) with those seen in mice expressing only N-acetylneuraminic acid (Neu5Ac). Viruses derived from plasmids were propagated in MDCK cells and then passaged in mice up to four times. Full-genome deep sequencing of the plasmids, cultured viruses, and viruses from mice at various passages revealed only small numbers of mutational changes. The H3N2 canine influenza virus showed increases in frequency of sporadic mutations in the PB2, PA, and NA segments. The H1N1 pandemic virus grew well in mice, and while it exhibited the maintenance of some minority mutations, there was no clear evidence for adaptive evolution. The H3N2 seasonal virus did not establish in the mice. Finally, there were no clear sequence differences associated with the presence or absence of Neu5Gc.IMPORTANCE Mice are commonly used as a model to study the growth and virulence of influenza A viruses in mammals but are not a natural host and have distinct sialic acid receptor profiles compared to humans. Using experimental infections with different subtypes of influenza A virus derived from different hosts, we found that evolution of influenza A virus in mice did not necessarily proceed through the linear accumulation of host-adaptive mutations, that there was variation in the patterns of mutations detected in each repetition, and that the mutation dynamics depended on the virus examined. In addition, variation in the viral receptor, sialic acid, did not affect influenza virus evolution in this model. Overall, our results show that while mice provide a useful animal model for influenza virus pathology, host passage evolution will vary depending on the specific virus tested.


Sm/Ti co-substituted bismuth ferrite multiferroics: reciprocity between tetragonality and piezoelectricity.
BiFeO3 (BFO) systems co-modified with Ti, Sm and Sm-Ti have been investigated for piezoelectricity together with dielectric and multiferroic properties. Structural studies revealed the coexistence of orthorhombic and rhombohedral (R3c) phases for x > 0.12. Impurity phases were shown to have hardly any effect on the remanent magnetization, which rather depends on the Fe-O-Fe bond angle. The dielectric loss was reduced considerably by substitution. A correlation between the piezoelectric coefficient and tetragonality was observed in these samples. BFO co-substituted with Sm-Ti exhibited a high piezoelectric coefficient with better ferroic properties, which revealed a unique combination of green piezoelectricity and multiferroicity.


Alcohol and college athletes.
This study examines heavy episodic alcohol consumption and associated harms in collegiate athletes in the United States. The factors which may promote or deter such use are explored. Randomly selected students in a nationally representative sample of 4-yr colleges in the United States completed self-report questionnaires in the spring of 1997. Athletes were defined as students who participated in one or more hours of intercollegiate athletics per day. Heavy episodic or "binge" drinking for men was defined as consuming five or more alcoholic drinks on at least one occasion in the past 2 wk and four or more for women. Athletes were compared with other students at their colleges. Athletes reported more binge drinking, heavier alcohol use, and a greater number of drinking-related harms. Athletes are more likely to exhibit the strong social ties found to be associated with binge drinking. Athletes, despite drinking more heavily than other students, report greater exposure to alcohol prevention efforts and possess unique motivations to limit their alcohol use. Athletes are a high-risk group for binge drinking and alcohol-related harms. Although special educational programs have targeted this group they have not sufficiently impacted the problem. Future prevention efforts targeted for athletes should address the unique social and environmental influences on athletes. Programs should also take advantage of motives of athletes for self-limiting alcohol intake. Colleges, athletic departments, coaches, and sports medicine professionals are urged to act to help reduce athletes risk of alcohol-related harms.


Acute lung injury and acute respiratory distress syndrome after pulmonary resection.
The occurrence of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) after thoracic surgery are perplexing and persistent problems. Variously described as postpneumonectomy pulmonary edema, noncardiogenic pulmonary edema, and postlung resection pulmonary edema, ALI and ARDS may be considered a single entity, with ALI being the less severe form of ARDS. It is characterized by the acute onset of hypoxemia with radiographic infiltrates consistent with pulmonary edema, without elevations in the pulmonary capillary wedge pressure. Although this syndrome does not occur frequently and is usually without identifiable cause, the mortality is high. However, the phenomenon has not been rigorously studied owing to the low incidence, with primarily retrospective case series reported. Thus, the nomenclature, risks, and pathogenesis are not well defined. Interest in this syndrome has recently been renewed as the rate of other perioperative complications has declined. ALI/ARDS is reviewed with a focus on potential etiologies and the spectrum of available interventions.


Altered biometal homeostasis is associated with CLN6 mRNA loss in mouse neuronal ceroid lipofuscinosis.
Neuronal ceroid lipofuscinoses, the most common fatal childhood neurodegenerative illnesses, share many features with more prevalent neurodegenerative diseases. Neuronal ceroid lipofuscinoses are caused by mutations in CLN genes. CLN6 encodes a transmembrane endoplasmic reticulum protein with no known function. We characterized the behavioural phenotype of spontaneous mutant mice modeling CLN6 disease, and demonstrate progressive motor and visual decline and reduced lifespan in these mice, consistent with symptoms observed in neuronal ceroid lipofuscinosis patients. Alterations to biometal homeostasis are known to play a critical role in pathology in Alzheimer's, Parkinson's, Huntington's and motor neuron diseases. We have previously shown accumulation of the biometals, zinc, copper, manganese and cobalt, in CLN6 Merino and South Hampshire sheep at the age of symptom onset. Here we determine the physiological and disease-associated expression of CLN6, demonstrating regional CLN6 transcript loss, and concurrent accumulation of the same biometals in the CNS and the heart of presymptomatic CLN6 mice. Furthermore, increased expression of the ER/Golgi-localized cation transporter protein, Zip7, was detected in cerebellar Purkinje cells and whole brain fractions. Purkinje cells not only control motor function, an early symptomatic change in the CLN6 mice, but also display prominent neuropathological changes in mouse models and patients with different forms of neuronal ceroid lipofuscinoses. Whole brain fractionation analysis revealed biometal accumulation in fractions expressing markers for ER, Golgi, endosomes and lysosomes of CLN6 brains. These data are consistent with a link between CLN6 expression and biometal homeostasis in CLN6 disease, and provide further support for altered cation transporter regulation as a key factor in neurodegeneration.


Should 1 or 2 Venous Anastomoses Be Done in Microsurgical Flap Transfer?
Venous compromise is still the most common cause of free flap failure. The need of a second venous anastomosis to prevent free flap failure is controversial. It is proposed that the use of dual venous anastomoses reduces venous compromise. However, some surgeons suggest that dual venous drainage reduces venous blood flow causing a potential risk of thrombosis. This study aimed to compare the frequency of reexploration secondary to venous thrombosis in free flap surgeries in reconstruction of soft tissue defects with 1-vein versus 2-vein anastomosis. We performed a retrospective cohort study including 298 flaps. In 180 of these patients, 2-vein anastomosis was done, and in 118, 1-vein anastomosis was done. The study was conducted at Aga Khan University Hospital from January 2017 to December 2018. The number of venous anastomosis was not associated with flap survival. The group with dual anastomosis required more frequent reexploration as compared with 1 venous anastomosis group (8% vs 1.7%).Outcome and salvage rate were better in the 2-vein group as compared with the 1-vein group (64% vs 50%). There is no difference in flap survival in single or dual venous anastomosis, but we have noticed higher reexploration rates in the 2-vein group. However, outcome is better in the 2-vein group.


Factors related to successful misoprostol treatment for early pregnancy failure.
To identify potential predictors for treatment success in medical management with misoprostol for early pregnancy failure. We conducted a planned secondary analysis of data from a multicenter trial that compared medical and surgical management of early pregnancy failure. Medical management consisted of misoprostol 800 mug vaginally on study day 1, with a repeat dose if indicated on day 3. Women returned on days 3 and 15, and a telephone interview was conducted on day 30. Failure was defined as suction aspiration for any reason within 30 days. Demographic, historical, and outcome variables were included in univariable analyses of success. Multivariable analyses were conducted using clinical site, gestational age, and variables for which the univariable analysis resulted in a P < .1 to determine predictors of overall treatment success and first-dose success. Of the 491 women who received misoprostol, 485 met the criteria for this secondary analysis. Lower abdominal pain or vaginal bleeding within the last 24 hours, Rh-negative blood type, and nulliparity were predictive of overall success. However, only vaginal bleeding within the last 24 hours and parity of 0 or 1 were predictive of first-dose success. Overall success exceeds 92% in women who have localized abdominal pain within the last 24 hours, Rh-negative blood type, or the combination of vaginal bleeding in the past 24 hours and nulliparity. Misoprostol treatment for early pregnancy failure is highly successful in select women, primarily those with active bleeding and nulliparity. Clinicians and patients should be aware of these differences when considering misoprostol treatment. II-2.


[The effect of external stimuli on movement of Asterias amurensis starfish].
Studies have been made on local and total motor reactions of the starfish to stimuli of different modalities. It is suggested that differences in the pattern of papillae excitation and those in total reactions to salt, mechanical stimulation and changes in the intensity of illumination are associated with structural and functional heterogeneity of receptors and afferent pathways in the lower regular layer of the nervous plexus. The ability of segment motoneurons to change the direction of tube feet movement in absence of influences from the nervous ring was demonstrated. Possible scheme of control of pedicellar movement evoked by external stimulation is discussed.


Bibliometric and visual analysis in the field of traditional Chinese medicine in cancer from 2002 to 2022.
Objective: Traditional Chinese medicine (TCM) has been used as a complementary treatment for cancer patients, but there has been no quantitative comprehensive analysis of TCM's efficacy. The purpose of this paper is to explore the current status and hotspots of TCM in cancer research from 2002 to 2022 and to provide a reference for future research. Methods: We retrieved articles published between 2002 and 2022 from the Web of Science database and analyzed them using R software, VOSviewer, and CiteSpace software. Results: A total of 7,129 articles were included in this study. The publication rate of TCM cancer research increased steadily from 2002 to 2022, with a rapid increase from 2010 to 2021. China was the country with the most published articles, followed by the United States, Republic of Korea, Germany, and Japan. China was also the country with the most international collaborations, and China Medical University and Shanghai University of Traditional Chinese Medicine were the most representative cooperation centers. The Journal of Ethnopharmacology was the most published and cited journal. Apoptosis, expression, in vitro, activation, and other related keywords were commonly used in these articles. Breast cancer, colorectal cancer, gastric cancer, liver cancer, and lung cancer were the most studied cancer types in TCM research. Pathway-related apoptosis, anti-inflammation, and oxidative stress were the hotspots and trends of TCM's anti-cancer mechanism. Metabolomics combined with network pharmacology was the main research method. Conclusion: Traditional Chinese medicine as an anti-cancer drug has received increasing attention from researchers worldwide, and it is expected to be a hotspot for developing new anti-cancer drugs in the future. Our study provides a comprehensive analysis of the current status and hotspots of TCM cancer research, which could serve as a valuable reference for future studies.


N-Functionalized MXenes: ultrahigh carrier mobility and multifunctional properties.
Two dimensional (2D) nanomaterials have demonstrated huge potential in wide applications from nanodevices to energy harvesting/storage. In this work, we propose a new class of 2D monolayers, nitrogen-functionalized MXenes (Nb2CN2 and Ta2CN2), based on density-functional theory (DFT). We find that these monolayers are direct semiconductors with near linear energy dispersions at the Γ point. M2CN2 monolayers have significant small effective mass and show an ultra-high mobility of up to 106 cm2 V-1 s-1. We show that the electronic structures of the M2CN2 monolayers can be easily controlled by biaxial and uniaxial strains. Importantly, the carrier mobility and direct band gap can be dramatically increased within a certain range of strain. A direct-indirect band gap transition can be triggered and the band gap can be tuned under strain. The tunable electronic properties are attributed to the structural changes and charge redistribution under stain. Our findings demonstrate that N-functionalized MXenes are promising materials for nanodevices with high speed and low power.


Effectiveness of a low intensity outpatient cognitive rehabilitation programme for patients in the chronic phase after acquired brain injury.
The aim of this prospective cohort study was to examine the effectiveness of a low intensity outpatient cognitive rehabilitation programme for patients with acquired brain injury in the chronic phase. Twenty-seven patients with acquired brain injury (i.e., stroke, traumatic brain injury, subarachnoid haemorrhage; 52% male) with a mean age of 49.5 (SD 9.2) years and 25 relatives with a mean age of 48.8 (SD 8.8) years were recruited to the study. Mean time since injury in the patient group was 1.9 years (SD 2.0). The group programme consisted of 15 weekly sessions of 2.5 hours and included cognitive strategy training, social skills training, and psycho-education. Patients also received homework. Relatives were invited to attend twice. Repeated measurements were taken: prior to treatment (baseline, T0); directly after treatment (T1, 21 weeks); and at follow-up (T2, 45 weeks). Primary outcome measures were individualised goals (GAS), cognitive failures (CFQ), and quality of life (SA-SIP). Patients did improve significantly on individual goals (p < .05) between T0 and T1 and the level of attainment remained stable between T1 and T2. Goals were mostly set in the cognitive and behavioural domains. There were no significant differences between the measurements (T0-T1-T2) on the CFQ and the SA-SIP. The programme had a positive effect on the individual goals set by the patients. However, this did not result in a higher participation level or a better quality of life. This may be due to the low intensity and short duration of the programme.


Adult Langerhans cell histiocytosis.
Langerhans cell histiocytosis (LCH) is a proliferative histiocytic disorder of unknown cause originating from dendritic cells. The clinical presentation of LCH is highly variable. Although the features of this disease have been well described in children, they remain poorly defined in adults. Here, we review the current knowledge about adult LCH, focussing on clinical presentation, diagnosis, treatment, and prognosis.


Comparison of mortality from acute myocardial infarction between 1979 and 1992 in a geographically defined stable population.
This study documents mortality from acute myocardial infarction (AMI), in hospital and at 1 year, for each of 3 selected 1-year periods in a stable community over a 13-year period beginning in 1979 and continuing into the thrombolytic era, to detect any changes occurring in conjunction with the introduction of new therapies. Every patient with AMI occurring in a geographically defined stable community (Hamilton, Ontario, Canada) in 3 1-year periods (1979 to 1980 [n = 816], 1986 to 1987 [n = 816], and 1991 to 1992 [n = 831]) was identified and clinically characterized by standardized criteria. Subsequent in-hospital and 1-year survival were ascertained prospectively. The 3 cohorts were similar in prognostic factors. Mean age was progressively greater over the study period from 63 years in 1979 to 1980, to 67 years in 1991 to 1992 (p = 0.02). There was no change in in-hospital mortality rates from 1979 to 1980 (17%) and 1986 to 1987 (16%). However, from 1986 to 1987 and 1991 to 1992, in-hospital mortality decreased from 16% to 9% (p < 0.001) and 1-year mortality decreased from 26% to 19% (p < 0.001). For patients who survived the hospital phase of AMI, 1-year mortality did not change and was between 11% and 12% in each of the 3 study periods. From 1986 to 1987 and 1991 to 1992, there was an increase in the use of thrombolytic therapy from 5% to 44% of patients. The acute use of aspirin increased from 30% to 88% and the acute use of beta blockers increased from 19% to 48% of patients. The observed increase in use of these agents could account for half of the actual mortality reduction observed. This prospective population-based survey demonstrates improved in-hospital survival after AMI associated with increased use of established effective therapies between 1987 and 1992. The 1-year mortality of hospital survivors of AMI was unchanged throughout the period of study, remaining at 11% to 12%.


Setting positive end-expiratory pressure: does the 'best compliance' concept really work?
Determining the optimal positive end-expiratory pressure (PEEP) setting remains a central yet debated issue in the management of acute respiratory distress syndrome (ARDS).The 'best compliance' strategy set the PEEP to coincide with the peak respiratory system compliance (or 2 cmH2O higher) during a decremental PEEP trial, but evidence is conflicting. The physiological rationale that best compliance is always representative of functional residual capacity and recruitment has raised serious concerns about its efficacy and safety, due to its association with increased 28-day all-cause mortality in a randomized clinical trial in ARDS patients.Moreover, compliance measurement was shown to underestimate the effects of overdistension, and neglect intra-tidal recruitment, airway closure, and the interaction between lung and chest wall mechanics, especially in obese patients. In response to these concerns, alternative approaches such as recruitment-to-inflation ratio, the nitrogen wash-in/wash-out technique, and electrical impedance tomography (EIT) are gaining attention to assess recruitment and overdistention more reliably and precisely. The traditional 'best compliance' strategy for determining optimal PEEP settings in ARDS carries risks and overlooks some key physiological aspects. The advent of new technologies and methods presents more reliable strategies to assess recruitment and overdistention, facilitating personalized approaches to PEEP optimization.


Determinants of Stroke in a General Male Population.
Background and Purpose- To further improve preventive strategies against stroke, there is a need for epidemiological long-term studies. The study aimed at a prospective investigation of stroke determinants in the general male population. Methods- During a period of 48 years, from 50 to 98 years of age, a population-based sample of 854 men was followed using repeated medical examinations, lifestyle questionnaires, data from hospital records and the National Cause of Death Register. Results- Determinants of ischemic stroke were atrial fibrillation (hazard ratio [HR], 6.61; 95% CI, 4.47-9.77); mother dead from cardiovascular disease (HR, 1.53; 1.09-2.17); high education (HR, 0.81; 0.69-0.96); and high physical activity level during leisure time (HR, 0.68; 0.50-0.93). For hemorrhagic stroke heart rate (HR, 1.04; 1.01-1.06) and mother dead from stroke (HR, 3.56; 1.43-8.87) constituted an increased risk. Statistically significant determinants for all stroke were atrial fibrillation (HR, 5.34; 3.68-7.75); high diastolic blood pressure (HR, 1.02; 1.01-1.03); high body weight (HR, 0.96; 0.94-0.99); high educational level (HR, 0.79; 0.68-0.92); wide waist circumference (HR, 1.04; 1.01-1.07); smoking (HR, 1.25; 1.06-1.48); mother dead from cerebrovascular disease (HR, 1.43; 1.05-1.94); and diabetes mellitus (HR, 1.65; 1.02-2.68). Of all men diagnosed with atrial fibrillation, 88% had a stroke during follow-up. Conclusions- Atrial fibrillation was by far the strongest determinant of stroke during 48 years of follow-up in a male population sample followed until the age of 98 years. The results warrant improved prophylaxis through intense treatment of modifiable determinants.


Extended investigation on high velocity pseudo surface waves.
Recent communication equipment such as mobile and cellular phones, radio systems, pagers, LANs, have demanded high performance components. Among these components, the last generation of SAW filters and signal processing devices, presenting low loss, flexible frequency and phase response characteristics, control of spurious, and so forth, have played a major role in designing new equipment and redesigning existing systems. The highest frequency obtainable with SAW technology in practical devices is limited to a couple of GHz, usually due to restrictions in the fabrication process involved and SAW propagation characteristics. The pseudo-SAW and the shear horizontal mode, presenting phase velocities circa 40% superior than the SAW and low attenuation along certain directions, have permitted the construction of devices operating at higher frequencies. The high velocity pseudo-SAW, with phase velocities about 100% higher than the SAW and low attenuation in many materials along certain directions, extends the high operating limit of SAW devices even further. In this paper the major characteristics of this new type of wave are reviewed. Extended topics such as: the boundary function magnitude behavior, the relationship between the "growing tilted bulk-like partial waves" and the bulk slowness, the number of roots (uncoupling of modes), and the Poynting vector behavior with depth are explored, enlightening the solution and behavior of this new type of high velocity pseudo-SAW.


Tumor analysis: freeze-thawing cycle of triple-negative breast cancer cells alters tumor CD24/CD44 profiles and the percentage of tumor-infiltrating immune cells.
The use of novel methods to characterize living tumor cells relies on well-conceived biobanks. Herein, we raised the question of whether the composition of fresh and freeze/thawed dissociated tumor samples is comparable in terms of quantitative and qualitative profiling. Breast cancer is a heterogeneous disease, encompassing luminal A and B, basal/triple-negative breast cancer (TNBC), and ERBB2-like tumors. We examined living cells dissociated from TNBC and found that a classical freeze/thaw protocol leads to a marked reduction in the number of CD45-CD44LowCD24Low tumor cells. This, in turn, changed the percentage of tumor cells with certain CD44/CD24 expression patterns and changed the percentage of tumor-infiltrating immune cells. These cryopreservation-driven alterations in cellular phenotype make it impossible to compare fresh and frozen samples from the same patient directly. Moreover, the freeze/thaw process changed the transcriptomic signatures of triple-negative cancer stem cells in such a manner that hierarchical clustering no longer ranked them according to expected inter-individual differences. Overall, this study suggests that all analyses of living tumor cells should be conducted only using freshly dissociated tumors if we are to generate a robust scoring system for prognostic/predictive markers.


Transcriptomic profiling reveals three molecular phenotypes of adenocarcinoma at the gastroesophageal junction.
Cancers occurring at the gastroesophageal junction (GEJ) are classified as predominantly esophageal or gastric, which is often difficult to decipher. We hypothesized that the transcriptomic profile might reveal molecular subgroups which could help to define the tumor origin and behavior beyond anatomical location. The gene expression profiles of 107 treatment-naïve, intestinal type, gastroesophageal adenocarcinomas were assessed by the Illumina-HTv4.0 beadchip. Differential gene expression (limma), unsupervised subgroup assignment (mclust) and pathway analysis (gage) were undertaken in R statistical computing and results were related to demographic and clinical parameters. Unsupervised assignment of the gene expression profiles revealed three distinct molecular subgroups, which were not associated with anatomical location, tumor stage or grade (p > 0.05). Group 1 was enriched for pathways involved in cell turnover, Group 2 was enriched for metabolic processes and Group 3 for immune-response pathways. Patients in group 1 showed the worst overall survival (p = 0.019). Key genes for the three subtypes were confirmed by immunohistochemistry. The newly defined intrinsic subtypes were analyzed in four independent datasets of gastric and esophageal adenocarcinomas with transcriptomic data available (RNAseq data: OCCAMS cohort, n = 158; gene expression arrays: Belfast, n = 63; Singapore, n = 191; Asian Cancer Research Group, n = 300). The subgroups were represented in the independent cohorts and pooled analysis confirmed the prognostic effect of the new subtypes. In conclusion, adenocarcinomas at the GEJ comprise three distinct molecular phenotypes which do not reflect anatomical location but rather inform our understanding of the key pathways expressed.


Algorithm to Correct Measurement Offsets Introduced by Inactive Elements of Transducer Arrays in Ultrasonic Flow Metering.
Ultrasonic flow meters (UFMs) based on transducer arrays offer several advantages. With electronic beam steering, it is possible to tune the steering angle of the beam for optimal signal-tonoise ratio (SNR) upon reception. Moreover, multiple beams can be generated to propagate through different travel paths, covering a wider section of the flow profile. Furthermore, in a clamp-on configuration, UFMs based on transducer arrays can perform self-calibration. In this manner, userinput is minimized and measurement repeatability is increased. In practice, transducer array elements may break down. This could happen due to aging, exposure to rough environments, and/or rough mechanical contact. As a consequence of inactive array elements, the measured transit time difference contains two offsets. One offset originates from non-uniform spatial sampling of the generated wavefield. Another offset originates from the ill-defined beam propagating through a travel path different from the intended one. In this paper, an algorithm is proposed that corrects for both of these offsets. The algorithm also performs a filtering operation in the frequency-wavenumber domain of all spurious (i.e., flow-insensitive) wave modes. The advantage of implementing the proposed algorithm is demonstrated on simulations and measurements, showing improved accuracy and precision of the transit time differences compared to the values obtained when the algorithm is not applied. The proposed algorithm can be implemented in both in-line and clamp-on configuration of UFMs based on transducer arrays.


[Wildlife damage mitigation in agricultural crops in a Bolivian montane forest].
Wildlife is often blamed for causing damage to human activities, including agricultural practices and the result may be a conflict between human interests and species conservation. A formal assessment of the magnitude of damage is necessary to adequately conduct management practices and an assessment of the efficiency of different management practices is necessary to enable managers to mitigate the conflict with rural people. This study was carried out to evaluate the effectiveness of agricultural management practices and controlled hunting in reducing damage to subsistence annual crops at the Cotapata National Park and Natural Area of Integrated Management. The design included seven fields with modified agricultural practices, four fields subjected to control hunting, and five fields held as controls. We registered cultivar type, density, frequency of visiting species to the field, crops lost to wildlife, species responsible for damage, and crop biomass. Most frequent species in the fields were Dasyprocta punctata and Dasypus novemcinctus. Hunted plots were visited 1.6 times more frequently than agriculturally managed plots. Crop lost to wildlife averaged 7.28% at agriculturally managed plots, 4.59% in plots subjected to hunting, and 27.61% in control plots. Species mainly responsible for damage were Pecari tajacu, D. punctata, and Sapajus apella. We concluded that both management strategies were effective to reduce damage by >50% as compared to unmanaged crop plots.


No relevant interaction with alprazolam, caffeine, tolbutamide, and digoxin by treatment with a low-hyperforin St John's wort extract.
We evaluated the pharmacokinetic interaction between a low-hyperforin St John's wort (SJW) extract and alprazolam, caffeine, tolbutamide, and digoxin. Previous reports on other SJW products had shown remarkably decreased plasma concentrations of certain co-medicated drugs, which was attributed to an inducing effect of SJW on cytochrome P-450 (CYP) and p-glycoprotein (p-gp) activity. Two randomised, placebo-controlled studies were performed with 28 healthy volunteers (age 18 - 55 years) in each study. In study A, single doses of alprazolam (1 mg; substrate of CYP3A4) and caffeine (100 mg; CYP1A2) were given on days 1 and 11. In study B, single doses of tolbutamide (500 mg, days 1 and 11; CYP2C9) and multiple doses of digoxin (0.75 mg on days -2 and -1, 0.25 mg/die on days 1 to 11; p-gp) were given. The participants received SJW (Esbericum capsules; 240 mg/die of extract, 3.5 mg hyperforin) or placebo on days 2 to 11. Blood for pharmacokinetic analysis was drawn on days 1 and 11. No statistically significant differences were found in the primary kinetic parameter, AUC0 - 24, of alprazolam, caffeine (AUC0 - 12), paraxanthine, tolbutamide, 4-hydroxytolbutamide, and digoxin between the placebo group and the SJW group at the end of the study. The SJW-induced change in AUCs was less than 12 % of the initial median AUC of the participants in studies A and B, thus clinically irrelevant. On day 11, trough concentrations were 2.0 (range 0.6 - 4.1) microg/L and 1.0 (0.2 - 3.9) microg/L for hypericin and pseudohypericin, respectively, whereas hyperforin concentrations were below the quantification limit (< 1 microg/L). Kinetics of investigated probe drugs were only marginally influenced by concomitant treatment with Esbericum capsules. This may be due in particular to the low hyperforin plasma concentration as this SJW component has been shown to activate the PXR receptor which regulates expression of CYP3A4 and p-gp. Our findings corroborate the view that reports about interactions of other SJW extracts seem not to be predictive for the product we studied.


Access From Above-Bailout Solution for Intraoperative Distal Migration of Abdominal Aortic Stent Graft.
The majority of the ruptured abdominal aortic aneurysms today is treated endovascularly. In cases with short aneurysm neck, chimney technique can be used to extend landing zone in emergency setting. Additionally, the repositioning ability of C3 delivery system (Gore & Associates) allows better positioning in cases with challenging anatomy. In our experience, proximal reposition of partially deployed device can be problematic in some patients. We present a case of endovascular repair of ruptured abdominal aortic aneurysm using chimney technique where proximal reposition was achieved by snaring the aortic device via axillary access.


Molecular genetic analysis of a dimethylsulfoniopropionate lyase that liberates the climate-changing gas dimethylsulfide in several marine alpha-proteobacteria and Rhodobacter sphaeroides.
The alpha-proteobacterium Sulfitobacter EE-36 makes the gas dimethylsulfide (DMS) from dimethylsulfoniopropionate (DMSP), an abundant antistress molecule made by many marine phytoplankton. We screened a cosmid library of Sulfitobacter for clones that conferred to other bacteria the ability to make DMS. One gene, termed dddL, was sufficient for this phenotype when cloned in pET21a and introduced into Escherichia coli. Close DddL homologues exist in the marine alpha-proteobacteria Fulvimarina, Loktanella Oceanicola and Stappia, all of which made DMS when grown on DMSP. There was also a dddL homologue in Rhodobacter sphaeroides strain 2.4.1, but not in strain ATCC 17025; significantly, the former, but not the latter, emits DMS when grown with DMSP. Escherichia coli containing the cloned, overexpressed dddL genes of R. sphaeroides 2.4.1 and Sulfitobacter could convert DMSP to acrylate plus DMS. This is the first identification of such a 'DMSP lyase'. Thus, DMS can be made either by this DddL lyase or by a DMSP acyl CoA transferase, specified by dddD, a gene that we had identified in several other marine bacteria.


C-terminal amino acid residues of the trimeric autotransporter adhesin YadA of Yersinia enterocolitica are decisive for its recognition and assembly by BamA.
The Bam complex is a highly conserved multiprotein machine essential for the assembly of β-barrel outer membrane proteins. It is composed of the essential outer membrane protein BamA and four outer membrane associated lipoproteins BamB-E. The Yersinia enterocolitica Adhesin A (YadA) is the prototype of trimeric auotransporter adhesins (TAAs), consisting of a head, stalk and a β-barrel membrane anchor. To investigate the role of BamA in biogenesis of TAAs, we expressed YadA in a BamA-depleted strain of Escherichia coli, which resulted in degradation of YadA. Yeast-two-hybrid experiments and immunofluorescence studies revealed that BamA and YadA interact directly and colocalize. As BamA recognizes the C-terminus of OMPs, we exchanged the nine most C-terminal amino acids of YadA. Substitution of the amino acids in position 1, 3 or 5 from the C-terminus with glycine resulted in DegP-dependent degradation of YadA. Despite degradation all YadA proteins assembled in the outer membrane. In summary we demonstrate that (i) BamA is essential for biogenesis of the TAA YadA, (ii) BamA interacts directly with YadA, (iii) the C-terminal amino acid motif of YadA is important for the BamA-dependent assembly and differs slightly compared with other OMPs, and (iv) BamA and YadA colocalize.


Predictors of using mental health services after sexual assault.
Sexual assault increases the risk for psychopathology. Despite the availability of effective interventions, relatively few victims who need treatment receive care in the months following an assault. Prior work identified several factors associated with utilizing care, including ethnicity, insurance, and posttraumatic stress disorder (PTSD) symptoms. Few studies, however, have examined predictors of treatment utilization prospectively from the time of assault. The present study hypothesized that White racial status, younger age, being partnered, having health insurance, having previously received mental health treatment, and having more PTSD and depression symptoms would predict utilization of care in the 6 months postassault. This was examined in a sample of 266 female sexual assault victims with an average age of 26.2 years, of whom 62.0% were White and 38.0% were African American assessed at 1.5 and 6 months postassault. Available information on utilizing care varied across assessments (1.5 months, n = 214; 3 months, n = 126; 6 months, n = 204). Significant predictors included having previously received mental health treatment (OR = 4.09), 1 day depressive symptoms (OR = 1.06), and having private insurance (OR = 2.24) or Medicaid (OR = 2.19). Alcohol abuse and prior mental health care were associated with a substantial increase in treatment utilization (OR = 4.07). The findings highlight the need to help victims at risk obtain treatment after sexual assault.


Kernel number as a positive target trait for prediction of hybrid performance under low-nitrogen stress as revealed by diallel analysis under contrasting nitrogen conditions.
Environmental sustainability concerns make improving yield under lower N input a desirable breeding goal. To evaluate genetic variation and heterosis for low-N tolerance breeding, 28 F1 hybrids from a diallel scheme, along with their eight parental lines, were tested for agronomic traits including kernel number per ear (KNE) and grain yield per plant (GY), in replicated plots over two years under low-nitrogen (LN, without nitrogen application) and normal-nitrogen (NN, 220 kg N ha(-1)) conditions. Taken together the heritability in this and our previous studies, the correlation with grain yield, and the sensitivity to the stress for target trait selection, KNE was a good secondary target trait for LN selection in maize breeding. KNE also showed much higher mid-parent heterosis than hundred-kernel weight under both nitrogen levels, particularly under LN, indicating that KNE contributed the majority of GY heterosis, particularly under LN. Therefore, KNE can be used as a positive target trait for hybrid performance prediction in LN tolerance breeding. Our results also suggest that breeding hybrids for LN tolerance largely relies on phenotypic evaluation of hybrids under LN condition and yield under LN might be improved more by selection for KNE than by direct selection for GY per se.


Twin-beam laser velocimeter for the investigation of spermatozoon motility.
Previous laser light-scattering studies of spermatozoon motility have been hampered by the large, asymmetric shape of spermatozoa, which causes difficulties in the interpretation of intensity fluctuations in the light scattered from a single laser beam. This paper describes an experimental arrangement for measuring the distribution of transit times for swimming spermatozoa using two slightly separated, focused laser beams. The theory of operation of the instrument is developed to enable the analysis of the experimentally obtained cross-correlation functions. The effects of the pronounced spermatozoon asymmetry and associated intensity modulation in the scattered light are also investigated and shown to be negligible for the twin beam experimental arrangement, provided that the swimming speed distribution has a coefficient of variation (sigma/upsilon greater than 0.1. Results obtained using this apparatus are presented for the velocity distribution of spermatozoa from a variety of bulls.


Vasoactive intestinal peptide concentrations and immunocytochemical studies in rectal biopsies from patients with inflammatory bowel disease.
Vasoactive intestinal polypeptide (VIP)-containing nerves and VIP content of endoscopic rectal biopsies from 47 patients with inflammatory bowel disease and 17 normal controls were examined by immunocytochemistry and radioimmunoassay. Immunocytochemistry revealed a consistent increase in, and abnormal appearance of, VIP nerves in patients with Crohn's disease not only those with rectal involvement but also patients with no histological evidence of rectal disease. Normal control biopsies contained 1.64 +/- 0.39 pmol VIP/mg protein as compared with 3.43 +/- 1.24 pmol VIP/mg protein in tissue from patients with rectal Crohn's disease and 5.37 +/- 1.23 pmol VIP/mg protein in those with Crohn's disease without rectal involvement. Ten of the 17 biopsies examined from ulcerative colitics showed a normal pattern of VIP innervation. Examination of the conventional histology of these biopsies showed that only areas with obvious active proctitis had increased VIP nerves and, unlike the appearance in Crohn's disease, these nerves had a normal morphology. The VIP content of these biopsies was similar to that of the controls; 1.34 +/- 0.37 pmol/mg protein.


Human Cytomegalovirus US28 Is Important for Latent Infection of Hematopoietic Progenitor Cells.
Human cytomegalovirus (HCMV) resides latently in hematopoietic progenitor cells (HPCs). During latency, only a subset of HCMV genes is transcribed, including one of the four virus-encoded G protein-coupled receptors (GPCRs), US28. Although US28 is a multifunctional lytic protein, its function during latency has remained undefined. We generated a panel of US28 recombinant viruses in the bacterial artificial chromosome (BAC)-derived clinical HCMV strain TB40/E-mCherry. We deleted the entire US28 open reading frame (ORF), deleted all four of the viral GPCR ORFs, or deleted three of the HCMV GPCRs but not the US28 wild-type protein. Using these recombinant viruses, we assessed the requirement for US28 during latency in the Kasumi-3 in vitro latency model system and in primary ex vivo-cultured CD34(+) HPCs. Our data suggest that US28 is required for latency as infection with viruses lacking the US28 ORF alone or in combination with the remaining HCMV-encoded GPCR results in transcription from the major immediate early promoter, the production of extracellular virions, and the production of infectious virus capable of infecting naive fibroblasts. The other HCMV GPCRs are not required for this phenotype as a virus expressing only US28 but not the remaining virus-encoded GPCRs is phenotypically similar to that of wild-type latent infection. Finally, we found that US28 copurifies with mature virions and is expressed in HPCs upon virus entry although its expression at the time of infection does not complement the US28 deletion latency phenotype. This work suggests that US28 protein functions to promote a latent state within hematopoietic progenitor cells. Human cytomegalovirus (HCMV) is a widespread pathogen that, once acquired, remains with its host for life. HCMV remains latent, or quiescent, in cells of the hematopoietic compartment and upon immune challenge can reactivate to cause disease. HCMV-encoded US28 is one of several genes expressed during latency although its biological function during this phase of infection has remained undefined. Here, we show that US28 aids in promoting experimental latency in tissue culture.


Involvement of the IGF system in fetal growth and childhood cancer: an overview of potential mechanisms.
Fetal growth is determined by a complex interplay of genetic, nutritional, environmental, and hormonal factors. Greater than expected fetal growth has been positively associated with the risk of the development of some cancers in childhood, particularly acute lymphoblastic leukemia, and the biological mechanisms underlying such associations are thought to involve insulin-like growth factors (IGFs). Circulating IGF levels are highly correlated with fetal growth, and IGFs are believed to play an important role in carcinogenesis; however, these two bodies of evidence have not been well integrated and, as a result, the potential underlying biological mechanisms linking the IGF system with the development of specific childhood cancers have not been elucidated. This review aims to draw together and summarize the literature linking the IGF system, rapidity of fetal growth, and risk of some specific childhood cancers; suggest explanations for some of the inconsistencies observed in previous studies of these associations; and propose an integrated framework for the putative involvement of the IGF system in the development of at least some childhood cancers. If the challenges involved in studying the complex IGF system can be overcome, this field presents an exciting opportunity to elucidate etiological pathways to childhood malignancies.


Short-Term Effects of Elastic Chest Wall Restriction on Pulmonary Function in Children with Cystic Fibrosis.
Elastic chest wall restriction introduced by Chevaillier is thought to reduce existing hyperinflation and improve mucus clearance from peripheral airways. In healthy adults, restriction decreases the functional residual capacity (FRC) and forced vital capacity (FVC), while ventilation inhomogeneity (lung clearance index [LCI]) increases. Pulmonary function response to restriction is unknown in individuals with cystic fibrosis (CF). To examine short-term effects of elastic chest wall restriction on pulmonary function in children with CF. Pulmonary function was first assessed twice 15 min apart at baseline and then again following 15 min of elastic chest wall restriction in 20 school-aged children with CF (12.3 ± 3.4 years). Primary outcomes were LCI from nitrogen multiple-breath washout, residual volume (RV), and FRC from plethysmography. Secondary outcomes were FVC and end-expiratory lung impedance (EELI) from electrical impedance tomography. Endpoints were test-retest reliability at baseline and lung function response to restriction, both on group and individual levels. Test-retest reliability was excellent (intra-class correlation coefficients range 0.84-0.99). Following restriction, FRC significantly declined on average (95% CI) by -0.09 (-0.17 to -0.02) L. Similarly, FVC declined while LCI did not change. RV and EELI declined, but this did not reach statistical significance. On the individuals' level, heterogeneous changes in pulmonary function occurred following elastic chest wall restriction. These findings indicate that the application of elastic chest wall restriction is safe, induces the intended decline in resting lung volume but does not systematically alter ventilation inhomogeneity in children with CF.


General Distributed Neural Control and Sensory Adaptation for Self-Organized Locomotion and Fast Adaptation to Damage of Walking Robots.
Walking animals such as invertebrates can effectively perform self-organized and robust locomotion. They can also quickly adapt their gait to deal with injury or damage. Such a complex achievement is mainly performed via coordination between the legs, commonly known as interlimb coordination. Several components underlying the interlimb coordination process (like distributed neural control circuits, local sensory feedback, and body-environment interactions during movement) have been recently identified and applied to the control systems of walking robots. However, while the sensory pathways of biological systems are plastic and can be continuously readjusted (referred to as sensory adaptation), those implemented on robots are typically static. They first need to be manually adjusted or optimized offline to obtain stable locomotion. In this study, we introduce a fast learning mechanism for online sensory adaptation. It can continuously adjust the strength of sensory pathways, thereby introducing flexible plasticity into the connections between sensory feedback and neural control circuits. We combine the sensory adaptation mechanism with distributed neural control circuits to acquire the adaptive and robust interlimb coordination of walking robots. This novel approach is also general and flexible. It can automatically adapt to different walking robots and allow them to perform stable self-organized locomotion as well as quickly deal with damage within a few walking steps. The adaptation of plasticity after damage or injury is considered here as lesion-induced plasticity. We validated our adaptive interlimb coordination approach with continuous online sensory adaptation on simulated 4-, 6-, 8-, and 20-legged robots. This study not only proposes an adaptive neural control system for artificial walking systems but also offers a possibility of invertebrate nervous systems with flexible plasticity for locomotion and adaptation to injury.


Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort.
Sleep-disordered breathing (SDB) is a treatable but markedly under-diagnosed condition of frequent breathing pauses during sleep. SDB is linked to incident cardiovascular disease, stroke, and other morbidity. However, the risk of mortality with untreated SDB, determined by polysomnography screening, in the general population has not been established. An 18-year mortality follow-up was conducted on the population-based Wisconsin Sleep Cohort sample (n = 1522), assessed at baseline for SDB with polysomnography, the clinical diagnostic standard. SDB was described by the number of apnea and hypopnea episodes/hour of sleep; cutpoints at 5, 15 and 30 identified mild, moderate, and severe SDB, respectively. Cox proportional hazards regression was used to estimate all-cause and cardiovascular mortality risks, adjusted for potential confounding factors, associated with SDB severity levels. All-cause mortality risk, adjusted for age, sex, BMI, and other factors was significantly increased with SDB severity. The adjusted hazard ratio (HR, 95% CI) for all-cause mortality with severe versus no SDB was 3.0 (1.4,6.3). After excluding persons who had used CPAP treatment (n = 126), the adjusted HR (95% CI) for all-cause mortality with severe versus no SDB was 3.8 (1.6,9.0); the adjusted HR (95% CI) for cardiovascular mortality was 5.2 (1.4,19.2). Results were unchanged after accounting for daytime sleepiness. Our findings of a significant, high mortality risk with untreated SDB, independent of age, sex, and BMI underscore the need for heightened clinical recognition and treatment of SDB, indicated by frequent episodes of apnea and hypopnea, irrespective of symptoms of sleepiness.


Inhibiting HSP90 to treat cancer: a strategy in evolution.
Since the identification of the first HSP90 inhibitor almost two decades ago, there has been substantial progress made in the development of potent and selective molecules that inhibit this chaperone and that have anticancer activity. In turn, these compounds have been invaluable for probing how HSP90 supports the profound changes in cellular physiology that characterize the malignant state. Unfortunately, when used as single agents HSP90 inhibitors have demonstrated disappointing activity against advanced cancers in most of the clinical trials reported to date. This problem may be due to the major pharmacological liabilities of the first-generation HSP90 inhibitors that have been most extensively studied. We suggest, however, that it may well be intrinsic to the target itself. Systemically tolerable exposure to HSP90 inhibitors may not be highly cytotoxic for the majority of common clinical cancers. Instead, HSP90 inhibitors might better be used to enhance the activity of other antineoplastic agents while simultaneously reducing the capacity of tumors to adapt and evolve drug resistance; the overall result being more durable disease control. This review will focus on these fundamental issues with the goal of suggesting ways to make the clinical development of HSP90 inhibitors become less empiric and ultimately more successful.


Interaction between alpha- and beta-adrenoceptor-mediated cardiovascular effects.
A survey is given of the mutual interaction of alpha- and beta-adrenoceptor mediated cardiovascular effects, with an emphasis on the effects of drugs which simultaneously block alpha- and beta-adrenoceptors. This discussion is preceded by a review of the various subtypes of adrenoceptors, including pre/postsynaptic, alpha 1/alpha 2- and beta 1/beta 2-receptors with an emphasis on their various selective agonists and antagonists and their functional aspects. For drugs which display comparable degrees of alpha- and beta-adrenoceptor blockade the following effects may be anticipated: vasodilatation, a reduction in total peripheral resistance (TPR) and a decrease in blood pressure, as a result of postsynaptic (alpha 1 + alpha 2) adrenoceptor blockade; a fall in blood pressure as a result of beta-receptor blockade; no reflex tachycardia in spite of the vasodilatation (alpha 1 + alpha 2 blockade) owing to beta-receptor blockade. For a drug which simultaneously blocks alpha 2- and beta 1-adrenoceptors the following effects may be anticipated: all cardiac changes usually induced by beta 1-blockade (reduced heart rate, contractility and A-V conduction); vasodilatation induced by postsynaptic alpha 2-adrenoceptor blockade; enhanced release of presynaptic noradrenaline, owing to presynaptic alpha 2-receptor blockade. Celiprolol is an example of a drug which combines alpha 2- and beta 1-adrenoceptor blocking properties. It should be realized, however, that the alpha 2-receptor affinity of the drug is much lower than its beta 1-receptor antagonism, which probably dominates the drug's profile.


Synthesis, evaluation and molecular modelling of piceatannol analogues as arginase inhibitors.
Arginase is involved in a wide range of pathologies including cardiovascular diseases and infectious diseases whilst it is also a promising target to improve cancer immunotherapy. To date, only a limited number of inhibitors of arginase have been reported. Natural polyphenols, among them piceatannol, are moderate inhibitors of arginase. Herein, we report our efforts to investigate catechol binding by quantum chemistry and generate analogues of piceatannol. In this work, we synthesized a novel series of amino-polyphenols which were then evaluated as arginase inhibitors. Their structure-activity relationships were elucidated by deep quantum chemistry modelling. 4-((3,4-Dihydroxybenzyl)amino)benzene-1,2-diol 3t displays a mixed inhibition activity on bovine and human arginase I with IC50 (K i) values of 76 (82) μM and 89 μM, respectively.