Antidepressant Use by Class: Association with Major Adverse Cardiac Events in Patients with Coronary Artery Disease.
To assess use of antidepressants by class in relation to cardiology practice recommendations, and the association of antidepressant use with the occurrence of major adverse cardiovascular events (MACE) including death. This is a historical cohort study of all patients who completed cardiac rehabilitation (CR) between 2002 and 2012 in a major CR center. Participants completed the Patient Health Questionnaire (PHQ-9) at the start and end of the program. A linkage system enabled ascertainment of antidepressant use and MACE through 2014. There were 1,694 CR participants, 1,266 (74.7%) of whom completed the PHQ-9 after the program. Depressive symptoms decreased significantly from pre- (4.98 ± 5.20) to postprogram (3.57 ± 4.43) (p < 0.001). Overall, 433 (34.2%) participants were on antidepressants, most often selective serotonin reuptake inhibitors (SSRI; n = 299; 23.6%). The proportion of days covered was approximately 70% for all 4 major antidepressant classes; discontinuation rates ranged from 37.3% for tricyclics to 53.2% for serotonin-norepinephrine reuptake inhibitors (SNRI). Antidepressant use was significantly associated with lower depressive symptoms after CR (before, 7.33 ± 5.94 vs. after, 4.69 ± 4.87; p < 0.001). After a median follow-up of 4.7 years, 264 (20.9%) participants had a MACE. After propensity matching based on pre-CR depressive symptoms among other variables, participants taking tricyclics had significantly more MACE than those not taking tricyclics (HR = 2.46; 95% CI 1.37-4.42), as well as those taking atypicals versus not (HR = 1.59; 95% CI 1.05-2.41) and those on SSRI (HR = 1.45; 95% CI 1.07-1.97). There was no increased risk with use of SNRI (HR = 0.89; 95% CI 0.43-1.82). The use of antidepressants was associated with lower depression, but the use of all antidepressants except SNRI was associated with more adverse events.


Construct validation of the English version of Readiness for Interprofessional Learning Scale (RIPLS): Are Chinese undergraduate students ready for 'shared learning'?
Interprofessional education has been receiving attention as a result of research suggesting the benefits of interpersonal collaboration in healthcare. In Hong Kong, the implementation of the Interprofessional Team-based Learning programme provides implicit call to study the psychometric properties of Readiness for Interprofessional Learning Scale (RIPLS) to clarify if this is a valid measure when used in the Chinese undergraduate healthcare context. This study examines the psychometric properties of RIPLS involving predominantly Chinese undergraduate healthcare students in Hong Kong. Using within- and between-network approaches to construct validity, we investigated the applicability of English version of RIPLS among 469 predominantly Hong Kong Chinese students who have competence in the English language. These participants were from complementary health professional programmes: biomedical sciences, chinese medicine, medicine, nursing, and pharmacy, from two universities in Hong Kong. The within-network test results indicated that RIPLS had good internal consistency reliability. Results of the confirmatory factor analysis lend support to the overall factor structure of hypothesized four-factor solution although one item obtained non-significant factor loading. The between-network test also suggests that various subscales of RIPLS correlated systematically with theoretically relevant constructs: collective efficacy, team impact on quality of learning, and team impact on clinical reasoning ability. The RIPLS is a valid measure to estimate the Chinese undergraduate healthcare students' readiness to engage in interprofessional learning.


Relapsing seroma in a uremic patient bearing a PTFE graft as vascular access.
Seroma is one of the most frequent complications of PTFE vascular grafts and its etiology is still unclear. A 51 year-old male on regular dialytic treatment for seven years underwent the surgical implantation of a vascular prosthesis of homologous safena due to the thrombosis of his native artero-venous fistula. Several years earlier the patient had suffered the amputation of the left forearm because of electric shock. A few months later the vascular prosthesis was replaced with a PTFE vascular graft as a result of aneurysm formation and thrombosis. During the following days a non pulsating swelling occurred near the arterial anasto-mosis. Ultrasonography, doppler sonography and aspiration confirmed the diagnosis of seroma and it was surgically removed. Some weeks later a new seroma was observed in the same site and associated with a skin ulcer. A new surgical removal had no benefit and about one month later a perigraft collection was found along with signs of bacterial infection. For this reason the patient underwent the surgical excision of the PTFE graft and a vascular access was warranted by placing a Tesio TM catheter. Usually surgery is considered mandatory in seromas larger than 2 cm in diameter and showing continuous growth. In our patient the poor vascular status might have suggested a more conservative management even with a seroma diameter of about 7 cm. Nevertheless the high risk of systemic infection prompted us to remove the PTFE graft.


Flying primates? Megabats have the advanced pathway from eye to midbrain.
The pattern of connections between the retina and midbrain has been determined with electrophysiological and neuroanatomical methods in bats representing the two major subdivisions of the Chiroptera. Megachiropteran fruit bats (megabats), Pteropus spp., were found to have an advanced retinotectal pathway with a vertical hemidecussation of the kind previously found only in primates. In contrast, the microchiropteran bat Macroderma gigas has the "ancestral" or symplesiomorphous pattern of retinotectal connections so far found in all vertebrates except primates. In addition to linking primates and megachiropteran bats, these findings suggest that flight may have evolved twice among the mammals.


[Development of the ideas of N.N. Petrov concerning the prevention of cancer in experimental studies devoted to transplacental carcinogenesis].
The principal N.N. Petrov's idea in oncology consists in the possibility of scientific organization of anticancer struggle, based in particular, on the development of the sanitary-hygienic aspects of tumor prophylaxis. N.N. Petrov's remarks on necessity of pregnancy hygiene, made by him 50 years ago, are confirmed now in experiments and sometimes in human research. The basal regulations of transplacental carcinogenesis -- one of the modern trends in experimental oncology -- are stated. Some considerations on possible applications of the results of animal experiments of human cancer prophylaxis are expressed.


Physician and practice characteristics associated with immunoglobulin test ordering.
Primary care test requests for serum immunoglobulins are rising rapidly, with concerns that many requests may be unnecessary. Evidence suggests some characteristics of general practitioners (GPs) and practices are associated with higher test ordering. To identify the physician and practice characteristics associated with immunoglobulin test ordering. Retrospective, cross-sectional study using routine laboratory data on primary care serum immunoglobulin requests. Data were linked with GP patient list size data. The primary outcome measure was the count of test requests per GP. Predictor variables were physician gender, years experience, practice region and type (number of GPs), GP patient list size and composition. Mixed-effects multilevel regression models were used to calculate incidence rate ratios (IRRs) with 95% confidence intervals (CIs) for the associations between physician and practice characteristics and GP requesting. Sensitivity analysis was performed by limiting the model to the more than 70 years age category. In total, 5990 immunoglobulin tests were ordered by 481 GPs in the South of Ireland during 2013. The number of tests ordered by individual GPs varied from one to 377. In the final fully adjusted Poisson regression analysis, female gender (IRR: 1.81; 95% CI: 1.45-2.26) and less experience (IRR: 2.27; 95% CI: 1.47-3.51) were associated with higher requesting (P < 0.001). None of the practice factors were associated with test ordering. Sensitivity analysis on the 70 years or more age category found similar results. Further research is required to explore the potential reasons for higher requesting among GPs with fewer years of experience and also among female GPs.


Trophectoderm differentiation in the bovine embryo: characterization of a polarized epithelium.
Blastocytst formation is dependent on the differentiation of a transporting epithelium, the trophectoderm, which is coordinated by the embryonic expression and cell adhesive properties of E-cadherin. The trophectoderm shares differentiative characteristics with all epithelial tissues, including E-cadherin-mediated cell adhesion, tight junction formation, and polarized distribution of intramembrane proteins, including the Na-K ATPase. The present study was conducted to characterize the mRNA expression and distribution of polypeptides encoding E-cadherin, beta-catenin, and the tight junction associated protein, zonula occludens protein 1, in pre-attachment bovine embryos, in vitro. Immunocytochemistry and gene specific reverse transcription--polymerase chain reaction methods were used. Transcripts for E-cadherin and beta-catenin were detected in embryos of all stages throughout pre-attachment development. Immunocytochemistry revealed E-cadherin and beta-catenin polypeptides evenly distributed around the cell margins of one-cell zygotes and cleavage stage embryos. In the morula, detection of these proteins diminished in the free apical surface of outer blastomeres. E-cadherin and beta-catenin became restricted to the basolateral membranes of trophectoderm cells of the blastocyst, while maintaining apolar distributions in the inner cell mass. Zonula occludens protein 1 immunoreactivity was undetectable until the morula stage and first appeared as punctate points between the outer cells. In the blastocyst, zonula occludens protein 1 was localized as a continuous ring at the apical points of trophectoderm cell contact and was undetectable in the inner cell mass. These results illustrate that the gene products encoding E-cadherin, beta-catenin and zonula occludens protein 1 are expressed and maintain cellular distribution patterns consistent with their predicted roles in mediating trophectoderm differentiation in in vitro produced bovine embryos.


Protective effects of Danshensu from the aqueous extract of Salvia miltiorrhiza (Danshen) against homocysteine-induced endothelial dysfunction.
Homocysteine (Hcy) is a by-product of methionine metabolism. An imbalance of Hcy in the body may lead to hyperhomocysteinemia, a condition with elevated Hcy concentration in blood that may be one of the risk factors responsible for the development of several vascular diseases (thromboembolism, atherosclerosis, stroke, vascular diseases and dementia). Radix Salvia miltiorrhiza (Danshen), a well-known Chinese medicinal herb that can activate and improve blood microcirculation, is noticeable for its beneficial effect in treating cardiovascular diseases. The present study is to demonstrate the protective effect of Danshen extract against the homocysteine-induced adverse effect on human umbilical vein endothelial cell (HUVEC). Homocysteine (5 mM) not only decreased the cell viability but also caused the disruption of capillary-like structure formation in vitro. The protective effect of Danshen aqueous extract and its active compounds on endothelial cell function were demonstrated through an in vitro tube formation assay, which mimics the new blood vessel formation. To identify the active components in the aqueous extract of Danshen, the content was characterized by instrumental analysis using high performance liquid chromatography with diode array detector (DAD) and electrospray tandem mass spectrometry (ESI-MS/MS). Interestingly, Danshen extract and its pure compounds showed different effectiveness in protecting HUVEC against Hcy-induced injury according to the following descending order: Danshen aqueous extract, 3-(3,4-dihydroxy-phenyl)-2-hydroxy-propionic acid (Danshensu), protocatechuic acid, catechin and protocatechualdehyde. We believed that such findings might provide evidence in understanding the beneficial effects of Danshen on the cardiovascular system.


Genotyping of enterotoxigenic Clostridium perfringens fecal isolates associated with antibiotic-associated diarrhea and food poisoning in North America.
Clostridium perfringens type A isolates producing enterotoxin (CPE) are an important cause of food poisoning and non-food-borne human gastrointestinal (GI) diseases, including antibiotic-associated diarrhea (AAD). Recent studies suggest that C. perfringens type A food poisoning is caused by C. perfringens isolates carrying a chromosomal cpe gene, while CPE-associated non-food-borne GI diseases, such as AAD, are caused by plasmid cpe isolates. Those putative relationships, obtained predominantly with European isolates, were tested in the current study by examining 34 cpe-positive, C. perfringens fecal isolates from North American cases of food poisoning or AAD. These North American disease isolates were all classified as type A using a multiplex PCR assay. Furthermore, restriction fragment length polymorphism and pulsed-field gel electrophoresis genotyping analyses showed the North American AAD isolates included in this collection all have a plasmid cpe gene, but the North American food poisoning isolates all carry a chromosomal cpe gene. Western blotting demonstrated CPE expression by nearly all of these disease isolates, confirming their virulence potential. These findings with North American isolates provide important new evidence that, regardless of geographic origin or date of isolation, plasmid cpe isolates cause most CPE-associated AAD cases and chromosomal cpe isolates cause most C. perfringens type A food poisoning cases. These findings hold importance for the development of assays for distinguishing cases of CPE-associated food-borne and non-food-borne human GI illnesses and also identify potential epidemiologic tools for determining the reservoirs for these illnesses.


Near-Infrared Spectroscopy Monitoring for Early Detection of Limb Ischemia in Patients on Veno-Arterial Extracorporeal Membrane Oxygenation.
This study aimed to investigate the effectiveness of near-infrared spectroscopy (NIRS) monitoring for the early detection of limb ischemia in patients who were placed on veno-arterial extracorporeal membrane oxygenation (VA-ECMO) via femoral artery. We prospectively used NIRS monitoring for the early detection of limb ischemia in 28 adult patients, who were supported with peripheral VA-ECMO between August 2013 and August 2014 (NIRS group). A decision to perform distal perfusion catheterization was made in accordance with the regional oxygen saturation (rSO2) values provided by the NIRS system. For the comparison of outcome, the medical records of 36 adult patients who had been previously supported with peripheral VA-ECMO without NIRS monitoring (Control group), between July 2012 and July 2013, were retrospectively reviewed. There was no significant difference between the frequency of distal perfusion in both groups (p = 0.435). The mean time to distal perfusion is shorter in the NIRS group (19.6 ± 21.4 vs. 42.0 ± 69.0 hours). No patient underwent fasciotomy in the NIRS group, while 13.9% did in the control group (p = 0.040). We think that NIRS monitoring is a useful and reliable method for the early detection of limb ischemia in patients undergoing peripheral VA-ECMO. Its application may allow timely correction of perfusion deficits and the prevention of compartment syndrome and limb complications.


Conformance to schizophrenia treatment guidelines in North West-Bank, Palestine: focus on antipsychotic dosing and polytherapy.
Analysis of the prescribing patterns of antipsychotic drugs can improve therapeutic outcomes. The purpose of this study was to evaluate the prescribing pattern of antipsychotics and its conformance to international treatment guidelines. A cross sectional study at primary psychiatric centers was carried out. Patients' medical files were used to obtain demographic, medication and clinical information. International guidelines for schizophrenia were used to create conformance indicators. All statistical analyses were conducted using Statistical Package for Social Sciences. 250 patients were included in this study. A total of 406 antipsychotic agents were used; 348 (85.7%) were first generation antipsychotics (FGA). The prevalence of antipsychotic combination was 50.4% (n=126). There was no significant difference in positive (p=0.3), negative (p=0.06) and psychopathology (p=0.5) scores of schizophrenia symptoms among patients on monotherapy versus those on antipsychotic combination. Furthermore, no significant difference was observed in the annual cost of antipsychotic monotherapy versus combination therapy. One hundred and five patients (42%) were using optimum dose of (300 - 600 mg CPZeq) while the remaining were using sub or supra therapeutic doses. Analysis showed that use of depot, use of anticholinergic agents and increasing amount of total CPZeq were significant factors associated with antipsychotic combination. This study indicated that antipsychotic prescribing was not in conformance with international guidelines with respect to maintenance dose and combination therapy. Type of antipsychotic treatment regimen, combination versus monotherapy, was not associated with better clinical or economic outcome.


Gabapentin: a pooled analysis of adverse events from three clinical trials in patients with postherpetic neuralgia.
Gabapentin has been shown to be well tolerated and effective in the management of the pain associated with postherpetic neuralgia (PHN). It is assumed that adverse events occurring with gabapentin are dose related, their frequency and severity increasing with increasing doses. The aim of this study was to assess the dose dependence of adverse events with gabapentin by determining the relationship between increasing doses of gabapentin and the onset and/or worsening of adverse events in patients with PHN. Data were pooled from 3 randomized, double-blind, placebo-controlled, parallel-group studies of gabapentin that focused on or included patients with PHN. Gabapentin was initiated at 300 mg/d and titrated to maintenance doses of 1800 to 3600 mg/d by day 12 to 24. The analysis of adverse events was based on 3 distinct groups: patients who received gabapentin <1800 mg/d, those who received gabapentin >or=1800 mg/d, and those who received placebo. Patients who were given higher doses of gabapentin had already received lower doses. An adverse event was recorded at the dose of its first onset and recorded again if its severity worsened at a higher dose. This study included data from 603 patients with PHN: 358 patients (196 [54.7%] women, 162 [45.3%] men; mean [SD] age, 72.3 [10.3] years) received gabapentin, and 245 (133 [54.3%] women, 112 [45.7%] men; mean [SD] age, 73.3 [10.7] years) received placebo. The 3 most common adverse events were dizziness, somnolence, and peripheral edema. Patients receiving gabapentin >or=1800 mg/d had a higher incidence of peripheral edema (7.5%) than those receiving gabapentin <1800 mg/d (1.4%) or placebo (1.6%) (P<0.002, gabapentin >or=1800 mg/d vs placebo). In contrast, the incidence of dizziness and somnolence was not higher in patients receiving gabapentin >or=1800 mg/d compared with those in the other groups. Compared with placebo recipients, patients receiving gabapentin <1800 mg/d reported a significantly greater frequency of dizziness (20.2% gabapentin <1800 mg/d vs 7.4% placebo; P<0.002) and somnolence (14.9% vs 5.8%, respectively; P=0.005). However, at >or=1800 mg/d, rates of dizziness (9.7%) and somnolence (6.9%) were comparable to those with placebo. Discontinuation rates were comparable between patients receiving gabapentin and those receiving placebo. In this pooled analysis of adverse-event data from 3 clinical trials in patients with PHN, the incidence of peripheral edema was increased when gabapentin was titrated to >or=1800 mg/d. Dizziness and somnolence, the other most commonly occurring adverse events, were transient and did not occur more frequently or worsen with titration to >or=1800 mg/d. Based on these findings, it does not appear that safety concerns should limit titration of gabapentin to achieve optimal efficacy.


Histopathology of the pulp of primary molars with active and arrested dentinal caries.
The purpose of this study was to compare the histological appearance of the pulp of human primary molars with active and arrested lesions. The sample consisted of 36 primary molars (18 with active lesions and 18 with arrested lesions) extracted from 35 children between 5 to 9 years of age. The histological diagnosis was classified in normal pulp, transitional stage, partial pulpitis, total pulpitis and total necrosis, and then subdivided in three subgroups: treatable, untreatable and questionable. Results showed that normal pulp or transitional stage (treatable category) was diagnosed in 50% of teeth with arrested lesions, compared to 11.1% of teeth with active lesions. Partial pulpitis (questionable category) was present in 38.8% with arrested lesions compared to 22.2% with active lesions. Total pulpitis and total necrosis (untreatable category) was diagnosed in 11.2% with arrested lesions compared to 66.7% with active lesions. The observed frequencies of histological categories between both groups were statistically significant (P < 0.05). Histologically, pulp reaction under active and arrested lesions in primary molars revealed the formation of a basophilic calcio-traumatic line at the junction of the primary and reparative dentin, formation of reparative dentin and a regular odontoblastic layer in 60% of the cases. Results indicated that the type of lesion (active or arrested) is a good indicator of the histological status of the pulp.


Multicomponent wavefield characterization with a novel scanning laser interferometer.
The in-plane component of the wavefield provides valuable information about media properties from seismology to nondestructive testing. A new compact scanning laser ultrasonic interferometer collects light scattered away from the angle of incidence to provide the absolute ultrasonic displacement for both the out-of-plane and an in-plane components. This new system is tested by measuring the radial and vertical polarization of a Rayleigh wave in an aluminum half-space. The estimated amplitude ratio of the horizontal and vertical displacement agrees well with the theoretical value. The phase difference exhibits a small bias between the two components due to a slightly different frequency response between the two processing channels of the prototype electronic circuitry.


Plasma Cholesterol- and Body Fat-Lowering Effects of Chicken Protein Hydrolysate and Oil in High-Fat Fed Male Wistar Rats.
Rest raw materials provide a new source of bioactive dietary ingredients, and this study aimed to determine the health effects of diets with chicken protein hydrolysate (CPH) and chicken oil (CO) generated from deboned chicken meat. Male Wistar rats (n = 56) were divided into seven groups in three predefined sub-experiments to study the effects of protein source (casein, chicken fillet, pork fillet, and CPH), the dose-effect of CPH (50% and 100% CPH), and the effects of combining CPH and CO. Rats were fed high-fat diets for 12 weeks, and casein and chicken fillet were used as controls in all sub-experiments. While casein, chicken-, or pork fillet diets resulted in similar weight gain and plasma lipid levels, the CPH diet reduced plasma total cholesterol. This effect was dose dependent and accompanied with the reduced hepatic activities of acetyl-CoA carboxylase and fatty acid synthase. Further, rats fed combined CPH and CO showed lower weight gain, and higher hepatic mitochondrial fatty acid oxidation, plasma L-carnitine, short-chain acylcarnitines, TMAO, and acetylcarnitine/palmitoylcarnitine. Thus, in male Wistar rats, CPH and CO lowered plasma cholesterol and increased hepatic fatty acid oxidation compared to whole protein diets, pointing to potential health-beneficial bioactive properties of these processed chicken rest raw materials.


A Composite-Likelihood Method for Detecting Incomplete Selective Sweep from Population Genomic Data.
Adaptive evolution occurs as beneficial mutations arise and then increase in frequency by positive natural selection. How, when, and where in the genome such evolutionary events occur is a fundamental question in evolutionary biology. It is possible to detect ongoing positive selection or an incomplete selective sweep in species with sexual reproduction because, when a beneficial mutation is on the way to fixation, homologous chromosomes in the population are divided into two groups: one carrying the beneficial allele with very low polymorphism at nearby linked loci and the other carrying the ancestral allele with a normal pattern of sequence variation. Previous studies developed long-range haplotype tests to capture this difference between two groups as the signal of an incomplete selective sweep. In this study, we propose a composite-likelihood-ratio (CLR) test for detecting incomplete selective sweeps based on the joint sampling probabilities for allele frequencies of two groups as a function of strength of selection and recombination rate. Tested against simulated data, this method yielded statistical power and accuracy in parameter estimation that are higher than the iHS test and comparable to the more recently developed nSL test. This procedure was also applied to African Drosophila melanogaster population genomic data to detect candidate genes under ongoing positive selection. Upon visual inspection of sequence polymorphism, candidates detected by our CLR method exhibited clear haplotype structures predicted under incomplete selective sweeps. Our results suggest that different methods capture different aspects of genetic information regarding incomplete sweeps and thus are partially complementary to each other.


The novel crystal structure with Zr6O4(OH)4 core and hydrazine carboxylate ligands, and its thermal properties.
The title compound, [Zr(6)(OH)(4)O(4)(N(2)H(3)COO)(12)] · 14H(2)O, was prepared with a novel multi-step synthetic pathway. The structure contains a Zr(6)(µ(3)-OH)(4)(µ(3)-O(4))(12+) core on which twelve hydrazine carboxylate anions are bound to form neutral coordination molecules. The coordination mode of carboxylate ligand is exclusively N,O-bidentate chelating, which is observed for the first time in this class of compounds. The title compound is also the first example of isolated Zr(IV) oxo clusters with cubic symmetry. The structure is stabilized with an extensive hydrogen bond network between coordination and water molecules, and amongst the solvent water molecules themselves. Thermogravimetric studies have shown that the prepared [Zr(6)(OH)(4)O(4)(N(2)H(3)COO)(12)] · (14)H(2)O decomposed in several consecutive steps characterized by evolution of H(2)O, CO, CO(2), N(2) and H(2), finally yielding ZrO(2). The decomposition mechanism is rather complex and includes the formation of a series of amorphous intermediates.


Hepatic cyst infection in an autosomal dominant polycystic kidney disease patient diagnosed by right pleural effusion.
A 64-year-old Japanese man with renal dysfunction caused by autosomal dominant polycystic kidney disease (ADPKD) was admitted to our hospital for evaluation of right back pain, fever, inflammation, and pleural effusion. Diagnostic investigations for tuberculous pleuritis were all negative. Although no radiographic abnormality suggesting hepatic cyst infection was detected by computed tomography, hepatic cyst drainage demonstrated purulent contents indicative of cyst infection. Conglutination of the cyst by minocycline 100 mg was performed five times in addition to drainage. After drainage, the symptoms of inflammation, right back pain and right pleural effusion subsided. Renal function and anemia, which had been resistant to darbepoetin treatment, also improved after the procedure. These results suggested that the infected hepatic cyst was associated with the patient's symptoms, exacerbation of renal dysfunction and anemia. The pleural effusion was due to the propagation of inflammation from the cyst infection. This is the first report of an infected hepatic cyst in an ADPKD patient presenting with and diagnosed by right pleural effusion.


Global Biodiversity of Aquatic Ammonia-Oxidizing Archaea is Partitioned by Habitat.
Archaea play an important role in nitrification and are, thus, inextricably linked to the global carbon and nitrogen cycles. Since the initial discovery of an ammonia monooxygenase α-subunit (amoA) gene associated with an archaeal metagenomic fragment, archaeal amoA sequences have been detected in a wide variety of nitrifying environments. Recent sequencing efforts have revealed extensive diversity of archaeal amoA sequences within different habitats. In this study, we have examined over 8000 amoA sequences from the literature and public databases in an effort to understand the ecological factors influencing the distribution and diversity of ammonia-oxidizing archaea (AOA), with a particular focus on sequences from aquatic habitats. This broad survey provides strong statistical support for the hypothesis that different environments contain distinct clusters of AOA amoA sequences, as surprisingly few sequences are found in more than one habitat type. Within aquatic environments, salinity, depth in the water column, and temperature were significantly correlated with the distribution of sequence types. These findings support the existence of multiple distinct aquatic AOA populations in the environment and suggest some possible selective pressures driving the partitioning of AOA amoA diversity.


Genetics of penicillin titre in lines of Aspergillus nidulans selected through recurrent mutagenesis.
Genetic analyses of mutations for increased penicillin titre were carried out on two strains of Aspergillus nidulans isolated after independent programmes of recurrent mutation and selection, similar to those used industrially for strain improvement. Both selected strains were stable in terms of colony morphology and penicillins titre. Backcrosses to the unselected ancestor indicated that the increased yield of each strain was due to an induced polygenic system with both additive and non-additive gene action. The titre-increasing mutations in one strain (A6-9) were recessive to their wild-type alleles, while those in the other (B6-27) were either semi-dominant or showed ambidirectional dominance. The diploid between A6-9 and B6-27 had a titre less than either component haploid, suggesting that the mutations in the two strains involved different genes. Strain B6-27 carried a translocation between chromosomes III and VII which had been induced during the selection programme. This investigation complements previous work on the genetics of penicillin production in A. nidulans and Penicillium chrysogenum and the results are directly relevant to industrial strain improvement by hybridization of divergent strains.


Organization and regulation of an operon that encodes a sporulation-essential sigma factor in Bacillus subtilis.
Deletion of sigE, the structural gene for the sporulation-induced RNA polymerase sigma factor, sigma E, prevented endospore formation by Bacillus subtilis. The effects of integration of plasmids into the sigE region of the chromosome and the use of complementation analyses demonstrated that sigE is part of an operon that includes a promoter-proximal gene, spoIIGA, that is essential for sporulation. Gene fusions to the promoter of this operon, spoIIG, demonstrated that transcription from this promoter is induced at the beginning of sporulation and is dependent on several spoO genes.


Cytogenetics and genome evolution in the subfamily Triatominae (Hemiptera, Reduviidae).
The subfamily Triatominae (Hemiptera, Reduviidae), vectors of Chagas disease, includes over 140 species. Karyotypic information is currently available for 80 of these species. This paper summarizes the chromosomal variability of the subfamily and how it may reveal aspects of genome evolution in this group. The Triatominae present a highly conserved chromosome number. All species, except 3, present 20 autosomes. The differences in chromosome number are mainly caused by variation in the number of sex chromosomes, due to the existence of 3 sex systems in males (XY, X(1)X(2)Y and X(1)X(2)X(3)Y). However, inter- and intraspecific differences in the position, quantity and meiotic behavior of constitutive heterochromatin, in the total genome size, and in the location of ribosomal 45S rRNA clusters, have revealed considerable cytogenetic variability within the subfamily. This cytogenetic diversity offers the opportunity to perform cytotaxonomic and phylogenetic studies, as well as structural, evolutionary, and functional analyses of the genome. The imminent availability of the complete genome of Rhodnius prolixus also opens new perspectives for understanding the evolution and genome expression of triatomines. The application of fluorescence in situ hybridization for the mapping of genes and sequences, as well as comparative analyses of genome homology by comparative genomic hybridization will be useful tools for understanding the genomic changes in relation to evolutionary processes such as speciation and adaptation to different environments.


Analysis and isolation of embryonic mammalian neurons by fluorescence-activated cell sorting.
Cells were dissociated from the CNS of the embryonic mouse and rat to produce cell suspensions suitable for analysis and separation on a fluorescence-activated cell sorter (FACS). Cells from the spinal cord of the embryonic mouse were analyzed in the most detail. Cell suspensions generated three major peaks in histograms of forward-angle light scatter. Examination of material isolated from each peak and labeling of cell suspensions with the nonvital and supravital fluorescent dyes propidium iodide, ethidium bromide, and acridine orange demonstrated that the three peaks represented live cells, dead cells, and subcellular fragments. Passage through the cell sorter did not detectably damage live cells, as shown by light microscopy, FACS analysis, and in vitro culture of sorted cells. Neurons and glial cells collected by sorting survived at least 4 weeks in culture. Cell suspensions dissociated from the dorsal root ganglia, hippocampus, hypothalamus, cerebellum, and cerebral cortex of the embryonic mouse and from the spinal cord of the embryonic rat produced similar results. Analysis of samples prepared at different developmental stages showed that viable cells could be recovered from each of these regions throughout the important stages of neurogenesis and early cellular differentiation, but that few viable cells could be recovered from animals beyond late embryonic or early postnatal ages. Quantitative FACS analysis of monoclonal antibody A2B5, tetanus toxin and cholera toxin, and lectins binding to live dissociated cells from the embryonic spinal cord demonstrated that these cells had already developed binding sites for these cell-surface ligands by embryonic day 13. These results demonstrate that a fluorescence-activated cell sorter can be used for quantitative analysis of specific cellular properties, that FACS analysis and sorting can be used to identify and isolate live cells from many regions of the embryonic mammalian CNS during important developmental periods, and that sorted neurons and glial cells can be maintained for weeks in culture.


RESPONSE OF VOLTA CHILDREN TO LIVE ATTENUATED MEASLES VIRUS VACCINE.
Experience so far with the Enders B-level Edmonston strain of live attenuated measles vaccine has been principally with children in the USA in whom natural measles carries a low mortality. Measles is associated with an appreciably higher mortality rate in developing countries; in Upper Volta, climate, nutritional status, degree of parasitic infestation and concurrent infections may contribute to this. The present report summarizes a pilot study in Ouagadougou, Upper Volta, designed to obtain information on the response of Volta children to Enders vaccine and to determine the feasibility of using this vaccine on a large scale.The observations indicate that Volta children, despite the hazards of natural measles, respond in essentially the same manner to live vaccine given alone or with gamma-globulin as do children in other areas. The febrile reactions which characterize infection with the attenuated measles virus were of insufficient importance to warrant the concurrent use of gamma-globulin in a forthcoming mass measles vaccination campaign in Upper Volta.


Projection of seasonal influenza severity from sequence and serological data.
Severity of seasonal influenza A epidemics is related to the antigenic novelty of the predominant viral strains circulating each year. Support for a strong correlation between epidemic severity and antigenic drift comes from infectious challenge experiments on vaccinated animals and human volunteers, field studies of vaccine efficacy, prospective studies of subjects with laboratory-confirmed prior infections, and analysis of the connection between drift and severity from surveillance data. We show that, given data on the antigenic and sequence novelty of the hemagglutinin protein of clinical isolates of H3N2 virus from a season along with the corresponding data from prior seasons, we can accurately predict the influenza severity for that season. This model therefore provides a framework for making projections of the severity of the upcoming season using assumptions based on viral isolates collected in the current season. Our results based on two independent data sets from the US and Hong Kong suggest that seasonal severity is largely determined by the novelty of the hemagglutinin protein although other factors, including mutations in other influenza genes, co-circulating pathogens and weather conditions, might also play a role. These results should be helpful for the control of seasonal influenza and have implications for improvement of influenza surveillance.


[Multiple risk factors prediction models for high risk population of colorectal cancer].
Colorectal cancer is caused by the interaction of genetic and environment factors. Domestic and foreign scholars have attempted to develop several colorectal cancer risk prediction models, in order to identity risk factors, to screen for high risk population and evaluate the risk of developing colorectal cancer, so as to provide personalized screening protocols for individuals with different risk, and eventually reduce the incidence and mortality rate of colorectal cancer. Currently, the common colorectal cancer risk prediction models were mainly developed based on case-control study and cohort study. Models developed in European and American regions and Asia (excluding China) only include common risk factors, while Chinese models also include hereditary factors on the bases of common risk factors. However, the development and verification of each model are mainly based on local population, whether it can be applied for other population need to be determined. This article reviews the development, validation and evaluation of the risk prediction models, in order to provide a basis for developing more precise risk prediction models for colorectal cancer.


Pretravel advice neglects rabies risk for travelers to tropical countries.
While the risk of acquiring rabies in Europe is low, there have been a number of reports on cases of human rabies "imported" from abroad in recent years. Few studies have been conducted concerning pretravel advice for international travelers about the risk of rabies. One-hundred and fifty German and 150 Swiss general practitioners (GPs) who give pretravel advice were interviewed to assess their awareness of the risk of rabies for travelers, and of the relevant preventive measures, using a pretested telephone interview followed by a written questionnaire with a multiple choice list. GPs were asked specifically about pretravel health advice for journeys to Thailand and Kenya. During the telephone interview a majority (76%) of the 300 GPs recommended "nothing" as a preventive measure against rabies for travelers. One or two important preventive measures were mentioned by only a few GPs. No major differences were detected between the German and the Swiss groups concerning their recommendations for rabies prevention. The 119 German and 121 Swiss GPs who returned the completed questionnaire said they would recommend the three important preventive measures in the future significantly more often than they had recommended them to their clients in the past. The risk of rabies in travelers to tropical countries appears to be neglected in pretravel advice provided by Swiss and German GPs. The recommendations on travel advice published in the Swiss Bulletin of the Federal Office of Public Health (BFOPH) and in the "Deutsches Arzteblatt" should be extended to "other specific health risks." In Switzerland this has now been done.


Comparison of Polyphenol, Sugar, Organic Acid, Volatile Compounds, and Antioxidant Capacity of Commercially Grown Strawberry Cultivars in Turkey.
The aim of this study was to compare certain important fruit quality parameters such as sugars, organic acids, total phenolic content, antioxidant capacity, and volatile compounds of 10 commercial strawberry cultivars grown in the research and experimental area in Yaltir Agricultural Company located in Adana provinces of Turkey. As for the sugar content of strawberry fruits, fructose was identified as the dominant sugar and the highest value (4.43%) was found in the cultivar "Rubygem". In terms of organic acid, among the examined strawberry cultivars, "Calinda" had the greatest level of citric acid (711.45 mg g-1). Regarding vitamin C content, the highest amount was found in the cultivar "Sabrina" (25.08 mg 100 g-1). Ellagic acid was the main phenolic acid in all examined cultivars (except the "Plared" cultivar), and the highest amount was detected in the "Fortuna" cultivar (3.18 mg 100 g-1). We found that the cultivar FL-127 had the highest total phenolic content (158.37 mg gallic acid equivalent 100 g-1 fresh weight base). Regarding antioxidant capacities, the highest value (88.92%) was found in the cultivar Victory among all the cultivars studied. The detailed analysis of volatile compounds was performed by gas chromatography/mass spectrometry (GC/MS) and 34 compounds were detected. Among them, esters, acids, and alcohols were found to be the major volatile compounds in strawberry fruits. In conclusion, strawberry fruits belong to ten cultivars showed abundant phenolic compounds and at the same time have high antioxidant activity.


Non-harvestable radial artery. A bilateral problem?
Since radial artery is preferably harvested from a non-dominant hand, our aim was to study whether there are contraindications for radial artery harvest in the dominant hand if the radial artery of the other hand is not suitable for harvesting. Thirty-three patients scheduled to coronary artery bypass grafting with contraindication for radial artery harvest in the non-dominant hand underwent Allen test, upper arm Doppler ultrasonography and digital pletysmography. In ultrasonography, both anatomical and circulatory measurements were performed. Both hands were then compared to each other. Furthermore, twelve control patients without contraindication for radial artery harvest in the non-dominant hand were examined. All 33 patients had contraindication for radial artery harvest in the non-dominant hand. Twenty-four (73%) had contraindication in the dominant hand as well. In terms of morphology, there was no statistically significant difference between the hands but circulatory parameters as a group suggested contraindication. Among controls, four patients (33%) had contraindication in the dominant hand. In the case of a non-harvestable radial artery in a hand there is clearly an increased risk for contraindication for radial artery harvest also in the other hand.


Histological changes in intervertebral discs after smoking and cessation: experimental study using a rat passive smoking model.
Passive smoking has been reported to induce intervertebral disc degeneration in rats, and the objective of the present study was to histologically investigate changes in smoking-induced intervertebral disc degeneration after cessation of smoking. Four-week-old rats were subjected to passive smoking for 8 weeks in a smoking box [20 cigarettes a day: one cigarette an hour (inhaled over 3 minutes and followed by ventilation with room air for 5 minutes)] to induce intervertebral disc degeneration. Smoke-free periods of different lengths were then established, and intervertebral discs were histologically analyzed. Immediately after 8 weeks of passive smoking, intervertebral discs exhibited cracks, tears, and misalignment of the annulus fibrosus, and increased fibrous tissue was seen in the nucleus pulposus. In addition, the level of interleukin-1beta in intervertebral discs was higher in the smoking group than in the non-smoking group. After cessation, progression of degeneration ceased, and the matrix of the nucleus pulposus and annulus fibrosus exhibited increased fibrous connective tissue and proteoglycan. However, there were no changes in annulus fibrosus misalignment. Interleukin-1beta levels also remained significantly elevated after 8 weeks of cessation. While the annulus fibrosus degeneration caused by smoking was partially irreversible after cessation of smoking, the amount of mucin (proteoglycan) in the nucleus pulposus and annulus fibrosus tended to increase after cessation, thus suggesting the possibility that smoking-induced intervertebral disc degeneration can be repaired to some degree by cessation of smoking.


Hollow ZrO2/PPy nanoplatform for improved drug delivery and real-time CT monitoring in synergistic photothermal-chemo cancer therapy.
With the aim of fabricating multifunctional nanoplatforms for cancer diagnosis and therapy, we design hollow ZrO2 nanospheres as novel nanocarriers with enhanced CT imaging properties to integrate NIR light absorbing agents and anti-cancer drugs into one nanosystem. Polypyrrole (PPy) is encapsulated into the hollow ZrO2 nanospheres to endow the nanosystem with strong photothermal transfer capability via an oxidative polymerization method. The anti-cancer drug, doxorubicin (DOX), was loaded into the hollow ZrO2 nanospheres with a high loading content and Dox could be released from the carrier by NIR photothermal stimulus. The hollow ZrO2 nanoplatform has been successfully demonstrated for synergistic photothermal-chemo therapy, both in vitro and in vivo. Due to the excellent X-ray attenuation ability of Zr, the biodistribution of this nanosystem was real-time monitored via CT imaging technology using mini swine as animal models. ICP-OES analysis of tissues obtained from the biopsy also confirms the biodistribution. The in vitro and in vivo toxicity evaluation shows that this nanosystem has good biocompatibility and has great prospects for imaging-guided photothermal-chemo cancer therapy.


Dementia due to Meningovascular Syphilis in Medial Temporal Lobe and Cognitive Rehabilitation.
The temporal lobe is essential in saving declarative memory and plays an important role along with the cerebral neocortex in creating and maintaining long-term memory. Damage to the temporal lobe is expected to result in cognitive impairment or dementia, which has characteristic symptoms such as cognitive and behavioral dysfunction and decreasing self-reliance in activities of daily living. We report on a patient, who suffered from dementia due to meningovascular syphilis affecting the medial temporal lobe, and on the outcome of cognitive rehabilitation.


Wallenberg's Syndrome: An Unusual Case of Dysphagia.
A 56-year-old man presented with sudden-onset oropharyngeal dysphagia and vomiting of central etiology. Neurological evaluation showed uvula deviation to the left, paresis of the mid-right portion of the soft palate, lateralization of gaze to the right side, and dysphonia. Magnetic resonance imaging (MRI) showed an infarction in the left lateral medullary region, therefore the diagnosis of Wallenberg's syndrome was established. The neurological issues along with the dysphagia gradually improved and the patient was discharged.


pH-Responsive Trihydroxylated Piperidines Rescue The Glucocerebrosidase Activity in Human Fibroblasts Bearing The Neuronopathic Gaucher-Related L444P/L444P Mutations in GBA1 Gene.
Engineering bioactive iminosugars with pH-responsive groups is an emerging approach to develop pharmacological chaperones (PCs) able to improve lysosomal trafficking and enzymatic activity rescue of mutated enzymes. The use of inexpensive l-malic acid allowed introduction of orthoester units into the lipophilic chain of an enantiomerically pure iminosugar affording only two diastereoisomers contrary to previous related studies. The iminosugar was prepared stereoselectively from the chiral pool (d-mannose) and chosen as the lead bioactive compound, to develop novel candidates for restoring the lysosomal enzyme glucocerebrosidase (GCase) activity. The stability of orthoester-appended iminosugars was studied by 1 H NMR spectroscopy both in neutral and acidic environments, and the loss of inhibitory activity with time in acid medium was demonstrated on cell lysates. Moreover, the ability to rescue GCase activity in the lysosomes as the result of a chaperoning effect was explored. A remarkable pharmacological chaperone activity was measured in fibroblasts hosting the homozygous L444P/L444P mutation, a cell line resistant to most PCs, besides the more commonly responding N370S mutation.


Municipalities collaborating in public health: the Danish Smoking Prevention and Cessation Partnership.
This study explored the Smoking Prevention and Cessation Partnership (SPCP) which builds upon a collaboration between two Danish municipalities targeted at the prevention of tobacco smoking. The aim of the study was to describe the processes of SPCP, to examine the difficulties this collaboration faced, and to assess how these experiences could be used to improve future partnership collaboration. We employed qualitative methodology comprising 12 semi-structured one-to-one interviews with SPCP's stakeholders and an analysis of the partnership documents and reports. The findings suggested that the main potentials of the partnership were the personal relations between the members and stakeholders with the possibilities of the creation of new connections with other actors. Barriers to successful partnership building were the implementation of the new Local Government Reform as a competing task, and that the two municipalities were heterogenic in respect to organizational issues and working methods. Other impediments included the lack of continuity in leadership, the lack of clarity regarding the form of collaboration and roles, as well as different expectations of the stakeholders. We conclude that four factors remain critical for partnerships. The first is the clarity of the collaborative effort. Second, partnerships need to take into account the structural circumstances and culture/value systems of all stakeholders. Third is the impact of contextual factors on the development of the partnership; and the fourth factor is the bearing of personal/individual factors on the partnership e.g., personal engagement in the project. Early attention to these four factors could contribute to more effective partnership working.


Differences in residual volume above different tracheostomy tube cuffs depending on tube structure, tube tilt angle, and liquid viscosity.
Proper management of aspirated material above the tracheostomy tube cuff is crucial to prevent complications, such as aspiration pneumonia. This study aimed to thoroughly examine the effects of aspirated liquid viscosity, suction port positioning, and tube tilt angle on residual volume above the cuff (RVAC). Five types of tracheostomy tubes (approximately 9 mm outer diameter) were placed through a transparent cylinder with an inner diameter of 18 mm. The cuff was inflated to completely seal the interior of the cylinder. Four liquids with different viscosities were poured onto the cuff, and the liquid above the cuff was suctioned from the side port. The cylinder was angled at 90° and 20°, and each test was performed thrice to determine the average RVAC. After side-port suctioning, some liquid residue was observed on the cuff of all tracheostomy tubes. The RVAC increased with higher liquid viscosity. The tubes with a longer distance from the suction port opening to the cuff top exhibited more RVAC. Moreover, the RVAC was almost the same regardless of the cylinder angle for tubes with a suction port on the lateral side. However, tubes with backside ports showed a decreased RVAC with cylinder tilt. This study underscores the persistence of residual material on cuffed tracheostomy tubes even with regular subglottic secretion drainage. This emphasizes the need for specialized tracheostomy tube development aimed at reducing post-suction RVAC. Improved designs can potentially minimize complications associated with residue accumulation.


Single nucleus genome sequencing reveals high similarity among nuclei of an endomycorrhizal fungus.
Nuclei of arbuscular endomycorrhizal fungi have been described as highly diverse due to their asexual nature and absence of a single cell stage with only one nucleus. This has raised fundamental questions concerning speciation, selection and transmission of the genetic make-up to next generations. Although this concept has become textbook knowledge, it is only based on studying a few loci, including 45S rDNA. To provide a more comprehensive insight into the genetic makeup of arbuscular endomycorrhizal fungi, we applied de novo genome sequencing of individual nuclei of Rhizophagus irregularis. This revealed a surprisingly low level of polymorphism between nuclei. In contrast, within a nucleus, the 45S rDNA repeat unit turned out to be highly diverged. This finding demystifies a long-lasting hypothesis on the complex genetic makeup of arbuscular endomycorrhizal fungi. Subsequent genome assembly resulted in the first draft reference genome sequence of an arbuscular endomycorrhizal fungus. Its length is 141 Mbps, representing over 27,000 protein-coding gene models. We used the genomic sequence to reinvestigate the phylogenetic relationships of Rhizophagus irregularis with other fungal phyla. This unambiguously demonstrated that Glomeromycota are more closely related to Mucoromycotina than to its postulated sister Dikarya.


[Efficacy of Amrubicin Monotherapy for Patients with Extrapulmonary Neuroendocrine Carcinomas Refractory to Platinum-Based Chemotherapy].
Standard regimens for extrapulmonary neuroendocrine carcinomas(EPNEC)are not established. Treatment used for small cell lung cancer is also used for EPNECs. Amrubicin(AMR) monotherapy is used as salvage therapy for small cell lung cancer, but its efficacy in EPNEC is not clear. The aim of this study was to estimate the efficacy of AMR monotherapy in EPNEC. We retrospectively investigated patients with EPNEC who received first-line platinum-based chemotherapy between April 2007 and March 2019. The time to treatment failure(TTF)and the efficacy and toxicity was analyzed in the patients who received AMR monotherapy. Among 43 patients with EPNEC, 14(13 males, one female; median age, 58 years)received AMR monotherapy. Primary site included the pancreas(n=3), stomach(n=3), rectum(n=1), anal canal(n=1), salivary glands(n= 1), urothelial(n=1), bladder(n=1), prostate(n=1), and 2 patients had primary unknown cancer. Pathological type included small cell(n=4), large cell(n=2), and other types(n=8). Prior chemotherapy comprised CDDP plus CPT-11(n =5), CDDP plus ETP(n=2), and CBDCA plus ETP(n=6). The median TTF was 49(20-61)days. One patient had a partial response and the disease control rate was 33%. The common adverse events of >Grade 3 were leukopenia(69%), neutropenia(62%), and febrile neutropenia(23%). AMR monotherapy was clinically effective and safe for EPNEC.


Simplified assessment of segmental colonic transit.
Transit times of radiopaque markers through the human gut were measured by published techniques and compared with a simplified method. Three sets of distinctive markers were ingested by 24 healthy persons on 3 successive days. In the first part of the study, daily abdominal x-rays were taken and individual stools were collected for radiography. Mouth-to-anus transits were assessed from the fecal output of markers and mean colonic and segmental colonic transits were calculated from the daily radiographs. These established methods were then compared with estimates of total colonic and segmental transits based on a single abdominal film, taken on the fourth day. The single-film technique correlated well with values obtained from the previous, but more inconvenient, methods. Using the simpler approach, colonic transit was assessed in 49 additional healthy subjects, for a total group of 73. Total colonic transit was 35.0 +/- 2.1 h (mean +/- SE); segmental transits was 11.3 +/- 1.1 h for the right colon, 11.4 +/- 1.4 h for the left colon, and 12.4 +/- 1.1 h for the rectosigmoid. Men had significantly shorter transits for the whole colon than did women (p less than 0.05), and this difference was apparent to some extent in the right (p = 0.06) and left colon (p = 0.07) but not in the rectosigmoid. Age did not influence transit significantly nor did a small dose of supplemental fiber. The technique is simple, convenient for clinical usage, and reduces the exposure to radiation to acceptable levels. There should be a role for this approach in the evaluation of colonic transit in selected patients.


MHC class I loss is a frequent mechanism of immune escape in papillary thyroid cancer that is reversed by interferon and selumetinib treatment in vitro.
To evaluate MHC class I expression on papillary thyroid cancer (PTC) and analyze changes in MHC expression and associated immune activation with current and experimental treatments for thyroid cancer using in vitro PTC cell lines. MHC class I expression and assessment of tumor-infiltrating leukocyte populations were evaluated by immunohistochemistry. PTC cell lines were analyzed for HLA-ABC expression by flow cytometry following tyrosine kinase inhibitor, IFNα or IFNγ, or radiation treatment. Functional changes in antigenicity were assessed by coculture of allogeneic donor peripheral blood leukocytes (PBL) with pretreated or untreated PTC cell lines and measurement of T-cell activation and cytokine production. Both MHC class I and β2-microglobulin expression was reduced or absent in 76% of PTC specimens and was associated with reduced tumor-infiltrating immune cells, including effector (CD3(+), CD8(+), CD16(+)) and suppressor (FoxP3(+)) populations. Treatment of PTC cell lines with the MEK1/2 inhibitor selumetinib or IFN increased HLA-ABC expression. This phenotypic change was associated with increased T-cell activation (%CD25(+) of CD3(+)) and IL2 production by PBL cocultured with treated PTC cell lines. Additive effects were seen with combination selumetinib and IFN treatment. MHC class I expression loss is frequent in human PTC specimens and represents a significant mechanism of immune escape. Increased antigenicity following selumetinib and IFN treatment warrants further study for immunotherapy of progressive PTC.


Dipeptidyl peptidase-4 inhibitors alleviate cognitive dysfunction in type 2 diabetes mellitus.
Patients with type 2 diabetes mellitus (T2DM) are commonly at high risk for developing cognitive dysfunction. Antidiabetic agents might be repurposed for targeting cognitive dysfunction in addition to modulation on glucose homeostasis. This study aimed to evaluate the impact of dipeptidyl peptidase-4 inhibitors (DPP-4i) on cognitive function in T2DM. PubMed, Embase, Cochrane Library and Web of Science were systematically searched from inception to September 30, 2023. Weighted mean differences were calculated using the Mantel-Haenszel (M-H) fixed or random effects model based on the degree of heterogeneity among studies. Heterogeneity was evaluated using a Chi-squared test and quantified with Higgins I2. Sensitivity analysis was performed with the leave-one-out method, and publication bias was evaluated according to Begg's and Egger's tests. Six clinical trials involving 5,178 participants were included in the pooled analysis. Administration of DPP-4i generally correlated with an increase of Mini-Mental State Examination (MMSE) scores (1.09, 95% CI: 0.22 to 1.96). DPP-4i alleviated cognitive impairment in the copying skill subdomain of MMSE (0.26, 95% CI: 0.12 to 0.40). Treatment with DPP-4i also resulted in an increase of Instrumental Activities of Daily Living (IADL) scores (0.82, 95% CI: 0.30 to 1.34). However, DPP-4i produced no significant effects on Barthel Activities of Daily Living (BADL) scores (0.37, 95% CI: -1.26 to 1.99) or other test scores. DPP-4i treatment favourably improved cognitive function in patients with T2DM. Further trials with larger samples should be performed to confirm these estimates and investigate the association of different DPP-4i with cognitive function among diabetic patients. CRD42023430873.


[Number needed to treat (NNT)-- misleading, misunderstood, misused?].
Number needed to treat (NNT) is one of several effect measures that does not capture the time dimension because it is based on observations at a given, random point in time. This aspect makes NNT a problematical measure of the effect of interventions against chronic disease processes in which time to event is an essential issue. Additionally, the statistical properties of NNT are not favorable. It may leave the impression that adverse disease events are completely avoided by intervention when in fact they are postponed. We suggest that NNT should be used and interpreted with caution.


Kinematics of preferred and non-preferred handballing in Australian football.
In Australian football (AF), handballing proficiently with both the preferred and non-preferred arm is important at elite levels; yet, little information is available for handballing on the non-preferred arm. This study compared preferred and non-preferred arm handballing techniques. Optotrak Certus (100 Hz) collected three-dimensional data for 19 elite AF players performing handballs with the preferred and non-preferred arms. Position data, range of motion (ROM), and linear and angular velocities were collected and compared between preferred and non-preferred arms using dependent t-tests. The preferred arm exhibited significantly greater forearm and humerus ROM and angular velocity and significantly greater shoulder angular velocity at ball contact compared to the non-preferred arm. In addition, the preferred arm produced a significantly greater range of lateral bend and maximum lower-trunk speed, maximum strike-side hip speed and hand speed at ball contact than the non-preferred arm. The non-preferred arm exhibited a significantly greater shoulder angle and lower- and upper-trunk orientation angle, but significantly lower support-elbow angle, trunk ROM, and trunk rotation velocity compared to the preferred arm. Reduced ROM and angular velocities found in non-preferred arm handballs indicates a reduction in the degrees of freedom and a less developed skill. Findings have implication for development of handballing on the non-preferred arm.


Aberrant expression of X-linked genes RbAp46, Rsk4, and Cldn2 in breast cancer.
The consequence of activation status or gain/loss of an X-chromosome in terms of the expression of tumor suppressor genes or oncogenes in breast cancer has not been clearly addressed. In this study, we investigated the activation status of the X-chromosomes in a panel of human breast cancer cell lines, human breast carcinoma, and adjacent mammary tissues and a panel of murine mammary epithelial sublines ranging from low to high invasive potentials. Results show that most human breast cancer cell lines were homozygous, but both benign cell lines were heterozygous for highly polymorphic X-loci (IDS and G6PD). On the other hand, 60% of human breast carcinoma cases were heterozygous for either IDS or G6PD markers. Investigation of the activation status of heterozygous cell lines revealed the presence of only one active X-chromosome, whereas most heterozygous human breast carcinoma cases had two active X-chromosomes. Furthermore, we determined whether or not an additional active X-chromosome affects expression levels of tumor suppressor genes and oncogenes. Reverse transcription-PCR data show high expression of putative tumor suppressor genes Rsk4 and RbAp46 in 47% and 79% of breast carcinoma cases, respectively, whereas Cldn2 was down-regulated in 52% of breast cancer cases compared with normal adjacent tissues. Consistent with mRNA expression, immunostaining for these proteins also showed a similar pattern. In conclusion, our data suggest that high expression of RbAp46 is likely to have a role in the development or progression of human breast cancer. The activation status of the X-chromosome may influence the expression levels of X-linked oncogenes or tumor suppressor genes.


Decreased catalepsy response to haloperidol in the genetically dystonic (dt) rat.
The rat mutant dystonic displays an autosomal recessive neurological disease characterized by slow, twisting movements of the limbs and trunk. Rats displaying clinical signs also show a decreased behavioral response to the dopaminergic blocker, haloperidol. Investigation of the development of the cataleptic response to haloperidol in the dystonic (dt) rat indicated that the response of the dt rat in the bar test is similar to that of normal littermates until after the appearance of clinical symptoms in the mutants on postnatal day 10. Mutant rats did not differ from their normal littermates in response to another cataleptic agent, morphine. Assessment of the integrity of the nigrostriatal dopamine (DA) system did not indicate the presence of any degenerative process or of any alterations in DA metabolism. No reliable differences were found between normal and dt rats in striatal DA levels or turnover rates; in DA levels in response to gamma-hydroxybutyrolactone; or in the number and affinity of striatal DA muscarinic acetylcholine receptors. Nor did qualitative light microscopic examination of Golgi-impregnated tissue from dt rats indicate the presence of any morphological abnormalities in the striatum. These findings suggest that dystonic symptoms can occur in the absence of an alteration in striatal DA metabolism and that the dt rat may have a defect in a pathway efferent to the striatum.


Indicators for Enteral Nutrition Use and Prophylactic Percutaneous Endoscopic Gastrostomy Placement in Patients With Head and Neck Cancer Undergoing Chemoradiotherapy.
Chemoradiotherapy (CRT) is a major risk factor for malnutrition and dehydration in patients with head and neck cancer. Enteral support is often needed, and a percutaneous endoscopic gastrostomy (PEG) is frequently placed. Specific indicators for PEG placement remain unclear. This study retrospectively determined which factors contributed to enteral nutrition (EN) use and PEG placement in a large patient group to gain insight on potential indicators for PEG placement protocol creation. A retrospective chart review of 240 patients with head and neck cancer who underwent CRT in 2012-2015 was conducted. Lifestyle, oncological, treatment, and nutrition outcome characteristics were examined and compared between patients who used EN and those who did not, as well as between patients who received a PEG and those who did not. In total, 195 patients used EN (via PEG or nasogastric tube). Multivariate analysis showed that nodal disease presence ( P = .01) and bilateral neck irradiation ( P = .01) were significantly related to EN use while increased age ( P = .01), nodal disease presence ( P = .02), reconstruction extent other than primary closure ( P = .02), bilateral neck irradiation ( P < .01), and an adapted intake consistency prior to treatment ( P = .03) were significantly related to PEG placement. Important factors for EN usage and PEG placement consideration include nodal disease and planned bilateral neck irradiation. Results from this study in combination with existing literature can be taken into consideration in the design of a PEG placement protocol. A better understanding of predictive indicators to PEG placement should be explored in further prospective studies.


miR-409-3p inhibits the proliferation and migration of human ovarian cancer cells by targeting Rab10.
Ovarian cancer is a leading cause of gynecological cancer-related mortality. It has been reported that miR-409-3p is involved in the proliferation and migration of cancer cells. However, the role of miR-409-3p in ovarian cancer has not been well studied. The present study aimed to investigate the functional role of miR-409-3p in the pathogenesis of ovarian cancer, and its potential mechanism. It was found that the expression levels of miR-409-3p in 6 ovarian cancer tissues were upregulated. Through proliferation, migration and colony formation assays, it was revealed that overexpression of miR-409-3p inhibited the proliferation and migration of ovarian cancer cells. It was predicted from bioinformatics assays that the complementary binding sites were within miR-409-3p and Rab10. It was also demonstrated that the downregulation of the expression of Rab10 reversed the miR-409-3p downregulation-induced abnormal proliferation of ovarian cancer cells. These results suggest that miR-409-3p expression can be used as a predictive marker for the prognosis of ovarian cancer. Thus, the miR-409-3p/Rab10 axis may be a novel therapeutic target for ovarian cancer.


The soluble and membrane-bound transhydrogenases UdhA and PntAB have divergent functions in NADPH metabolism of Escherichia coli.
Pentose phosphate pathway and isocitrate dehydrogenase are generally considered to be the major sources of the anabolic reductant NADPH. As one of very few microbes, Escherichia coli contains two transhydrogenase isoforms with unknown physiological function that could potentially transfer electrons directly from NADH to NADP+ and vice versa. Using defined mutants and metabolic flux analysis, we identified the proton-translocating transhydrogenase PntAB as a major source of NADPH in E. coli. During standard aerobic batch growth on glucose, 35-45% of the NADPH that is required for biosynthesis was produced via PntAB, whereas pentose phosphate pathway and isocitrate dehydrogenase contributed 35-45% and 20-25%, respectively. The energy-independent transhydrogenase UdhA, in contrast, was essential for growth under metabolic conditions with excess NADPH formation, i.e. growth on acetate or in a phosphoglucose isomerase mutant that catabolized glucose through the pentose phosphate pathway. Thus, both isoforms have divergent physiological functions: energy-dependent reduction of NADP+ with NADH by PntAB and reoxidation of NADPH by UdhA. Expression appeared to be modulated by the redox state of cellular metabolism, because genetic and environmental manipulations that increased or decreased NADPH formation down-regulated pntA or udhA transcription, respectively. The two transhydrogenase isoforms provide E. coli primary metabolism with an extraordinary flexibility to cope with varying catabolic and anabolic demands, which raises two general questions: why do only a few bacteria contain both isoforms, and how do other organisms manage NADPH metabolism?


Module-based multiscale simulation of angiogenesis in skeletal muscle.
Mathematical modeling of angiogenesis has been gaining momentum as a means to shed new light on the biological complexity underlying blood vessel growth. A variety of computational models have been developed, each focusing on different aspects of the angiogenesis process and occurring at different biological scales, ranging from the molecular to the tissue levels. Integration of models at different scales is a challenging and currently unsolved problem. We present an object-oriented module-based computational integration strategy to build a multiscale model of angiogenesis that links currently available models. As an example case, we use this approach to integrate modules representing microvascular blood flow, oxygen transport, vascular endothelial growth factor transport and endothelial cell behavior (sensing, migration and proliferation). Modeling methodologies in these modules include algebraic equations, partial differential equations and agent-based models with complex logical rules. We apply this integrated model to simulate exercise-induced angiogenesis in skeletal muscle. The simulation results compare capillary growth patterns between different exercise conditions for a single bout of exercise. Results demonstrate how the computational infrastructure can effectively integrate multiple modules by coordinating their connectivity and data exchange. Model parameterization offers simulation flexibility and a platform for performing sensitivity analysis. This systems biology strategy can be applied to larger scale integration of computational models of angiogenesis in skeletal muscle, or other complex processes in other tissues under physiological and pathological conditions.


Impression cytology on conjunctiva and cornea in dry eye patients establishes a correlation between squamous metaplasia and dry eye clinical severity.
To obtain deeper knowledge of the cellular transition in squamous metaplasia, and to look for a correlation between the clinical grade of severity of dry eye and the grade of squamous metaplasia of the corneal and conjunctival epithelium, studied by impression cytology. A total of 143 patients with dry eye disorders of different grades of clinical severity and 33 control subjects of matched age and sex were studied. Symptoms, clinical tests (including Schirmer test, slit-lamp examination, break-up time, rose Bengal staining, vanishing lacunar sulci, and neovascularization), and tear osmolarity were used to establish the diagnosis of dry eye. The subjects were classified into six clinical grades, grade 0 indicating normal and grades 1 to 5 progressively more severe dry eye. Impression cytology specimens were taken from the central cornea and different areas of the conjunctiva of one eye from all patients. A morphologic and morphometric study of the photographs obtained by light microscopy showed cell size, nuclear size, nuclear-cytoplasmic ratio (N:C) in nonsecretory epithelial cells, and density of goblet cells. Morphometric and morphologic studies of the ocular surface cells indicated significant differences, mainly in cell sizes, nuclear alterations, and the N:C ratio, in nonsecretory epithelial cells of the conjunctiva and cornea, and in goblet cell densities from the conjunctiva, between the clinically normal eyes and those with the five grades of clinical severity of dry eye, with different degrees of squamous metaplasia. A morphologic and morphometric analysis of the ocular surface from patients with dry eye obtained by impression cytology led us to draft a new grading system containing one normal level and five levels of squamous metaplasia. This new grading system is based on a significant decrease in the number of goblet cells with less periodic acid-Schiff-hematoxylin-positive staining, an increase in nonsecretory cell size, more marked cell separation, a lower N:C ratio, and an increase in nuclear alterations. The clinical severity of the dry eye correlates with these alterations.


A recruited protease is involved in catabolism of pyrimidines.
In nature, the same biochemical reaction can be catalyzed by enzymes having fundamentally different folds, reaction mechanisms and origins. For example, the third step of the reductive catabolism of pyrimidines, the conversion of N-carbamyl-beta-alanine to beta-alanine, is catalyzed by two beta-alanine synthase (beta ASase, EC 126.96.36.199) subfamilies. We show that the "prototype" eukaryote beta ASases, such as those from Drosophila melanogaster and Arabidopsis thaliana, are relatively efficient in the conversion of N-carbamyl-beta A compared with a representative of fungal beta ASases, the yeast Saccharomyces kluyveri beta ASase, which has a high K(m) value (71 mM). S. kluyveri beta ASase is specifically inhibited by dipeptides and tripeptides, and the apparent K(i) value of glycyl-glycine is in the same range as the substrate K(m). We show that this inhibitor binds to the enzyme active center in a similar way as the substrate. The observed structural similarities and inhibition behavior, as well as the phylogenetic relationship, suggest that the ancestor of the fungal beta ASase was a protease that had modified its profession and become involved in the metabolism of nucleic acid precursors.


Ocular morbidities of juvenile idiopathic arthritis-associated uveitis in adulthood: results from a tertiary center study.
To describe the clinical and visual outcomes of juvenile idiopathic arthritis (JIA)-associated uveitis in adults and to examine risk factors for ongoing inflammation in adulthood. Medical records were reviewed for patients with JIA-associated uveitis who were >16 years old at the final visit (the last visit prior to data collection). In total, 135 eyes of 77 patients (70 female, 7 male) were included. The mean age of patients at the final visit was 29.72 ± 11.27 years. The number of eyes with visual acuity of ≤20/50 and ≤20/200 at the final visit was 37 (28 %) and 20 (15 %), respectively; at least one ocular complication was present in 72 % of eyes. Band keratopathy was the most frequent complication (42 %), followed by cataract (25 %), posterior synechiae (22 %), maculopathy (22 %), ocular hypertension (13 %), and hypotony (5 %). At the final visit, patients who were >16 years of age at presentation to the Massachusetts Eye Research and Surgery Institution had more ocular complications and a greater degree of vision loss than patients who were ≤16 years of age. Ongoing inflammation at the final visit was noted in 40 patients (52 %). The presence of posterior synechiae, hypotony, cataract at presentation, and a history of cataract surgery prior to presentation were predictive of ongoing inflammation in adulthood in univariate analysis. The presence of hypotony and posterior synechiae at the initial visit were predictive factors in multivariate analysis. JIA-associated uveitis may be associated with ongoing inflammation, ocular complications, and severe visual impairment in adulthood. The presence of posterior synechiae and hypotony at the initial visit is predictive of ongoing inflammation.


Epidemiology of end-stage renal disease in Dubai: Single-center data.
Hemodialysis (HD) was first established in Dubai in the year 1980 and was in its full capacity by the year 1983. Since then, the HD population has been growing rapidly. This report represents the demographic data and clinical characteristics of our HD patients during the period between January 2012 and October 2016. Diabetic nephropathy (57%) and hypertension (12.4%) are emerging as the most common causes of end-stage renal disease (ESRD) in our data, followed by undetermined causes in those who presented as ESRD (10.9%), and then by rejected transplant in 4.6%. Obstructive uropathy in our data was 4.37% among all causes. The causes were primary glomerulonephritis (only proven cases in kidney biopsy were counted) in 3.6%, adult polycystic kidney disease in 2.43%, and lupus nephritis in 1.45% of cases. The prevalence of ESRD in the current study was 152 patients per million population per year.


Functional ability and physical and psychosocial well-being of hypermobile schoolchildren.
To compare the functional ability and the physical and psychosocial well-being of children with joint hypermobility to those of age- and sex-matched non-hypermobile subjects. 311 healthy Italian schoolchildren aged 6.3 to 19.3 years were examined for hypermobility of the joints. Functional ability was assessed through the Childhood Health Assessment Questionnaire (CHAQ) and the physical and psychosocial well-being through the Childhood Health Questionnaire (CHQ). The parent's assessment of the child's overall well-being and of the child's pain was measured on a visual analogue scale. The overall prevalence of articular hypermobility was 34% (106/311), with the median hypermobility score being 3 (interquartile range 1, 5). Although the hypermobility score of girls (median 3: interquartile range 2, 5) exceeded that of boys (median 2.5; interquartile range 0, 5), this difference was not statistically significant (p = 0.16). The level of hypermobile children's pain in the preceding weeks, as assessed by the parents, was comparable to that recorded in the non-hypermobile peers. There was a weak negative correlation between the hypermobility score and the age of the child (r = -0.14, p=0.01). All instrument scores were comparable between hypermobile and non-hypermobile subjects, with the sole exception of a borderline significant greater impairment of the Role/social limitations-physical subscale of the CHQ in the hypermobile group. The hypermobility score was not correlated with any instrument score. The presence of joint hypermobility does not affect the functional ability and the physical and psychosocial well being of otherwise healthy children. These results suggest that the physical functioning in everyday life and the general health status of hypermobile children are not impaired.


Image analysis algorithms for cell contour recognition in budding yeast.
Quantification of protein abundance and subcellular localization dynamics from fluorescence microscopy images is of high contemporary interest in cell and molecular biology. For large-scale studies of cell populations and for time-lapse studies, such quantitative analysis can not be performed effectively without some kind of automated image analysis tool. Here, we present fast algorithms for automatic cell contour recognition in bright field images, optimized to the model organism budding yeast (Saccharomyces cerevisiae). The cell contours can be used to effectively quantify cell morphology parameters as well as protein abundance and subcellular localization from overlaid fluorescence data.


Effective gene delivery of shBMP-9 using polyethyleneimine-based core-shell nanoparticles in an animal model of insulin resistance.
Bone morphogenetic protein (BMP)-9 has been associated with insulin resistance and type 2 diabetes mellitus. However, methods for delivering exogenous BMP-9 genes in vivo are lacking. In this study, we developed a gene delivery system using polyethyleneimine (PEI)-based core-shell nanoparticles (PCNs) as gene delivery carriers, and investigated the effectiveness and safety for delivery of the shBMP-9 gene. PCNs possessed a well-defined core-shell nanostructure with hydrophobic polymer cores and dense PEI shells of uniform particle size and highly positively charged surfaces. In vitro evaluation suggested that PCNs had high loading capacity for exogenous genes and low cytotoxicity toward hepatocytes. The transfection efficiency of PCNs/pENTR-shBMP9 complexes was higher than that of commercial lipofectamine 2000/shBMP9. In vivo studies showed that PCNs/pENTR-shBMP9 transfection led to a significant decrease in hepatic BMP9 expression compared with pENTR-shBMP9 transfection. Under high fat diet (HFD) feeding, PCNs/pENTR-shBMP9 mice exhibited aggravated glucose and insulin tolerance. At a molecular level, PCNs/pENTR-shBMP9 mice displayed elevated PEPCK protein levels and lower levels of InsR and Akt phosphorylation than pENTR-shBMP9 mice. These results suggest that the biological effects of PCNs/pENTR-shBMP9 in vivo are much more effective than those of pENTR-shBMP9. Therefore, the polyethyleneimine (PEI)-based core-shell nanoparticle can be applied as promising nanocarriers for effective and safe gene delivery.


Genetic evidence for a second asparaginase in Aspergillus nidulans.
The apnA1 mutation strongly reduces L-asparagine utilization in Aspergillus nidulans. The ahrA1 mutation, leading to loss of an L-asparaginase (Drainas et al., 1977), eliminates residual L-asparagine utilization in double mutant strains also carrying apnA1. This additivity suggests that A. nidulans, like Saccharomyces cerevisiae (Jones, 1977; Dunlop et al., 1978), has two L-asparaginases specified by apnA and Ahr A, respectively, apnA has been mapped to a position on the left arm of linkage group II, in the sequence adH--acrA--apnA--wA--methA--palcA--(centromere).


In vivo mapping of hemodynamic responses mediated by tubuloglomerular feedback in hypertensive kidneys.
The kidney has a sophisticated vascular structure that performs the unique function of filtering blood and managing blood pressure. Tubuloglomerular feedback is an intra-nephron negative feedback mechanism stabilizing single-nephron blood flow, glomerular filtration rate, and tubular flow rate, which is exhibited as self-sustained oscillations in single-nephron blood flow. We report the application of multi-scale laser speckle imaging to monitor global blood flow changes across the kidney surface (low zoom) and local changes in individual microvessels (high zoom) in normotensive and spontaneously hypertensive rats in vivo. We reveal significant differences in the parameters of TGF-mediated hemodynamics and patterns of synchronization. Furthermore, systemic infusion of a glucagon-like-peptide-1 receptor agonist, a potential renoprotective agent, induces vasodilation in both groups but only alters the magnitude of the TGF in Sprague Dawleys, although the underlying mechanisms remain unclear.


Successive multisite peripheral nerve catheters for treatment of complex regional pain syndrome type I.
Complex regional pain syndrome (CRPS) type I is a painful and disabling syndrome that is accompanied by physical changes in the affected extremity. It generally occurs after trauma, manifesting as pain that is out of proportion to the inciting event. Treatment of the disorder is difficult, with many patients being refractory to multiple pharmacologic regimens. Regional anesthetic techniques, including neuraxial blockade, sympathetic blockade, Bier block, or peripheral nerve catheters, have been used with varying degrees of success. We describe, for the first time, the use of multiple peripheral nerve catheters to treat CRPS type I in a 10-year-old girl when multimodal pharmacologic regimens failed. At separate times, a peripheral nerve catheter was placed to treat CRPS of the distal left lower extremity as well as the right upper extremity. The goal of this therapy was to relieve pain and thereby allow the reinitiation of intensive physical therapy. A continuous infusion of 0.1% ropivacaine was infused via the catheters for ~60 hours. The patient was subsequently able to participate in physical therapy as well as activities of daily living with improved eating, sleeping, and mood. Although many therapeutic modalities have been tried in CRPS type I, given the debilitating nature of the disorder and the variable response to therapy, new and alternative therapeutic interventions, such as continuous peripheral nerve catheters, are needed.


Knockdown of reticulon 4C by lentivirus inhibits human colorectal cancer cell growth.
Colorectal cancer is the third most common type of cancer worldwide with high cell motility and metastatic potential. Reticulon 4C (RTN4-C) is the shortest isoform of the reticulon family protein RTN4, which may act to induce cell apoptosis and suppress tumor development. The aim of the present study was to determine the role of RTN4-C in colorectal cancer, and potentially identify a novel target for anti-tumor therapy. To investigate the biological role of RTN4-C in colorectal cancer, the expression levels of RTN4-C were initially analyzed in six colorectal cancer cell lines by reverse transcription-quantitative polymerase chain reaction and western blot analysis. In addition, lentivirus-based RNA interference was utilized to knock down RTN4-C expression in RKO and DLD-1 cells with low and high levels of RTN4-C, respectively. The rate of proliferation decreased in RTN4-C silenced RKO and DLD-1 cells compared with the control, as determined using MTT and colony formation assays. Flow cytometric analysis revealed that RTN4-C knockdown in RKO cells led to cell cycle arrest at the G0/G1 phase, particularly at the sub-G1 phase representing apoptotic cells. These results indicate that RTN4-C has an important role in colorectal cancer cell growth, which may provide a potential therapeutic approach for human colorectal cancer.


Intense supercontinuum generation exceeding 300eV using a two-color field in combination with a 400-nm few-cycle control pulse.
We propose a method to control the harmonic process by using a two-color field in combination with a 400-nm few-cycle control pulse for the generation of an ultra-broadband supercontinuum with high efficiency. The ionization and acceleration steps in the harmonic process can be simultaneously controlled by using a three-color field synthesized by a 2000-nm driving pulse and two weak 800-nm and 400-nm control pulses. Then an intense supercontinuum covered by the spectral range from 140 eV to 445 eV is produced. The 3D macroscopic propagation is also employed to select the short quantum path of the supercontinuum, then intense isolated sub-100-as pulses with tunable central wavelengths are directly obtained within water window region. In addition, the generation of isolated attosecond pulses in the far field is also investigated. An isolated 52-as pulse can be generated by using a filter centered on axis to select the harmonics in the far field.


Detection of knee unlock during stance by accelerometry.
Detection of knee unlock is a crucial part of finite state artificial reflex control of paraplegic standing supported by functional neuromuscular stimulation (FNS). This paper investigates knee unlock detection schemes using small uniaxial accelerometers mounted on the thigh and shank. Four single and two differential accelerometer configurations were evaluated with respect to knee unlock detection. Their performances were compared to goniometer-based knee unlock detection. Two accelerometers were mounted on the thigh, one just distal to the hip and one just proximal to the knee. The other two accelerometers were mounted on the shank, one just distal to the knee and the other just proximal to the ankle. The sensitive axes of all four accelerometers were directed in the sagittal plane, perpendicular to the long axes of the body segments. The first differential configuration consisted of the two accelerometers on the thigh, the second of the accelerometer on the thigh just proximal to the knee and on the shank just distal to the knee. Detection thresholds were set such that anterior-posterior body sways with locked knees would not yield false knee unlock detections. Experiments were performed in five healthy adult subjects, performing fast and slow knee flexions and anterior-posterior body sways. The first differential accelerometer configuration and the single accelerometer just proximal to the knee gave the earliest detection of fast knee unlocks, earlier than the goniometer-based detection. The second differential accelerometer configuration gave the earliest detection of slow knee unlocks, comparable to the goniometer-based detection. The first differential accelerometer configuration did not provide a reliable detection of slow knee unlocks. The single accelerometer configurations could only detect slow knee unlocks, while rejecting whole body movements, at relatively large knee flexion.


Reevaluation of the utility of mean cell hemoglobin (MCH) screening in infants for iron deficiency.
Iron deficiency (ID) at the stage of latent deficiency (LID) or frank anemia (IDA) is still common in pediatric practice. We have assessed the prevalence of LID and IDA in an infant population with an age range of 9-11 months, in Paris. Red cell indices, hemoglobin level, serum iron, transferrin saturation and serum ferritin levels were assayed. There was considerable prevalence of ID as 82% of the children exhibited low levels in one of the above parameters. We found low mean cell hemoglobin (MCH) to be predictive of LID in one third of cases. Since MCH value is routinely available to the physician, it appears that a close examination of this red cell index should allow for the diagnosis of ID in a large number of children at risk, without the need to resort to more elaborate and expensive laboratory tests.


Phase I/IIa, open-label, multicentre study to evaluate the optimal dosing and safety of ODM-203 in patients with advanced or metastatic solid tumours.
Genetic alterations in fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR) signalling are observed in various tumours. We report a first-in-human phase I/IIa trial evaluating tolerability, pharmacokinetics and preliminary antitumour activity of ODM-203, a novel FGFR and VEGFR inhibitor. Open-label, non-randomised, multicentre, phase I/IIa dose escalation and expansion study in patients with advanced or metastatic solid tumours. Overall, 84 patients received treatment; optimal tablet dose was found to be 400 mg/day with food. All patients experienced at least one adverse event; the majority (89.2%) were grade 1 or 2% and 70.4% were considered treatment related. The most commonly reported events were bilirubin increase-related events (75%) and diarrhoea (50%).Overall response rate was 9.2% and median progression-free survival was 16.1 and 12.4 weeks for patients with aberrant or non-aberrant FGFR tumours. Median time on treatment was 10.1 weeks for all patients and 14.5 weeks for patients who received 400 mg tablets. This study suggests ODM-203 400 mg/day results in sufficient plasma concentrations and acceptable tolerability in most patients. Preliminary signs of therapeutic activity of ODM-203 in patients with solid tumours was observed. NCT02264418.


Endogenous HMGB1 regulates autophagy.
Autophagy clears long-lived proteins and dysfunctional organelles and generates substrates for adenosine triphosphate production during periods of starvation and other types of cellular stress. Here we show that high mobility group box 1 (HMGB1), a chromatin-associated nuclear protein and extracellular damage-associated molecular pattern molecule, is a critical regulator of autophagy. Stimuli that enhance reactive oxygen species promote cytosolic translocation of HMGB1 and thereby enhance autophagic flux. HMGB1 directly interacts with the autophagy protein Beclin1 displacing Bcl-2. Mutation of cysteine 106 (C106), but not the vicinal C23 and C45, of HMGB1 promotes cytosolic localization and sustained autophagy. Pharmacological inhibition of HMGB1 cytoplasmic translocation by agents such as ethyl pyruvate limits starvation-induced autophagy. Moreover, the intramolecular disulfide bridge (C23/45) of HMGB1 is required for binding to Beclin1 and sustaining autophagy. Thus, endogenous HMGB1 is a critical pro-autophagic protein that enhances cell survival and limits programmed apoptotic cell death.


Two-photon absorption properties of two-dimensional π-conjugated chromophores: combined experimental and theoretical study.
The two-photon absorption (TPA) properties of four TPEB [tetrakis(phenylethynyl)benzene] derivatives (TD, para, ortho, and meta) with different donor/acceptor substitution patterns have been investigated experimentally by the femtosecond open-aperture Z-scan method and theoretically by the time-dependent density-functional theory (TDDFT) method. The four compounds show relatively large TPA cross sections, and the all-donor substituted species (TD) displays the largest TPA cross-section σ(2) = 520 ± 30 GM. On the basis of the calculated electronic structure, TD shows no TPA band in the lower energy region of the spectrum because the transition density is concentrated on particular transitions due to the high symmetry of the molecular structure. The centrosymmetric donor-acceptor TPEB para shows excitations resulting from transitions centered on D-π-D and A-π-A moieties, as well as transition between the D-π-D and A-π-A moieties; this accounts for the broad nature of the TPA bands for this compound. Calculations for two noncentrosymmetric TPEBs (ortho and meta) reveal that the diminished TPA intensities of higher-energy bands result from destructive interference between the dipolar and three-state terms. The molecular orbitals (MOs) of the TPEBs are derivable with linear combinations of the MOs of the two crossing BPEB [bis(phenylethynyl)benzene] derivatives. Overall, the characteristics of the experimental spectra are well-described based on the theoretical analysis.


Rapid electronic autofluorography of labeled macromolecules on two-dimensional gels.
The feasibility of electronically locating and measuring tritium-labeled macromolecules directly on dried electrophoretic gels has been demonstrated. This new procedure eliminates the usual long film exposure in autofluorography and the attendant delay in processing and data reduction. An image intensifier and electronic camera tube are used to integrate the light produced by the tritium interaction with a scintillator incorporated in the gel. Preliminary results show that, compared to film, the exposure is reduced 100 to 1000 times. The response to low activity levels is improved, and spatial resolution is maintained. A proposed instrument could be used for measuring other isotopes as well as fluorescent and visible stains.