Ionic currents traverse the slime mould physarum.
Self generated electric currents were studied in protoplasmic drops and small plasmodia of Physarum polycephalum with the aid of an extracellularly measuring vibrating electrode. Ionic currents up to 15 microamperemetercm-2 density were found to traverse the objects. In protoplasmic drops current always enters the numerous protrusions and leaves areas with a smooth surface. In monopodial plasmodia current enters the strand and leaves both the advancing front and the retracting end. This result points toward large changes in membrane arrangement or properties occurring during development of plasmodia from protoplasmic drops.


A standard knockout procedure alters expression of adjacent loci at the translational level.
The Saccharomyces cerevisiae gene deletion collection is widely used for functional gene annotation and genetic interaction analyses. However, the standard G418-resistance cassette used to produce knockout mutants delivers strong regulatory elements into the target genetic loci. To date, its side effects on the expression of neighboring genes have never been systematically assessed. Here, using ribosome profiling data, RT-qPCR, and reporter expression, we investigated perturbations induced by the KanMX module. Our analysis revealed significant alterations in the transcription efficiency of neighboring genes and, more importantly, severe impairment of their mRNA translation, leading to changes in protein abundance. In the 'head-to-head' orientation of the deleted and neighboring genes, knockout often led to a shift of the transcription start site of the latter, introducing new uAUG codon(s) into the expanded 5' untranslated region (5' UTR). In the 'tail-to-tail' arrangement, knockout led to activation of alternative polyadenylation signals in the neighboring gene, thus altering its 3' UTR. These events may explain the so-called neighboring gene effect (NGE), i.e. false genetic interactions of the deleted genes. We estimate that in as much as ∼1/5 of knockout strains the expression of neighboring genes may be substantially (>2-fold) deregulated at the level of translation.


Insights into the mechanism of the interference of sulfadiazine on soil microbial community and function.
The accumulation of sulfonamides in the soil environment possessed the potential to change soil microbial community and function. Metabolomics is capable of providing insights into the carbon metabolic pool and molecular mechanisms associated with external stressors. Here we evaluated alternations in soil bacterial community and soil metabolites profiles under sulfadiazine (SDZ) exposure and proposed a potential mechanism that SDZ accumulation in soil affected soil organic matter (SOM) cycling. Sequencing analysis showed that the relative abundance of bacterial species associated with carbon cycling significantly decreased under high concentrations of SDZ exposure. Untargeted metabolomics analysis showed that 78 metabolites were significantly changed with the presence of SDZ in soil. The combination of functional predictions and pathway analysis both demonstrated that high concentrations of SDZ exposure could cause disturbance in anabolism and catabolism. Moreover, the noticeable decline in the relative content of carbohydrates under high concentrations of SDZ exposure might weaken physical separation and provide more chances for microbes to degrade SOM. The above results provided evidence that SDZ accumulation in soil held the potential to disturb SOM cycling. These findings spread our understanding about the environmental risk of antibiotic in the soil environment beyond the dissemination of antibiotic resistance.


Effects and mechanisms of anionic and nonionic surfactants on biochar removal of chromium.
This work found that the removal of chromium by a straw-derived biochar was significantly promoted or inhibited by various surfactants. For example, the anionic surfactant sodium dodecyl benzene sulfonate (SDBS) inhibited the removal of Cr(VI) by the biochar but significantly promoted the removal of Cr(III) by the biochar. The nonionic surfactant Triton X-100 (TX-100) promoted the removal of Cr(VI) at low concentrations (< 100 mg L-1) but inhibited the removal at high concentrations. Different mechanisms were found for the two surfactants. As an anionic surfactant, surface-sorbed SDBS changed the surface functional groups of the biochar, making the biochar negative charged and changing the sorption ability of the biochar. For the nonionic TX-100, monomers and micelles in the aqueous phase had a major influence on the sorption of chromium due to the impact on the interfacial tension between the biochar and the solution phase as well as the solution pH. The results suggest that when biochar is used to treat heavy metal wastewater containing coexisting surfactants, the type and concentration of surfactants must be considered as important factors. Under certain surfactant conditions, biochar will enable the simultaneous and efficient removal of heavy metals and surfactants.


High throughput FAMS - A fatty acid mass spectrometry method for monitoring polysorbate hydrolysis in QC.
Surfactant degradation in biopharmaceuticals has recently gained significant attention in the pharmaceutical industry. Specifically, hydrolytic degradation of polysorbates, leading to the release of free fatty acids potentially forming visible particles, is a key theme in technical development. To address this emerging topic, we present the development of a fully automated liquid-chromatography single quad mass detector method for the quantification of free fatty acids in biopharmaceuticals. For the first time, we have quantified the longer chain fatty acid degradation products of polysorbate, palmitic and stearic acid, allowing reliable detection and early critical insights for process improvements. This high-throughput method was validated underlining its robust performance in an interlaboratory trial as well as high flexibility allowing different robotic platforms and preparation techniques. The combination of automated sample preparation, separation by liquid chromatography and single quad mass detection makes the validated fatty acid mass spectrometry assay ready for routine use in a regulated environment.


Observations on cytoplasmic transport along ovarian nutritive tubes of polyphagous coleopterans.
The ovarioles of Coccinella and Tenebrio are shown to be telotrophic--a characteristic normally associated with hemipterans rather than coleopterans. The possess an anterior region of trophic cells and a chain of oocytes. The trophic cells are connected with the latter by a series of nutritive tubes, and autoradiography has shown that RNA is transported along the tubes to the oocytes. However, the system in these beetles differs markedly from that of hemipterans in that the nutritive tubes do not contain an extensive complement of aligned microtubules. The significance of this to both the mechanism and the selectivity of transport is discussed.


In vitro recrudescence of Plasmodium falciparum parasites suppressed to dormant state by atovaquone alone and in combination with proguanil.
We studied the viability of Plasmodium falciparum parasites reappearing in long-term cultures after repetitive exposure to atovaquone and proguanil. Parasites (F32 and FCR3) exposed to 100-5000 nM atovaquone for 96 hours were reduced to <5% of initial parasitaemia but recrudesced after 9-15 days. Also, parasites exposed to 1000 nM atovaquone for 48, 72, 96 and 144 hours recrudesced after 9, 14, 21 and 23 days respectively. Immediately after removal of the drug, only 1-3 schizonts per 10000 red blood cells were found consistently, apparently unable to produce trophozoites and thus, possibly, adopting a "dormant state". Parasites (F32 and FCR3) exposed to 500 nM atovaquone for 72 hours reappeared after 14 days. These recrudescing parasites were then re-exposed and suppressed by atovaquone in three consecutive follow-up experiments. They reappeared after 12, 11 and 9 days respectively. No known point mutations in cytochrome b gene (cytb), associated with atovaquone resistance, were detected in any recrudescing parasites. Finally, parasites (F32) exposed to various concentrations of atovaquone and proguanil in combination for 72 hours reappeared after 9-17 days. The baseline susceptibilities of the parasites to individual drugs were similar before and after recrudescence in all experiments.


GABAergic control of basal forebrain cholinergic neurons and memory.
The involvement of the GABAergic innervation of basal forebrain neurons in the rats' conditional visual discrimination performance was examined. Performance in such a task is based on the subjects's ability to retrieve information about response rules, and previous experiments have demonstrated that basal forebrain lesions interfere with this ability. Following the acquisition of the task, chronic guide cannulae were stereotaxically implanted into the substantia innominata of both hemispheres, and the animals were retrained. Administration of the GABAA-agonist muscimol into the substantia innominata (0, 25, 50 ng/0.5 microliters/hemisphere) dose-dependently decreased the number of correct responses, increased the number of errors of omission, increased response latency, but did not affect side bias. Systemic co-administration of the cholinesterase inhibitor physostigmine (0, 0.1, 0.2 mg/kg; i.p.) exclusively interacted with the effects of muscimol on correct responding. Specifically, physostigmine dose-dependently intensified and attenuated the muscimol-induced reduction in correct responding. Although it cannot be excluded that alternative neuronal mechanisms were involved in the mediation of the effects of muscimol and their interaction with physostigmine, these findings support previous evidence indicating that the activity of basal forebrain cholinergic neurons is controlled by a GABAergic input, and that this neuronal link is involved in mnemonic processing.


Evaluation of HER2 protein expression in gastric carcinomas: comparative analysis of 1,414 cases of whole-tissue sections and 595 cases of tissue microarrays.
Recent advances in molecular targeted therapy have identified HER2 as an important target for anti-cancer therapy in gastric cancer (GC). Although the clinical relevance and prognostic significance of HER2 in breast cancer has been well acknowledged, it remains controversial in GC. HER2 expression was investigated in two independent series of GC by immunohistochemical staining. One series corresponded to 1,414 cases of whole-tissue sections and the other corresponded to 595 cases of tissue microarrays (TMAs). Results were compared and correlated with clinicopathologic parameters. HER2-positivity was detected in 12.3% of whole-tissue sections and 17% of TMAs. Among samples scored 3+, 90.1% stained ≥50% of the tumor area, but only 40.9% in score 2+ cases stained ≥50% of the tumor area. In whole-tissue sections, HER2-positivity was correlated with age (P = 0.002), histological type (differentiated or intestinal, P < 0.001), lymphovascular invasion (P = 0.005), and lymph node metastasis (P = 0.009). In TMAs, HER2-positivity was correlated only with age (P = 0.003) and histological type (P < 0.001). Multivariate analyses of the differentiated GC subgroup revealed that HER2-positivity was an independent poor prognostic factor (P = 0.042). The cases with HER2-positive in ≥50% of the tumor area showed worse prognosis than those of <50% (P = 0.021). Despite discrepancies in the results from whole-tissue sections and TMAs, HER2 overexpression was positively correlated with aggressive biological behavior and was an independent poor prognostic factor for recurrence in differentiated GCs. Therefore, HER2-positive GCs should be considered for adjuvant trastuzumab therapy.


Safety of blind liver biopsy.
The aim of the study was to observe the safety of blind liver biopsy in children. One hundred fifteen consecutive liver biopsies in hospitalized children were evaluated retrospectively. Using a standard percussion technique biopsy sites were chosen and through intercostal space blind liver biopsies were performed by TruCut biopsy needle. The first biopsy sample was considered macroscopically adequate in 94.8% of cases. A definitive histological diagnosis was possible in 99.1% of cases. Sixty nine children were more than 5 years of age and of these 8 (11.6%) complained of pain at the biopsy site. External hemorrhage from the biopsy site was seen in 1 (0.9%) case but no sign of internal hemorrhage was detected during the 24 hours follow up period. No child died following the procedure. Blind liver biopsy in the studied hospitalized children was found to be a safe procedure.


Acquired Immune Deficiency Syndrome-Associated Kaposi Sarcoma in a Child Presenting as a Solitary Plantar Hyperkeratotic Plaque.
Acquired immune deficiency syndrome (AIDS)-associated Kaposi sarcoma (KS) among the pediatric population is a rare entity in North America and Europe, and its cutaneous manifestations are not well defined in the literature. The investigators report the case of a boy with an AIDS-associated KS presenting as an infiltrated hyperkeratotic plaque of the plantar arch. An 11-year-old African boy with congenital human immunodeficiency virus (HIV) had a skin biopsy of the plantar lesion that was consistent with a KS. The patient also presented intestinal and pulmonary symptoms; combined chemotherapy regimen and highly active antiretroviral therapy were given in the presence of systemic involvement. AIDS-associated KS poses a particular challenge to clinical diagnosis, since it can manifest with a variety of lesions. Dermatologists should have a low threshold for performing a skin biopsy in patients with HIV.


[Use of plasma- and thrombocytapheresis in patients with stenocardia].
Marked microcirculatory changes, hemorheologic and immunologic disorders were found in anginal patients. Plasmapheresis with repeated thrombocytopheresis sessions as part of combined treatment improves these parameters, the improvement correlating with a stable clinical remission.


Fibrofog in Daily Life: An Examination of Ambulatory Subjective and Objective Cognitive Function in Fibromyalgia.
Perceived cognitive dysfunction in fibromyalgia (FM), "fibrofog," is common. Prior laboratory-based studies have limited our understanding of cognitive function in FM in daily life. The objective of this study was to explore levels of subjective and objective cognitive functioning and the association between subjective and objective aspects of cognition in people with and without FM in the lived environment. Participants (n = 50 adults with FM; n = 50 adults without FM, matched for age, sex, and education) completed baseline measures of subjective and objective cognitive functioning (NIH Toolbox). They also completed ecological momentary assessments of cognitive clarity and speed and tests of processing speed and working memory, via a smart phone app, 5×/day for 8 days. On baseline objective measures, the FM group demonstrated poorer cognitive functioning across 3 NIH Toolbox tests. There were no strong correlations between subjective and objective cognitive functioning in both the FM and control groups. In the lived environment, the FM group demonstrated poorer subjective cognition and objective working memory; groups did not differ on processing speed. Momentary ratings of subjective cognitive dysfunction were significantly related to changes in objective processing speed but not working memory, with no group differences. Findings indicate worse laboratory-based and ambulatory subjective and objective cognitive function for those individuals with FM compared to those without FM. Similar associations between measures of subjective and objective cognitive functioning for the groups suggest that people with FM are not overstating cognitive difficulties. Future research examining contributors to ambulatory fibrofog is warranted.


Utilization of methyltrioctylammonium chloride as new ionic liquid in pretreatment of sugarcane bagasse for production of cellulase by novel thermophilic bacteria.
Fermentation of carbohydrates present in lignocellulosic (LC) biomass is facilitated by lignin removal, which is usually achieved by adopting various pretreatment methods to provide the enzymes proper access to their respective substrates. Pretreatment using ionic liquid (IL) is relatively recent advancement and considered as mild and green process. ILs can dissolve extensive quantities of biomass and depolymerize the cellulose. In this context, an abundantly available LC biomass, sugarcane bagasse (SB), was pretreated using alkali or with an IL, methyltrioctylammonium chloride, and was used for cellulase production from thermophilic bacteria. In all, 26 indigenously isolated thermophilic bacterial strains were quantitatively screened for cellulase production. 16S rDNA sequences of the promising isolates UE10 and UE27 revealed relatedness with Brevibacillus borstelensis, while the strain UE1 belonged to Aneurinibacillus thermoaerophilus. Cellulase production was compared by utilizing alkali pretreated and IL pretreated SB and the later was found more appropriate. UE1, UE10 and UE27 yielded 22.2, 22.18 and 33.3 IU mL-1 of endoglucanase, respectively, by fermenting IL pretreated SB. The changes in SB structure after pretreatment were evaluated by scanning electron microscopy. This study demonstrated the potential of novel thermophilic bacterial strains to utilize IL pretreated SB for production of industrially important enzyme, cellulase.


A novel fluorescent aptasensor based on exonuclease-assisted triple recycling amplification for sensitive and label-free detection of aflatoxin B1.
Aflatoxins are the most toxic type of mycotoxins, which may cause serious carcinogenesis, teratogenesis, and mutagenesis to humans and animals. In this work, we demonstrate a novel label-free fluorescent aptasensor based on exonuclease-assisted triple recycling amplification for the sensitive detection of aflatoxin B1 (AFB1). With the close cooperation of T7 exonuclease and three elaborately designed hairpin probes, the target AFB1 can perform three consecutive cycles of amplification reactions. In this process, each hairpin probe is fully utilized, and the target AFB1, the secondary target and the tertiary target are recycled, thereby achieving a high amplification. Interestingly and importantly, the secondary and tertiary targets generated by amplification are also excellent DNA template sequences for silver nanoclusters (AgNCs). In the presence of NaBH4 and AgNO3, a great number of DNA-AgNCs are synthesized, thereby producing a strong fluorescent signal. Under optimal conditions, the developed aptasensor exhibited high sensitivity to AFB1 with a low detection limit of 0.19 pg mL-1 and a wide dynamic range of 1 × 10-6-1 μg mL-1. In addition, the aptasensor also performed well in the determination of AFB1 in real samples.


Potential for the cross-contamination of the hides of cattle while they are held in lairage.
Foodborne pathogens that may contaminate the carcase are often found on the hides of cattle presented for slaughter for human consumption, and can be transferred from animal to animal during the immediate preslaughter phase. This study quantifies the opportunities for such cross-contamination to occur during lairage of cattle. Cattle were most active in the first 10 minutes of holding, when at 2.5 m(2) or less space allowance per animal there were 12.55 animal-to-animal and 0.99 animal-to-wall contacts per minute, compared with 8.17 and 0.60 per minute, respectively, in the subsequent 20 minutes. During holding, contact between animals can be reduced by manipulating the stocking density. When the animals were given 2.5 m(2) or more each, there were 9.63 animal-to-animal contacts per minute over 30 minutes holding, whereas at 5 m(2) or more, there were only 1.71 contacts per minute. Whatever the space allowance, animal-to-wall contacts were 0.66 to 0.73 per minute over 30 minutes' holding. When space allowance is optimised, contacts with the lairage structure become more important than contacts between animals. The immediate preslaughter handling equipment (race, crush and stun box) was a significant source of potential indirect cross-contamination.


Identification of a novel allele HLA-C*03:560N by next-generation sequencing in a hematopoietic stem cell recipient.
A frameshift because of a single nucleotide deletion results in a novel null allele, HLA-C*03:560N.


Vitamin D and innate and adaptive immunity.
In the last 5 years there has been renewed interest in the health benefits of vitamin D. A central feature of this revival has been new information concerning the nonclassical effects of vitamin D. In particular, studies of the interaction between vitamin D and the immune system have highlighted the importance of localized conversion of precursor 25-hydroxyvitamin D (25OHD) to active 1,25-dihydroxyvitamin D (1,25(OH)(2)D) as a mechanism for maintaining antibacterial activity in humans. The clinical relevance of this has been endorsed by increasing evidence of suboptimal 25OHD status in populations across the globe. Collectively these observations support the hypothesis that vitamin D insufficiency may lead to dysregulation of human immune responses and may therefore be an underlying cause of infectious disease and immune disorders. The current review describes the key mechanisms associated with vitamin D metabolism and signaling for both innate immune (antimicrobial activity and antigen presentation) and adaptive immune (T and B lymphocyte function) responses. These include coordinated actions of the vitamin D-activating enzyme, 1α-hydroxylase (CYP27B1), and the vitamin D receptor (VDR) in mediating intracrine and paracrine actions of vitamin D. Finally, the review will consider the role of immunomodulatory vitamin D in human health, with specific emphasis on infectious and autoimmune disease.


Mechanochemical effects underlying the mechanically activated catalytic hydrogenation of carbon monoxide.
In this work, we highlight and measure the intensity of mechanochemical effects at work in the hydrogenation of carbon monoxide by comparing the activity of a supported Co-Fe catalyst subjected, respectively, to ball milling and simple powder agitation. Paying due regard to the discontinuous nature of ball milling, we show that mechanochemical hydrogenation proceeds at significantly higher rate and disclose its connection with individual impacts. Experimental evidence suggests that the enhanced catalytic activity we observe can be ascribed to local processes affecting the amount of powder that gets involved in individual impacts.


Short-term toxic effects of chlorobenzenes on broadbean (Vicia faba) seedlings.
The root growth, changes in superoxide dismutase (SOD, EC 18.104.22.168) activity, malonyldialdehyde (MDA) and total soluble protein level of broadbean (Vicia faba) seedlings were researched at different soil concentrations of chlorobenzene (CB), 1,2,4-trichlorobenzene (TCB) and hexachlorobenzene (HCB). The results showed that root growth of seedlings was interrupted after 5 d of 50-200 microg x g(-1) TCB treatment. During a 3 d recovery period, root growth was, however, restored to some extent although there was a delay in returning to the control level. The total soluble protein content in seedlings increased with TCB concentration and duration of exposure. Effect of TCB stress on SOD activity in seedlings displayed a significant dose-effect relationship for 1-5 d of 50-200 microg x g(-1) treatment. When broadbean seedlings were placed in clean tap water for 3 d following exposure to 5 d of TCB stress to clear tap water for 3 d, SOD activity at 50 microg x g(-1) TCB recovered towards control level (P>0.05) while a significant increase in SOD activity was observed at 100 and 200 microg x g(-1) TCB compared to control (P<0.05). The experiments also revealed that a significant increase of MDA level in seedlings occurred after 3 and 5 d of 100 and 200 microg x g(-1) TCB treatment (P<0.05 and P<0.01), and there was a positive correlation between TCB concentration and MDA level. All the above results showed that SOD activity and MDA level of broadbean seedlings might be proposed as the biomarkers for short-term TCB contamination in soil. Compared to TCB, the toxicity of 50-1000 microg x g(-1) CB or HCB in soil to broadbean seedlings was not observed after a 3 d exposure.


The DRE/DREF transcriptional regulatory system: a master key for cell proliferation.
The coordinate expression of many cell proliferation-related genes is required for the cellular shift from the resting state into the proliferating state. One regulatory factor involved in this process, the transcription regulatory factor named DREF (DNA replication-related element-binding factor) was discovered in Drosophila and later found to have orthologues in other species including human. Drosophila DREF is a homo-dimer of a polypeptide of 709 amino acid residues, and shares about 22% identity in its amino acid sequence with the human homolog of 694 amino acid residues. The Drosophila DREF homo-dimer binds specifically to the DRE sequence (5'-TATCGATA) in the promoters of many DNA replication/ cell proliferation-related genes to activate their transcription, and the N-terminal region of DREF carries a domain for specific DRE-binding and homo-dimer formation. Ectopic expression of DREF in eye imaginal discs induces abnormal DNA synthesis, apoptosis and failure to differentiate. Conversely, expression of the dominant negative N-terminal region in larval salivary glands reduces endo-replication. Furthermore, RNA interference-mediated knockdown of DREF in vivo demonstrated its requirement for normal progression through the cell cycle and consequently for growth of imaginal discs and the endoreplicating organs. Both Drosophila and human DREF's interact genetically and physically with regulatory factors related to chromatin structures, suggesting that DREF activates the expression of proliferation-related genes through modification of the 3-D conformation of DNA. A search of the Drosophila genome database identified about 150 genes carrying DRE sequences in their promoter regions, many of which are related to reactions required for cell proliferation such as DNA replication, transcriptional regulation, cell cycle regulation, growth signal transduction and protein metabolism. Thus, DREF appears to be a master key-like factor for cell proliferation. Several differentiation-related transcription factors containing homeodomains down-regulate the function or expression of DREF by distinct mechanisms, suggesting a differentiation-coupled repression of cell proliferation via the DRE/DREF system.


Management of medical and health big data based on integrated learning-based health care system: A review and comparative analysis.
We present a Health Care System (HCS) based on integrated learning to achieve high-efficiency and high-precision integration of medical and health big data, and compared it with an internet-based integrated system. The method proposed in this paper adopts the Bagging integrated learning method and the Extreme Learning Machine (ELM) prediction model to obtain a high-precision strong learning model. In order to verify the integration efficiency of the system, we compare it with the Internet-based health big data integration system in terms of integration volume, integration efficiency, and storage space capacity. The HCS based on integrated learning relies on the Internet in terms of integration volume, integration efficiency, and storage space capacity. The amount of integration is proportional to the time and the integration time is between 170-450 ms, which is only half of the comparison system; whereby the storage space capacity reaches 8.3×28TB. The experimental results show that the integrated learning-based HCS integrates medical and health big data with high integration volume and integration efficiency, and has high space storage capacity and concurrent data processing performance.


Towards functionally individualised designed footwear recommendation for overuse injury prevention: a scoping review.
Injury prevention is essential in running due to the risk of overuse injury development. Tailoring running shoes to individual needs may be a promising strategy to reduce this risk. Novel manufacturing processes allow the production of individualised running shoes that incorporate features that meet individual biomechanical and experiential needs. However, specific ways to individualise footwear to reduce injury risk are poorly understood. Therefore, this scoping review provides an overview of (1) footwear design features that have the potential for individualisation; and (2) the literature on the differential responses to footwear design features between selected groups of individuals. These purposes focus exclusively on reducing the risk of overuse injuries. We included studies in the English language on adults that analysed: (1) potential interaction effects between footwear design features and subgroups of runners or covariates (e.g., age, sex) for running-related biomechanical risk factors or injury incidences; (2) footwear comfort perception for a systematically modified footwear design feature. Most of the included articles (n = 107) analysed male runners. Female runners may be more susceptible to footwear-induced changes and overuse injury development; future research should target more heterogonous sampling. Several footwear design features (e.g., midsole characteristics, upper, outsole profile) show potential for individualisation. However, the literature addressing individualised footwear solutions and the potential to reduce biomechanical risk factors is limited. Future studies should leverage more extensive data collections considering relevant covariates and subgroups while systematically modifying isolated footwear design features to inform footwear individualisation.


Artificial intelligence-based detection of epimacular membrane from color fundus photographs.
Epiretinal membrane (ERM) is a common ophthalmological disorder of high prevalence. Its symptoms include metamorphopsia, blurred vision, and decreased visual acuity. Early diagnosis and timely treatment of ERM is crucial to preventing vision loss. Although optical coherence tomography (OCT) is regarded as a de facto standard for ERM diagnosis due to its intuitiveness and high sensitivity, ophthalmoscopic examination or fundus photographs still have the advantages of price and accessibility. Artificial intelligence (AI) has been widely applied in the health care industry for its robust and significant performance in detecting various diseases. In this study, we validated the use of a previously trained deep neural network based-AI model in ERM detection based on color fundus photographs. An independent test set of fundus photographs was labeled by a group of ophthalmologists according to their corresponding OCT images as the gold standard. Then the test set was interpreted by other ophthalmologists and AI model without knowing their OCT results. Compared with manual diagnosis based on fundus photographs alone, the AI model had comparable accuracy (AI model 77.08% vs. integrated manual diagnosis 75.69%, χ2 = 0.038, P = 0.845, McNemar's test), higher sensitivity (75.90% vs. 63.86%, χ2 = 4.500, P = 0.034, McNemar's test), under the cost of lower but reasonable specificity (78.69% vs. 91.80%, χ2 = 6.125, P = 0.013, McNemar's test). Thus our AI model can serve as a possible alternative for manual diagnosis in ERM screening.


Mixed fungal lung infection with Aspergillus fumigatus and Candida albicans in a immunocomprimised patient: case report.
The frequency of invasive, opportunistic mycoses has increased significantly over the past 2 decades. In the immune-compromised host, many fungi, including species of fungi typically considered non-pathogenic, have the potential to cause serious morbidity and mortality. Here we report a rare case of mixed fungal infection of the lung with Candida albicans and Aspergillus fumigatus in a patient on prolonged steroid therapy.


C2CD4A/B variants in the predisposition of lung cancer in the Chinese Han population.
The mRNA levels of C2CD4A and C2CD4B were dysregulation in lung cancer (LC). We aimed to evaluate the role of C2CD4A/B variants in LC susceptibility. There were 710 cases with LC and 710 healthy controls enrolled in the study. The genotyping of twelve variants in C2CD4A/B was carried out by Agena MassARRAY system. Odds ratios (ORs) were calculated by logistic regression analysis to assess the relationship between these variants and LC predisposition. Rs8037894 (OR = 0.81, p = 0.005), rs7172432 (OR = 0.83, p = 0.013), rs11856307 (OR = 0.86, p = 0.043), and rs1436953 (OR = 0.79, p = 0.002) were related to the reduced risk of LC. Besides, the relation of rs7172432 with LC risk in subjects aged > 60 years was observed. Rs4502156 conferred to the increased LC risk, while rs1436953 was associated with the lower susceptibility to LC among males. Rs731820, rs4502156, rs11071657, rs7172432, and rs11856307 contributed to the predisposition of LC among subjects with BMI > 24 kg/m2, while rs7495253 was associated with an increased risk of LC in subjects with BMI ≤ 24 kg/m2. The increased LC risk was found in rs4502156, while the protective risk effect of rs8037894, rs7172432, rs11856307, and rs1436953 on the occurrence of LC was observed in smokers and non-drinkers. Moreover, rs7495253 and rs7495931 had a higher risk of lymphatic metastasis. Rs1436953 was related to the reduced risk of lung adenocarcinoma, while rs4502156, rs8037894, rs7172432, rs11856307, and rs1436953 were related to the risk of small cell carcinoma. Our results first display that C2CD4A/B polymorphisms served as protective factors for LC predisposition in a Chinese Han population. These findings could provide new biological insight into the understanding of C2CD4A/B genes on LC pathogenesis.


Cadmium toxicity and uptake by mats of the freshwater diatom: Navicula pelliculosa (Bréb) Hilse.
Contaminant uptake by algae, and its subsequent toxicity, has important ramifications for aquatic biomonitoring and environmental risk assessment. To study the effects of cadmium on diatom mats, a series of experiments was undertaken. These investigated the sensitivity of Navicula pelliculosa mats to cadmium, uptake of cadmium across a range of exposure concentrations, influence of mat biomass and thickness on uptake, and cadmium uptake by mats over time. Diatom mat formation proved to be sensitive to cadmium exposure, with a 96-h EC(50) of 31 microg/L. The rapid uptake of cadmium over 15 min was a linear function of exposure concentration and was not significantly affected by mat thickness. Cadmium uptake over time was also a linear function of exposure concentration for time periods up to 5 h. Linear uptake was likely due to the availability of algal binding sites as cadmium ions diffused through the diatom mats. Internal high-pH microenvironments may also have influenced uptake, through cadmium precipitation or enhanced adsorption within the mats. The lack of a significant relationship between mat biomass and uptake could be explained by the static water exposure conditions. Other studies have shown that cadmium uptake by algal mats was only significantly affected by biomass under flowing water conditions. Flowing water appeared to facilitate the diffusion of cadmium ions through the algal mats. Our research demonstrates the propensity of diatom mats to adsorb cadmium to achieve concentrations that could inhibit macroinvertebrate grazing. Overall, these findings contribute to a greater understanding of cadmium bioavailability in aquatic ecosystems and to the further development of benthic algae as an effective biomonitoring tool.


Neuro-ophthalmic manifestations of cerebellar disease.
The cerebellum is responsible for refining ocular movements, thereby guaranteeing the best possible visual acuity and clarity despite changes in body or head positions or movement of the object of interest. The cerebellum is involved in the control of all eye movements, in their real-time, immediate modulation, and in their long-term adaptive calibration. The flocculus-paraflocculus complex and the caudal vermis (nodulus and uvula) together constitute the vestibulocerebellum. Lesions affecting these different regions give rise to 3 principal clinical cerebellar syndromes. This article discusses the various neuro-ophthalmic manifestations of various cerebellar disorders, as well as some therapeutic options for oscillopsia.


Lymphatic absorption of nonvolatile oxidation products of heated oils in the rat.
The lymphatic absorption of nonvolatile oxidation products (NVOP) formed during heating of fats was studied. Heated colza or soybean oils or synthetic triglycerides containing a definite aromatic or alicyclic fatty acid were fed to thoracic duct-cannulated rats. Tritium-labeled triolein was added to each dietary fat, as an internal standard, in order to calculate the percentage of lymphatic absorption of the ingested NVOP. Results show that 4% of the total polymeric acids, 53% of the total oxidized monomeric acids and 96% of the total cyclic monomeric acids were recovered in the lymphatic lipids. Gas liquid and quantitative thin layer chromatography of these 3 classes indicated that, within a NVOP class, the various constituents did not present the same absorption rate. The lymphatic absorptions of individual oxidized monomers were between 25 and 93%. Concerning the polymer fraction, the lymphatic recoveries were 1% (nonpolar dimers), 6.8% (polar dimers) and 12% (polar oligomers). Aromatic acids were absorbed to a lesser degree (50-60%) than cyclohexenic acids (91-98%).


Phenotypic variability in RDH5 retinopathy (Fundus Albipunctatus).
To describe phenotypic variability and report novel mutational data in patients with mutation in RDH5 (fundus albipunctatus). Retrospective case series. Nine patients from 8 families (aged 7-55 years) with night blindness and electrophysiologic or fundoscopic findings in keeping with RDH5 mutation were ascertained. Detailed ophthalmologic examination, fundus photography, fundus autofluorescence imaging, spectral domain optical coherence tomography (SD-OCT), and electrophysiologic assessment were performed. The coding region and intron-exon boundaries of RDH5 were analyzed. RDH5 mutation status and resultant clinical and functional characteristics. Eleven mutations in RDH5 were detected in the 8 families in the study, with 9 of these changes being novel. Visual acuity was normal in all but 1 eye of a patient with adult-onset central visual loss. Most patients had white dots extending into the mid-periphery on fundus examination, consistent with fundus albipunctatus, but 1 patient had normal fundi. Autofluorescence imaging revealed an association between the white dots and the hyperautofluorescent foci in younger subjects. The overall autofluorescence signal appeared low in all patients. The SD-OCT changes included deposits associated with the white dots that extended from Bruch's membrane to the external limiting membrane and focal loss of outer segments. Full-field electroretinogram (ERG) performed after standard dark adaptation showed moderate to severe generalized rod system dysfunction. Dim flash rod system ERGs were undetectable (N = 3) or subnormal (N = 6), but normalized after prolonged dark adaptation in 7 cases. Scotopic bright flash ERGs contained a reduced b:a ratio ("negative" ERG) in most cases; the use of a red stimulus under dark adaptation and extended recordings in the dark-adapted state in 1 patient identified dark-adapted cones as the probable source of the ERG signals. Photopic responses were abnormal in 6 of 9 cases. The clinical and electrophysiologic phenotype of patients with RDH5 retinopathy is variable. Mutations in RDH5 lead to reduced autofluorescence signal possibly because of absence of retinoid-derived fluorophores. The dark-adapted bright flash ERG is often electronegative and likely a manifestation of the dark-adapted cone system exposed in the absence of normal rod function. The author(s) have no proprietary or commercial interest in any materials discussed in this article.


About 13% of women may have the wrong method of oocyte insemination when undergoing in vitro fertilization by failure to evaluate the abnormal hypo-osmotic swelling test score.
To determine the percentage of males with a low hypoosmotic swelling (HOS) test score in couples having in vitro fertilization-embryo transfer (IVF-ET) where the male partner had normal motile densities and no antisperm antibodies. The results were also analyzed according to the percentage of HOS scores < 50% when morphology using strict criteria was < or = 4% or > 4%. A retrospective review was performed. There were 250 subnormal HOS scores out of 1993 otherwise normal semen specimens. 12.5% of couples would have had conventional oocyte inseminations rather than ICSI if the HOS test had not been not performed (it is rarely performed by other IVF centers). Without ICSI expected live delivered pregnancy rates would be close to zero for males with low HOS tests < 50%. Intracytoplasmic sperm injection allows pregnancy rates almost as good as completely normal sperm.


Titanium basal joint arthroplasty: a finite element analysis and clinical study.
To define the mechanics and determine the clinical outcome of titanium implant arthroplasty in trapeziometacarpal arthritis. For the finite element analysis (FEA) a 2-dimensional FEA mesh of the titanium arthroplasty was constructed with 8-node quadrilateral elements and analyzed. Flexion-extension displacement of the metacarpal was analyzed. For the clinical study, between 1996 and 2003, 47 patients (50 thumbs) with Eaton stage 3 trapeziometacarpal arthritis were treated with titanium basal joint arthroplasty. The average follow-up period was 2 years. Disabilities of the Arm, Shoulder, and Hand questionnaire answers and grip and pinch measurements were obtained before surgery and at the final follow-up evaluation. Failure was defined strictly as the point when revision to the standard soft-tissue interposition arthroplasty became inevitable. In the FEA the titanium implant showed pistoning behavior with maximum stress concentration in the midmetacarpal shaft of 1.92 MPa. The convex sphere of the implant rotates and lifts out of the trapezial crater with a high stress concentration of 0.51 MPa at the radial and ulnar corner of the trapezium. In the clinical study treatment failed in 10 of the patients before 9 months. All were converted successfully to a standard ligament reconstruction tendon interposition. The remaining 80% of the patients showed significant improvement in Disabilities of the Arm, Shoulder, and Hand questionnaire scores albeit with continued weakness at the 2-year follow-up evaluations. The reconstructed thumbs never attained the strength of the contralateral thumbs; even in the success group residual swelling was not uncommon with any increase in activity level. Anecdotal quotations show success rates for titanium implant arthroplasty for basal joint arthritis to be as high as 97%. Our results are quite to the contrary in that high failure rates were common early in the follow-up period. Our FEA results are confirmed by the clinical study. Titanium implant arthroplasty may have a role in low-demand patients with good bone stock; however, we have stopped offering titanium hemiarthroplasty to patients at our institution.


[Estimation of the dialysis time based on a simplified algorithm for urea kinetics].
A simplified method of calculating the dialysis time based upon urea kinetic modeling equation: Ct = C0 e exp - (Kt/V) is presented together with a table of urea clearance values for most commonly used dialyzers. The method is handy and helpful to prescribe dialysis time either in chronic uraemics or in patients with acute renal failure on hemodialysis. Estimation of a patient's urea distribution volume equal to the total body water and blood flow through the dialyzer are the key points in the described calculations.


The effects of various fluoride concentrations on new bone formation in intramuscular implants of bone matrix in mice.
The efficacy of fluoride therapy of osteoporosis remains a controversial issue, specially in clinical trials. The effect of fluoride on heterotopic bone formation in mice was analyzed with respect to the dose of the drug administered. Thirty days after implantation of demineralized bone matrix, the ash weight and mineral content of implants from animals receiving the highest dose of fluoride was approximately 49% lower than that of the controls. Thirty days of fluoride administration had no effect on blood composition. On the other hand, small concentrations of fluoride ions increased the dry and ash weight of implants (36%) and promoted bone mineralization. The results derived from this study may be directly applicable to the treatment of osteoporosis with fluoride and support our clinical trials.


Mandibular invasion by oral squamous cell carcinoma. Clinical aspects.
In this paper we have tried to correlate the clinical and radiological aspects to the histological findings in squamous cell carcinomas of the oral cavity, in relation to bone involvement in the mandible. 52 patients were analyzed and we conclude that there is a positive indication for mandible sparing surgery, even if there is fixation to the jaw or radiologically visible bone involvement.


Serum carcinoembryonic antigen level is associated with epidermal growth factor receptor mutations in recurrent lung adenocarcinomas.
The presence of epidermal growth factor receptor (EGFR) gene mutations is a good indicator of the clinical efficacy of gefitinib in patients with nonsmall cell lung cancer. It was recently reported that the serum carcinoembryonic antigen (CEA) level could be a predictive factor for the efficacy of gefitinib treatment; therefore, it is suggested that the EGFR gene mutation is associated with the serum CEA level. The current study analyzed the association between EGFR gene mutations and clinical features, including the serum CEA level, in patients with recurrent lung adenocarcinomas. A total of 48 lung adenocarcinoma patients with postoperative disease recurrence who underwent chemotherapy were investigated. EGFR gene mutations at exons 18, 19, and 21 were measured using surgical specimens taken from the primary tumor. Mutations of the EGFR gene were detected in 25 of the 48 patients and the abnormal serum CEA concentration at the time of disease recurrence was found to be significantly associated with the incidence of EGFR gene mutations (P = .045). The rate of EGFR gene mutations significantly increased as the serum CEA level increased (serum CEA level; <5 vs > or =5 <20 vs > or =20 = 35% vs 55% vs 87.5%, respectively, P = .040). A multivariate analysis revealed that a higher serum CEA level at the time of disease recurrence is independently associated with EGFR gene mutations (P = .036) with an odds ratio of 4.70 (95% confidence interval, 1.1-21.1). The serum CEA level appears to be closely associated with the presence of EGFR gene mutations in patients with pulmonary adenocarcinomas.


Pediatric patients' reasons for visiting dentists in all WHO regions.
Oral Function, Orofacial Pain, Orofacial Appearance, and Psychosocial Impact are the four oral health-related quality of life (OHRQoL) dimensions (4D) or areas in which oral disorders impact pediatric patients. Using their dentists' assessment, the study aimed to evaluate whether pediatric dental patients' oral health concerns fit into the 4D of the Oral Health-Related Quality of Life (OHRQoL) construct. Dentists who treat children from 32 countries and all WHO regions were selected from a web-based survey of 1580 international dentists. Dentists were asked if their pediatric patients with current or future oral health concerns fit into the 4D of the Oral Health-Related Quality of Life (OHRQoL) construct. Proportions of all pediatric patients' oral health problems and prevention needs were computed. Data from 101 dentists treating children only and 523 dentists treating children and adults were included. For 90% of pediatric patients, their current oral health problems fit well in the four OHRQoL dimensions. For 91% of oral health problems they intended to prevent in the future were related to these dimensions as well. Both numbers increased to at least 96% when experts analyzed dentists´ explanations of why some oral health problems would not fit these four categories. The study revealed the four fundamental components of dental patients, i.e., the four OHRQoL dimensions (Oral Function, Orofacial Pain, Orofacial Appearance, and Psychosocial Impact) are also applicable for pediatric patients, regardless of whether they have current or future oral health concerns, and should be considered when measuring OHRQoL in the pediatric dental patient population.


Gender differences in animal cognition science.
Women's representation in science is increasing steadily, with some fields closing gender parity in terms of participation and scientific output. Animal cognition appears to fall into that category. Our current analysis of gender author balance (women versus men) in 600 animal cognition papers supported parity in many aspects, but also revealed some remaining disparities. Women animal cognition scientists often held first authorship positions (58% of the studies), received similar numbers of citations, and published in equally high impact factor journals as men. Women were still under represented in last-author position, which often reflects seniority status (37% of last authors were women). There were interesting results when we considered the gender of teams (of two or more authors): all-women author teams were the minority in our dataset and received on average fewer citations than all men or mixed author teams, regardless of the quality of the journal (as measured by the journal's impact factor). Women more often focussed on mammals, whereas men more often focussed on fish, both as first authors and as same-gender teams. Men, as first author or in men-only teams, restricted their research more often to organisms of a single sex, compared to women, as first author and as members of a team. Our study suggests that there are many indices of the significant contribution of both women and men scientists in animal cognition, although some gender biases may remain.


No evidence for genetic association between DARPP-32 (PP1R1B) polymorphisms and attention deficit hyperactivity disorder.
Attention deficit hyperactivity disorder (ADHD) has a strong genetic basis, and evidence from human and animal studies suggests that a dopamine system dysfunction plays a role in the disorder pathophysiology. Several genes involved in dopamine neurotransmission have shown replicated genetic association with ADHD. These include the dopamine receptors D4 (DRD4), D5 (DRD5), and the dopamine transporter (DAT1) genes. Recently, evidence has also accumulated in favor of the dopamine receptor D1 gene (DRD1). The dopamine- and cAMP-regulated phosphoprotein of relative molecular mass of 32 kDa (DARPP-32) is a key component of dopamine signaling, acting as a converging point for several neurotransmitter systems influencing dopaminergic neurons and regulating a wide variety of downstream effectors. Here, we tested the DARPP-32 gene, PPP1R1B, for association with ADHD using four polymorphic markers selected across the gene in a sample of 255 ADHD families. We did not detect evidence of association of individual marker alleles and haplotype analysis did not reveal significant association in this sample of families. Moreover, we found no relationship between the same alleles or haplotypes and symptom scores of inattention or hyperactivity/impulsivity in these families using a quantitative approach. In conclusion, albeit a key regulatory role in dopamine signaling, our data do not support a major contribution of the DARPP-32 gene in ADHD.


In vitro transformation assays for chemical carcinogens.
A variety of in vitro mammalian cell assays, designed specifically for the identification of carcinogenic compounds, have been in operation for more than a decade. Although no individual transformation system has won universal acceptance during this time, recent advances have led to the improved reliability and sensitivity of a number of these short-term tests. The underlying problems associated with the most widely used assays are identified and new developments in this rapidly expanding field are noted and discussed.


Site-directed mutation makes rabbit calcyclin dimer.
Unlike human, rat and mouse calcyclin, purified rabbit calcyclin did not form a dimer on Tricine SDS-PAGE under non-reduced conditions. Based on the internal peptide sequence of rabbit calcylin, we isolated and sequenced a cDNA clone encoding calcyclin. The sequence of this clone (pCalC) is 629 bp long and codes 90 amino acid residues of a protein with a molecular mass of 10,153 Da. By Northern blot analysis, a major band of 0.9 kbp and a minor band of 2.6 kbp were detected in the lung. The recombinant calcyclin mutated serine at the third position to cysteine was expressed in E. coli and made dimer formation under non-reduced conditions on SDS-PAGE. Whether or not this type of mutation which prevents dimer formation of calcyclin plays a physiological role in the rabbit lung is the subject of an ongoing study.


Creating Effective Models for Delivering Palliative Care in Advanced Liver Disease.
The current healthcare system is not fully equipped to provide comprehensive support for patients with advanced liver disease (ALD) and their caregivers resulting in concomitant suffering and reduced quality of life (QoL). Integration of palliative care (PC) within routine care has demonstrated benefits in improving symptoms and QoL and reducing healthcare utilization for other serious illnesses but has been underutilized or delayed for ALD care. The purpose of this article is to outline the domains and benefits of PC and discuss the misconceptions and barriers for PC integration, and healthcare delivery models supporting PC integration within ALD care. PC has eight key domains related to physical and mental health, goals for future care, and care of the caregivers. PC offers benefits to improve health outcomes and patient satisfaction and reduce healthcare utilization. To date there have been successful models of PC that are primarily hospital- or community-based; successful models have been PC specialist- or primary/generalist-led. Concurrent PC within oncology has formed the basis for most evidence-based guidelines. PC integration within ALD care is still in its infancy. While amassing evidence in ALD, hepatology organizations can promote consensus-based integrated PC models that can guide research and practice efforts to increase supportive care for these patients in need and their family caregivers.


Turning down the heat: new routes to inhibition of inflammatory signaling by prostaglandin H2 synthases.
Many nonsteroidal anti-inflammatory drugs act by inhibiting the cyclooxygenase activity of prostaglandin H2 synthase (PGHS), a key enzyme in the biosynthesis of prostaglandins. Gastric toxicity remains a serious problem with the current drugs, however. Recent advances in the understanding of PGHS now suggest two possible approaches to producing drugs with fewer side effects.


Plasmid-like properties of the four virulence-associated factors of Yersinia pestis.
The virulence-associated factors of Yersinia pestis, which determine the abilities to produce pesticin I (Pst+), capsular fraction I antigen (Fra+), V and W antigen complex (Vwa+) and a cell-surface component for adsorption of exogenous pigments (Pgm+), were independently eliminated by cultivation of the cells in the presence of acridine orange, ethidium bromide or sodium dodecyl sulfate at a subinhibitory concentration. A virulent Y. pestis strain, Yreka, harbored at least five extrachromosomal DNA molecules of different sizes. In these molecules, a novel 13-megadalton DNA which was cured concomitantly with the elimination of the Fra factor was found, in addition to the known species of 7 and 44 megadaltons which were lost with the conversions to Pst- and Vwa-, respectively. Although the conversion to Pgm- could not be correlated with the lack of any proper extra-chromosomal DNA, the factor was transmitted to Pgm- cells with the aid of self-conjugative RP4 plasmid. The cells acquiring the Pgm factor regained virulence for mice.


A historical review and bibliometric analysis of research on fracture nonunion in the last three decades.
Nonunion continues to be the most frequent and challenging complication to treat following fracture fixation. Herein, we carried out a bibliometric analysis aiming to identify the key researchers, centres and research trends developed during the past 30 years in this important clinical condition. The Science Citation Index Expanded database and the Web of Science Core Collection were interrogated for manuscripts published between 1990 and 2019 in the topic domain, utilising title, abstract, author keywords and KeyWords Plus. Overall, such citation indicators were used as TCyear, Cyear and CPPyear to help analyse the identified manuscripts. Over the prespecified period, there was a steady increase in the number of articles published in fracture nonunion. In total, 12 languages were the primary languages in the documents, with English being the most prevalent. The CPP sharply increased to reach a plateau in three full years and up to a peak in ten full years. A total of 8976 nonunion-related articles in Science Citation Index Expanded (SCI-EXPANDED) were published in 790 journals. The 8976 articles were published by 26,079 authors among 101 different countries. There is a slightly fluctuating steady increase of articles from 116 in 1991 to 201 in 2003, and thereafter, the number of articles sharply increased to reach a plateau in 2015. Seven possible main research foci in nonunion-related research were identified including: epidemiology, classification, aetiology, diagnosis/prediction, treatment modalities, functional outcomes and health economics. This bibliometric analysis revealed information on citation number, publication outputs, categories, journals, institutions, countries, research highlights and tendencies. The current research activity on fracture nonunion identified key opinion leaders and leading research institutions focusing on this important clinical condition. It is hoped that the informed included will aid to guide research work in the foreseeable future.


D-[3H]galactose incorporation into glycogen in retinal cone cells.
Previous studies have shown that bovine retinas incubated with [3H]galactose incorporated it, unmodified, into large molecules. Light and electron microscope autoradiography showed a significant proportion of the label to be in cone inner segments, and pulse-chase studies showed it was subsequently transported to the synaptic pedicles. In this report, evidence is presented to show that the galactose-labelled macromolecules are resistant to hydrolysis by proteolytic enzymes, testicular hyaluronidase, chondroitinase ABC, beta-glucosidase and beta-glucuronidase, but are readily degraded by alpha-amylase and beta-galactosidase, and to a lesser extent by beta-amylase. Treatment with alpha-amylase also leads to specific removal of radioactivity from cone inner segments and pedicles, as judged by light-microscopic autoradiography. These studies appear to indicate that the cone-specific galactose label is in glycogen or glycogen-like molecules.


Cooperative inhibitory effect of n,n,n-trimethylsphingosine and sphingosine-1-phosphate, co-incorporated in liposomes, on b16 melanoma cell metastasis - cell-membrane signaling as a target in cancer-therapy .4.
Two N-methylated derivatives of sphingosine (Sph), N,N-dimethyl-Sph (DMS) and N,N,N-trimethyl-Sph (TMS), have been shown to stereospecifically inhibit activity of protein kinase C and other kinases essential for active proliferation of tumor cells, as well as for activation of platelets and endothelial cells (ECs). DMS and TMS thereby inhibit tumor growth in vivo, and TMS inhibits in vivo metastatic potential of B16 melanoma cells. When TMS was administered in liposomes, its drug efficacy was increased and its undesirable side-effects were greatly reduced (Park YS, er al, Cancer Res 54: 2213, 1994). Sph-1-P, long known as the initial catabolite of Sph metabolism, has aroused considerable interest recently because of its inhibitory effect on cell motility (Sadahira Y, et al, Proc Natl Acad Sci USA 89: 9686, 1992). We now report that liposomes containing both TMS and Sph-1-P, in comparison to liposomes containing TMS or Sph-1-P alone, exert a much stronger inhibitory effect on B16 melanoma cell metastasis. This is ascribable to their inhibitory effect on tumor cell invasiveness through motility inhibition, in conjunction with the previously-observed inhibitory effect of TMS on activation of platelets and ECs. Furthermore, the liposomal formulation resulted in prolonged circulation time of both TMS and Sph-1-P in blood, and consequent higher concentration of these compounds in tumor tissues.


Normative database of donor keratographic readings in an eye-bank setting.
To generate a normative donor topographic database from rasterstereography images of whole globes acquired in an eye-bank setting with minimal manipulation or handling. Eye-bank laboratory. In a retrospective study, rasterstereography topographic images that had been prospectively collected in duplicate of donor eyes received by the Central Ohio Lions Eye Bank between 1997 and 1999 were analyzed. Best-fit sphere (BFS) and simulated keratometry (K) values were extracted. These values were recalculated after application of custom software to correct any tilt of the mapped surfaces relative to the image plane. The mean value variances between right eyes and left eyes, between consecutive scans, and after untilting were analyzed by repeated-measures analysis of variance and t tests (P<or=.05). A keratographic database of 556 pair-matched right and left eyes was generated. Normal distributions were observed in frequency histograms of each value (P>.05, Kolmogorov-Smirnov). There was no difference between right and left eyes or consecutive scans (P>.05). The mean values changed when the images were tilt-corrected (P<.05). The right eye BFS, Kflat, and Ksteep values of 42.03 diopters (D) +/- 1.88 (SD), 42.21 +/- 2.10 D, and 43.82 +/- 2.00 D, respectively, increased to 42.52 +/- 1.73 D, 43.05 +/- 1.99 D, and 44.57 +/- 2.02 D, respectively, after tilt correction. Keratometric parameter frequency distributions from the donor database of tilt-corrected data were normal in distribution and comparable to parameters reported for normal eyes in a living population. These findings show the feasibility and reliability of routine donor-eye topography by rasterstereography. No author has a financial or proprietary interest in any material or method mentioned. Additional disclosures are found in the footnotes.


Eye movement-related brain potentials during assisted navigation in real-world environments.
Conducting neuroscience research in the real-world remains challenging because of movement- and environment-related artifacts as well as missing control over stimulus presentation. The present study overcame these restrictions by mobile electroencephalography (EEG) and data-driven analysis approaches during a real-world navigation task. During assisted navigation through an unfamiliar city environment, participants received either standard or landmark-based auditory navigation instructions. EEG data were recorded continuously during navigation. Saccade- and blink-events as well as gait-related EEG activity were extracted from sensor level data. Brain activity associated with the navigation task was identified by subsequent source-based cleaning of non-brain activity and unfolding of overlapping event-related potentials. When navigators received landmark-based instructions compared to those receiving standard navigation instructions, the blink-related brain potentials during navigation revealed higher amplitudes at fronto-central leads in a time window starting at 300 ms after blinks, which was accompanied by improved spatial knowledge acquisition tested in follow-up spatial tasks. Replicating improved spatial knowledge acquisition from previous experiments, the present study revealed eye movement-related brain potentials to point to the involvement of higher cognitive processes and increased processing of incoming information during periods of landmark-based instructions. The study revealed neuronal correlates underlying visuospatial information processing during assisted navigation in the real-world providing a new analysis approach for neuroscientific research in freely moving participants in uncontrollable real-world environments.


Outcomes of semiconstrained total elbow arthroplasty performed for arthritis in patients under 55 years old.
Total elbow arthroplasty (TEA) is a treatment option for end-stage arthritis. Even though results are satisfactory for the elderly population, TEA surgery is subject to controversy in younger patients. The purpose of this study was to evaluate clinical and radiographic outcomes of semiconstrained TEA performed for arthritis in patients younger than 55 years. Between 1998 and 2008, 19 TEAs were implanted in 17 patients younger than 55 years (mean age, 46 years; range, 29-54 years). We assessed the indication for further surgery; range of motion; mean Mayo Elbow Performance Score; QuickDASH (short version of the Disabilities of the Arm, Shoulder and Hand questionnaire) score; radiolucent lines; and outcome measures that included implant survival, complications, and revisions. The average follow-up period was 10 years (range, 2-16 years). Average range of motion significantly improved, from 120° (range, 90°-140°) to 140° (range, 130°-155°) for flexion and from 40° (range, 0°-60°) to 25° (range, 0°-90°) for extension. The average Mayo Elbow Performance Score was 85 (range, 55-100). During the study period, 11 elbows (58%) experienced complications and 8 (42%) underwent revision. Aseptic loosening (3 ulnar and 2 bipolar) was the main indication for revision. The survivorship rate without revision was 94% at 5 years and 75% at 10 years. TEA gave satisfactory results in a younger patient population. However, a high rate of complications and revisions was observed with follow-up. Thus, TEA should be considered with caution in young patients, and other therapeutic options must be discussed.


Study of the differentially expressed genes in pleomorphic adenoma using cDNA microarrays.
Recent studies have determined that gene expression profiling using microarray technology can be used to identify tumor-related molecules. The objective of this study was to screen the differentially expressed genes between pleomorphic adenoma (PA) and the normal tissue adjacent to PA using cDNA microarrays and to further validate the differentially expressed genes by real-time PCR. In this study, we selected five pairs of PA and the surrounding normal salivary gland tissues. The total RNA was isolated from tumor and normal tissues and purified to mRNA. The mRNA was reverse-transcribed to cDNA with the incorporation of fluorescent-labeled dUTP to prepare the hybridization probes. The mixed probes were hybridized to Whole Human Gene Expression Microarrays by Agilent. Tumor-related genes were screened by analyzing the fluorescence intensity. As a result, a total of 447 genes were found to be differentially expressed between PA and normal tissue adjacent to PA. Among them, 185 genes were up-regulated and 262 genes were down-regulated in PA. By constructing a network from the differentially expressed genes, some genes, such as Gli2 and CTNNB1, were identified as being at the core of the network. In addition, differential gene expression was validated for 2 up-regulated genes, Gli2 and LOX, using real-time PCR and the results were consistent with those of the cDNA microarray analysis thus verifying the credibility of the microarray data. Therefore, our microarray data may provide clues for finding novel genes involved in the development of PA, and shed light on finding new targets for diagnosis and therapy of PA. Further characterization of these differentially expressed genes will be useful in understanding the genetic basis for PA.


Autoradiographic demonstration of an increase in muscarinic cholinergic receptors in cerebellar granule cells treated with tetrahydroaminoacridine.
The neurotrophic and neurosurviving effects of 9-amino-1,2,3,4-tetrahydroacridine (THA), a putative antidementia agent, were studied in cultured granule cells using biochemical and morphological methods. The addition of 30 microM THA to cultures grown in 15 mM K(+)-containing media markedly increased cell survival and enhanced [3H]N-methylscopolamine binding to muscarinic cholinergic receptors (mAChRs). Furthermore, receptor autoradiographic studies revealed that neuronal cells were labelled over both cell bodies and fibers by the [3H]receptor ligand. These observations provide direct evidence that THA promotes the expression of mAChR binding sites in differentiating cerebellar granule cells.


Surface-assisted laser desorption/ionization-mass spectrometry using TiO2-coated steel targets for the analysis of small molecules.
Matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) measurements in the low-molecular-mass region, ranging from 0 to 1000 Daltons are very often difficult to perform because of signal interferences originating from matrix ions. In order to overcome this problem, a stainless steel target was coated with a homogeneous titanium dioxide layer. The layer obtained was further investigated for its ability to desorb small molecules, e.g., amino acids, sugars, poly(ethylene glycol) (PEG) 200, or extracts from Cynara scolymus leaves. The stability of the layer was determined by repeated measurements on the same target location, which was monitored by X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM) before and after surface-assisted laser desorption/ionization (SALDI) analysis. In addition, this titanium dioxide layer was compared with an already published method with titanium dioxide nanopowder as inorganic matrix. As a result of this work, the titanium dioxide layer produced minimal background interference, enabling simple interpretation of the detected mass spectra. Furthermore, the TiO(2) coating provides a target that can be reused many times for SALDI-MS measurements.


Distribution of the various radiation-induced chromosomal rearrangements in relation to the dose and sampling time.
The quantitative analysis of the chromosome rearrangements detected in 2128 R-banded metaphases, obtained from gamma-irradiated human lymphocytes after 48 to 96 h in culture is reported. Depending on the culture time, and possibly on the dose of radiation (from 1 to 3 Gy), the most frequent type of rearrangement was either dicentrics or reciprocal translocations. In first generation mitoses, the frequency of cells without rearrangement ranged from 0.66 to 0.18, and the mean number of rearranged chromosomes per cell from 0.79 to 3.28. The dose-response curve follows a quadratic function for dicentric aberration yields, but not for other rearrangements.


Lung involvement in rheumatologic diseases in children.
Lung involvement in rheumatologic disease in children has been described with low frequency. To describe the lung function test and the radiological findings in a group of paediatric patients with rheumatologic diseases. Descriptive study. Pulmonary function was evaluated with spirometry, carbon monoxide diffusing capacity, blood arterial gas at rest and post exercise in addition to chest radiography and high resolution computed tomography were performed in children with rheumatologic disease. Of the fourteen patients studied: 11 were diagnosed with juvenile idiopathic arthritis (JIA), two with systemic lupus erythematosus (SLE), and one with juvenile dermatomyositis (JDM). Mean age: 13 years (range 7-18 years). Nine females, duration of disease 4 ± 2.8 years (range 1-11 years). Four patients had any grade of abnormalities in one or more lung function tests and/or radiological test. We recommend routine checks of pulmonary function in all patients with rheumatologic diseases even in the absence of respiratory symptoms.


Exposure to the Endocrine Disruptor Bisphenol A Alters Susceptibility for Mammary Cancer.
Bisphenol A (BPA) is a synthetically made chemical used in the production of polycarbonate plastics and epoxy resins. Recent studies have shown over ninety percent of humans investigated have detectable BPA concentrations. Yet, the biggest concern for BPA is exposure during early development because BPA has been shown to bind to the estrogen receptors (ER) and cause developmental and reproductive toxicity. We have investigated the potential of perinatal BPA to alter susceptibility for chemically-induced mammary cancer in rats. We demonstrate that prepubertal exposure to low concentrations of orally administered BPA given to lactating dams resulted in a significantly decreased tumor latency and increased tumor multiplicity in the dimethylbenz[a]anthracene (DMBA) model of rodent mammary carcinogenesis. Our data suggested that the mechanism of action behind this carcinogenic response was mediated through increased cell proliferation, decreased apoptosis, and centered on an up-regulation of steroid receptor coactivators (SRCs) 1-3, erbB3, and increased Akt signaling in the mammary gland.Also, we demonstrate that prenatal exposure to BPA shifts the time of susceptibility from 50 days to 100 days for chemically-induced mammary carcinogenesis. Proteomic data suggest that prenatal BPA exposure alters the expression of several proteins involved in regulating protein metabolism, signal transduction, developmental processes, and cell cycle and proliferation. Increases in ER-alpha, SRCs 1-3, Bcl-2, epidermal growth factor-receptor (EGFR), phospho-IGF-1R, phospho-c-Raf, phospho-ERKs 1/2, phospho-ErbB2 and phospho-Akt are accompanied by increase in cell proliferation. We conclude that exposure to low concentrations of BPA during the prenatal and early postnatal periods of life can predispose for chemically-induced mammary cancer.


Effects of Tulp4 deficiency on murine embryonic development and adult phenotype.
Genetically engineered mouse models have the potential to unravel fundamental biological processes and provide mechanistic insights into the pathogenesis of human diseases. We have previously observed that germline genetic variation at the TULP4 locus influences clinical characteristics in patients with myeloproliferative neoplasms. To elucidate the role of TULP4 in pathological and physiological processes in vivo, we generated a Tulp4 knockout mouse model. Systemic Tulp4 deficiency exerted a strong impact on embryonic development in both Tulp4 homozygous null (Tulp4-/-) and heterozygous (Tulp4+/-) knockout mice, the former exhibiting perinatal lethality. High-resolution episcopic microscopy (HREM) of day 14.5 embryos allowed for the identification of multiple developmental defects in Tulp4-/- mice, including severe heart defects. Moreover, in Tulp4+/- embryos HREM revealed abnormalities of several organ systems, which per se do not affect prenatal or postnatal survival. In adult Tulp4+/- mice, extensive examinations of hematopoietic and cardiovascular features, involving histopathological surveys of multiple tissues as well as blood counts and immunophenotyping, did not provide evidence for anomalies as observed in corresponding embryos. Finally, evaluating a potential obesity-related phenotype as reported for other TULP family members revealed a trend for increased body weight of Tulp4+/- mice. RESEARCH HIGHLIGHTS: To study the role of the TULP4 gene in vivo, we generated a Tulp4 knockout mouse model. Correlative analyses involving HREM revealed a strong impact of Tulp4 deficiency on murine embryonic development.


Assessing consumer expectations about pizza: A study on celiac and non-celiac individuals using the word association technique.
The word association (WA) technique was used to investigate the perception of two groups of consumers (72 celiac and 78 non-celiac individuals; 150 in total) to pizza dough (thick or thin) and the raw material used at the manufacture (cassava flour or rice flour). Different perceptions of the four stimuli were detected by Chi-square test (X2=314.393, p<0.0001) for both groups. Seven categories were used for both groups: food/composition, health, doubt/uncertainty, novelty, negative feelings, positive feelings, and sensory aspects. The stimulus 'pizza dough made with cassava flour' was associated with the category "food/composition" and the stimuli 'pizza made with rice flour', 'pizza made with cassava flour' and 'thin dough' were associated with "positive feelings". The stimulus 'thick dough' was related only to the category "negative feelings". WA indicated that gluten-free pizza should have thin dough and us cassava flour or rice flour as the raw material.


Using translational research to tailor the use of chemotherapy in the treatment of NSCLC.
The treatment of advanced non-small-cell lung cancer (NSCLC) has improved over the past two decades with the availability of new agents such as gemcitabine, the taxanes and vinorelbine. Despite these advances, survival prospects remain disappointingly low for most patients. Further improvements in response rate and survival requires the development of new agents with novel mechanisms of action, such as molecularly targeted therapies, which are currently being tested in clinical trials. The conventional treatment approach to NSCLC is beginning to shift towards the application of specific strategies and techniques, such as pharmacogenomics, to tailor treatment to individual patients. Many efforts are in progress to identify the clinical predictors of outcome. The discovery of prognostic molecular markers, such as the putative suppressor gene (RRM1), represents a novel and potential parameter to help guide clinical treatment decisions.


The N-terminus of MTRR plays a role in MTR reactivation cycle beyond electron transfer.
In eucaryotic cells, methionine synthase reductase (MSR/MTRR) is capable of dominating the folate-homocysteine metabolism as an irreplaceable partner in electron transfer for regeneration of methionine synthase. The N-terminus of MTRR containing a conserved domain of FMN_Red is closely concerned with the oxidation-reduction process. Maternal substitution of I22M in this domain can bring about pregnancy with high risk of spina bifida. A new variation of Arg2del was identified from a female conceiving a fetus with spina bifida cystica. Although the deletion is far from the N-terminal FMN_Red domain, the biochemical features of the variant had been seriously investigated. Curiously, the deletion of arginine(s) of MTRR could not affect the electron relay, if only the FMN_Red domain was intact, but by degrees reduced the ability to promote MTR catalysis in methionine formation. Confirmation of the interaction between the isolated MTRR N-terminal polypeptide and MTR suggested that the native MTRR N-terminus might play an extra role in MTR function. The tandem arginines at the end of MTRR N-terminus conferring high affinity to MTR were indispensable for stimulating methyltransferase activity perhaps via triggering allosteric effect that could be attenuated by removal of the arginine(s). It was concluded that MTRR could also propel MTR enzymatic reaction relying on the tandem arginines at N-terminus more than just only implicated in electron transfer in MTR reactivation cycle. Perturbance of the enzymatic cooperation due to the novel deletion could possibly invite spina bifida in clinics.


Spontaneous neonatal renal vein thrombosis, a known pathology without clear management guidelines: An overview.
Renal vein thrombosis (RVT) was first described in 1837 by Rayer. Although tremendous progress has been achieved in the comprehension of its pathophysiology, its management remains controversial over 20 decades later. Therapeutic modalities vary from supportive measures alone to the utilization of thrombolytic agents whose protocols are derived from adult medicine. This review aims to show how difficult the treatment of RVT still is, especially with regard to the prognosis. The majority of affected neonates end with various renal complications (renal atrophy, dysfunction, hypertension, etc.). Like others, we suggest that simple unilateral RVT be managed conservatively, while thrombolytic agents may be attempted in unilateral RVT with extension to VCI and in bilateral RVT. Further studies are needed to reach appropriate consensual guidelines.


Indomethacin modifies the fetal hemodynamic response induced by percutaneous umbilical blood sampling.
Percutaneous umbilical blood sampling induces a marked decrease of impedance to flow in the umbilical artery. Because these changes are believed to be the result of the release of prostanoids, we conducted a study to determine whether indomethacin administration before percutaneous umbilical blood sampling affects the hemodynamic response induced by this procedure. Percutaneous umbilical blood sampling was performed in 20 singleton pregnancies that were treated for 3 days before the procedure with indomethacin (25 mg orally 6 hours apart) as tocolytic agent and in 22 untreated pregnancies. All the procedures were uncomplicated, and sampling of the umbilical vein was confirmed by blood pressure measurement at the time of the procedure. The umbilical artery pulsatility index and the fetal heart rate were measured immediately before and after the procedure. The first and last aliquots of umbilical vein plasma obtained at the beginning and closing of the procedure were assayed for endothelin-1, 6-keto-prostaglandin F1 alpha and thromboxane B2. In untreated pregnancies percutaneous umbilical blood sampling induced a decrease of the umbilical artery pulsatility index (p < 0.0001) and an increase in 6-keto-prostaglandin F1 alpha (p < 0.001) and endothelin-1 levels (p = 0.001), whereas no significant changes were present in fetal heart rate and thromboxane B2 levels. In pregnancies treated with indomethacin, 6-keto-prostaglandin F1 alpha, and thromboxane B2, concentrations at the beginning of the procedure were both significantly less (p < 0.0001) than those found in untreated pregnancies. In pregnancies treated with indomethacin percutaneous umbilical blood sampling did not affect umbilical artery pulsatility index, and 6-keto-prostaglandin F1 alpha and thromboxane B2 levels did not vary during the procedure. However, endothelin-1 (p < 0.001) and fetal heart rate (p < 0.0001) increased after the procedure. Indomethacin affects the fetal hemodynamic response to percutaneous umbilical blood sampling by inhibiting the release of prostanoids and the fall in umbilical artery pulsatility index. Under this condition the fetus adapts to the procedure by increasing the heart rate.


Nitrate-induced improvements in exercise performance are coincident with exuberant changes in metabolic genes and the metabolome in zebrafish (Danio rerio) skeletal muscle.
Dietary nitrate supplementation improves exercise performance by reducing the oxygen cost of exercise and enhancing skeletal muscle function. However, the mechanisms underlying these effects are not well understood. The purpose of this study was to assess changes in skeletal muscle energy metabolism associated with exercise performance in a zebrafish model. Fish were exposed to sodium nitrate (60.7 mg/L, 303.5 mg/L, 606.9 mg/L), or control water, for 21 days and analyzed at intervals (5, 10, 20, 30, 40 cm/s) during a 2-h strenuous exercise test. We measured oxygen consumption during an exercise test and assessed muscle nitrate concentrations, gene expression, and the muscle metabolome before, during, and after exercise. Nitrate exposure reduced the oxygen cost of exercise and increased muscle nitrate concentrations at rest, which were reduced with increasing exercise duration. In skeletal muscle, nitrate treatment upregulated expression of genes central to nutrient sensing (mtor), redox signaling (nrf2a), and muscle differentiation (sox6). In rested muscle, nitrate treatment increased phosphocreatine (P = 0.002), creatine (P = 0.0005), ATP (P = 0.0008), ADP (P = 0.002), and AMP (P = 0.004) compared with rested-control muscle. Following the highest swimming speed, concentration of phosphocreatine (P = 8.0 × 10-5), creatine (P = 6.0 × 10-7), ATP (P = 2.0 × 10-6), ADP (P = 0.0002), and AMP (P = 0.004) decreased compared with rested nitrate muscle. Our data suggest nitrate exposure in zebrafish lowers the oxygen cost of exercise by changing the metabolic programming of muscle prior to exercise and increasing availability of energy-rich metabolites required for exercise.NEW & NOTEWORTHY We show that skeletal muscle nitrate concentration is higher with supplementation at rest and was lower in groups with increasing exercise duration in a zebrafish model. The higher availability of nitrate at rest is associated with upregulation of key nutrient-sensing genes and greater availability of energy-producing metabolites (i.e., ATP, phosphocreatine, glycolytic intermediates). Overall, nitrate supplementation may lower oxygen cost of exercise through improved fuel availability resulting from metabolic programming of muscle prior to exercise.


The Use of a 3D Simulator Software and 3D Printed Biomodels to Aid Autologous Breast Reconstruction.
Aesthetically pleasing and symmetrical breasts are the goal of reconstructive breast surgery. However, multiple procedures are sometimes needed to improve a reconstructed breast's symmetry and appearance. Since all breasts vary in terms of volume, height, width, projection, orientation, and shape, the lack of attention to these details at the moment of flap shaping in autologous reconstruction can lead to poor results. Recent advances in 3-dimensional (3D) surface imaging and printing technologies have allowed for improvement in autologous breast reconstruction symmetry. While 3D printing technology is becoming faster, more accurate, and less expensive, the technology required to obtain proper 3D breast images remains expensive, including laser scanners or 3D photogrammetric cameras. In this study, we present a novel use of an aesthetic surgery simulator software as an affordable alternative to obtaining 3D breast images and creating 3D printed biomodels to aid in the precise shaping of the flap. This approach aims to optimize aesthetic results in autologous breast reconstruction avoiding surgical revisions and reducing surgical times. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


The same "TATA" box beta-thalassemia mutation in Chinese and US blacks: another example of independent origins of mutation.
A Chinese beta +-thalassemia gene in a new haplotype was chosen for cloning and sequencing. The mutation identified was an A-G transition at position -29 in the TATA box of the beta-globin gene. This mutation has not been seen previously in Chinese but has been documented in American blacks on a different chromosomal background. This observation provides further evidence for independent origins of the same mutation in distinct ethnic groups.


Direct oral anticoagulants increase bleeding risk after endoscopic sphincterotomy: a retrospective study.
Bleeding can be a serious adverse event of endoscopic sphincterotomy (EST). However, the risk of EST bleeding between direct oral anticoagulant (DOAC) users and those who received no antithrombotic agents has not been clarified. This study analyzed the risk factors for bleeding after EST in patients on DOAC and evaluated the Japan Gastroenterological Endoscopy Society (JGES) guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment. We retrospectively analyzed 524 patients treated with EST who received DOAC or no antithrombotic drug from May 2016 to August 2019. We investigated the risk factors for bleeding. DOAC was typically discontinued for ≤ 1-day based on the JGES guideline. Although DOAC therapy recommenced the next morning after EST in principle, the duration of DOAC cessation and heparin replacement were determined by the attending physician based on each patient's status. The number of patients on DOAC (DOAC group) and those not on antithrombotic drug (no-drug group) was 42 (8.0%) and 482 (92.0%), respectively. DOAC was discontinued for ≤ 1-day in 17 (40.0%) patients and for > 1-day in 25 (60.0%). Of the 524 patients, 21 (4.0%) had EST bleeding. The bleeding rate was higher in the DOAC group (14.0%) (p = 0.004). Multivariate analysis showed that bleeding occurred more frequently in patients on DOAC (odds ratio [OR] 3.95, 95% confidence interval [CI] 1.37-11.4, p = 0.011), patients with low platelet counts (< 100,000/µl) (OR 6.74, 95% CI 2.1-21.6, p = 0.001), and elderly patients (> 80 years old) (OR 3.36, 95%CI 1.17-9.65, p = 0.024). DOAC treatment, low platelet count, and old age (> 80 years old) are risk factors for EST bleeding. Although the bleeding incidence increased in patients on DOAC who received antithrombotic therapy according to the JGES guidelines, successful hemostasis was achieved with endoscopy in all cases, and no thrombotic events occurred after cessation of DOAC. Thus, the JGES guidelines are acceptable.


Tailor-Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals.
Structural analysis of modern pharmaceutical practices allows for the identification of two rapidly growing trends: the introduction of tailor-made amino acids and the exploitation of fluorinated motifs. Curiously, the former represents one of the most ubiquitous classes of naturally occurring compounds, whereas the latter is the most xenobiotic and comprised virtually entirely of man-made derivatives. Herein, 39 selected compounds, featuring both of these traits in the same molecule, are profiled. The total synthesis, source of the corresponding amino acids and fluorinated residues, and medicinal chemistry aspects and biological properties of the molecules are discussed.


Evaluation of the mitigation efficacy of a yeast cell wall extract toward deoxynivalenol contaminated diet fed to turbot (Scophthalmus maximus).
Deoxynivalenol (DON) is one of the most common mycotoxins in animal feed worldwide and causes significant threats to the animal health. Increased use of plant ingredients in aquaculture feeds increased the risk of mycotoxin contamination. To evaluate the effects of dietary deoxynivalenol (DON) on growth performance, immune response and intestinal health of turbot and the mitigation efficacy of yeast cell wall extract (YCWE) toward DON, nine isonitrogenous and isolipidic diets were formulated: Diet 1 (control): No DON added; Diets 2-5 or Diets 6-9: 0.5 or 3.0 mg added DON/kg diet + 0%, 0.1%, 0.2%, or 0.4% YCWE, respectively. Results showed that Diet 6 (3 mg/kg DON, 0% YCWE) significantly decreased weight gain, specific growth rate and feed efficiency ratio of fish and reduced immunoglobulin M and complement 4 concentrations in serum. Fish fed Diet 6 presented morphological alterations, lower activity of superoxide dismutase, catalase and total antioxidant capacity but higher malondialdehyde content, lower claudin-4 and occludin expression but higher interleukin-1β expression in intestine. Besides, Diet 6 decreased the abundance of potential helpful bacteria but increased the abundance of potential pathogens in intestine. While, dietary YCWE, especially Diet 8 (3 mg/kg DON, 0.2% YCWE) and 9 (3 mg/kg DON, 0.4% YCWE), markedly improved growth performance and immune response and enhanced the intestinal health of turbot. In conclusion, dietary YCWE could mitigate the toxic effects induced by DON in turbot, and could be used as an effective strategy to control DON contamination in fish feed.


Aqueous chlorination of diclofenac: kinetic study and transformation products identification.
Diclofenac reactivity and fate during water chlorination was investigated in this work. In the first step, chlorination kinetic of diclofenac (DCF) was studied in the pH range of 4-10 at 20 ± 2 °C and in the presence of an excess of total chlorine. A second-order reaction (first-order relative to DCF concentration and first-order relative to free chlorine concentration) was shown with rate constant about 3.89 ± 1.17 M(-1) s(-1) at pH 7. The elementary reactions (i.e. reactions of hypochlorous acid (HOCl) with neutral and ionized forms of DCF, and acid-catalysed reaction of HOCl with neutral and ionized forms of DCF) were proposed to explain the pH-dependence of the rate constants and intrinsic constant of each of them were calculated. In the second step, several degradation products formed during chlorination of DCF were identified. These compounds could come from an initial chlorine electrophilic attack on aromatic ring or amine function of DCF. Some of these chlorinated derivatives seem to accumulate in solution in the presence of an excess of chlorine.


The size of adrenal incidentalomas correlates with insulin resistance. Is there a cause-effect relationship?
Adrenal incidentalomas (AI) have often been associated with a high prevalence of insulin resistance (IR) and cardiovascular risk factors, although direct measurement of insulin sensitivity (IS) has never been carried out. We aimed to investigate whether the morphological and hormonal features of AI correlate with the presence and severity of IR, using the hyperinsulinaemic euglycaemic clamp (HEC). Forty patients with AI (22 women) with a mean age of 58.5±11.1 years underwent hormonal and morphological evaluation. Nineteen patients with AI without known history of diabetes mellitus (DM) or impaired glucose tolerance (IGT) and 17 matched controls underwent oral glucose tolerance test (OGTT) and hyperinsulinaemic euglycaemic clamp (HEC). Diabetes mellitus was observed in 13 patients (33%), while three (8%) had IGT. Thirty-one of the AI were nonfunctioning (82.5%), whereas two (5%) secreted cortisol (Cushing's syndrome) and seven (12.5%) showed subclinical secretion of cortisol. The 19 patients with nonfunctioning AI were more insulin resistant than controls (glucose up-take: 4.58±1.80 vs 5.85±2.48 mg/kg/min respectively; P=0.01); IS was inversely related to the mass size (r=-0.57; P=0.04), free urinary cortisol (r=-0.68; P=0.01), serum cortisol after 1-mg dexamethasone suppression (-0.65; P=0.02) and percentage of trunk fat mass (-0.77; P=0.02) and directly related to serum adreno cortico tropic hormone (ACTH) (r=0.62; P=0.03). After performing multivariate regression, the mass size was found to be the most powerful predictor of IR. Our study showed a high prevalence of insulin resistance in patients with nonfunctioning AI and suggests its possible involvement in AI growth.


Determination of safe depth of pin penetration for repair of distal femoral physeal fractures in immature dogs: a comparison of normograde and retrograde pin placement.
The purpose of this study was to determine the depth that implants may be safely placed into the distal femoral epiphysis (DFE) for the repair of distal femoral physeal fractures. The depth of the DFE was related to the radiographic thickness of the patella in this experimental study. Twenty immature canine cadavers. Patella thicknesses were measured from lateral radiographs. Actual DFE depths were determined for pins driven in normograde fashion and for pins driven retrograde from the central depression between the metaphyseal pegs and from the cranial pegs. The association of DFE depth and patella thickness was evaluated using linear regression analysis. Using 95% confidence intervals, rules for estimating the safe depth of implant placement into the DFE were determined. DFE depth had significant correlation with patella thickness for pins placed in retrograde fashion from the central depression between the metaphyseal pegs (r2 = .83) and from the cranial pegs (r2 = .82) and for pins placed in normograde fashion (r2 = .65). Based on 95% confidence intervals, pins placed in retrograde fashion from the central depression between the metaphyseal pegs may be safely driven into the DFE a distance equal to 140% of patella thickness. Pins placed from the cranial metaphyseal pegs may be driven to a depth equal to 80% of patella thickness, and pins placed in normograde fashion may be driven to a depth equal to 30% of patella thickness. Measurement of patella thickness assists the surgeon in determining the approximate depth that pins may be driven into the DFE without penetrating the articular surface of the stifle joint.


Assessment of the current computer literacy and future computer needs of emergency medicine residents and faculty.
The purpose of this study was to assess the current computer literacy and future computer needs of emergency medicine residents and faculty to aid in developing a computer literacy curriculum. All emergency medicine residents and full-time faculty from a random sample of emergency medicine residencies were mailed questionnaires assessing current computer familiarity and future computer needs. Twenty-one residencies were surveyed; 15 resident and 17 faculty questionnaires were returned. Thirty-seven percent (116 of 314) faculty and 29% (135 of 470) resident questionnaires were completed and returned. Eighty percent (12 of 15) of residencies had a designated computer for resident use; 93% (14 of 15) had a computer for use in the emergency department. Forty-seven percent of residents owned their own computer; 68% of faculty had a computer in their home, and 52% had computers in their office. Less than 30% of residents and faculty had formal computer training. Residents and faculty rated the current familiarity and future needs for various software applications on a five-point scale. Data were analyzed using the Wilcoxon-Rank Sum Test. Residents and faculty had the most anticipated need for word processing, graphics, literature searching, data base, and patient management programs. Future computer need was rated significantly higher than current computer familiarity in all computer application areas (P < or = .0002). It seems that emergency medicine residents and faculty have adequate access to computers, but minimal computer training. Residents and faculty have a high anticipated need for various basic computer applications.(ABSTRACT TRUNCATED AT 250 WORDS)