Bioremediation of chromium contaminated water by diatoms with concomitant lipid accumulation for biofuel production.
Hexavalent chromium compounds such as chromate and dichromate, commonly designated as Cr (VI) compounds, are widely used heavy metals in different industries and are considered highly toxic to most life forms. Unfortunately, they have become a major pollutant of groundwater and rivers around dichromate using industries. Bioremediation is widely used to decrease the amount of dichromate in wastewater but requires large amounts of precious fresh water. Here we tested two marine micro-algal species, Phaeodactylum tricornutum strain CCY0033 and Navicula pelliculosa strain CCMP543, for their ability of dichromate bioremediation and concomitantly producing lipids that can serve as biofuel. Dichromate tolerance of the strains was investigated under different growth conditions in order to obtain high biomass yields, high lipid accumulation and high dichromate removal from the medium. Both algal strains grew well and produced high biomass in media containing up to 1 mg of dichromate per liter. Variations in growth conditions revealed that dichromate removal from the medium correlated positively with biomass yield. Dichromate removal using living cells was in the same order of magnitude as with autoclaved dead cells or when using extracted extracellular polymeric substances (EPS). This suggests biosorption of dichromate to cell-associated polymeric substances as the major mechanism of the bioremediation process. For both strains, optimal dichromate removal and lipid production were achieved at a light intensity of 55 μmol m-2s-1 and at a sodium nitrate concentration of 3 mM. The optimal temperature for dichromate removal and lipid production was 23 °C for P. tricornutum and 27 °C for N. pelliculosa. Compared to P. tricornutum strain CCY0033, N. pelliculosa strain CCMP543 produced an overall higher lipid yield under these conditions.


Meet the authors: Nausica Arnoult.
Molecular Cell talks to Nausica Arnoult about her paper "The APE2 nuclease is essential for DNA double-strand break repair by microhomology-mediated end joining," the lab environment she looks to create, and barriers faced by women pursuing careers in science.


Medication adherence among patients with cardiovascular diseases: a cross-sectional study.
Medication adherence has been recognised as one of the greatest areas to improve health outcomes and reduce health expenditure. Poor medication adherence has multifactorial causes that need to be understood. To determine the levels of medication adherence and examine the factors associated with medication adherence among patients with cardiovascular diseases (CVDs) in Jordan. A cross-sectional, descriptive correlational design was used to conduct this study. A convenience sample was used to recruit 250 patients with CVDs from outpatient clinics of Jordanian hospitals. Data were collected using the Multidimensional Scale of Perceived Social Support and Morisky Medication Adherence Scale, in addition to sociodemographic and clinical-related factors during the period from June to September 2019. It was found that the total mean score of medication adherence was 2.84 (standard deviation = 1.9), which reflected low adherence. A significant positive correlation was found between medication adherence and marital status and the number of diseases. However, smoking was negatively correlated with medication adherence. Smoking was the predictor of medication adherence. Medication adherence among patients with CVDs needs to be improved. Thus, healthcare professionals should develop strategies and interventions based on identifying factors to enhance medication adherence among those patients.


Antibiotics and the transplant patient: The good, the bad, and the ugly.
As a heart transplant recipient for 34 years, I have been asked to write an experience-based opinion on antibiotic stewardship programs (ASPs) in the transplant setting. The aim of this piece is to provide real-life examples-the good, the bad, and the ugly-to help contextualize the potential impact of an effective transplant-specific ASP model. The exigency of transplant ASPs is illuminated, and suggested changes that can help patients right away are provided.


Safety and immunogenicity of a single-shot live-attenuated chikungunya vaccine: a double-blind, multicentre, randomised, placebo-controlled, phase 3 trial.
VLA1553 is a live-attenuated vaccine candidate for active immunisation and prevention of disease caused by chikungunya virus. We report safety and immunogenicity data up to day 180 after vaccination with VLA1553. This double-blind, multicentre, randomised, phase 3 trial was done in 43 professional vaccine trial sites in the USA. Eligible participants were healthy volunteers aged 18 years and older. Patients were excluded if they had history of chikungunya virus infection or immune-mediated or chronic arthritis or arthralgia, known or suspected defect of the immune system, any inactivated vaccine received within 2 weeks before vaccination with VLA1553, or any live vaccine received within 4 weeks before vaccination with VLA1553. Participants were randomised (3:1) to receive VLA1553 or placebo. The primary endpoint was the proportion of baseline negative participants with a seroprotective chikungunya virus antibody level defined as 50% plaque reduction in a micro plaque reduction neutralisation test (μPRNT) with a μPRNT50 titre of at least 150, 28 days after vaccination. The safety analysis included all individuals who received vaccination. Immunogenicity analyses were done in a subset of participants at 12 pre-selected study sites. These participants were required to have no major protocol deviations to be included in the per-protocol population for immunogenicity analyses. This trial is registered at ClinicalTrials.gov, NCT04546724. Between Sept 17, 2020 and April 10, 2021, 6100 people were screened for eligibility. 1972 people were excluded and 4128 participants were enrolled and randomised (3093 to VLA1553 and 1035 to placebo). 358 participants in the VLA1553 group and 133 participants in the placebo group discontinued before trial end. The per-protocol population for immunogenicity analysis comprised 362 participants (266 in the VLA1553 group and 96 in the placebo group). After a single vaccination, VLA1553 induced seroprotective chikungunya virus neutralising antibody levels in 263 (98·9%) of 266 participants in the VLA1553 group (95% CI 96·7-99·8; p<0·0001) 28 days post-vaccination, independent of age. VLA1553 was generally safe with an adverse event profile similar to other licensed vaccines and equally well tolerated in younger and older adults. Serious adverse events were reported in 46 (1·5%) of 3082 participants exposed to VLA1553 and eight (0·8%) of 1033 participants in the placebo arm. Only two serious adverse events were considered related to VLA1553 treatment (one mild myalgia and one syndrome of inappropriate antidiuretic hormone secretion). Both participants recovered fully. The strong immune response and the generation of seroprotective titres in almost all vaccinated participants suggests that VLA1553 is an excellent candidate for the prevention of disease caused by chikungunya virus. Valneva, Coalition for Epidemic Preparedness Innovation, and EU Horizon 2020.


A promoter variant of SHANK1 affects auditory working memory in schizophrenia patients and in subjects clinically at risk for psychosis.
Mutations in postsynaptic scaffolding genes contribute to autism, thus suggesting a role in pathological processes in neurodevelopment. Recently, two de novo mutations in SHANK3 were described in schizophrenia patients. In most cases, abnormal SHANK3 genotype was also accompanied by cognitive disruptions. The present study queries whether common SHANK variants may also contribute to neuropsychological dysfunctions in schizophrenia. We genotyped five common coding or promoter variants located in SHANK1, SHANK2 and SHANK3. A comprehensive test battery was used to assess neuropsychological functions in 199 schizophrenia patients and 206 healthy control subjects. In addition, an independent sample of 77 subjects at risk for psychosis was analyzed for replication of significant findings. We found the T allele of the SHANK1 promoter variant rs3810280 to lead to significantly impaired auditory working memory as assessed with digit span (12.5 ± 3.6 vs. 14.8 ± 4.1, P < .001) in schizophrenia cases, applying strict Bonferroni correction for multiple testing. This finding was replicated for forward digit span in the at-risk sample (7.1 ± 2.0 vs. 8.3 ± 2.0, P = .044). Previously, altered memory functions and reduced dendritic spines and postsynaptic density of excitatory synapses were reported in SHANK1 knock-out mice. Moreover, the atypical neuroleptic clozapine was found to increase SHANK1 density in rats. Our findings suggest a role of SHANK1 in working memory deficits in schizophrenia, which may arise from neurodevelopmental changes to prefrontal cortical areas.


Prevalence and risk factors of bacterial enteric pathogens in men who have sex with men: A cross-sectional study at the UK's largest sexual health service.
Outbreaks of bacterial enteric pathogens (BEPs) in men who have sex with men (MSM) associated with antimicrobial resistance are a public health concern. We investigated the prevalence and risk factors of BEPs in MSM to inform infection control. We conducted a cross-sectional study at a London sexual health clinic between 20/12/2017 and 06/02/2018. Residual rectal swabs from MSM attending for sexually transmitted infection (STI) testing were anonymously tested for a range of BEPs using real-time PCR. A sub-set of samples were tested for the mphA gene (a marker of azithromycin resistance). Results were linked to electronic health records. BEPs were detected in 207 of 2116 participants, giving an overall prevalence of 9.8% (95% CI 8.5%-11.1%) ranging from 0.8% (0.4%-1.2%) for Shigella to 4.9% (4.0%-5.9%) for Enteroaggregative E. coli. MSM with BEPs were more likely to have a history of bacterial STIs (p = 0.010), to report more sexual partners (p<0.001), and among HIV-negative MSM, to report current HIV pre-exposure prophylaxis use (p<0.001). Gastrointestinal symptoms were rare (1.7%) and not associated with BEPs. 41.3% of MSM with BEPs and 14.1% of those without BEPs carried mphA (p<0.001). Among the former, this was associated with a history of bacterial STIs (51.5% vs 31.1%, p = 0.003). One in ten MSM had a BEP detected and most did not report symptoms. MphA carriage was common, particularly among those with BEPs. Bacterial STI treatment might contribute to selection of resistant gut organisms, emphasising the need for better antimicrobial stewardship.


Variations in the relationship between the frequency content of EMG signals and the rate of torque development in voluntary and elicited contractions.
Our purpose was to characterize the relationship between EMG mean power frequency (MPF) or median frequency (MF) and rate of torque development in voluntary ballistic and electrically elicited isometric contractions. Twenty-three healthy adults participated in two sets of experiments performed on elbow flexor muscles. For Experiment 1, subjects were asked to generate voluntary ballistic contractions by reaching four different target torque levels (20, 40, 60 and 100% of the maximal voluntary contraction (MVC)) as fast as they could. For Experiment 2, electrical (M-waves) and mechanical (twitches) responses to electrical stimulation of the nerves supplying the biceps brachii and brachioradialis muscles were recorded with the subjects at rest and with a background isometric contraction of 15% MVC. MPF, MF and rate of torque development (% MVC/s) were calculated for both voluntary and elicited contractions. Significant positive correlations were observed between MPF and rate of torque development for the voluntary contractions, whereas significant negative correlations were observed between the two variables for elicited contractions. This suggests that factors other than muscle fiber composition influence the frequency content of EMG signals and/or the rate of torque development, and that the effect of these factors will vary between voluntary and elicited contractions.


Interactive effects of ethanol on ulcerative colitis and its associated testicular dysfunction in pubertal BALB/c mice.
Available epidemiological reports have indicated an increase in the incidence of ulcerative colitis, as well as alcohol consumption, globally. The present study investigated the possible interactive effects of ethanol consumption on ulcerative colitis and its associated testicular dysfunction using six groups of 12 pubertal mice each. Group I (Control) mice received drinking water alone. Group II mice received ethanol alone at 5 g/kg body weight. Group III mice received 2.5% dextran sulphate sodium (DSS) in drinking water followed by normal drinking water. Groups IV, V, and VI mice received DSS followed by ethanol at 1.25, 2.5, and 5 g/kg, respectively. Administration of ethanol to mice with ulcerative colitis intensified the disease-activity index with marked reduction in colon length, colon mass index, body weight gain, and organo-somatic indices of testes and epididymis when compared with the DSS-alone group. Moreover, ethanol exacerbated colitis-mediated decrease in enzymatic and non-enzymatic antioxidants but increased the oxidative stress and inflammatory biomarkers in the testes and epididymis. The diminution in luteinizing hormone, follicle stimulating hormone, and testosterone levels was intensified following administration of ethanol to mice with ulcerative colitis that were administered 5 g/kg ethanol alone. The decrease in sperm functional parameters and testicular spermatogenic indices as well as histopathological damage in colon, testes, and epididymis was aggravated following administration of ethanol to mice with ulcerative colitis. In conclusion, the exacerbating effects of ethanol on ulcerative colitis-induced testicular dysfunction are related to increased oxidative stress and inflammation in the treated mice.


Effects of high-dose radiotherapy on implantable cardioverter defibrillators: an in vivo porcine study.
Although the effects of radiotherapy (RT) on implantable cardioverter defibrillators (ICDs) have been studied in vitro, and some information has been gathered from case reports and series, no in vivo experiments have previously been performed. In vivo effects of photon RT applied directly to five modern ICD generators from different manufacturers implanted in pigs were studied. The devices were interrogated between and after increasing doses of ionizing radiation. Afterwards, the shock function was tested. All ICDs withstood fractionated irradiations with a cumulative dose of 18.5 gray (Gy) of 6 megavolt (MV) photons and 18.5 Gy of 18 MV photons and were still fully functional. Especially, no oversense was recorded. Induced ventricular fibrillation was detected and treated properly by shock therapy in all cases. However, one of the ICDs converted to back-up mode later the same night. The animal model is feasible for investigating RT effects on implanted cardiac devices. During irradiations with 37 Gy, one recoverable malfunction was present in the tested devices. Additional animal studies could provide supplementary evidence for treating ICD patients, including recommendations for reprogramming of the ICD during RT and avoidance of relocating the device.


Long-term remission after resection, chemotherapy, and irradiation of a metastatic myxoma.
Malignant local or metastatic myxomatous tumors of the heart are rare and sometimes present with an unpredictable outcome. The present report demonstrates an unusual case of left atrial myxoma with a rather strange distribution of metastases that had long-term remission after combined surgical resection, chemotherapy, and irradiation of cerebral and pulmonary metastases.


90-kDa ribosomal S6 kinase 1 is inhibited by S-glutathionylation of its active-site cysteine residue during oxidative stress.
Previously, we reported that p90-RSK1 phosphorylates neuronal nitric oxide synthase (nNOS) at Ser847 in cells treated with mitogens, leading to the inhibition of NOS activity. Here, we show RSK1 Cys223 glutathionylation limits the activity of the enzyme following an oxidative stimulus and attenuates the nNOS phosphorylation. Treatment of RSK1 with diamide/glutathione results in inactivation of the enzyme in vitro. Mutagenesis studies confirmed that S-glutathionylation of Cys223 is both necessary and sufficient for this inhibition of RSK1. In transfected cells expressing RSK1 and nNOS, treatment with diamide caused a decrease in EGF-induced phosphorylation of nNOS at Ser847. Cells expressing mutant RSK1 (C223S) proved resistant in this regard. Thus, RSK1 Cys223 glutathionylation may contribute to regulate the levels of NO in the brain.


Dose--Response Study of Colestipol Tablets in Patients with Moderate Hypercholesterolemia.
The purpose of the study was to evaluate the efficacy and safety of a new formulation of colestipol provided in table form. This was a randomized, double-blind, placebo-controlled, multicenter, dose-ranging study. A total of 196 patients with primary hypercholesterolemia who were following a low-fat, low-cholesterol diet (NCEP Step I diet), and having mean low-density lipoprotein cholesterol (LDL-C) levels greater-than-or-equal4.14 mmol L(minus sign1) (160 mg dl(minus sign1)) and less-than-or-equal6.46 mmol L(minus sign1) (250 mg dl(minus sign1)) were studied. Study medication was taken twice daily, with breakfast and supper, for 8 weeks. The five parallel treatment groups consisted of colestipol tablets 1, 2, 4, and 8 g BID, and matching placebo tablets BID. The main outcome measures were absolute change and percent change from baseline in selected lipid, lipoprotein, and apolipoprotein measurements; LDL-C was considered primary. Statistically significant (p less-than-or-equal 0.05) dose-dependent reductions in LDL-C from 5.2% to 25.8% and in total cholesterol from 2.8% to 16.8% were observed. Colestipol tablet treatment also resulted in statistically significant dose-dependent increases in LpAl levels reaching 25.8% at 16 g day(minus sign1). The treatment was well tolerated, and no serious adverse events were reported. Colestipol administered in tablet form was efficacious in lowering LDL-C and total cholesterol and was well tolerated in patients with primary hypercholesterolemia.


Generation of superoxide anion by succinate-cytochrome c reductase from bovine heart mitochondria.
Production of superoxide anion (O-2), measured as the chemiluminescence of the 2-methyl-6-(p-methoxyphenyl)-3, 7-dihydroimidazo[1,2-a]pyrazin-3-one hydrochloride (MCLA)-O-2 adduct, was observed during electron transfer from succinate to cytochrome c by reconstituted succinate-cytochrome c reductase-phospholipid vesicles replenished with succinate dehydrogenase. Addition of carbonyl cyanide p-trifluoromethoxyphenylhydrazone or detergent to the reconstituted reductase-phospholipid vesicles abolished O-2 production, suggesting that O-2 generation is caused by the membrane potential generated during electron transfer through the cytochrome bc1 complex. Production of O-2 was also observed during electron transfer from succinate to cytochrome c by antimycin-treated reductase, in which approximately 99.7% of the reductase activity was inhibited. The rate of O-2 production was closely related to the rate of antimycin-insensitive cytochrome c reduction. Factors affecting antimycin-insensitive reduction of cytochrome c also affected O-2 production and vice versa. When the oxygen concentration in the system was decreased, the rate of O-2 production and cytochrome c reduction by antimycin-treated reductase decreased. When the concentrations of MCLA and cytochrome c were increased, the rate of O-2 production and cytochrome c reduction by antimycin-treated reductase increased. The rate of antimycin-insensitive cytochrome c reduction was sensitive to Qo site inhibitors such as 5-undecyl-6-hydroxy-4,7-dioxobenzothiazole. These results indicate that generation of O-2 during the oxidation of ubiquinol by the cytochrome bc1 complex results from a leakage of the second electron of ubiquinol from its Q cycle electron transfer pathway to interact with oxygen. The electron-leaking site is located at the reduced cytochrome b566 or ubisemiquinone of the Qo site because addition of MCLA to antimycin-treated cytochrome bc1 complex, in the presence of catalytic amounts of succinate-cytochrome c reductase, delayed cytochrome b reduction by succinate. In the presence of oxidized cytochrome c, purified succinate dehydrogenase also catalyzed oxidation of succinate to generate O-2. When succinate dehydrogenase was reconstituted with the bc1 particles to form succinate-cytochrome c reductase, the production of O-2 diminished. These results suggest that reduced FAD of succinate dehydrogenase is the electron donor for oxygen to produce O-2 in the absence of their immediate electron acceptor and in the presence of cytochrome c.


Response properties of C-type horizontal cells in the retina of the bowfin.
Intracellular recordings were obtained from biphasic- and triphasic-type horizontal cells (C cells) in the retina of the bowfin. For steady-state responses, both cell types displayed a linear stimulus-response function for responses up to at least 20% of maximum. In the linear range, responses to red/green mixtures were well predicted from the assumption that opposed inputs combine by simple summation. Action spectra were measured in the linear range for 30 biphasic and 12 triphasic cells. Biphasic cells showed their peak hyperpolarization near 530 nm and peak depolarization near 680 nm. Triphasic cells showed peak hyperpolarization near 450 nm, peak depolarization near 570 nm and small hyperpolarizing responses to deep red flashes (greater than 670 nm). The response to deep red test flashes was reduced by chromatic backgrounds which either depolarized or hyperpolarized the cell, in contrast to past findings in carp triphasic cells. In both classes of cells, the depolarizing input mechanism had a shorter latency than the hyperpolarizing mechanism, a result not previously observed in other fish retinas. Color opponency was maintained in both classes of C cells for stimuli of small diameter. The findings in bowfin and other species suggest that both feedback and direct pathways shape the depolarizing response of C cells.


Ciprofloxacin mediates cancer stem cell phenotypes in lung cancer cells through caveolin-1-dependent mechanism.
Cancer stem cells (CSCs), a subpopulation of cancer cells with high aggressive behaviors, have been identified in many types of cancer including lung cancer as one of the key mediators driving cancer progression and metastasis. Here, we have reported for the first time that ciprofloxacin (CIP), a widely used anti-microbial drug, has a potentiating effect on CSC-like features in human non-small cell lung cancer (NSCLC) cells. CIP treatment promoted CSC-like phenotypes, including enhanced anchorage-independent growth and spheroid formation. The known lung CSC markers: CD133, CD44, ABCG2 and ALDH1A1 were found to be significantly increased, while the factors involving in epithelial to mesenchymal transition (EMT): Slug and Snail, were depleted. Also, self-renewal transcription factors Oct-4 and Nanog were found to be up-regulated in CIP-treated cells. The treatment of CIP on CSC-rich populations obtained from secondary spheroids resulted in the further increase of CSC markers. In addition, we have proven that the mechanistic insight of the CIP induced stemness is through Caveolin-1 (Cav-1)-dependent mechanism. The specific suppression of Cav-1 by stably transfected Cav-1 shRNA plasmid dramatically reduced the effect of CIP on CSC markers as well as the CIP-induced spheroid formation ability. Cav-1 was shown to activate protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) pathways in CSC-rich population; however, such an effect was rarely found in the main lung cancer cells population. These findings reveal a novel effect of CIP in positively regulating CSCs in lung cancer cells via the activation of Cav-1, Akt and ERK, and may provoke the awareness of appropriate therapeutic strategy in cancer patients.


Selenoprotein W was Correlated with the Protective Effect of Selenium on Chicken Myocardial Cells from Oxidative Damage.
Selenium (Se) mainly performs its function through Se-containing proteins. Selenoprotein W (SelW), one member of the selenoprotein family, plays important roles in the normal function of the heart. To investigate the possible relationship between Se and SelW for the regulation of oxidative damage in chicken embryo myocardial cells, we treated myocardial cells with Se and H2O2. Then, the levels of lactate dehydrogenase (LDH) and 3,4-methylenedioxyamphetamine in the culture media, levels of SelW, inflammatory genes NF-κB, tumor necrosis factor (TNF)-α, p53, and the cell cycle were analyzed. Furthermore, the correlation between SelW and the levels of these factors was determined. The results indicated that Se treatment increased the expression of SelW (P < 0.05) and caused a downregulation of p53, NF-κB, and TNF-α (P < 0.05). In contrast, H2O2 increased the expression of p53, NF-κB, TNF-α, and LDH (P < 0.05) and induced early cell apoptosis, which was alleviated by treatment with Se. In addition, SelW had a positive correlation with the levels of inflammatory genes investigated. Taken together, our findings suggested that SelW is sensitive to Se levels and oxidative stress, and may play a role in the protective function of Se against oxidative damage and inflammation in chicken myocardial cells.


Na3PbII[B(O3POH)4]: an alkali-metal lead borophosphate with heterocubane-like units Na3PbO4.
Na 3Pb (II)[B(O 3POH) 4] was synthesized under hydrothermal conditions. The crystal structure determination from single-crystal X-ray diffraction data ( I4 1/ a, Z = 4, a = 6.9182(8) A, c = 27.309 (3) A, V = 1307.0(3) A (3)) revealed the presence of [B(O 3POH) 4] (5-) oligomers and heterocubane-like units Na 3PbO 4 with mixed-occupied metal cation sites.


Arthroscopic Bankart procedure: two- to five-year followup with clinical correlation to severity of glenoid labral lesion.
We report our results using the arthroscopic Bankart technique described by Morgan (transglenoid suture) on 60 consecutive patients with anterior instability. All had detachment of the glenoid labrum at surgery. Forty-seven patients were available for final followup, which ranged from 2 to 5 years. Of these patients, 18 had experienced recurrent dislocation and 3 had experienced episodes of subluxation after surgery, for an overall failure rate of 42%. Partway into the study, we began to correlate severity of glenoid labral lesion with outcome. We classified the labral lesion in 37 patients using stringent criteria at the time of surgery. Followup among these patients averaged 37 months. Of 22 cases of simple detachment of the labrum with no other significant lesion (Type II labrum), there was one failure (4.5%). Of the 15 cases with significant or complete degeneration of the glenoid labrum-inferior glenohumeral ligament complex (Types IV or V labra), 13 failed (87%). Of the patients without recurrent instability, loss of external rotation averaged 1.5 degrees, strength was 5+/5+ in abduction and external rotation. Average postoperative function was 94% of preinjury levels subjectively, and most patients were able to return to previous activities, including throwing and other overhead sports. Our findings indicate that rates of redislocation after this arthroscopic Bankart procedure correlate directly with the degree of glenoid labrum-inferior glenohumeral ligament complex lesion.


Dynamic Contributions of Slow Wave Sleep and REM Sleep to Cognitive Longevity.
The purpose of this paper was to address how sleep changes with aging, with the broader goal of informing how REM sleep and slow wave activity mechanisms interact to promote cognitive longevity. We conducted novel analyses based on the National Sleep Research Resource database. Over approximately five years, middle-to-older aged adults, on average, showed dramatically worse sleep fragmentation, a steady decrease in slow wave sleep, and yet a small increase in REM sleep. Averaging across participants, however, masked a major theme: Individuals differ substantially in their longitudinal trajectories for specific components of sleep. We considered this individual variability in light of recent theoretical and empirical work that has shown disrupted sleep and decreased slow wave activity to impair frontal lobe restoration, glymphatic system functioning, and memory consolidation. Based on multiple recent longitudinal studies, we contend that preserved or enhanced REM sleep may compensate for otherwise disrupted sleep in advancing age. The scientific community has often debated whether slow wave activity or REM sleep mechanisms are more important to cognitive aging. We propose that a more fruitful approach for future work will be to investigate how REM and slow wave processes dynamically interact to affect cognitive longevity.


Compatibility of alkaline xylanases from an alkaliphilic Bacillus NCL (87-6-10) with commercial detergents and proteases.
Alkaline xylanases from alkaliphilic Bacillus strains NCL (87-6-10) and Sam III were compared with the commercial xylanases Pulpzyme HC and Biopulp for their compatibility with detergents and proteases for laundry applications. Among the four xylanases evaluated, the enzyme from the alkaliphilic Bacillus strain NCL (87-6-10) was the most compatible. The enzyme retained its full activity (40 degrees C for 1 h) in the presence of detergents, whereas Pulpzyme HC and Sam III showed only 30% and 50% of their initial activity, respectively. Biopulp, though stable to detergents, had only marginal activity (5%)at pH 10. However, all four enzymes retained significant activity (80%) for 60 min in the presence of the proteases Alcalase and Conidiobolus protease. Supplementation of the enzyme enhanced the cleaning ability of the detergents.


Allergies to food and airborne allergens in children and adolescents: role of epigenetics in a changing environment.
Allergic diseases affect millions of children and adolescents worldwide. In this Review, we focus on allergies to food and airborne allergens and provide examples of prevalence trends during a time when climate change is of increasing concern. Profound environmental changes have affected natural systems in terms of biodiversity loss, air pollution, and climate. We discuss the potential links between these changes and allergic diseases in children, and the clinical implications. Several exposures of relevance for allergic disease also correlate with epigenetic changes such as DNA methylation. We propose that epigenetics could be a promising tool by which exposures and hazards related to a changing environment can be captured. Epigenetics might also provide promising biomarkers and help to elucidate the mechanisms related to allergic disease initiation and progress.


Exploring the compatibility between hydrothermal depolymerization of alkaline lignin from sugarcane bagasse and metabolization of the aromatics by bacteria.
Although hydrothermal treatments for biomass fractionation have been vastly studied, their effect on the depolymerization of isolated lignins in terms of yield, composition, and compatibility of the produced lignin bio-oils with bioconversion is still poorly investigated. In this study, we evaluated the hydrothermal depolymerization of an β-O-4'-rich lignin extracted from sugarcane bagasse by alkaline fractionation, investigating the influence of temperature (200-350 °C), time (30-90 min), and solid-liquid ratio (1:10-1:50 m.v-1) on yield of bio-oils (up to 31 wt%) rich in monomers (light bio-oils). Principal Components Analysis showed that the defunctionalization of the aromatic monomers was more pronounced in the most severe reaction conditions and that the abundance of more hydrophobic monomers increased in more diluted reactions. While the high-molecular-weight (heavy) bio-oil generated at 350 °C, 90 min, and 1:50 m.v-1 failed to support bacterial growth, the corresponding light bio-oil rich in aromatic monomers promoted the growth of bacteria from 9 distinct species. The isolates Pseudomonas sp. LIM05 and Burkholderia sp. LIM09 showed the best growth performance and tolerance to lignin-derived aromatics, being the most promising for the future development of biological upgrading strategies tailored for this lignin stream.


Synaptic contacts between nerve terminals originating from the ventrolateral medullary catecholaminergic area and median preoptic neurons projecting to the paraventricular hypothalamic nucleus.
A significant role of catecholaminergic projection to the median preoptic nucleus (POMe) which activates vasopressin-producing cells of the paraventricular hypothalamic nucleus (PVN) has been suggested. We investigated the existence of the synaptic contacts between catecholaminergic fibers from the ventrolateral medulla and the POMe neurons projecting to the PVN. Rats received a retrograde tracer in the PVN and subsequently an anterograde tracer into the catecholaminergic area of the ventrolateral medulla at the level of the area postrema. In the POMe, anterogradely labeled nerve terminals were found to make axo-somatic and axo-dendritic synaptic contacts onto retrogradely labeled neurons. Additional studies in which a retrograde tracer was injected into the POMe revealed that almost all retrogradely labeled neurons in the ventrolateral medulla at the level of the area postrema were immunoreactive to tyrosine hydroxylase, suggesting that projection to the POMe from the ventrolateral medulla is largely limited to catecholamine neurons. These results provide, for the first time, direct evidence that catecholaminergic inputs from the ventrolateral medulla affect POMe neurons projecting to the PVN by way of direct synaptic contact.


Effect of cytosolic pH on epithelial Na+ channel in normal and cystic fibrosis sweat ducts.
The activities of cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel and the amiloride-sensitive epithelial Na(+) channel (ENaC) are acutely coordinated in the sweat duct. However, the mechanisms responsible for cross-talk between these ion channels are unknown. Previous studies indicated that luminal pH of sweat ducts varies over 3 pH units and that the cytoplasmic pH affects both CFTR and ENaC. Therefore, using basolaterally alpha-toxin-permeabilized apical membrane preparations of sweat ducts as an experimental system, we tested the hypothesis that the cytosolic pH may mediate the cross-talk between CFTR and ENaC. We showed that while luminal pH had no effect, cytosolic pH acutely affected ENaC activity. That is, acidic pH inhibited, while basic pH activated, ENaC. pH regulation of ENaC appears to be independent of CFTR or endogenous kinase activities because basic pH independently stimulated ENaC (1) in normal ducts even when CFTR was deactivated, (2) in CF ducts that lack CFTR in the plasma membranes and (3) after blocking endogenous kinase activity with staurosporine. Considering the evidence of Na(+)/H(+) exchange (NHE) activity as shown by the expression of mRNA and function of NHE in the basolateral membrane of the sweat duct, we postulate that changes in cytosolic Na(+) ([Na(+)]( i )) may alter cytosolic pH (pH( i )) as salt loads into the cell during electrolyte absorption. These changes may play a role in coordinating the activities of ENaC and CFTR during transepithelial salt transport.


An affinity purification procedure to isolate oxidized p53.
Oxidation of cysteine is now known to serve as a fundamental mechanism to control protein function or activity. Many redox-regulated proteins do not oxidize to homogeneity, resulting in a mixture of reduced and oxidized species which cannot be separated chromatographically. Here we describe a protocol for the separation of reduced and oxidized forms of the tumor suppressor protein p53. This purification method relies on the reversible labeling of thiol groups with biotin and exploitation of the ultrastrong biotin-avidin interaction. This purification procedure can be applied to other cysteine-containing proteins where enrichment of the oxidized form is required.


Examining four types of anti-vaccination attitudes prior to and during the COVID-19 pandemic.
People hold different anti-vaccination attitudes. Having an understanding of how these attitudes have changed prior to and during the COVID-19 pandemic is critical for combatting anti-vaccination attitudes and increasing vaccine intention and uptake. Data were collected from different samples in the United States at three time points prior to (n = 840) and four time points during (n = 1543) the pandemic. All participants completed a multi-dimensional measure of anti-vaccination attitudes (VAX Scale) through an online platform. Results showed that, when it comes to vaccines, worries about unforeseen side effects, concerns about commercial profiteering, and preference for natural immunity were higher during the COVID-19 pandemic than they were prior to it. However, mistrust of vaccine benefit was lower during the COVID-19 pandemic than prior to it. These differences were found even after controlling for the potential effects of participant sex, education, socioeconomic status, age, and race/ethnicity. Additionally, worries about unforeseen side effects, concerns about commercial profiteering, and preference for natural immunity increased linearly alongside the persistence of COVID-19; whereas, mistrust of vaccine benefit showed no change. Although it might be intuitive to emphasize vaccines' effectiveness to increase uptake, the public's trust in vaccine effectiveness did not appear to be the major concern. Thus, public health efforts to increase uptake of vaccines should also focus on reducing concerns about potential side effects from the vaccine, tempering the attention on financial benefits to pharmaceutical companies, and rebuffing the overreliance on natural immunity.


Long-term amelioration of bilirubin glucuronidation defect in Gunn rats by transplanting genetically modified immortalized autologous hepatocytes.
Ex vivo gene therapy, in which hepatocytes are harvested from mutants, retrovirally transduced with a normal gene and transplanted back into the donor, has been used for correction of inherited metabolic defects of liver. Major drawbacks of this method include limited availability of autologous hepatocytes, inefficient retroviral transduction of primary hepatocytes, and the limited number of hepatocytes that can be transplanted safely. To obviate these problems, we transduced primary hepatocytes derived from inbred bilirubin-UDP-glucuronosyl-transferase (BUGT)-deficient Gunn rats by infection with a recombinant retrovirus expressing temperature-sensitive mutant SV40 large T antigen (tsT). The immortalized cells were then transduced with a second recombinant retrovirus expressing human B-UGT, and a clone expressing high levels of the enzyme was expanded by culturing at permissive temperature (33 degrees C). At 37 degrees C, tsT antigen was degraded and the cells expressed UGT activity toward bilirubin at a level approximately twice that present in normal rat liver homogenates. For seeding the cells into the liver bed, 1 x 10(7) cells were injected into the spleens of syngeneic Gunn rats five times at 10-day intervals. Excretion of bilirubin glucuronides in bile was demonstrated by HPLC analysis and serum bilirubin levels were reduced by 27 to 52% in 40 days after the first transplantation and remained so throughout the duration of the study (120 days). None of the transplanted Gunn rats or SCID mice transplanted with the immortalized cells developed tumors.


C-terminal peptide alcohol, acid and amide analogs of desulfato hirudin54-65 as antithrombin agents.
Analogs of the antithrombin peptide hirudin54-65 with C-terminal modifications have been synthesized in order to examine the requirements for alpha-thrombin inhibition. The C-terminal residue, Gln65, could be replaced with L-amino acids or amino alcohols with neutral or charged hydrophilic side chains without greatly affecting the peptide's antithrombin potency as determined by inhibition of thrombin-induced clot formation in human plasma in vitro. Derivatives with D- or L-amino carboxamides at position 65 had significantly reduced potency, but still retained activity. Deletion of residue 65 with conversion of residue 64 to the amide or alcohol derivative resulted in a three-fold loss of potency. In addition to these results the solid-phase synthesis of peptide alcohols via direct displacement of p-nitrobenzhydrylideneisonitroso resin attached peptides with the desired C-terminal amino alcohol is reported.


The forgotten science: reviving morphology.
Are modern science and clinicians forgetting or ignoring the importance of morphology and microscopy in studying disease and disease patterns? Here we ponder that current science research over-emphasizes the value of molecules and disease modelling, or rather under-estimate the usefulness of microscopy and morphology. We debate the usefulness of morphology in contemporary research and wonder whether our techniques are too old-fashioned or whether our field is seen as redundant.


The recovery of fibres from non-textile items using a static charge.
This study investigated a new method of fibre recovery from non-textile items using polystyrene rods which have a static charge. A range of natural and man-made fibres were used on a number of substrates, including weapons, paper and plastic bags. The average recovery rate from all substrates was 99.1%. The effect of humidity on fibre recovery was also studied and it was found to reduce the ability of the rods to recover fibres. However this is unlikely to be an issue if recovery takes place in a forensic laboratory. It was concluded that the rods would prove a beneficial addition to the forensic laboratory as a relatively quick method of fibre recovery from non textile items where the standard method of recovery using tape lifts cannot be used.


Dissolution of dense non-aqueous phase liquids in vertical fractures: effect of finger residuals and dead-end pools.
Understanding the dissolution behavior of dense non-aqueous phase liquids (DNAPLs) in rock fractures under different entrapment conditions is important for remediation activities and any related predictive modeling. This study investigates DNAPL dissolution in variable aperture fractures under two important entrapment configurations, namely, entrapped residual blobs from gravity fingering and pooling in a dead-end fracture. We performed a physical dissolution experiment of residual DNAPL blobs in a vertical analog fracture using light transmission techniques. A high-resolution mechanistic (physically-based) numerical model has been developed which is shown to excellently reproduce the experimentally observed DNAPL dissolution. We subsequently applied the model to simulate dissolution of the residual blobs under different water flushing velocities. The simulated relationship between the Sherwood number Sh and Peclet number Pe could be well fitted with a simple power-law function (Sh=1.43Pe⁰·⁴³). To investigate mass transfer from dead-end pools, another type of trapping in rock fractures, entrapment and dissolution of DNAPL in a vertical dead-end fracture was simulated. As the entrapped pool dissolves, the depth of the interface between the DNAPL and the flowing water increases linearly with decreasing DNAPL saturation. The interfacial area remains more or less constant as DNAPL saturation decreases, unlike in the case of residual DNAPL blobs. The decreasing depth of the contact interface changes the flow field and causes decreasing water flow velocity above the top of the DNAPL pool, suggesting the dependence of the mass transfer rate on the depth of the interface, or alternatively, the remaining mass percentage in the fracture. Simulation results show that the resultant Sherwood number Sh is significantly smaller than in the case of residual blobs for any given Peclet number, indicating slower mass transfer. The results also show that the Sh can be well fitted with a power-law function of Pe and remaining mass percentage. The obtained relationships of dimensionless groups concerning the mass transfer characteristics at the level of individual fractures can be further used in predictive modeling of dissolution at a larger (fracture network) scale.


The multitude of iron-sulfur clusters in respiratory complex I.
Respiratory complex I couples the electron transfer from NADH to ubiquinone with the translocation of protons across the membrane. Complex I contains one non-covalently bound flavin mononucleotide and, depending on the species, up to ten iron-sulfur (Fe/S) clusters as cofactors. The reason for the presence of the multitude of Fe/S clusters in complex I remained enigmatic for a long time. The question was partly answered by investigations on the evolution of the complex revealing the stepwise construction of the electron transfer domain from several modules. Extension of the ancestral to the modern electron input domain was associated with the acquisition of several Fe/S-proteins. The X-ray structure of the complex showed that the NADH oxidation-site is connected with the quinone-reduction site by a chain of seven Fe/S-clusters. Fast enzyme kinetics revealed that this chain of Fe/S-clusters is used to regulate electron-tunneling rates within the complex. A possible function of the off-pathway cluster N1a is discussed. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.


Relations between hepatotoxicity and pharmacokinetics of paracetamol in rats and mice.
A dose-dependent increase of paracetamol serum half-life (t1/2) was found after oral and intravenous application in rats and oral application in mice. The hepatotoxic effects of paracetamol were not correlated with this prolongation of t1/2. Dithiocarb protected rats against paracetamol liver damage but did not change paracetamol t1/2. Paracetamol t1/2 was not influenced either by a hepatotoxic dose of carbon tetrachloride. In conclusion, the dose-dependent prolongation of paracetamol serum half-life is not due to paracetamol-induced liver damage but merely the consequence of saturated elimination processes.


Evolutionary origin of β-defensins.
β-Defensins are a group of vertebrate-specific antimicrobial peptides (AMPs) with microbicidal and immune regulatory functions. In spite of their conservation across the vertebrate lineage ranging from bony fish to human, the evolutionary origin of these molecules remains unsolved. We addressed this issue by comparing three-dimensional (3D) structure and genomic organization of β-defensins with those of big defensins, a family of invertebrate-derived β-defensin-related peptides with two distinct structural and functional domains. β-Defensins and the carboxyl-terminal domain of big defensins adopt a conserved β-sheet topology stabilized by three identical disulfide bridges. Genomic organization analysis revealed that the defensin domain of these two classes of molecules is encoded by a single exon with a positionally conserved phase-1 intron in its upstream. The genomic and 3D structural conservation provides convincing evidence for their evolutionary relationship, in which β-defensins emerged from an ancestral big defensin through exon shuffling or intronization of exonic sequences. The phylogenetic distribution of big defensins in Arthropoda, Mollusca and Cephalochordata suggests an early origin of the β-defensin domain, which can be traced to the common ancestor of bilateral metazoans.


Cytokine-induced signaling networks prioritize dynamic range over signal strength.
Signaling networks respond to diverse stimuli, but how the state of the signaling network is relayed to downstream cellular responses is unclear. We modeled how incremental activation of signaling molecules is transmitted to control apoptosis as a function of signal strength and dynamic range. A linear relationship between signal input and response output, with the dynamic range of signaling molecules uniformly distributed across activation states, most accurately predicted cellular responses. When nonlinearized signals with compressed dynamic range relay network activation to apoptosis, we observe catastrophic, stimulus-specific prediction failures. We develop a general computational technique, "model-breakpoint analysis," to analyze the mechanism of these failures, identifying new time- and stimulus-specific roles for Akt, ERK, and MK2 kinase activity in apoptosis, which were experimentally verified. Dynamic range is rarely measured in signal-transduction studies, but our experiments using model-breakpoint analysis suggest it may be a greater determinant of cell fate than measured signal strength.


Effects of Bacillus licheniformis on the growth performance and expression of lipid metabolism-related genes in broiler chickens challenged with Clostridium perfringens-induced necrotic enteritis.
Necrotic enteritis (NE), caused by Clostridium perfringens, has cost the poultry industry $2 billion in losses. This study aimed to investigate the effect of Bacillus licheniformis as dietary supplement on the growth, serum antioxidant status, and expression of lipid-metabolism genes of broiler chickens with C. perfringens-induced NE. A total of 240 one-day-old broilers were randomly grouped into four: a negative control, an NE experimental model (PC), chickens fed a diet supplemented with 30 % of fishmeal from day 14 onwards and challenged with coccidiosis vaccine (FC), and NE group supplied with feed containing 1.0 × 10(6) CFU/g B. licheniformis (BL). Body weight gain, feed conversion ratio, serum antioxidant status, and lipid-metabolism-gene expression were analyzed. In the PC group, FCR increased significantly whereas serum catalase and glutathione peroxidase activity decreased compared with NC group. Dietary B. licheniformis supplementation improved FCR and oxidative stress in experimental avian NE. Using Bacillus licheniformis as a direct-fed microbial (DFM) could also significantly upregulate catabolism-related genes, namely, peroxisome proliferator-activated receptor-α and carnitine palmitoyltransferase-1, in livers and changed the expression of lipid-anabolism genes. These results suggested that dietary B. licheniformis supplementation can enhance growth and antioxidant ability, as well as change the expression of genes related to fatty-acid synthesis and oxidation in the livers of NE-infected broilers.


Histological Validation of 11Carbon-Acetate Positron Emission Tomography/Computerized Tomography in Detecting Lymph Node Metastases in Prostate Cancer.
Conventional imaging cannot definitively detect nodal metastases of prostate cancer. We histologically validated C-acetate positron emission tomography/computerized tomography to identify nodal metastases, examining prostate cancer factors that influence detection rates. Patients with C-acetate avid positron emission tomography/computerized tomography imaged pelvic/retroperitoneal lymph nodes underwent high extended robotic lymphadenectomy. A standardized mapping template comprising 8 predetermined anatomical regions was dissected during lymphadenectomy, allowing for matched, region based analysis and comparison of imaging and histological data. In 25 patients a total of 2,149 lymph nodes were excised (mean 86 per patient, range 27 to 136) and 528 (22%) harbored metastases (mean 21 positive nodes per patient, range 0 to 109). A total of 174 anatomical regions had matching imaging histological data. C-acetate positron emission tomography/computerized tomography accurately identified 48 node-positive regions and accurately ruled out 88 regions as metastasis-free. C-acetate sensitivity, specificity, and positive and negative predictive values were 67%, 84%, 74% and 79%, respectively. An increasing, histologically measured metastatic lesion size in long axis diameter of 5 or less, 6 to 10, 11 to 15, 16 to 20 and 21 mm or greater correlated with improved C-acetate detection rates of 45%, 62%, 81%, 89% and 100%, respectively. Each standard uptake value unit increase correlated with a 1.9 mm increase in nodal long axis diameter (p <0.001) and a 1.2 mm increase in short axis diameter (p <0.001). Positive C-acetate positron emission tomography/computerized tomography findings correlated with histological lymph node size (long axis diameter 12 mm and short axis diameter 6 mm), metastatic lesion size (long axis diameter 11 mm and short axis diameter 6 mm) and extranodal extension (positive 88% vs false-negative 58%, p = 0.005). C-acetate positron emission tomography/computerized tomography can identify prostate cancer metastatic nodal disease. However, it underestimates the true cephalad extent of nodal involvement, performing better in the pelvis than in the retroperitoneum. Standard uptake value, histological nodal size, intranodal metastasis size and extranodal extension correlate with cancer bearing nodes.


Oleylamine and stearylamine increase phosphatidylserine synthesis in T cells by synergy with calcium ions.
Oleylamine and stearylamine, two cationic amphiphilic drugs, strongly increase phosphatidylserine synthesis in human T cells. The two compounds had little effect on either phosphatidylcholine or phosphatidylethanolamine synthesis. A decrease in the formation of phosphatidylethanolamine through decarboxylation of phosphatidylserine was observed, but this effect is only marginally involved in increased phosphatidylserine synthesis. The high incorporation of [3H]-serine into phosphatidylserine is a protein kinase C independent process and is due to a synergy of either oleyamine or stearylamine with calcium ions.


Illicit drug use and harms, and related interventions and policy in Canada: A narrative review of select key indicators and developments since 2000.
By the year 2000, Canada faced high levels of illicit drug use and related harms. Simultaneously, a fundamental tension had raisen between continuing a mainly repression-based versus shifting to a more health-oriented drug policy approach. Despite a wealth of new data and numerous individual studies that have emerged since then, no comprehensive review of key indicators and developments of illicit drug use/harm epidemiology, interventions and law/policy exist; this paper seeks to fill this gap. We searched and reviewed journal publications, as well as key reports, government publications, surveys, etc. reporting on data and information since 2000. Relevant data were selected and extracted for review inclusion, and subsequently grouped and narratively summarized in major topical sub-theme categories. Cannabis use has remained the principal form of illicit drug use; prescription opioid misuse has arisen as a new and extensive phenomenon. While new drug-related blood-borne-virus transmissions declined, overdose deaths increased in recent years. Acceptance and proliferation of - mainly local/community-based - health measures (e.g., needle exchange, crack paraphernalia or naloxone distribution) aiming at high-risk drug users has evolved, though reach and access limitations have persisted; Vancouver's 'supervised injection site' has attracted continued attention yet remains un-replicated elsewhere in Canada. While opioid maintenance treatment utilization increased, access to treatment for key (e.g., infectious disease, psychiatric) co-morbidities among drug users remained limited. Law enforcement continued to principally focus on cannabis and specifically cannabis users. 'Drug treatment courts' were introduced but have shown limited effectiveness; several attempts cannabis control law reform have failed, except for the recent establishment of 'medical cannabis' access provisions. While recent federal governments introduced several law and policy measures reinforcing a repression approach to illicit drug use, lower-level jurisdictions (e.g., provincial/municipal levels) and non-governmental organizations increasingly promoted social- and health-oriented intervention frameworks and interventions, therefore creating an increasingly bifurcated - and inherently contradictory - drug policy landscape and reality in Canada.


How Strong is the Evidence for the Anxiolytic Efficacy of Lavender?: Systematic Review and Meta-analysis of Randomized Controlled Trials.
Although lavender is purported to possess anxiolytic and sedative properties and is often recommended for relieving anxiety, the efficacy of lavender has not been well established. Thus, this review aimed to evaluate the anxiolytic effects of lavender aromatherapy. Ten data bases were searched for studies published between 2000 and 2018. Randomized controlled trials investigating the anxiolytic effects of lavender aromatherapy with any type of application for persons with or without clinical anxiety were included. The outcome variables included self-rated anxiety, vital signs, and salivary cortisol and chromogranin A (CgA) levels. In the meta-analysis, standardized mean difference and 95% confidence interval were calculated as effect measures by applying the random effect model and inverse variance method. Twenty-two trials met our inclusion criteria. Lavender aromatherapy was found to have favorable effects in relieving anxiety (Hedges' ĝ = -0.65; 95% CI, -0.84 to -0.46) and decreasing systolic blood pressure (ĝ = -0.22; 95% CI, -0.43 to -0.02), heart rate (ĝ = -0.53; 95% CI, -0.74 to -0.32), and salivary cortisol (ĝ = -1.29; 95% CI, -2.23 to -0.35) and CgA (ĝ = -2.29; 95% CI, -3.24 to -1.34) levels. However, the meta-analysis did not reveal any significant effects of lavender on diastolic blood pressure (effect size: -0.17; 95% CI, -0.37-0.04). Aromatherapy using lavender oil might have favorable effects on anxiety and its physiological manifestations. Future studies are recommended with an emphasis on methodological quality. In nursing practice, it is suggested that lavender aromatherapy be included in programs intended to manage anxiety in patients across diverse healthcare settings.


Chromoplexy: a new paradigm in genome remodeling and evolution.
Early massively-parallel sequencing studies have revealed the mutational landscape of protein-coding genes in prostate cancer. However, most of these studies have not explored the extensive influence of genomic rearrangement in prostate cancer. In a recent Cell article, Baca and colleagues used whole-genome sequencing to tackle this issue, comprehensively surveying the abundance of genomic rearrangements present in a large cohort of 57 prostate cancers. They characterized a wide-spread phenomenon termed 'chromoplexy', which may drive cancer evolution through the phenomena of punctuated equilibrium by concurrently dysregulating numerous cancer genes across multiple chromosomes. While the causes of this event still require elucidation, this defining discovery undoubtedly offers an important glimpse into the evolutionary process of prostate cancer.


Sonographic evaluation of lateral meniscal extrusion: implementation and validation.
Meniscal extrusion (ME) is an important indicator of and prognostic factor for various knee pathologies. To date, no standardized protocol for the ultrasound-based examination of lateral ME exists. The purpose of the present study was to test the reliability and validity of lateral ME measurements using a standardized ultrasound-based examination protocol. A group consisting of 11 healthy volunteers (Group I, male and female, 18-45 years) as well as a group of 10 consecutive patients who had undergone all-inside lateral meniscal radial tear repair were included (Group II, male and female, 23-43 years). Lateral ME, the main outcome parameter, was measured by ultrasound (US; both groups) and magnetic resonance imaging (MRI; Group II only). Both knees of all subjects were examined in an unloaded state and under axial compression of the knee (50% of body weight). Repeated measurements obtained in Group I by 2 observers were used for reliability testing, and the validity of US was assessed through comparison with MRI data (Group II). A total of 66 US images of Group I, obtained by each observer, were analyzed for reliability testing. Forty US and MR images of Group II were assessed for validation. Results showed good interrater (ICC = 0.904) and excellent intrarater (ICC = 0.942) reliability of US-based measurements of lateral ME. Agreement with MRI results was poor (ICC = 0.439), with US systematically overestimating results by 1.1 mm on average. Ultrasound is a reliable, quick and cost-effective technique for lateral ME measurement, but results are not readily comparable with MRI. The study was registered in the European Union Clinical Trials Register (EudraCT-Number: 2017-005037-24).


Comparative lipidomic analysis of mammalian retinal ganglion cells and Müller glia in situ and in vitro using High-Resolution Imaging Mass Spectrometry.
In order to better understand retinal physiology, alterations to which underlie some ocular diseases, we set out to establish the lipid signature of two fundamental cell types in the retina, Müller Glia and Retinal Ganglion Cells (RGCs). Moreover, we compared the lipid signature of these cells in sections (in situ), as well as after culturing the cells and isolating their cell membranes (in vitro). The lipidome of Müller glia and RGCs was analyzed in porcine retinal sections using Matrix Assisted Laser Desorption Ionization Imaging Mass Spectrometry (MALDI-IMS). Isolated membranes, as well as whole cells from primary cell cultures of RGCs and Müller glia, were printed onto glass slides using a non-contact microarrayer (Nano Plotter), and a LTQ-Orbitrap XL analyzer was used to scan the samples in negative ion mode, thereafter identifying the RGCs and Müller cells immunohistochemically. The spectra acquired were aligned and normalized against the total ion current, and a statistical analysis was carried out to select the lipids specific to each cell type in the retinal sections and microarrays. The peaks of interest were identified by MS/MS analysis. A cluster analysis of the MS spectra obtained from the retinal sections identified regions containing RGCs and Müller glia, as confirmed by immunohistochemistry in the same sections. The relative density of certain lipids differed significantly (p-value ≤ 0.05) between the areas containing Müller glia and RGCs. Likewise, different densities of lipids were evident between the RGC and Müller glia cultures in vitro. Finally, a comparative analysis of the lipid profiles in the retinal sections and microarrays identified six peaks that corresponded to a collection of 10 lipids characteristic of retinal cells. These lipids were identified by MS/MS. The analyses performed on the RGC layer of the retina, on RGCs in culture and using cell membrane microarrays of RGCs indicate that the lipid composition of the retina detected in sections is preserved in primary cell cultures. Specific lipid species were found in RGCs and Müller glia, allowing both cell types to be identified by a lipid fingerprint. Further studies into these specific lipids and of their behavior in pathological conditions may well help identify novel therapeutic targets for ocular diseases.


The capability of Bacillus pseudomycoides from soil to remove Cu(II) in water and prevent it from entering plants.
Copper ion is widespread in wastewater and threatens the condition and human health. Micro-organisms have unique advantages to remove heavy-metal ions from water, but are rarely reported in the removal of copper ion. This aims to develop micro-organisms that can remove copper ion in water, characterize their properties and analyse their potential application in practice. Sewage sludge was used as the source to isolate wild bacteria that can remove copper ion in water. The most efficient strain was screened out from 23 obtained isolates, identified as Bacillus pseudomycoides and coded as C6. The properties of C6 in the removal of copper ion in water were investigated in the aspects of reaction conditions, reaction groups, reaction dynamic and the application in oat planting. The reaction at pH 7 within 10 min yielded the highest removal rate of copper ion, 83%. The presence of lead ion in the reaction system could promote the removal rate of copper ion. Carboxyl groups and amidogen of C6 biomass were mainly involved in the removal of copper ion. The removal of copper ion was in accord with single-layer adsorption and Langmuir adsorption isotherm model. In application, C6 biomass reduced the copper content in the oat seedlings grown in copper ion containing water by more than seven times. B. pseudomycoides C6 can efficiently remove copper ion in water and inhibit it from entering plants. This is the first time to report the capability of B. pseudomycoides to remove copper ion in water, which is also more efficient than the currently reported chemical and biological methods.


Solid-phase synthesis of N-substituted amidinophenoxy pyridines as factor XA inhibitors.
An arylamidine linker has been employed for the solid-phase synthesis of N-substituted amidinoaryloxypyridine analogs 2 via nucleophilic substitution on a fluoropyridyl template. Two novel N-substituted amidinoaryloxypyridine derivatives 2a and 2b were discovered via this approach.


A quantitative study of the composition of cerebellar cortical dysplasias.
The areas of molecular and granular layers in four large cerebellar cortical dysplasias were measured with the planimeter and the Purkinje cells were counted. There was a relative deficit of molecular layer and a still greater deficit of Purkinje cells in three of the four dysplasias. The fourth one had normal numbers of Purkinje cells per molecular layer and a relative deficit of granular layer. These abnormal proportions in the composition of a dysplasia may relate to the timing of its origin.


Biological autoluminescence as a perturbance-free method for monitoring oxidation in biosystems.
Biological oxidation processes are in the core of life energetics, play an important role in cellular biophysics, physiological cell signaling or cellular pathophysiology. Understanding of biooxidation processes is also crucial for biotechnological applications. Therefore, a plethora of methods has been developed for monitoring oxidation so far, each with distinct advantages and disadvantages. We review here the available methods for monitoring oxidation and their basic characteristics and capabilities. Then we focus on a unique method - the only one that does not require input of additional external energy or chemicals - which employs detection of biological autoluminescence (BAL). We highlight the pros and cons of this method and provide an overview of how BAL can be used to report on various aspects of cellular oxidation processes starting from oxygen consumption to the generation of oxidation products such as carbonyls. This review highlights the application potential of this completely non-invasive and label-free biophotonic diagnostic method.


Hydration of B-DNA: comparison between the water network around poly(dG).poly(dC) and poly(dG-dC).poly(dG-dC) on the basis of Monte Carlo computations.
A computational method is elaborated for studying the water environment around regular polynucleotide duplexes; it allows rigorous structural information on the hydration shell of DNA to be obtained. The crucial aspect of this Monte Carlo simulation is the use of periodical boundary conditions. The output data consists of local maxima of water density in the space near the DNA molecule and the properties of one- and two-membered water bridges as function of pairs of polar groups of DNA. In the present paper the results for poly(dG).poly(dC) and poly(dG-dC).poly(dG-dC) are presented. The differences in their hydration shells are of a purely structural nature and are caused by the symmetry of the polar groups of the polymers under study, the symmetry being reflected by the hydration shell. The homopolymer duplex hydration shell mirrors the mononucleotide repeat. The water molecules contacting the polynucleotide in the minor groove are located nearly in the plane midway between the planes of successive base pairs. One water molecule per base pair forms a water bridge facing two polar groups of bases from adjacent base pairs and on different strands making a "spine"-like structure. In contrast, the major groove hydration is stabilized exclusively by two-membered water bridges; the water molecules deepest in the groove are concentrated near the plane of the corresponding base pair. The alternating polymer is characterized by a marked dyad symmetry of the hydration shell corresponding to the axis between two successive base pairs. The minor groove hydration of the dCpdG step resembles the characteristic features of the homopolymer, but the bridge between the O2 oxygens of the other base-stacking type is formed by two water molecules. The major groove hydration is characterized by high probability of one-membered water bridges and by localization of a water molecule on the dyad axis of the dGpdC step. The found structural elements are discussed as reasonable invariants of a dynamic hydration shell.


Intimate Partner Violence and the HIV Care and Treatment Cascade Among Adolescent Girls and Young Women in DREAMS, South Africa.
Intimate partner violence (IPV) may affect the HIV-treatment cascade. Four high HIV-prevalence DREAMS health districts in South Africa. Secondary analysis of cross-sectional data collected March 2017-June 2018, using random household sample of young (12-24 years) girls and women. Face-to-face interviews assessed IPV and HIV-status knowledge, and finger-prick blood draws assessed ART (antiretroviral therapy) uptake and viral suppression. We used logistic regression to estimate crude and adjusted effects of IPV on HIV knowledge, ART uptake, and viral suppression. Of 18,230 adolescent girls and young women, 8413 (46%) reported ever having had sex, of whom 1118 (13%) were HIV positive. The 90:90:90 benchmarks were 61% knew their status, 86% had ART present in their blood sample, and 91% were virally suppressed. Among the entire sample of young women living with HIV, 65.6% were virally suppressed. Past year IPV was reported by 15%. In adjusted models, IPV trended toward increasing the odds that a young woman was aware she was living with HIV [adjusted odds ratios (aOR) = 1.40, 2.00-9.98, P = 0.067]. There was no association between IPV and reduced treatment use (aOR = 0.73, 0.41-1.29). IPV was independently associated with reduced viral suppression (aOR = 0.30, 0.13-0.66). Addressing the role of IPV in undermining the treatment cascade for adolescent and young women is a critical issue for HIV programming.


Serum metabolomics provides clues in understanding colitis exacerbating experimental periodontitis in female mice.
To evaluate the pathogenic role of colitis in experimental periodontitis and explore the potential serum metabolites of colitis exacerbating experimental periodontitis in mice model. C57BL/6 mice were divided into four groups (five mice in each group), including control, periodontitis, colitis and colitis+periodontitis group. Mice treated with 1.5 % dextran sulfate sodium for 14 days to induce colitis. On the seventh to fourteenth days, the experimental periodontitis model was established by installing a bacterially retentive ligature between two molars. Histological alteration of periodontium and colon was observed by hematoxylin and eosin staining. Tartrate-resistant acid phosphatase staining and micro-computed tomography was applied to evaluate alveolar bone loss. Gas chromatography-mass spectrometry was used to characterize serum metabolic profiles. Mice in colitis+periodontitis group displayed increased periodontal inflammation and alveolar bone loss when compared with the mice of periodontitis group, suggesting colitis aggravated periodontitis. Metabolomics analysis combined with enrichment analysis showed that colitis significantly (P<0.05) altered the content of compounds associated with five metabolic pathways (e.g. fatty acid biosynthesis) of periodontitis mice. Notably, colitis significantly reduced the level of serum metabolites that inhibited the formation of osteoclasts (e.g. oleic acid) or anti-inflammatory metabolites (e.g. palmitoleic acid, palmitelaidic acid and chlorogenic acid) of periodontitis mice. Our findings showed that colitis might aggravate periodontitis and this might be associated with alteration of serum metabolic profiles.


Comparative Study of Subcritical Water and Microwave-Assisted Extraction Techniques Impact on the Phenolic Compounds and 5-Hydroxymethylfurfural Content in Pomegranate Peel.
Two environmentally friendly innovative extraction techniques - subcritical water (SWE) and microwave-assisted extraction (MAE) were applied for the extraction of phenolics from pomegranate peel. The impact of process conditions (SWE: temperature 100-220 °C, extraction time 5-30 min; MAE: solvent water and 50% ethanol, irradiation power 470 and 800 W) on the quality of extracts in terms of the content of total phenolics, total flavonoids, major phenolic constituents (gallic acid, ellagic acid, punicalin, punicalagin), as well as 5-hydroxymethylfurfural(HMF) amount was investigated. For SWE, temperature of 130 °C and 20 min extraction time were found optimal for obtaining high content of bioactive compounds and minimizing the yield of HMF. During MAE, phenolic compounds were effectively extracted by using lower microwave power and 50% ethanol. Comparing two techniques, MAE is more efficient than SWE for the extraction of phenolics from pomegranate peel while obtaining a HMF-free extracts.


[Mechanisms of hemodynamic disorders in occlusion and subsequent revascularization of the mesenteric arteries].
The author studied the main mechanisms of homeostasis disorders, systemic hemodynamics and metabolism in particular, in visceral-ischemic shock. Two complex hemocorrectors were elaborated. One of the hemocorrectors contains rheopolyglucin, mannitol, crystalloids, sodium succinate, and a derivative of 1,4-naphthoquinone which is a modifier of the respiratory chain of mitochondria; it is suggested for use in the treatment of the irreversible phase of shock. The hemocorrector in combination with the respiratory chain modifier possesses some advantages, evidence of which are the values of systemic hemodynamics and terms of survival of the experimental animals.


Patients phenotypes and cardiovascular risk in type 2 diabetes: the Jackson Heart Study.
Cardiovascular prognosis related to type 2 diabetes may not be adequately captured by information on comorbid conditions such as obesity and hypertension. To inform the cardiovascular prognosis among diabetic individuals, we conducted phenotyping using a clustering approach based on clinical data, echocardiographic indices and biomarkers. We performed a cluster analysis on clinical, biochemical and echocardiographic variables from 529 Blacks with diabetes in the Jackson Heart Study. An association between identified clusters and major adverse cardiovascular events (MACE- composite of coronary heart disease, stroke, heart failure and atrial fibrillation) was assessed using Cox proportional hazards modeling. Cluster analysis separated individuals with diabetes (68% women, mean age 60 ± 10 years) into three distinct clusters (Clusters 1,2 &3 - with Cluster 3 being a hypertrophic cluster characterized by highest LV mass, levels of brain natriuretic peptide [BNP] and high-sensitivity cardiac troponin-I [hs-cTnI]). After a median 12.1 years, there were 141 cardiovascular events. Compared to Cluster1, Clusters 3 had an increased risk of cardiovascular disease (hazard ratio [HR] 1.60; 95% confidence interval [CI] 1.08, 2.37), while Cluster 2 had a similar risk of outcome (HR 1.11; 95% CI 0.73, 168). Among Blacks with diabetes, cluster analysis identified three distinct echocardiographic and biomarkers phenotypes, with cluster 3 (high LV mass, high cardiac biomarkers) associated with worse outcomes, thus highlighting the prognostic value of subclinical myocardial dysfunction.


Isolation of two neuropeptides in the AKH/RPCH-family from horseflies (Diptera).
Two neuropeptides (DCCI and DCCII) in the adipokinetic/red pigment concentrating hormone-family have been isolated and purified from the corpora cardiaca of horseflies (Diptera : Tabanidae). Both peptides were purified by a sequence of three reversed phase-high performance liquid chromatographic steps. Amino acid analysis of the purified peptides indicated the following composition for DCCI: Glx(l), Gly(1), Leu(1), Phe(1), Pro(1), Thr(2) and for DCCII: Glx(1), Gly(2), Leu(1), Phe(1), Pro(1), Thr(2), and Tyr(1). Photodiode array ultraviolet spectroscopy indicated the presence of tryptophan in both DCCI and II. Both DCCI and II had red pigment concentrating hormone activity in the crab, Uca pugilator.


Hippocampal damage produced in rats by alpha-dendrotoxin--a selective K+ channel blocker--involves non-NMDA receptor activation.
The epileptogenic and neurodegenerative effects induced by intra-hippocampal injection of a selective K+ channel inhibitor, alpha-dendrotoxin (DTx), were investigated in normal rats and those bearing a monolateral surgical lesion of the Schaffer collaterals that causes degeneration of their nerve terminals and also, isolates the CA3 area. In addition, these effects have also been studied in rats pretreated with NBQX, an AMPA receptor antagonist. Injection of DTx (35 pmol) into one dorsal hippocampus induced motor and electrocortical (ECoG) seizures in all the treated animals that were rapid in onset (within 2-3 min). The seizures were accompanied at 24 h by significant neuronal cell loss which occurred in the CA1, CA3 and CA4 pyramidal cell layers of the hippocampus, ipsilateral to the side of injection. This neuronal loss was paralleled by a significant decrease in the density of radioiodinated DTx labelled acceptors. Lesioning of the excitatory afferents to the CA1 pyramidal cells, gave a substantial reduction in the density of radioiodinated DTx labelled acceptors in the strata oriens and radiatum, revealing that a proportion of these K+ channels are present on the Schaffer collateral terminals. Under these conditions, motor and ECoG seizures persisted. As expected, the lesion prevented loss of the isolated CA3 pyramids, normally produced by the administration of DTx, leaving unaffected CA1 and CA4 pyramidal cell damage, consistent with an observed diminution of DTx binding sites in the latter areas. In unlesioned rats pre-treated with NBQX (30 mg/kg i.p.), subsequent injection of DTx evoked epileptogenic effects after a latency of 15 min and caused significant cell loss in the CA1 but not in the CA3 and CA4 pyramidal cell layers, ipsilateral to the side of toxin injection. A lower dose of NBQX (15 mg/kg i.p.) proved ineffective. In conclusion, these data together with our published results on NMDA antagonists indicate that motor and ECoG seizures and CA1 pyramidal cell loss elicited by intra-hippocampal injection of the K+ channel blocker, DTx, are independent from mechanisms involving glutamate-mediated excitotoxicity whereas CA3 and CA4 pyramidal cell loss may be the consequence of excessive activation of AMPA receptors.


Clinical and Radiographic Success of 2% Chlorhexidine Gluconate with Mineral Trioxide Aggregate in Indirect Pulp Treatment of Primary Molars.
Purpose: To compare the clinical and radiographic success rates of indirect pulp treatment (IPT) in primary molars using mineral trioxide aggregate (MTA) with and without two percent chlorhexidine gluconate (CHX).
Methods: A blinded, randomized, controlled clinical trial was performed in a split-mouth desi gn. Eighty primary molars in 40 subjects from four to eight years of age were randomly allocated so that each subject had one tooth treated with MTA and CHX and the other tooth treated with MTA alone. Study teeth had deep caries without signs and symptoms of pulpal inflammation or necrosis. All teeth were restored with stainless steel crowns. Follow-up was done at 12 months to evaluate the teeth clinically and radiographically.
Results: At the follow-up, one tooth from each group had failed. Upon the clinical and radiographic evaluations, the overall success rate for both groups was 97 percent. No statistically significant difference was found in the success rate between the two groups.
Conclusions: IPT in primary molars using MTA with or without CHX demonstrated satisfactory clinical and radiographic outcomes in a period of 12 months.


Dual-targeting nanozyme for tumor activatable photo-chemodynamic theranostics.
Tumor phototheranostics holds a great promise on account of its high spatiotemporal resolution, tumor-specificity, and noninvasiveness. However, physical limitation of light penetration and "always on" properties of conventional photothermal-conversion agents usually cause difficulty in accurate diagnosis and completely elimination of tumor. Meanwhile, nanozymes mediated Fenton reactions can well utilize the tumor microenvironment (TME) to generate hydroxyl radicals for chemodynamic therapy (CDT), but limited by the concentration of H2O2 in TME and the delivery efficiency of nanozymes. To overcome these problems, a dual-targeting nanozyme (FTRNPs) is developed for tumor-specific in situ theranostics, based upon the assembling of ultrasmall Fe3O4 nanoparticles, 3,3',5,5'-tetrameth-ylbenzidine (TMB) and the RGD peptide. The FTRNPs after H2O2 treatment exhibits superior photothermal stability and high photothermal conversion efficiency (η = 50.9%). FTRNPs shows extraordinary accumulation and retention in the tumor site by biological/physical dual-targeting, which is 3.54-fold higher than that without active targeting. Cascade-dual-response to TME for nanozymes mediated Fenton reactions and TMB oxidation further improves the accuracy of both photoacoustic imaging and photothermal therapy (PTT). The tumor inhibition rate of photo-chemodynamic therapy is ~ 97.76%, which is ~ 4-fold higher than that of PTT or CDT only. Thus, the combination of CDT and PTT to construct "turn on" nanoplatform is of great significance to overcome their respective limitations. Considering its optimized "all-in-one" performance, this new nanoplatform is expected to provide an advanced theranostic strategy for the future treatment of cancers.


Combination therapy of resistant warts in a patient with AIDS.
An AIDS patient on anti-HIV therapy consisting of two reverse transcriptase inhibitors had a low CD4+ lymphocyte count, a high HIV viral RNA load, and facial warts that were resistant to ablative therapy. To find a regimen to treat resistant warts in an AIDS patient with a depressed CD4 count and high HIV viral load. A protease inhibitor was added to his regimen and he was treated with ablative therapy using a 585 nm flashlamp-pumped pulsed dye laser (FPPDL). Observed resolution of the warts one month later, with no recurrence at seven-month follow-up. Treatment of resistant warts in patients with AIDS may be enhanced by triple-drug therapy which includes a protease inhibitor, used in combination with ablative therapy, such as the FPPDL.


Determinants of outcome in patients with heart failure with reduced ejection fraction & secondary mitral regurgitation.
The outcome of secondary mitral regurgitation (MR) in patients with heart failure is poor. Survival is related to the severity of MR. We sought to investigate the effect of left ventricular contractility, the ratio of left ventricular end-diastolic volume (LVEDV) to effective orifice area (EROA) and the ratio of regurgitant volume (RVol) to stroke volume (SV) on cardiovascular survival. 188 patients with a left ventricular ejection fraction (LVEF) < 50% and secondary MR were included. Groups were divided into tertiles. The Kaplan Meier method and log rank test were used to identify differences in survival between groups. Cox regression was used to identify independent predictors of cardiac mortality. Median follow-up was 30.4 months. Patients with a more abnormal global longitudinal strain (GLS) had lower survival, p = 0.001. There was no difference in survival between patients with an LVEF <30%, 30%-40% and >40%, p = 0.27. Patients with a higher RVol/SV ratio had lower survival than those with a lower ratio, p < 0.0001. Patients with a lower LVEDV/EROA ratio had worse survival than those with a higher ratio, p < 0.0001. Independent predictors of cardiovascular mortality were GLS (<5.6%) hazard ratio (HR) 2.7, the ratio of RVol/SV (>1.38) HR 4.96 and the ratio of LVDEV to EROA (<263) HR 4.49. The main determinants of cardiovascular mortality in patients with secondary MR and heart failure are more abnormal GLS, lower LVEDV/EROA ratio and higher RVol/SV ratio. These may help risk stratify patients to help determine the optimal management strategy.


A feasibility study: evaluation of radiofrequency ablation therapy to hepatocellular carcinoma using image registration of preoperative and postoperative CT.
The therapeutic response to radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC) often is evaluated by comparing pre- and post-RFA computed tomography (CT). However, judgment about whether an ablative margin, ie, 5-10 mm of normal hepatic tissue, is ensured sometimes is difficult. The aim of this study is to assess the feasibility of fusion images of pre- and post-RFA CT. HCCs (n = 20) sized 13 +/- 5 mm (range, 4-23 mm) were included. For pre-RFA CT, the arterial phase of intravenous dynamic CT (n = 17), CT arterioportography (n = 2), and CT hepatic arteriography (n = 1) was used. Using automatic image registration software (n = 20) and a manual segmentation technique (n = 4), fusion images were created in combination with post-RFA CT (equilibrium phase of intravenous CT). Automatic image registration and manual segmentation technique took approximately 2-3 and 5 minutes, respectively. Total time required for the creation of fusion images was less than 10 minutes in all cases. Fusion images enabled easier understanding of the relationship between the tumor and ablation zone, helping judge whether an ablative margin was ensured. Fusion of pre- and post-RFA CT images is considered a feasible tool in the evaluation of RFA therapy for HCC.


The usability of the ratio of bi-humerus breadth to maximum pelvic breadth in sex estimation.
Although sex can be determined with high accuracy in forensic anthropology, additional parameters are still required. To estimate with known simple statistical methods, the usability of the bi-humerus/maximum pelvic breadth ratio in sex estimation. Bi-humerus breadth and maximum pelvic breadth were measured using the topogram images (196 males, 171 females), the ratio between them was calculated. We examined the usability of the ratio of the distance between the lateral edges of the right and left humeral heads to the maximum distance between the two most lateral parts of the iliac crests in sex estimation. There was significant difference in the bi-humerus breadth and "bi-humerus breadth/maximum pelvic breadth" according to sex. The greatest breadth of the pelvis was higher in females, yet the difference was not statistically significant. The ratio yielded 80.6%-90.3% accuracy for females and 73.6%-74.7% for males, depending on arm position. The obtained data may contribute to the development of formulas created with metric measurements used in sex estimation. This can be used as a parameter to help in estimating the sex of skeletal remains found as a whole or excavated without losing their integrity, and also in the reconstruction of body structure.


Inhibition of acetylcholinesterase and phosphodiesterase-9A has differential effects on hippocampal early and late LTP.
Donepezil is the current standard symptomatic treatment of mild-to-moderate Alzheimer's disease (AD) patients. It aims to compensate for the deficit in cholinergic neurotransmission by blocking acetylcholinesterase (AChE) and thus increases the concentration of extracellular acetylcholine. However, experience from clinical practice demonstrated that AChE inhibitors only have moderate treatment effects. As a potential new approach for memory enhancement, inhibition of specific phosphodiesterases (PDEs) has gained attention. Among those are PDE9A inhibitors which increase the levels of the second messenger cyclic guanosine monophosphate (cGMP) intracellularly. In order to gain more insight into the potential impact of extracellularly acting AChEs and intracellularly acting PDE9A inhibitors on synaptic plasticity, we analyzed the effects of the AChE inhibitor donepezil and the PDE9A inhibitor BAY 73-6691 on long-term potentiation (LTP) in rat hippocampal slices, a widely accepted cellular experimental model of memory formation. Generally, LTP can be differentiated into an early and a late form, being protein-synthesis independent and protein-synthesis dependent, respectively. Donepezil was found to increase early LTP, but did not affect late LTP. In contrast, BAY 73-6691 demonstrated enhancing effects on both early and late LTP and even transformed early into late LTP. Furthermore, it was shown that this transformation into late LTP was dependent on the NO-cGMP-PKG pathway. In conclusion, this study demonstrates that BAY 73-6691 exhibits a stronger effect in enhancing and prolonging LTP than donepezil suggesting that PDE9 inhibition might be more efficacious in enhancing learning and memory.


Uncomplicated Distal Radius Fractures: An Opportunity to Reduce Emergency Medicine Opioid Prescribing?
To assess emergency physician prescribing for simple extremity fractures-specifically, distal radius fractures-and describe the opportunity for reducing opioid prescribing. An electronic survey was distributed to 1238 emergency physicians employed by a nationwide practice serving 220 sites in 20 states. The survey presented two plain film views of a simple Colles fracture and asked: "For the last patient you discharged . . . with the above injury, which pain medications did you prescribe or recommend?" Responses were collected using a clickable checklist of common opioid and nonopioid pain medications. Respondents also specified the number of days covered by any prescription. We assessed associations between physician characteristics and opioid prescribing using the χ2 test, the Wilcoxon rank-sum test, and multivariable regression models. Responses were received from 447 (36%) physicians working in 18 states; 93% were trained in emergency medicine, 33% worked at academic sites, 68% had site volumes between 25,000 and 75,000, and the median experience was 10 (interquartile range 5-19) years. Overall, 92% (95% confidence interval 89%-95%) had prescribed an opioid for a median of 3 (interquartile range 3-4) days. The most commonly prescribed opioids were hydrocodone/acetaminophen (55%) and oxycodone/acetaminophen (20%). Physicians at academic sites prescribed opioids less frequently than those at nonacademic sites (88% vs 94%), but in multivariable regression there were no significant associations between physician characteristics and opioid prescribing. Emergency physicians commonly prescribe opioids for simple distal radius fractures. This represents a potential opportunity to reduce opioid prescribing.


A Deep-Learning System for Fully-Automated Peripherally Inserted Central Catheter (PICC) Tip Detection.
A peripherally inserted central catheter (PICC) is a thin catheter that is inserted via arm veins and threaded near the heart, providing intravenous access. The final catheter tip position is always confirmed on a chest radiograph (CXR) immediately after insertion since malpositioned PICCs can cause potentially life-threatening complications. Although radiologists interpret PICC tip location with high accuracy, delays in interpretation can be significant. In this study, we proposed a fully-automated, deep-learning system with a cascading segmentation AI system containing two fully convolutional neural networks for detecting a PICC line and its tip location. A preprocessing module performed image quality and dimension normalization, and a post-processing module found the PICC tip accurately by pruning false positives. Our best model, trained on 400 training cases and selectively tuned on 50 validation cases, obtained absolute distances from ground truth with a mean of 3.10 mm, a standard deviation of 2.03 mm, and a root mean squares error (RMSE) of 3.71 mm on 150 held-out test cases. This system could help speed confirmation of PICC position and further be generalized to include other types of vascular access and therapeutic support devices.


D2-40 negative pyogenic granuloma-like Kaposi's sarcoma: Diagnostic features and histogenetic hypothesis of an uncommon skin tumor in HIV-negative patients.
Pyogenic granuloma-like Kaposi's sarcoma (PGLKS) is a recently described skin tumor showing features both of pyogenic granuloma (PG) and Kaposi's sarcoma (KS). The differential diagnosis is often challenging. We reviewed a series of 50 PG and 23 Ks located on distal extremities with the aid of an immunohistochemical panel comprising CD34, CD31, FVIII, SMA, D2-40, HHV8. After revision, 6/50 PG lesions previously diagnosed as PG, showed positive immunostaining for LNA1-HHV8 and focal positivity for CD31 and FVIII in the endothelial cells of the proliferating vessels, with some SMA positive pericytes. D2-40, a marker of lymphatic endothelium positive in KS, stained negatively. These lesions were renamed PGLKS. Of note, in our series, PGLKS represented the only form of KS localized in the hand; all the patients were HIV-negative, older than PG patients, with a prevalence for male gender. PGLKS and PG need a different management and a follow-up is advisable for PGLKS, as for the other variants of KS. To date, D2-40 negative immunostaining has not yet been reported in PGLKS and should not lead to a misdiagnosis of PG. The morphological similarities with PG and the immunohistochemical findings, showing a defective phenotype of the neoplastic cells, suggest a histogenetic hypothesis in which D2-40 negative PGLKS could represent an early stage of HHV8 infection of a pre-existing PG, whose vessels loose progressively their blood vascular markers but have not still acquired the lymphatic ones.


fMRI brain activation in patients with insomnia disorder during a working memory task.
This study used functional magnetic resonance imaging (fMRI) to investigate differences in the functional brain activation of patients with insomnia disorder (n = 21, mean age = 36.6) and of good sleepers (n = 26, mean age = 33.2) without other comorbidities or structural brain abnormalities during a working memory task. All participants completed a clinical questionnaire, were subjected to portable polysomnography (PSG), and performed the working memory task during an fMRI scan. The subjects who were suspected of major sleep disorder and comorbid psychiatric disorders except insomnia disorder were excluded. To compare the brain activation on working memory from the insomnia group with those from the good-sleeper group, a two-sample t test was performed. Statistical significance was determined using 3DClustSim with the updated algorithm to obtain a reasonable cluster size and p value for each analysis. We observed higher levels of brain activation in the right lateral inferior frontal cortex and the right superior temporal pole in the insomnia group compared to good sleepers (cluster-based multiple comparison correction, p < 0.001, k = 34 @ α = 0.01). Thus, patients with insomnia disorder showed increased brain activation during working memory relative to good sleepers, and this may be indicative of compensatory brain activation to maintain cognitive performance in patients with insomnia disorder without other comorbidities.


A Novel Temporal Similarity Measure for Patients Based on Irregularly Measured Data in Electronic Health Records.
Patient similarity measurement is an important tool for cohort identification in clinical decision support applications. A reliable similarity metric can be used for deriving diagnostic or prognostic information about a target patient using other patients with similar trajectories of health-care events. However, the measure of similar care trajectories is challenged by the irregularity of measurements, inherent in health care. To address this challenge, we propose a novel temporal similarity measure for patients based on irregularly measured laboratory test data from the Multiparameter Intelligent Monitoring in Intensive Care database and the pediatric Intensive Care Unit (ICU) database of Children's Healthcare of Atlanta. This similarity measure, which is modified from the Smith Waterman algorithm, identifies patients that share sequentially similar laboratory results separated by time intervals of similar length. We demonstrate the predictive power of our method; that is, patients with higher similarity in their previous histories will most likely have higher similarity in their later histories. In addition, compared with other non-temporal measures, our method is stronger at predicting mortality in ICU patients diagnosed with acute kidney injury and sepsis. H.3.3 [Information Storage and Retrieval]: Retrieval models and rankings - similarity measures; J.3 [Applied Computing]: Life and medical sciences - health and medical information systems. Algorithm.