Dose escalation to hypoxic subvolumes in head and neck cancer: A randomized phase II study using dynamic [18F]FMISO PET/CT.
Tumor hypoxia is a major cause of resistance to radiochemotherapy in locally advanced head-and-neck cancer (LASCCHN). We present results of a randomized phase II trial on hypoxia dose escalation (DE) in LASCCHN based on dynamic [18F]FMISO (dynFMISO) positron emission tomography (PET). The purpose was to confirm the prognostic value of hypoxia PET and assess feasibility, toxicity and efficacy of hypoxia-DE. Patients with LASCCHN underwent baseline dynFMISO PET/CT. Hypoxic volumes (HV) were derived from dynFMISO data. Patients with hypoxic tumors (HV > 0) were randomized into standard radiotherapy (ST: 70Gy/35fx) or dose escalation (DE: 77Gy/35fx) to the HV. Patients with non-hypoxic tumors were treated with ST. After a minimum follow-up of 2 years feasibility, acute/late toxicity and local control (LC) were analyzed. The study was closed prematurely due to slow accrual. Between 2009 and 2017, 53 patients were enrolled, 39 (74%) had hypoxic tumors and were randomized into ST or DE. For non-hypoxic patients, 100% 5-year LC was observed compared to 74% in patients with hypoxic tumors (p = 0.039). The difference in 5-year LC between DE (16/19) and ST (10/17) was 25%, p = 0.150. No relevant differences related to acute and late toxicities between the groups were observed. This study confirmed the prognostic value of hypoxia PET in LASCCHN for LC. Outcome after hypoxia DE appears promising and may support the concept of DE. Slow accrual and premature closure may partly be due to a high complexity of the study setup which needs to be considered for future multicenter trials.


Propofol-Induced Masseter Muscle Spasm in a Woman with a Major Depressive Disorder.
Masseter muscle rigidity is a known complication of drugs such as succinylcholine and volatile agents. However, muscle rigidity is an uncommon complication of propofol. We report the case of a 56-year-old ASA-PS class I woman refereeing for colonoscopy due to chronic constipation under deep intravenous sedation. She suffered masseter spasm after the injection of propofol. Masseter spasm should not be considered limited to special drug groups. In any case of difficult mouth opening, masseter spasm should be kept in mind and deepening of anesthesia or complete blockade of neuromuscular junction should be considered by the use of non-depolarizing muscle relaxants.


[Medial femoral neck fracture. Controversies in treatment].
The treatment of the medial femoral neck fracture remains controversial until today. The goal of this paper is therefore, based on the literature, to show guidelines for optimal treatment: conservative treatment vs. operation, osteosynthesis vs. prosthesis, timing for osteosynthesis, open vs. closed reduction, choice of implant for osteosynthesis, postoperative treatment (weight bearing vs. non weight bearing), Pauwels-Osteotomy vs. prosthesis in cases op pseudarthrosis, femoral head prosthesis vs. total hip arthroplasty, bipolar vs. monopolar femoral head prosthesis, choice of classification. Further we want to point out which statements are evidence based and where we need further investigation.


Patient-reported experiences of cancer care related to the COVID-19 pandemic in Switzerland.
This study aims to describe the experience of Swiss oncological patients during the COVID-19 pandemic. A national multi-center study including five hospitals covering the three main language regions of Switzerland was conducted between March and July 2021. Patients with melanoma, breast, lung, or colon cancer receiving active systemic anti-cancer treatment at the time of the COVID-19 pandemic were included. We conducted semi-structured telephone or onsite interviews alongside the administration of distress and resilience-validated questionnaires. Thematic analysis was performed for the qualitative data and descriptive statistics for the quantitative data. Sixty-two cancer patients with a mean age of 61 (SD=14) (58% female) were interviewed. Based on the interviews, we identified that the experience of having cancer during the COVID-19 pandemic was related to five dimensions: psychological, social, support, healthcare, and vaccination. Three themes transverse the five dimensions: (a) needs, (b) positive changes, and (c) phases of the pandemic. In general, patients did not experience delays or disruptions in their cancer treatment nor felt additionally burdened by the pandemic. Lockdown and isolation were reported as mixed experiences (positive and negative), and access to vaccination reassured patients against the risk of infection and instilled hope to return to normalcy. Additionally, we found low distress levels (M=2.9; SD=2.5) and high resilience scores (M=7; SD=1.3) in these patients. Swiss patients with cancer did not express major needs or disruptions in their care during this period of the COVID-19 pandemic. Results identify the mixed experiences of patients and highlight the high resilience levels.


PCNA degradation exhibits superior pharmacological effects over stoichiometric inhibition.
In this issue of Cell Chemical Biology, Chang et al. report that a PCNA-targeting bioPROTAC, an engineered E3 ligase linked to a PCNA-binding peptide, has superior pharmacological effects over inhibition of PCNA. Their findings demonstrate the feasibility of translating bioPROTACs from a concept to a candidate therapeutic modality.


Real life adherence of chronic hepatitis B patients to entecavir treatment.
Real-life prospective data on adherence to nucleos(t)ide analogues in chronic hepatitis B patients are scarce. We investigated adherence to entecavir in relation to virological response. In this prospective study, we provided 100 consecutive chronic hepatitis B patients with a medication dispenser that monitored entecavir intake during 16 weeks therapy. Hepatitis B virus (HBV) DNA was measured at baseline and after 16 weeks. Beliefs about medicines were evaluated using a questionnaire. Adherence over 16 weeks averaged 85 ± 17%, with 70% of patients exhibiting good (i.e. ≥ 80%) adherence. Patients with poor (i.e. <80%) adherence were significantly younger (p=0.01), with more often indifferent attitudes towards entecavir (p=0.03) Viral breakthrough did not occur during the study. Adherence in patients with HBV DNA after 16 weeks > 20 IU/mL (n=18) and ≤ 20 IU/mL (n=81) averaged 83% and 91% respectively (p=0.19). In multivariate analysis, adherence was not a significant predictor of HBV DNA negativity (adjusted OR 1.02; p=0.34), after adjustment for duration of entecavir treatment (p<0.001) and HBe-status (p=0.001). 70% of chronic hepatitis B patients exhibited good adherence to entecavir, with younger age and an indifferent attitude being risk factors for poor adherence. Poor adherence was not an independent predictor of virological response.


Silent information regulator 1 protects the brain against cerebral ischemic damage.
Sirtuin 1 (SIRT1) is a member of NAD+-dependent protein deacetylases implicated in a wide range of cellular functions and has beneficial properties in pathologies including ischemia/reperfusion processes and neurodegeneration. However, no direct evidence has been reported on the direct implication of SIRT1 in ischemic stroke. The aim of this study was to establish the role of SIRT1 in stroke using an experimental model in mice. Wild-type and Sirt1-/- mice were subjected to permanent focal ischemia by permanent ligature. In another set of experiments, wild-type mice were treated intraperitoneally with vehicle, activator 3 (SIRT1 activator, 10 mg/kg), or sirtinol (SIRT1 inhibitor, 10 mg/kg) for 10 minutes, 24 hours, and 40 hours after ischemia. Brains were removed 48 hours after ischemia for determining the infarct volume. Neurological outcome was evaluated using the modified neurological severity score. Exposure to middle cerebral artery occlusion increased SIRT1 expression in neurons of the ipsilesional mouse brain cortex. Treatment of mice with activator 3 reduced infarct volume, whereas sirtinol increased ischemic injury. Sirt1-/- mice displayed larger infarct volumes after ischemia than their wild-type counterparts. In addition, SIRT1 inhibition/deletion was concomitant with increased acetylation of p53 and nuclear factor κB (p65). These results support the idea that SIRT1 plays an important role in neuroprotection against brain ischemia by deacetylation and subsequent inhibition of p53-induced and nuclear factor κB-induced inflammatory and apoptotic pathways.


Proteomic view of mitochondrial function.
Genomic and proteomic studies have identified hundreds of proteins from mitochondria. A recent study has added a functional twist to these systematic approaches and identified novel mitochondrial modifiers and regulators.


Prenatal SSRI alters the hormonal and behavioral responses to stress in female mice: Possible role for glucocorticoid resistance.
Life time prevalence of major depression disorder (MDD) is higher in women compared to men especially during the period surrounding childbirth. Women suffering from MDD during pregnancy use antidepressant medications, particularly Selective Serotonin Reuptake Inhibitors (SSRI). These drugs readily cross the placental barrier and impact the developing fetal brain. The present study assessed the effects of prenatal exposure to fluoxetine (FLX), an SSRI antidepressant drug, on corticosterone and behavioral responses to stress in female mice. In young females, prenatal FLX significantly elevated corticosterone response to continuous stress. In adults, prenatal FLX augmented corticosterone response to acute stress and suppressed the response to continuous stress. Additionally, prenatal FLX significantly augmented stress-induced increase in locomotion and reduced anxiety- and depressive-like behaviors in adult, but not young mice. The dexamethasone suppression test revealed that prenatal FLX induced a state of glucocorticoid resistance in adult females, indicating that the negative feedback control of the hypothalamic-pituitary-adrenal axis response to stress was disrupted. These findings provide the first indication of altered hormonal and behavioral responses to continuous stress and suggest a role for the development of glucocorticoid resistance in these effects. According to these findings, prenatal environment may have implications for stress sensitivity and responsiveness to life challenges. Furthermore, this study may assist in understanding the limitations and precautions that should be taken in the use of SSRIs during pregnancy.


Fully Light-Controlled Memory and Neuromorphic Computation in Layered Black Phosphorus.
Imprinting vision as memory is a core attribute of human cognitive learning. Fundamental to artificial intelligence systems are bioinspired neuromorphic vision components for the visible and invisible segments of the electromagnetic spectrum. Realization of a single imaging unit with a combination of in-built memory and signal processing capability is imperative to deploy efficient brain-like vision systems. However, the lack of a platform that can be fully controlled by light without the need to apply alternating polarity electric signals has hampered this technological advance. Here, a neuromorphic imaging element based on a fully light-modulated 2D semiconductor in a simple reconfigurable phototransistor structure is presented. This standalone device exhibits inherent characteristics that enable neuromorphic image pre-processing and recognition. Fundamentally, the unique photoresponse induced by oxidation-related defects in 2D black phosphorus (BP) is exploited to achieve visual memory, wavelength-selective multibit programming, and erasing functions, which allow in-pixel image pre-processing. Furthermore, all-optically driven neuromorphic computation is demonstrated by machine learning to classify numbers and recognize images with an accuracy of over 90%. The devices provide a promising approach toward neurorobotics, human-machine interaction technologies, and scalable bionic systems with visual data storage/buffering and processing.


Characterization of GEXP15 as a Potential Regulator of Protein Phosphatase 1 in Plasmodium falciparum.
The Protein Phosphatase type 1 catalytic subunit (PP1c) (PF3D7_1414400) operates in combination with various regulatory proteins to specifically direct and control its phosphatase activity. However, there is little information about this phosphatase and its regulators in the human malaria parasite, Plasmodium falciparum. To address this knowledge gap, we conducted a comprehensive investigation into the structural and functional characteristics of a conserved Plasmodium-specific regulator called Gametocyte EXported Protein 15, GEXP15 (PF3D7_1031600). Through in silico analysis, we identified three significant regions of interest in GEXP15: an N-terminal region housing a PP1-interacting RVxF motif, a conserved domain whose function is unknown, and a GYF-like domain that potentially facilitates specific protein-protein interactions. To further elucidate the role of GEXP15, we conducted in vitro interaction studies that demonstrated a direct interaction between GEXP15 and PP1 via the RVxF-binding motif. This interaction was found to enhance the phosphatase activity of PP1. Additionally, utilizing a transgenic GEXP15-tagged line and live microscopy, we observed high expression of GEXP15 in late asexual stages of the parasite, with localization predominantly in the nucleus. Immunoprecipitation assays followed by mass spectrometry analyses revealed the interaction of GEXP15 with ribosomal- and RNA-binding proteins. Furthermore, through pull-down analyses of recombinant functional domains of His-tagged GEXP15, we confirmed its binding to the ribosomal complex via the GYF domain. Collectively, our study sheds light on the PfGEXP15-PP1-ribosome interaction, which plays a crucial role in protein translation. These findings suggest that PfGEXP15 could serve as a potential target for the development of malaria drugs.


Interplay of global multi-scale human mobility, social distancing, government interventions, and COVID-19 dynamics.
This work quantifies mobility changes observed during the different phases of the pandemic world-wide at multiple resolutions -- county, state, country -- using an anonymized aggregate mobility map that captures population flows between geographic cells of size 5 km 2 . As we overlay the global mobility map with epidemic incidence curves and dates of government interventions, we observe that as case counts rose, mobility fell and has since then seen a slow but steady increase in flows. Further, in order to understand mixing within a region, we propose a new metric to quantify the effect of social distancing on the basis of mobility.Taking two very different countries sampled from the global spectrum, We analyze in detail the mobility patterns of the United States (US) and India. We then carry out a counterfactual analysis of delaying the lockdown and show that a one week delay would have doubled the reported number of cases in the US and India. Finally, we quantify the effect of college students returning back to school for the fall semester on COVID-19 dynamics in the surrounding community. We employ the data from a recent university outbreak (reported on August 16, 2020) to infer possible R eff values and mobility flows combined with daily prevalence data and census data to obtain an estimate of new cases that might arrive on a college campus. We find that maintaining social distancing at existing levels would be effective in mitigating the extra seeding of cases. However, potential behavioral change and increased social interaction amongst students (30% increase in R eff ) along with extra seeding can increase the number of cases by 20% over a period of one month in the encompassing county. To our knowledge, this work is the first to model in near real-time, the interplay of human mobility, epidemic dynamics and public policies across multiple spatial resolutions and at a global scale.


Space is a late heuristic of elapsing time: New evidence from the STEARC effect.
To get a concrete representation of its intangible flow, culture frames elapsing time along spatially oriented mental or graphical lines, which are organised according to reading habits, from left to right in western cultures. One of the strongest evidence for this spatial representation of time is the STEARC effect (Spatial-Temporal Association of Response Codes), which consists of faster coding of "short" durations with motor responses in the left side of space and of "long" durations with responses in the right side. Here, we investigated the STEARC as a function of response speed in two different experiments in healthy participants. Surprisingly, in both sub- and supra-second ranges, we found the STEARC only when decisions on time durations were slow, while no spatial representation of time was present with fast decisions. This first demonstrates that space slowly takes over faster non-spatial processing of time flow and that it is possible to empirically separate the behavioural manifestations of the non-spatial and the nurtured spatial mechanisms of time coding.


Disturbance of sleep maintenance, but not sleep duration, activates nuclear factor-κB and signal transducer and activator of transcription family proteins in older adults: sex differences.
Disturbances of sleep maintenance and sleep duration are common in older adults and associated with an increased risk for age-related mortality and morbidity. Converging evidence implicates inflammation as an underlying mechanism, especially in females. However, it is unknown what specific aspects of sleep disturbance impact inflammatory mechanisms in older adults. Using data from community-dwelling older adults who participated in the Sleep Health and Aging Research (SHARE) field study (n = 262, mean age 71.9 ± 8.0 years), we conducted a secondary analysis to examine whether disturbance of sleep maintenance (i.e. greater amount of wake time after sleep onset [WASO]) and sleep duration (i.e. shorter total sleep time [TST]) assessed by sleep diary and actigraphy are associated with greater activation of nuclear factor (NF)-κB and signal transducer and activator of transcription (STAT) family proteins STAT1, STAT3, and STAT5 in peripheral blood monocytic cells. In addition, moderation effects of sex were explored. Data were available for sleep diary (n = 82), actigraphy (n = 74), and inflammatory signaling and transcriptional measures (n = 132). As assessed by sleep diary, greater amount of WASO (β = 0.39, p < 0.01), but not TST, was associated with higher levels of NF-κB. Whereas diary-assessed sleep measures were not associated with STAT family proteins, a moderation analysis revealed that greater diary-assessed WASO was associated with higher levels of STAT1 (p < 0.05), STAT3 (p < 0.05), and STAT5 (p < 0.01) in females, but not in males. Actigraphy-assessed sleep measures were not associated either with NF-κB or STAT activation. In older adults, self-reported disturbance of sleep maintenance assessed by sleep diary was uniquely associated with higher levels of NF-κB, along with higher levels of STAT family proteins in females, but not in males. Our data suggest that improvingself-reported sleep maintenance might mitigate age-related increases in inflammatory signaling and transcriptional pathways, possibly more strongly in females, with the potential to reduce mortality risk in older adults.


Analysis of polymorphisms and haplotypes in genes associated with vascular tone, hypertension and oxidative stress in Mexican-Mestizo women with severe preeclampsia.
Several studies have reported the association of genes related to vascular tone, hypertension, oxidative stress and preeclampsia. We investigated the possible association among three polymorphisms in eNOS (as well their haplotypes): one of MTHFR, one of GSTP1 and one of AGT, with severe preeclampsia in Mexican-Mestizo women. Two hundred thirty women with severe preeclampsia and 350 control subjects were genotyped; for rs2070744 and rs1799983 of eNOS, rs1801133 of MTHFR, rs1695 of GSTP1 and rs699 of AGT we used real-time PCR allelic discrimination and for VNTR of eNOS, PCR. Allele frequency differences were assessed by χ(2). Logistic regression was used to test for associations and for haplotype frequencies using Haploview 4.2. Genotypic and allelic distribution of the polymorphisms was similar between cases and controls; likewise, haplotype frequencies of the three polymorphisms of eNOS did not differ significantly. To our knowledge, this is the first time that these polymorphisms have been analyzed together and exclusively in women with severe preeclampsia. However, we did not find an association between polymorphisms of eNOS, MTHFR, GSTP1 and AGT with severe preeclampsia in our population. Additionally, we observed differences in the distribution of the alleles and genotypes of these polymorphisms in our population in comparison to those described in other ethnic groups.


Biotransport of persistent organic pollutants in the southern Hemisphere by invasive Chinook salmon (Oncorhynchus tshawytscha) in the rivers of northern Chilean Patagonia, a UNESCO biosphere reserve.
Biotransport is often associated with migration patterns of species, including large, anadromous salmonids. Several studies have reported biotransport of persistent organic pollutants in the Northern Hemisphere, but there is no published information on biotransport ocurring south of the equator. Chile's Patagonia is one of the last largely intact natural areas in the world. The objective of this study was to determine whether persistent organic pollutants are transported by the invasive Pacific Chinook salmon (O. tshawytscha) from the Pacific Ocean to Chilean Patagonia. Samples of juvenile and adult Chinook salmon were analyzed for polychlorinated biphenyls, pesticides and polybrominated diphenyl ethers. The results revealed that concentrations of POPs in adults migrating into Patagonian rivers were significantly higher than those found in juveniles migrating seaward. A mass balance analysis indicates that Chinook salmon are a source of persistent organic pollutants to Chilean Patagonia inland waters. Capsule: Biotransport of Persistent Organic Pollutants (POPs) by Chinook salmon (O. tshawytscha) from the Pacific Ocean to Chilean Patagonia has been confirmed by mass balance of POPs.


Angiotensin II signal transduction pathways.
It has been 100 years since the discovery of renin by Tigerstedt and Bergman. Since that time, numerous discoveries have advanced our understanding of the renin-angiotensin system, including the observation that angiotensin II is the effector molecule of this system. A remarkable aspect of angiotensin II is the many different physiological responses this simple peptide induces in different cell types. Here, we focus on the signal transduction pathways that are activated as a consequence of angiotensin II binding to the AT1 receptor. Classical signaling pathways such as the activation of heterotrimeric G proteins by the AT1 receptor are discussed. In addition, recent work examining the role of tyrosine phosphorylation in angiotensin II-mediated signal transduction is also examined. Understanding how these distinct signaling pathways transduce signals from the cell surface will advance our understanding of how such a simple molecule elicits such a wide variety of specific cellular responses.


Reliability and validity of an instrument to describe burnout among collegiate athletic trainers.
The existing investigations of professional burnout among certified athletic trainers (ATs) were conducted before 2000. Since 2000, several educational and legal changes have redefined the job duties and responsibilities of the AT working in collegiate athletics. To develop an instrument to determine factors that contribute to burnout in ATs employed within the collegiate athletics setting. Descriptive study. National Collegiate Athletic Association (NCAA) Division I-A universities. Instrument design experts and ATs employed in various NCAA Division I-A athletic programs. The Athletic Training Burnout Inventory (ATBI) included the Maslach Burnout Inventory (18 items) plus 45 new items to address established factors that lead to burnout and to address workload issues specific to athletic training. We initially developed 3 constructs (emotional exhaustion and depersonalization, level of stress, and level of organizational support) and included them in the 2 field tests and first pilot test of the ATBI. For the second pilot test, the instrument comprised 4 constructs: emotional exhaustion and depersonalization, administrative responsibility, time commitment, and organizational support. The 2 field tests were conducted to establish face and content validity of the ATBI. Reliability analyses were conducted twice on the 2 separate pilot tests using a Cronbach alpha set a priori at .70 and an item-to-total correlation. The second pilot test of the ATBI with the 4 constructs was determined reliable (emotional exhaustion and depersonalization, alpha = .85; administrative responsibility, alpha = .82; time commitment, alpha = .86; and organizational support, alpha = .80); however, some items within 2 constructs appeared suspect with low item-to-total correlations (<0.25). The second administration of the ATBI produced an acceptable response rate. All 4 constructs were reliable; however, the suspect items within the constructs need further investigation. Researchers need to evaluate the conceptual worth of these items to the entire instrument.


Whose voice matters? The gaming sphere and the Blitzchung controversy in eSports.
With eSports and video games rapidly gaining popularity, we are witnessing a rise of semi-autonomous gaming communities. I propose using Alexander's civil sphere theory and my concept of the gaming sphere to understand the dynamics of the meaning-making processes herein. I ask: why did the Blitzchung controversy spark such outrage? I explore the hidden meanings behind the controversy where the professional Hearthstone eSports player Ng Wai Chung was punished for expressing his opinion during post-game interview by calling to "Liberate Hong Kong," losing $4000-all happening in the ostensibly apolitical gaming sphere. I first build the gaming sphere from the civil sphere, establishing the constitutive and communicative institutions of gaming as well as identifying the sacred and profane binary oppositions within the gaming sphere. Second, I provide a thick description and interpretation of the Blitzchung controversy using my concept of the gaming sphere. Lastly, I conclude that despite winning fairly, Blitzchung's punishment for being "political" was not removed entirely. However, as the civil sphere was invited into the gaming sphere, the controversy shifted toward Hong Kong protests. The gaming sphere was partially restored as apolitical, even supporting a noble cause, but the Blitzchung controversy never achieved full societalization.


Predictors and outcomes of tricuspid regurgitation improvement after radiofrequency catheter ablation for persistent atrial fibrillation.
Little has been reported on the predictors and outcomes of improvement of tricuspid regurgitation (TR) after radiofrequency catheter ablation (RFCA) for persistent atrial fibrillation (AF). We enrolled 141 patients with persistent AF and moderate or severe TR assessed by transthoracic echocardiography (TTE) who underwent an initial RFCA between February 2015 and August 2021. These patients underwent follow-up TTE at 12 months after the RFCA, and were categorized into two groups based on the improvement (defined as at least one-grade improvement of TR) and non-improvement of TR: IM group and Non-IM group, respectively. We compared the patient characteristics, ablation procedures, and recurrences after the RFCA between the two groups. In addition, we examined the major event (defined as admission for heart failure or all-cause death) more than 12 months after the RFCA. IM group consisted of 90 patients (64%). A multivariate analysis revealed that age <71 years old and absence of late recurrence (LR, defined as recurrence of atrial tachyarrhythmia between 3 and 12 months after the RFCA) were independently associated with the improvement of TR after the RFCA. Furthermore, IM group had the higher incidence of major event-free survival than Non-IM group. Relatively young age and absence of LR were good predictors of improvement of TR after the RFCA for persistent AF. In addition, the improvement of TR was related to better clinical outcomes.


Emission behavior and impact assessment of gaseous volatile compounds in two typical rural domestic waste landfills.
Landfill sites are sources of gaseous volatile compounds. The dumping area (LDA) and leachate storage pool (LSP) of two typical rural domestic waste landfill sites in north China (NLF) and southwest China (SLF) were investigated. We found that 45, 46, 61 and 68 volatile organic compounds (VOC) were present in the air of NLF-LDA, NLF-LSP, SLF-LDA, and SLF-LSP, respectively. And there were 27, 29, 35 and 37 kinds of odorous compounds being detected. Oxygenated compounds (>48.88%), chlorinated compounds (>6.85%), and aromatics (>5.46%), such as organic acid, 1-chlorobutane, and benzene, were the most abundant compounds in both landfills. The SLF-LDA had the highest olfactory effect, with a corresponding total odor activity value of 29,635.39. The ozone-formation potential analysis showed that VOCs emitted from SLF landfills had significantly higher potential for ozone formation than those from NLF landfills, with ozone generation potentials of 166.02, 225.86, 2511.82, and 1615.99 mg/m3 for the NLF-LDA, NLF-LSP, SLF-LDA, and SLF-LSP, respectively. Higher chronic toxicity and cancer risk of VOCs were found in the SLF according to method of Risk Assessment Information System. Based on the sensitivity analysis by the Monte Carlo method, concentrations of benzene, propylene oxide, propylene, trichloroethylene, and N-nitrosodiethylamine, along with exposure duration, daily exposure time, and annual exposure frequency, significantly impacted the risk levels. We provide a scientific basis, which reflects the need for controlling and reducing gaseous pollutants from landfills, particularly rural residential landfills, which may improve rural sanitation.


A facile synthesis of graphene oxide/locust bean gum hybrid aerogel for water purification.
Graphene oxide/locust bean gum (GO/LBG) aerogels, synthesized in an ice crystal template without using any chemical modifiers, were used for the treatment of water pollution. Various characterization results showed that GO/LBG aerogel exhibited a network-like three-dimensional (3D) structure with large specific surface area. The adsorption data revealed that GO/LBG aerogels with GO/LBG mass ratio of 1:4 (GO/LBG-1 aerogels) exhibited more prominent adsorption properties for Rhodamine-B (RhB, 514.5 mgg-1) than Indigo Carmine (IC, 134.6 mgg-1). Simultaneously, GO/LBG-1 aerogels could selectively remove RhB from a binary mixed solution of RhB-IC dyes. Furthermore, GO/LBG-1 aerogels also displayed excellent reusability and could still reach 92.4 % after ten cycles. Based on the above results, GO/LBG-1 aerogel could be considered as an ideal adsorbent with potential application value for removing water-soluble RhB from wastewater.


Cell Death, Inflammation and Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Cytoprotective Molecules.
Neurodegenerative diseases are the most common chronic neurological pathologies associated with age, with a major impact on the patient's quality of life [...].


The interaction between histamine H1 receptor and μ- opioid receptor in scratching behavior in ICR mice.
In this study, we examined the interaction between histamine H1 receptor and μ-opioid receptor in scratching behavior in ICR mice. Both histamine and morphine caused scratching and simultaneous injection of histamine and morphine had an additive effect. Chlorpheniramine and naloxone inhibited histamine-induced scratching behavior. These two drugs also inhibited morphine-induced scratching behavior. Simultaneous injection of chlorpheniramine and naloxone caused a significant inhibition of histamine-induced scratching compared with separate injections. The same findings were also noted for morphine-induced scratching. These results strongly indicate a close relationship between histamine H1 receptor and μ-opioid receptor in scratching behavior in ICR mice.


Variations in soil N cycling and trace gas emissions in wet tropical forests.
We used a previously described precipitation gradient in a tropical montane ecosystem of Hawai'i to evaluate how changes in mean annual precipitation (MAP) affect the processes resulting in the loss of N via trace gases. We evaluated three Hawaiian forests ranging from 2200 to 4050 mm year-1 MAP with constant temperature, parent material, ecosystem age, and vegetation. In situ fluxes of N2O and NO, soil inorganic nitrogen pools (NH4+ and NO3-), net nitrification, and net mineralization were quantified four times over 2 years. In addition, we performed 15N-labeling experiments to partition sources of N2O between nitrification and denitrification, along with assays of nitrification potential and denitrification enzyme activity (DEA). Mean NO and N2O emissions were highest at the mesic end of the gradient (8.7+/-4.6 and 1.1+/-0.3 ng N cm-2 h-1, respectively) and total oxidized N emitted decreased with increased MAP. At the wettest site, mean trace gas fluxes were at or below detection limit (<or=0.2 ng N cm-2 h-1). Isotopic labeling showed that with increasing MAP, the source of N2O changed from predominately nitrification to predominately denitrification. There was an increase in extractible NH4+ and decline in NO3- , while mean net mineralization and nitrification did not change from the mesic to intermediate sites but decreased dramatically at the wettest site. Nitrification potential and DEA were highest at the mesic site and lowest at the wet site. MAP exerts strong control N cycling processes and the magnitude and source of N trace gas flux from soil through soil redox conditions and the supply of electron donors and acceptors.


Higher expression of latency-associated peptide on the surface of peripheral blood monocytes in patients with rheumatoid arthritis may be protective against articular erosions.
Latency-associated peptide (LAP) forms small latent complexes with transforming growth factor beta 1 (TGF-β1). TGF-β-LAP complexes can be detected on the surfaces of immune cells and have been recently shown to play a role in immune regulation through TGF-β1-mediated functions. A study was undertaken to investigate the correlation of LAP expression on the surface of immune cells and presence of articular erosions in patients with rheumatoid arthritis (RA). Venous blood was obtained from patients with severe RA as well as from healthy control subjects. Surface expression of LAP on peripheral blood mononuclear cells was analyzed by flow cytometry, measured as flow cytometric intensity separately on CD14(+) and CD14(-) cells, and compared between RA patients and healthy subjects. Patients with RA demonstrated higher surface expression of LAP on both CD14(+) and CD14(-) mononuclear cells than healthy individuals. Patients with erosive RA had significantly reduced intensity of anti-LAP staining on the CD14(+) cells when compared to RA patients without erosions (p = 0.01). The intensity of anti-LAP staining on CD14(-) cells was not different between groups of RA patients. Higher expression of LAP on the surface of the cells of monocyte lineage may be protective of formation of articular erosions in RA. Further studies are needed to elaborate the mechanism of this phenomenon.


The combination of chemical fixation procedures with high pressure freezing and freeze substitution preserves highly labile tissue ultrastructure for electron tomography applications.
The emergence of electron tomography as a tool for three dimensional structure determination of cells and tissues has brought its own challenges for the preparation of thick sections. High pressure freezing in combination with freeze substitution provides the best method for obtaining the largest volume of well-preserved tissue. However, for deeply embedded, heterogeneous, labile tissues needing careful dissection, such as brain, the damage due to anoxia and excision before cryofixation is significant. We previously demonstrated that chemical fixation prior to high pressure freezing preserves fragile tissues and produces superior tomographic reconstructions compared to equivalent tissue preserved by chemical fixation alone. Here, we provide further characterization of the technique, comparing the ultrastructure of Flock House Virus infected DL1 insect cells that were (1) high pressure frozen without fixation, (2) high pressure frozen following fixation, and (3) conventionally prepared with aldehyde fixatives. Aldehyde fixation prior to freezing produces ultrastructural preservation superior to that obtained through chemical fixation alone that is close to that obtained when cells are fast frozen without fixation. We demonstrate using a variety of nervous system tissues, including neurons that were injected with a fluorescent dye and then photooxidized, that this technique provides excellent preservation compared to chemical fixation alone and can be extended to selectively stained material where cryofixation is impractical.


Quantification of Muscle Satellite Stem Cell Divisions by High-Content Analysis.
High-content screening is commonly performed on 2D cultured cells, which is high throughput but has low biological relevance. In contrast, single myofiber culture assay preserves the satellite cell niche between the basal lamina and sarcolemma and consequently has high biological relevance but is low throughput. We describe here a high-content screening method that utilizes single myofiber culture that addresses the caveats of both techniques. Our method utilizes the transgenic reporter allele Myf5-Cre:R26R-eYFP to differentiate stem and committed cells within a dividing couplet that can be quantified by high-content throughput immunodetection and bioinformatic analysis.


Suicidal thoughts in patients with Parkinson's disease treated by deep brain stimulation of the subthalamic nuclei: two case reports and review of the literature.
Deep brain stimulation (DBS) of the subthalamic nuclei (STN) can result in depression despite the obvious motor improvement. Two patients with serious life-threatening depressive episodes are described. In the first case, the trigger for depression was a slight adjustment of the left stimulating electrode's contact. In the second case, reducing both the dopaminergic therapy and the voltage of DBS resulted in the manifestation of depressive symptoms. DBS-induced depression possibly has pathogenetic differences from ordinary Parkinson's disease depression. The STN region seems to be a sensitive zone that influences emotions.


The complete mitochondrial genome of water flea Ceriodaphnia dubia (Crustacea: Cladocera) NIES strain.
Water flea Ceriodaphnia dubia has been widely used for risk assessments of chemicals and environmental contamination. In this study, the complete mitochondrial genome (mitogenome) of this species NIES strain was determined using short-read high throughput and long-read sequencing technologies. The mitogenome of C. dubia was 15,170 bp in length and consisted of 13 protein-coding genes (PCGs), 2 ribosomal RNAs (rRNAs), and 22 transfer RNAs (tRNAs). The gene order was identical to the pattern conserved across crustaceans. The complete mitogenome of the NIES strain will serve as genetical reference in ecological risk assessments in Japan, as well as resources for future phylogenetical studies using cladocerans.


Inhibition of human endothelial cell proliferation by ShIF, a vacuolar H(+)-ATPase-like protein.
ShIF is a bone marrow stroma cell-derived factor originally identified to support proliferation of bone marrow cells in vitro. This protein shares high sequence homology to the yeast vacuolar H(+)-ATPase subunit, Vph1p, and the 116 kDa proton pump of the rat and bovine synaptic vesicle, Vpp1. We examined the function of ShIF in the proliferation of human umbilical vein endothelial cells (HUVEC). ShIF inhibited HUVEC proliferation in a dose-dependent manner. Recombinant ShIF added at 10 and 20 ng/ml inhibited HUVEC proliferation by 21.6 and 44.3%, respectively and increasing the concentration of ShIF to 100 ng/ml inhibited proliferation by as much as 55.5%. When HUVEC cells were cultured at various concentrations of ShIF in the presence of anti-ShIF antibody, the inhibitory effects of ShIF to HUVEC proliferation were abrogated by 89-91% indicating that the activity of ShIF to HUVEC was specific. HUVEC cultured in the presence of ShIF and bafilomycin, a specific inhibitor of ATPase, resulted to a 90% growth inhibition. Thus, ShIF may act as an antagonist to the ATPase complex by disrupting the production of cellular ATP thereby decreasing the ability of HUVEC to proliferate.


Volar fixation of dorsally displaced distal radius fractures using the 2.4-mm locking compression plates.
To determine whether volar fixed-angle plate fixation with a new plate system could be used to treat dorsally unstable distal radius fractures. We hypothesized that volar fixed-angle plate fixation with or without radial styloid fixed-angle plate fixation would provide sufficient rigidity to allow early active range of motion without compromising fracture reduction. The initiation of early active motion may improve functional outcomes. A retrospective review was conducted of one institution's initial experience using a new volar fixed-angle plate system to treat dorsally displaced intra-articular and extra-articular distal radius fractures. Thirty-two fractures in 32 patients with dorsally displaced distal radius fractures were treated with a volar fixed-angle plate with or without a radial styloid fixed-angle plate. Fractures were classified using the AO classification. Radiographic parameters on preoperative, postoperative, and final follow-up radiographs were compared. The time to initiation of active range of motion was determined. Final follow-up ranges of motion and complications were reported. Finally, comparisons were made between the 23 fractures treated with a volar plate alone and the 9 fractures treated with a volar plate and a radial styloid plate. The average follow-up period was 13 months. Two thirds of the fractures were intra-articular. Average loss of reduction from initial postoperative to final follow-up radiographs was 0 degrees of volar tilt, 1 degrees of radial inclination, and 0 mm of radial length. Active wrist and forearm ranges of motion were initiated at an average of 11 days after surgery. The final follow-up flexion-extension and pronation-supination arcs averaged 112 degrees and 151 degrees , respectively. The 9 fractures treated with the combination of a fixed-angle volar plate with a fixed-angle radial styloid plate had greater initial displacement than did the 23 fractures treated with a volar plate alone. Otherwise, differences between the 2 groups were not significant. Only 1 radial styloid plate became symptomatic. Volar plate fixation using a new fixed-angle plate system successfully can stabilize dorsally unstable distal radius fractures. Early active range of motion was facilitated without compromising fracture reduction.


Modelling of n-Hexadecane bioremediation from soil by slurry bioreactors using artificial neural network method.
Diesel oil is known to be one of the major petroleum products that can pollute water and soil. Soil pollution caused by petroleum hydrocarbons has substantially impacted the environment, especially in the Middle East. In this study, modeling and optimization of hexadecane removal from soil was performed using two pure cultures of Acinetobacter and Acromobacter and consortium culture of both bacterial species using artificial neural network (ANN) method. Then the best ANN structure was proposed based on mean square error (MSE) as well as correlation coefficient (R) for pure cultures of Acinetobacter and Acromobacter as well as their consortium. The results showed that the correlations between the actual data and the data predicted by ANN (R2) in Acromobacter, Acinetobacter and consortium of both cultures were 0.50, 0.47 and 0.63, respectively. Despite the low correlation between the experimental data and the data predicted by the ANN, the correlation coefficient and the precision of ANN for the consortium was higher. As a result, ANN had desirable precision to predict hexadecan removal by the cobsertium culture of Ochromobater and Acintobacter.


Seasonal expression of arginine vasotocin mRNA and its correlations to gonadal steroidogenic enzymes and sexually dimorphic coloration during sex reversal in the gilthead seabream (Sparus aurata).
Arginine vasotocin is a hormone produced in the hypothalamus of teleost fish that has been shown to regulate gonad development and sexual behavior. To study the role of arginine vasotocin in the gonadal cycle of the hermaphrodite gilthead seabream, Sparus aurata, we cloned the seabream arginine vasotocin (avt) complementary DNA (cDNA). We investigated the expression of brain avt throughout the gonad cycle using real-time quantitative PCR and compared its expression levels to the expression levels of two key gonadal steroidogenic enzymes, cyp19a1a and cyp11b2. In July, when the process of sex reversal is thought to begin, avt expression was elevated over the previous 2 months. Avt in the brain remained at or above the level of July until November then peaked again in December. There was no difference between males and females in the expression levels of brain avt throughout the year. However, only in ambisexual fish was the expression of the cyp19a1a gonadal aromatase correlated to the expression of avt in the brain. Cyp11b2 did not show any correlation to brain avt expression. We also found that females had more intense body coloration than males and that this intensity peaked prior to spawning. Avt expression and female coloration were positively correlated. The fact that brain avt expression was lowest during gonad quiescence, together with the observation of a correlation between brain avt with gonadal cyp19a1a and body coloration during that time suggests that avt may play a role during the process of sex reversal and spawning of the gilthead seabream.


Physician weight influences responses to a public health message about the genetics of obesity.
Many patients prefer lean physicians to physicians with obesity and place higher credence in their weight management advice. Because genetic information about weight can be viewed as self-serving for individuals with overweight or obesity, physicians with obesity may be discounted when sharing such information. As provision of genetic information regarding weight becomes increasingly common in public health messaging, could a physician's own weight influence how these messages are received by the public? In an online survey, 967 participants were randomly assigned a physician profile (lean v. has obesity) with a media interview transcript discussing genetic factors of a common health condition (obesity v. osteoporosis). Participants perceived the physician with obesity who discussed genetic factors in obesity as less trustworthy and less credible. Participants were also less likely to anticipate following her advice on weight-related issues. Participants with higher BMI had less negative perceptions of this physician. Physicians with obesity, when providing public health messaging regarding genetic information about obesity, may be met with distrust and negative attitudes toward the physician. Future research should investigate health communication strategies that address this form of weight stigma while accurately conveying genetic factors that contribute to weight.


Wave space interpretation of scattered ultrasound.
Wave space is described nonmathematically for design and interpretation of ultrasound scattering experiments. By considering ultrasound scattering from a variety of targets and geometries, the wave space approach is shown to describe target characteristics in terms of spatial frequencies and their amplitudes. Experimental limitations for determining effective spacing of scattering structures and scattering medium anisotropy are discussed.


The function of BED finger domain of Zbed3 in regulating lung cancer cell proliferation.
Zbed3, a BED finger domain-containing protein was found to promote cancer proliferation by regulating β-catenin expression through interacting with Axin. But whether and how BED finger domain function in regulating cancer proliferation is unknown. We constructed five mutants of Zbed3, which lacks the Axin-Zbed3 binding site, and the 43 to 52, 69 to 77, 87 to 92, and 97 to 104 sequences in BED finger domain, respectively and named them as Z-A, Z1, Z2, Z3, and Z4. Transfection of both wild-type of Zbed3 and the mutants Z1, Z3, and Z4 (P < 0.05), but not Z2 (P > 0.05) significantly upregulated β-catenin expression in NCI-H1299 cells. Overexpression of both wild-type of Zbed3 and the mutants Z1, Z3, and Z4 (P < 0.05) but not Z2 (P > 0.05) significantly promoted cancer cell proliferation and invasion. The ability of proliferation (P < 0.05) but not invasion (P < 0.05) of cancer cells transfected with Z1 and Z4 was significantly lower than that with wild-type Zbed3 and Z3. Overexpression of wild-type Zbed3 (P < 0.05) but not the mutant Z-A, which lacks the binding site with Axin and Z2 (P > 0.05) significantly upregulated the interaction of Axin and Zbed3, β-catenin expression and the activity of Wnt signaling. Both overexpression of wild-type Zbed3 and the mutant Z1 and Z4 significantly upregulated the activity of Wnt signaling and promoted cancer cell proliferation (P < 0.05) but only overexpression of wild-type Zbed3 (P < 0.05), but not the mutant Z1, and Z4 (P > 0.05), significantly upregulated the expression of proliferating cell nuclear antigen (PCNA) in NCI-H1299 cells. These results indicate that Zbed3 may promote lung cancer cell proliferation through regulating PCNA expression besides regulating β-catenin expression and BED finger domain can impact on this function.


Sudden death and laryngeal papillomatosis: a case report.
Laryngeal papillomatosis is an uncommon respiratory disease. Often misdiagnosed, it can cause acute respiratory insufficiency, quickly fatal if not promptly faced. A case of sudden death due to laryngeal papillomatosis is described in a woman presenting to the Emergency Department (ED). Laryngeal obstruction was not diagnosed in previous medical examinations nor recognised at the time of attempted intubation in ED; only post-mortem investigation allowed discovering a large fleshy mass occluding the larynx in the region of the vocal folds.


Improving the efficiency and biosafety of respiratory syncytial virus identification using a nucleic acid extraction-free reagent.
Respiratory syncytial virus (RSV) is the most important virus that causes lower respiratory tract disease in children; efficient viral identification is an important component of disease prevention and treatment. Here, we developed and evaluated a ready-to-use (RTU) nucleic acid extraction-free direct reagent for identification of RSV (RTU-Direct test) in clinical samples. The limit of detection (LOD) of the RSV RTU-Direct test was consistent with the LOD of the standard test using extracted nucleic acids. The virus inactivation ability of RTU-Direct reagent was confirmed by viral infectivity assays involving RTU-Direct-treated samples containing RSV and human coronavirus OC43. RSV RNA stability was significantly better in RTU-Direct reagent than in conventional virus transport medium (VTM) at room temperature and 4°C (p < 0.05). The clinical performance of the RTU-Direct test was evaluated using 155 respiratory specimens from patients with suspected RSV infection. Positive agreement between the RTU-Direct test and the VTM standard test was 100% (42/42); negative agreement was 99.1% (112/113), and the kappa statistic was 0.968 (p < 0.001). The distributions of Ct values did not significantly differ between the RTU-Direct test and the standard test (p > 0.05). Overall, the RTU-Direct reagent can improve the efficiency and biosafety of RSV detection, while reducing the cost of detection.


Deltamethrin-mediated survival, behavior, and oenocyte morphology of insecticide-susceptible and resistant yellow fever mosquitos (Aedes aegypti).
Insecticide use is the prevailing control tactic for the mosquito Aedes aegypti, a vector of several human viruses, which leads to ever-increasing problems of insecticide resistance in populations of this insect pest species. The underlying mechanisms of insecticide resistance may be linked to the metabolism of insecticides by various cells, including oenocytes. Oenocytes are ectodermal cells responsible for lipid metabolism and detoxification. The goal of this study was to evaluate the sublethal effects of deltamethrin on survival, behavior, and oenocyte structure in the immature mosquitoes of insecticide-susceptible and resistant strains of A. aegypti. Fourth instar larvae (L4) of both strains were exposed to different concentrations of deltamethrin (i.e., 0.001, 0.003, 0.005, and 0.007 ppm). After exposure, L4 were subjected to behavioral bioassays. Insecticide effects on cell integrity after deltamethrin exposure (at 0.003 or 0.005 ppm) were assessed by processing pupal oenocytes for transmission electron microscopy or TUNEL reaction. The insecticide resistant L4 survived all the tested concentrations, whereas the 0.007-ppm deltamethrin concentration had lethal effects on susceptible L4. Susceptible L4 were lethargic and exhibited less swimming activity than unexposed larvae, whereas the resistant L4 were hyperexcited following exposure to 0.005 ppm deltamethrin. No sublethal effects and no significant cell death were observed in the oenocytes of either susceptible or resistant insects exposed to deltamethrin. The present study illustrated the different responses of susceptible and resistant strains of A. aegypti following exposure to sublethal concentration of deltamethrin, and demonstrated how the behavior of the immature stage of the two strains varied, as well as oenocyte structure following insecticide exposure.


DJ-1 facilitates the interaction between STAT1 and its phosphatase, SHP-1, in brain microglia and astrocytes: A novel anti-inflammatory function of DJ-1.
Parkinson's disease (PD) is a progressive neurodegenerative movement disorder caused by the death of dopaminergic neurons in the substantia nigra. Importantly, altered astrocyte and microglial functions could contribute to neuronal death in PD. In this study, we demonstrate a novel mechanism by which DJ-1 (PARK7), an early onset autosomal-recessive PD gene, negatively regulates inflammatory responses of astrocytes and microglia by facilitating the interaction between STAT1 and its phosphatase, SHP-1 (Src-homology 2-domain containing protein tyrosine phosphatase-1). Astrocytes and microglia cultured from DJ-1-knockout (KO) mice exhibited increased expression of inflammatory mediators and phosphorylation levels of STAT1 (p-STAT1) in response to interferon-gamma (IFN-γ) compared to cells from wild-type (WT) mice. DJ-1 deficiency also attenuated IFN-γ-induced interactions of SHP-1 with p-STAT1 and STAT1, measured 1 and 12h after IFN-γ treatment, respectively. Subsequent experiments showed that DJ-1 directly interacts with SHP-1, p-STAT1, and STAT1. Notably, DJ-1 bound to SHP-1 independently of IFN-γ, whereas the interactions of DJ-1 with p-STAT1 and STAT1 were dependent on IFN-γ. Similar results were obtained in brain slice cultures, where IFN-γ induced much stronger STAT1 phosphorylation and inflammatory responses in KO slices than in WT slices. Moreover, IFN-γ treatment induced neuronal damage in KO slices. Collectively, these findings suggest that DJ-1 may function as a scaffold protein that facilitates SHP-1 interactions with p-STAT1 and STAT1, thereby preventing extensive and prolonged STAT1 activation. Thus, the loss of DJ-1 function may increase the risk of PD by enhancing brain inflammation.


The impact of self-efficacy based prebriefing on nursing student clinical competency and self-efficacy in simulation: An experimental study.
Prebriefing is the first phase of simulation; however, the literature does not adequately identify prebriefing standards and implementation strategies, providing little direction for simulation facilitators to conduct prebriefing in a manner that promotes student self-efficacy and clinical competency. The aim of this study was to examine the effects of the Self-Efficacy Prebriefing Model (SEPM) on nursing student self-efficacy and clinical competency. An experimental design with group randomization was used to compare self-efficacy and clinical competency in nursing students who received prebriefing per the SEPM compared to a control group. The study was conducted in one public Midwestern university in the United States. 66 senior Bachelor of Science in Nursing students enrolled in a clinical course completed the study. Clinical competency and self-efficacy were examined between an experimental group that received prebriefing per the SEPM and a control group that received standard prebriefing. The relationship between self-efficacy and clinical competency was examined. Clinical competency and self-efficacy were evaluated using the Creighton Competency Evaluation Instrument and Revised Clinical and Simulation General Self-Efficacy Scale. The experimental group had statistically significantly higher self-efficacy (p = .001) and clinical competency (p < .001) as compared to the control group. There was no significant relationship noted between self-efficacy and clinical competency (p = .207). The SEPM promoted nursing student self-efficacy and clinical competency in simulation. Prebriefing has an essential role in the simulation process and in promoting student outcomes.


Etoricoxib-Cannabidiol Combo: Potential Role in Glioblastoma Treatment and Development of PLGA-Based Nanoparticles.
Glioblastoma (GBM) is the most frequently occurring primary malignant central nervous system tumor, with a poor prognosis and median survival below two years. Administration of a combination of non-steroidal anti-inflammatory drugs and natural compounds that exhibit a curative or prophylactic effect in cancer is a new approach to GBM treatment. This study aimed to investigate the synergistic antitumor activity of etoricoxib (ETO) and cannabidiol (CBD) in a GBM cell line model, and to develop poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) for these two substances. The activity of ETO+CBD was determined using the MTT test, cell-cycle distribution assay, and apoptosis analysis using two GBM cell lines, namely, T98G and U-138 MG. The PLGA-based NPs were developed using the emulsification and solvent evaporation method. Their physicochemical properties, such as shape, size, entrapment efficiency (EE%), in vitro drug release, and quality attributes, were determined using scanning electron microscopy, diffraction light scattering, high-performance liquid chromatography, infrared spectroscopy, and differential scanning calorimetry. The combination of ETO and CBD reduced the viability of cells in a dose-dependent manner and induced apoptosis in both tested GBM cell lines. The developed method allowed for the preparation of ETO+CBD-NPs with a spherical shape, mean particle size (MPS) below 400 nm, zeta potential (ZP) values from -11 to -17.4 mV, polydispersity index (PDI) values in the range from 0.029 to 0.256, and sufficient EE% of both drugs (78.43% for CBD, 10.94% for ETO). The combination of ETO and CBD is a promising adjuvant therapeutic in the treatment of GBM, and the prepared ETO+CBD-NPs exhibit a high potential for further pharmaceutical formulation development.


Methylmercury bioaccumulation in invertebrates of boreal streams in Norway: effects of aqueous methylmercury and diet retention.
Transfer of aqueous methylmercury (MeHg) to primary consumers in aquatic foodwebs is poorly understood despite its importance for bioaccumulation of MeHg. We studied bioaccumulation of MeHg in simple aquatic food chains of two humic boreal streams in relation to streamwater chemistry, food web characteristics and dietary fatty acid (FA) biomarkers. Transfer of aqueous MeHg into primary consumers was similar in both streams, resulting in higher MeHg in consumers in the MeHg-rich stream. Trophic enrichment of MeHg and dietary retention of FA biomarkers was the same in both streams, suggesting that exposure to aqueous MeHg at the base of the food chain determined levels of MeHg in biota. In addition, contents of dietary biomarkers suggested that ingestion of algae reduced MeHg bioaccumulation, while ingestion of bacteria stimulated MeHg uptake. Dietary uptake of bacteria could thus be an important pathway for MeHg-transfer at the bottom of food chains in humic streams.


Virtual reality for pain and anxiety of pediatric oncology patients: A systematic review and meta-analysis.
The aim of this paper is to systematically evaluate the effects of virtual reality (VR) on pain, anxiety, and fear symptoms of pediatric patients with cancer. PubMed, Web of Science, Embase, Cochrane Library, Scopus, CINAHL, and four Chinese medical databases were searched from January 1, 1975, to February 22, 2022. Randomized controlled trials on the effects of VR technology on pediatric cancer patients were searched. Two researchers independently screened literatures, extracted data, and evaluated literature quality according to inclusion and exclusion criteria, and meta-analysis was performed by RevMan 5.3. A total of 379 children with cancer were included in six randomized controlled trials. Overall, there were significant differences in favor of VR in pain (MD = -4.82, 95% CI [-7.74, -1.89], P<0.01; I 2 = 95%, P<0.01), anxiety (SMD = -1.47, 95% CI [-2.46, -0.48], P<0.01; I 2 = 92%, P<0.01), and fear (MD = -1.25, 95% CI [-1.78,0.72], P<0.01; I 2 = 0%, P = 0.69). VR is beneficial to improve the pain, anxiety, and fear mood of pediatric cancer patients. Larger sample sizes and more rigorous studies are needed.


10 years of experience with intratympanally applied streptomycin (gentamycin) in the therapy of Morbus Menière.
During the last 10 years a total of 83 patients with severe cases of unilateral Morbus Menière were treated in our clinic. The proposed therapy was to administer streptomycin (gentamycinsulfate) intratympanically by applying two different ways of procedure. In the first group of 40 patients we attempted to destroy the vestibular organ without harming the cochlea whereby we avoided surgical intervention. In the second group of 43 patients we integrated more recent findings in the pathophysiological mechanism underlying the pathogenesis of Morbus Menière into our therapeutic considerations and attempted to exclusively destroy the secretorial epithelium with minimal dosages of aminoclycoside antibiotics. The results after treatment were clearly better for the second group of patients.


Tumor-initiating cells establish a niche to overcome isolation stress.
While the tumor microenvironment is a critical contributor to cancer progression, early steps of tumor initiation and metastasis also rely on the ability of individual tumor cells to survive and thrive at locations where tumor stroma or immune infiltration has yet to be established. In this opinion article, we use the term 'isolation stress' to broadly describe the challenges that individual tumor cells must overcome during the initiation and expansion of the primary tumor beyond permissive boundaries and metastatic spread into distant sites, including a lack of cell-cell contact, adhesion to protumor extracellular matrix proteins, and access to nutrients, oxygen, and soluble factors that support growth. In particular, we highlight the ability of solitary tumor cells to autonomously generate a specialized fibronectin-enriched extracellular matrix to create their own pericellular niche that supports tumor initiation. Cancer cells that can creatively evade the effects of isolation stress not only become more broadly stress tolerant, they also tend to show enhanced stemness, drug resistance, tumor initiation, and metastasis.


Antifungal efficacy of atorvastatin-containing emulgel in the treatment of oral and vulvovaginal candidiasis.
Drug repositioning has been an important ally in the search for new antifungal drugs. Statins are drugs that act to prevent sterol synthesis in both humans and fungi and for this reason they are promissory candidates to be repositioned to treat mycoses. In this study we evaluated the antifungal activity of atorvastatin by in vitro tests to determine the minimum inhibitory concentration against azole resistant Candida albicans and its mechanisms of action. Moreover, the efficacy of both atorvastatin-loaded oral and vaginal emulgels (0.75%, 1.5% and 3% w/w) was evaluated by means of in vivo experimental models of oral and vulvovaginal candidiasis, respectively. The results showed that atorvastatin minimal inhibitory concentration against C. albicans was 31.25 μg/ml. In oral candidiasis experiments, the group treated with oral emulgel containing 3.0% atorvastatin showcased total reduction in fungal load after nine days of treatment. Intravaginal delivery atorvastatin emulgel showed considerable effectiveness at the concentration of 3% (65% of fungal burden reduction) after nine days of treatment. From these findings, it is possible to assert that atorvastatin may be promising for drug repositioning towards the treatment of these opportunistic mycoses.


Synthesis and antiproliferative evaluation of N,N-disubstituted-N'-[1-aryl-1H-pyrazol-5-yl]-methnimidamides.
A series of N,N-disubstituted-N'-[1-aryl-1H-pyrazol-5-yl]-methnimidamides was synthesized by a newly developed microwave reaction and their antiproliferative activities were evaluated. Microwave irradiation of 5-amino-1,3-disubstituted pyrazoles with various amide solvents in the presence of POCl(3) provided the corresponding 2a-2k, 3a-3c, and 4a-4f in good to excellent yields. The obtained methnimidamides were tested against NCI-H661, NPC-TW01, and Jurkat cancer cell lines and the results indicated that compounds 2d and 2e were the most potent with IC(50) values in low micromolar range.


Spasmolytic activity of some plants used by the Otomi Indians of Quéretaro (México) for the treatment of gastrointestinal disorders.
The present study was performed to investigate the effect of chloroform-methanol (1:1) extracts derived from Baccharis heterophylla H. B. K (Asteraceae), Desmodium grahami Gray (Leguminosae), Dyssodia pinnata var. pinnata Rob. (Asteraceae), Gentiana spathacea H. B. K. (Gentianaceae), Loeselia mexicana Brand. (Polemoniaceae), Selaginella pallescens Spring. (Selaginellaceae) and Zornia diphylla Pers. (Fabaceae) on the spontaneous contractions of isolated rat ileum. The concentration-response curves and IC50 values were obtained and the respective relaxant potencies were compared with that of the CHCl3-MeOH (1:1) extract of Datura lanosa. The data showed that all the extracts produce a concentration-dependent inhibition of spontaneous ileum contractions. In addition, the antimicrobial activity of the extracts against pathogenic enterobacteria was tested. The pharmacological actions shown by the extracts of the selected species tend to support ethnomedical use of the plants for the treatment of gastrointestinal disorders.


Autonomic nervous system activity and anxiety and depressive symptoms in mothers up to 2 years postpartum.
We investigated the association between autonomic nervous system (ANS) activity and symptoms of anxiety and depression for the first 2 years postpartum. A total of 108 participants within 2 years postpartum underwent physiological measurements of ANS activity using the heart rate variability (HRV) power spectrum and self-reported questionnaires (14-item Hospital Anxiety and Depression Score). The cutoff points for anxiety and depressive symptom scores in this questionnaire were as follows: 7 or less, non-cases; 8-10, doubtful cases; 11 or more, definite cases. This study was conducted from 2012 to 2014 at University Hospital in Kyoto Prefectural University of Medicine and a nearby obstetrics and gynecology department clinic in Japan. Anxiety and depression non-cases accounted for 67.6% (n = 73) of subjects, anxiety non-cases and depression doubtful and definite cases 7.4% (n = 8), anxiety doubtful and definite cases and depression non-cases 8.3% (n = 9), and anxiety and depression doubtful and definite cases 16.7% (n = 18). Findings were similar for women with anxiety or depression, with total power (TP), low-frequency (LF) and high-frequency (HF) components of HRV among doubtful and definite cases significantly lower than among non-cases for both anxiety (p = 0.006, 0.034, 0.029, respectively) and depression (p = 0.001, 0.004, 0.007). Significant correlations were observed between TP, LF and HF and anxiety and depression scores (respective values for anxiety: rs = -0.331, p <0.001; rs = -0.286, p = 0.003; rs = -0.269, p = 0.005; and depression: rs = -0.389, rs = -0.353, rs = -0.337, all p <0.001). The present study demonstrated that mothers with anxiety or depressive symptoms had significantly lower HRV (HF, LF and TP) than those without.


A randomized study of direct coronary stent delivery compared with stenting after predilatation: the NIR future trial. On behalf of the NIR Future Trial Investigators.
This randomized trial compared a strategy of direct stenting without predilatation (n = 39) with conventional stenting with predilatation (n = 42) in patients with suitable lesions in native vessels > or = 2. 5-mm diameter to be covered by either a 9- or 16-mm-length NIR Primo stent. Equipment cost [mean (median) +/- SD] was less in those with direct stenting [$1,199 (979) +/- 526] than in those with predilatation [$1,455 (1,285) +/- 401, P < 0.001]. There was no significant difference in contrast use or fluoroscopy time. Procedural time was shorter in the direct stenting group. The clinical outcome at 1 month was satisfactory in both groups. In selected patients, a strategy of direct stenting is feasible, costs less, and is quicker to perform than the conventional strategy of stenting following predilatation.


In Vivo Analysis of mtDNA Replication at the Single Molecule Level and with High Resolution.
Single molecule analysis of replicating DNA (SMARD) is a powerful methodology that allows in vivo analysis of replicating DNA; identification of origins of replication, assessment of fork directionality, and measurement of replication fork speed. SMARD, which has been extensively used to study replication of nuclear DNA, involves incorporation of thymidine analogs to nascent DNA chains and their subsequent visualization through immune detection. Here, we adapt and fine-tune the SMARD technique to the specifics of human and mouse mitochondrial DNA. The mito-SMARD protocol allows researchers to gain in vivo insight into mitochondrial DNA (mtDNA) replication at the single molecule level and with high resolution.


Control of segregation of chromosomal DNA by sex factor F in Escherichia coli. Mutants of DNA gyrase subunit A suppress letD (ccdB) product growth inhibition.
The letA (ccdA) and letD (ccdB) genes, located just outside the sequence essential for replication of the F plasmid, apparently contribute to stable maintenance of the plasmid. The letD gene product acts to inhibit partitioning of chromosomal DNA and cell division of the host bacteria, whereas the letA gene product acts to suppress the activity of the letD gene product. To identify the target of the letD gene product, temperature-sensitive growth-defective mutants were screened from bacterial mutants that had escaped the letD product growth inhibition that occurs in hosts carrying an FletA mutant. Of nine mutants analysed, three mutants were shown, by phage P1-mediated transduction and complementation analysis, to have mutations in the gyrA gene and the other six in the groE genes. The nucleotide sequence revealed that one of the gyrA mutants has a base change from G to A at position 641 (resulting in an amino acid change from Gly to Glu at position 214) of the gyrA gene. The mutant GyrA proteins produced by these gyrA(ts) mutants were trans-dominant over wild-type GyrA protein for letD tolerance. The wild-type GyrA protein, produced in excess amounts by means of a multicopy plasmid, overcame growth inhibition of the letD gene product. These observations strongly suggest that the A subunit of DNA gyrase is the target of the LetD protein.


Does photobiomodulation influence the resting-state brain networks in young human subjects?
Using fMRI (functional magnetic resonance imaging), we explored the effect of transcranial photobiomodulation on four major resting-state brain networks, namely the sensorimotor, salience, default mode and central executive networks, in normal young subjects. We used a vielight transcranial device (810 nm) and compared the scans in 20 subjects (mean age 30.0 ± 2.8 years) after active- and sham-photobiomodulation sessions. Four sets of analysis-independent components, network connectivity, infra-slow oscillatory power and arterial spin labelling-were undertaken. Our results showed that when comparing pre- with post-active and pre- with post-sham photobiomodulation scans, there were no substantial differences in activity across any of the four resting-state networks examined, indicating no clear photobiomodulation effect. When taken together with previous findings, we suggest that the impact of photobiomodulation becomes much clearer only after brain circuitry is altered, for example, after a neurone undergoes some change in its equilibrium or homeostasis, either during pathology or ageing, or during a change in functional activity when individuals are engaged in a specific task (e.g. evoked brain activity).


Median nerve compression at the wrist caused by a reversed palmaris longus muscle.
A case of median nerve compression at the wrist caused by a reversed palmaris longus muscle is described. Symptoms included paresthesias in the median nerve distribution and swelling on the flexor aspect of the wrist resembling tenosynovitis. The patient was a 13-year old girl, which we believe is the youngest recorded case in the literature.


Pharmacokinetics of the thymidine analog 2'-fluoro-5-[(14)C]-methyl-1-beta-D-arabinofuranosyluracil ([(14)C]FMAU) in rat prostate tumor cells.
2'-Fluoro-5-[(14)C]-methyl-1-beta-D-arabinofuranosyluracil (FMAU) is an analog of thymidine (TdR) that is resistant to catabolism, is incorporated into DNA, and has been labeled with (11)C for use with positron emission tomography. We compared the uptake and metabolism of [(14)C]FMAU with that of [(3)H]TdR in fast- and slow-growing cell lines of a rat prostate tumor. Although FMAU was incorporated much less rapidly than TdR, FMAU behaved very similarly to TdR with respect to correlation between uptake velocity and cell growth rate, saturability of cellular incorporation, and intracellular metabolite pools. Thus, FMAU warrants further evaluation as an in vivo indicator of tumor cell division.


Photochemistry of kynurenine, a tryptophan metabolite: properties of the triplet state.
Photolysis of aqueous kynurenine (KN) solutions results in the formation of triplet kynurenine TKN. In low pH solutions, triplet formation occurs with almost 100% efficiency, while in neutral solutions the triplet quantum yield is PhiT = 0.018 +/- 0.004. The dissociation constant of TKN, which is attributed to deprotonation of the anilino group, has a pKa value of 4.7. Similar triplet absorption spectra were obtained under direct and acetone-sensitized photolysis. The large difference in quantum yields as a function of pH is attributed to excited-state properties of the first excited singlet state of KN. The rate constant quenching for TKN by oxygen is kq = 2 x 10(9) M(-1) s(-1).


Metabolites in the root exudates of groundnut change during interaction with plant growth promoting rhizobacteria in a strain-specific manner.
Plant growth promoting rhizobacteria (PGPR) are extensively used as biofertilizers to improve the soil nutrition for a variety of crop plants. The plant-PGPR interaction, with special reference to chemical signalling molecules is not understood clearly, unlike other beneficial plant-microbe interactions. Chemo-attraction of a PGPR from soil microbial pool towards a plant could be dependent on some of the molecules in the plant root exudates (REs), similar to the beneficial association of legume-rhizobia. In this study, a few functional properties of PGPR like growth, chemotaxis, and biofilm formation by two PGPR strains viz., Bacillus sonorensis RS4 and Pseudomonas aeruginosa RP2 were assessed in the presence of groundnut REs. Functional properties of both the strains were significantly influenced by the REs in a strain-dependent manner. Metabolite profiling of the REs from PGPR-bacterized (RS4 or RP2) and non-bacterized seedlings was performed with GC-MS/MS after 12 and 24 days of growth. A total of 75 metabolites were detected in groundnut REs. Threonine and glyoxylic oxime acid were detected in RP2-bacterized REs, while serine, pentanoic acid, glucopyranoside, tartaric acid, and 2-pyrrolidinone were detected in REs of seedlings bacterized with RP2 and RS4. The results suggested that the PGPR induced distinct variations in the REs. Identification of the interaction-specific metabolites will be useful to develop effective PGPR based bio-formulations for better PGPR colonization and improving crop yields.


N-MYC Downstream Regulated Gene 4 (NDRG4), a Frequent Downregulated Gene through DNA Hypermethylation, plays a Tumor Suppressive Role in Esophageal Adenocarcinoma.
The incidence of esophageal adenocarcinoma (EAC) has been rising dramatically in the past few decades in the United States and Western world. The N-myc downregulated gene 4 (NDRG4) belongs to the human NDRG family. In this study, we aimed to identify the expression levels, regulation, and functions of NDRG4 in EAC. Using an integrative epigenetic approach, we identified genes showing significant downregulation in EAC and displaying upregulation after 5-Aza-deoxycitidine. Among these genes, likely to be regulated by DNA methylation, NDRG4 was among the top 10 candidate genes. Analyses of TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus) data sets and EAC tissue samples demonstrated that NDRG4 was significantly downregulated in EAC (p < 0.05). Using Pyrosequencing technology for quantification of DNA methylation, we detected that NDRG4 promoter methylation level was significantly higher in EAC tissue samples, as compared to normal esophagus samples (p < 0.01). A strong inverse correlation between NDRG4 methylation and its gene expression levels (r = -0.4, p < 0.01) was observed. Treatment with 5-Aza restored the NDRG4 expression, confirming that hypermethylation is a driving force for NDRG4 silencing in EAC. Pathway and gene set enrichment analyses of TCGA data suggested that NDRG4 is strongly associated with genes related to cell cycle regulation. Western blotting analysis showed significant downregulation of Cyclin D1, CDK4 and CDK6 in EAC cells after overexpression of NDRG4. Functionally, we found that the reconstitution of NDRG4 resulted in a significant reduction in tumor cell growth in two-dimensional (2D) and three-dimensional (3D) organotypic culture models and inhibited tumor cell proliferation as indicated by the EdU (5-ethynyl-2'-deoxyuridine) proliferation assay.


Reconfigurable broadband metasurfaces with nearly perfect absorption and high efficiency polarization conversion in THz range.
Reconfigurable metasurfaces (RMSs) that enable the switching function of absorption and polarization conversion have attracted increasing attention. However, the design of RMSs to achieve wideband and high efficiency for both absorption and polarization conversion functions simultaneously remains a great challenge. Here, we propose the design of a RMS structure with a high-efficiency cross-polarization conversion and nearly perfect absorption. The reconfiguration between different functions of polarization conversion and absorption is obtained based on the reversible insulator-to-metal phase transition of Vanadium dioxide (VO[Formula: see text]). When the VO[Formula: see text] is in insulator state, the RMS realizes the cross-polarization conversion function in the wideband of 1.04-3.75 THz with a relative bandwidth up to 113 [Formula: see text] due to the multi-resonant modes of electric and magnetic resonances. Meanwhile, the nearly-perfect absorption is achieved in the range of 1.36-3.38 THz with the corresponding relative bandwidth up to 85 [Formula: see text] for the VO[Formula: see text] in metallic state. Specially, the wideband and high-efficiency performance of these functionalities is maintained for a wide angle incidence. The capability of bi-functional switch and integration with polarization conversion and absorption in a single metasurface structure endowed with both wideband and high-efficiency characteristics for a wide incident angle is very promising for emerging RMS devices in the terahertz region.


Effect of creatinine and specific gravity normalization techniques on xenobiotic biomarkers in smokers' spot and 24-h urines.
Renal excretion mechanisms are xenobiotic-specific; therefore, accurate exposure assessment requires an understanding of relationships of xenobiotic biomarker concentration and excretion rate to urine flow, specific gravity and creatinine concentration. Twenty-four-hour urine collection for xenobiotic exposure assessment is considered the "gold standard" procedure. Random spot-urine collection is convenient and minimizes subject compliance concerns but requires that normalization techniques be employed to account for diuresis and diurnal variation in xenobiotic biomarker excretion. This paper examines and makes recommendations concerning normalization techniques and conditions under which spot-urine results most accurately reflect 24-h urine results. Specific gravity, creatinine, and xenobiotic biomarkers were determined in smokers' spot and 24-h urines. Normalization techniques were applied, variance-component analyses were performed to estimate variability, spot urines were pooled mathematically to simulate 24-h urines and analyses of variance were performed to evaluate spot urines' ability to reflect 24-h urine concentrations. For each xenobiotic biomarker concentration, log-linear relationships were observed with urine flow, specific gravity, and creatinine. For most xenobiotic biomarker excretion rates, log-linear relationships were observed with urine flow; creatinine, however, was unaffected by urine flow. The conventional creatinine ratio-normalization technique demonstrated greater variability (within-day, between-day and between-subject) than other normalization techniques. Comparisons of simulated 24-h urines to spot urines suggest that spot-urine collection be performed only between 2 p.m. and 2 a.m. and that the modified specific-gravity-adjusted-creatinine ratio-normalization technique and the creatinine-regression normalization technique yield the best agreement between spot- and simulated 24-h urine results.


Zebrafish diras1 Promoted Neurite Outgrowth in Neuro-2a Cells and Maintained Trigeminal Ganglion Neurons In Vivo via Rac1-Dependent Pathway.
The small GTPase Ras superfamily regulates several neuronal functions including neurite outgrowth and neuron proliferation. In this study, zebrafish diras1a and diras1b were identified and were found to be mainly expressed in the central nervous system and dorsal neuron ganglion. Overexpression of green fluorescent protein (GFP)-diras1a or GFP-diras1b triggered neurite outgrowth of Neuro-2a cells. The wild types, but not the C terminus truncated forms, of diras1a and diras1b elevated the protein level of Ras-related C3 botulinum toxin substrate 1 (Rac1) and downregulated Ras homologous member A (RhoA) expression. Glutathione S-transferase (GST) pull-down assay also revealed that diras1a and diras1b enhanced Rac1 activity. Interfering with Rac1, Pak1, or cyclin-dependent kinase 5 (CDK5) activity or with the Arp2/3 inhibitor prevented diras1a and diras1b from mediating the neurite outgrowth effects. In the zebrafish model, knockdown of diras1a and/or diras1b by morpholino antisense oligonucleotides not only reduced axon guidance but also caused the loss of trigeminal ganglion without affecting the precursor markers, such as ngn1 and neuroD. Co-injection with messenger RNA (mRNA) derived from mouse diras1 or constitutively active human Rac1 restored the population of trigeminal ganglion. In conclusion, we provided preliminary evidence that diras1 is involved in neurite outgrowth and maintains the number of trigeminal ganglions through the Rac1-dependent pathway.


A variant e13a3 BCR-ABL1 fusion transcript in refractory adult B-cell acute lymphoblastic leukemia achieving complete remission with CAR-Tcell therapy.
Acute lymphoblastic leukemia (ALL) cases with e13a3 fusion transcripts are extremely rare. We report a 24-year-old male with Ph-positive (Ph+) ALL with an aberrant e13a3 fusion transcript treated with CD19-specific chimeric antigen receptor T-cell (CAR-T) therapy. He developed refractory disease post-chemotherapy induction, andreceived allogeneic hematopoietic stem cell transplantation (allo-HSCT) after salvage with imatinib in combination with chemotherapy regimen. Unfortunately, the patient relapsed after +90 days post-transplant. He was consented to CAR-T therapy trial and achieved complete remission, highlighting the efficacy of CAR-T treatment in relapsed-refractory B-ALL irrespective of the underlying genetic drivers in leukemia cells .


Nose-to-Brain Delivery of Diazepam from an Intranasal Aqua-Triggered In-Situ (ATIS) Gelling Microemulsion: Monitoring Brain Uptake by Microdialysis.
An innovative intranasal aqua-triggered in-situ (ATIS) gel is a polymer-free in-situ gelling microemulsion which gels instantaneously on contact with minute quantities of water to form a mucoadhesive gel. The objective of the study was to develop ATIS diazepam (ATIS-diazepam) as an alternative to the injection for epileptic emergencies and evaluate its brain uptake and nose-to-brain targeting efficiency in rats. ATIS-diazepam (1 mg/100 µL) was prepared and characterized for in vitro formulation characteristics. An LC-MS/MS method was developed and validated for the bioanalysis of diazepam. In vivo studies for pharmacokinetics, brain uptake and nasal irritation of intranasal ATIS-diazepam were conducted in rats. Brain uptake was investigated with brain microdialysis, a highly sensitive technique enabling quantification of free drug, which correlates to efficacy. ATIS-diazepam exhibited globule size < 200 nm, low viscosity, negative zeta potential and good stability. A significant increase in mucoadhesion was exhibited by ATIS-diazepam following the addition of a small quantity of water. ATIS-diazepam showed burst release in pH 6.4 with 50% diazepam release in ~ 10 min, which was sustained over 1 h. The absolute bioavailability was ~ 50% with both intranasal free-diazepam and ATIS-diazepam. Intranasal administration of ATIS-diazepam revealed immediate absorption with rapid and high brain extracellular fluid concentration compared to intravenous free-diazepam solution. The estimated direct transport potential and drug targeting efficiency of intranasal ATIS-diazepam was significantly higher (2-fold) than intranasal free-diazepam solution, which was attributed to the mucoadhesive and microemulsion properties of ATIS-diazepam. The nasal irritation study revealed the safety of ATIS-diazepam compared to free-diazepam solution. Intranasal ATIS-diazepam showed promise of higher direct nose-to-brain targeting, better safety and hence has an immense implication in the treatment of epileptic emergencies.


The role of viruses in the pathogenesis of peritonsillar abscess.
Peritonsillar abscess (PTA) is the most frequent complication of acute tonsillitis and a prevalent cause for acute admission to otorhinolaryngology departments. Our aim was to examine the role of viruses in the pathogenesis of PTA, as this has not previously been considered. We examined both palatine tonsils from 25 patients undergoing acute tonsillectomy for PTA, using PCR-based assays for herpes simplex virus-1 and -2 (HSV-1 and -2), adenovirus, Epstein-Barr virus (EBV), influenza A and B, and respiratory syncytial virus (RSV) A and B. We similarly examined tonsils from 55 patients undergoing elective tonsillectomy due to chronic tonsillar conditions. These patients served as a control group, as they did not have a clinically apparent infection at the time of surgery. Only HSV-1 (5/80, 6.3%), adenovirus (11/80, 13.8%), and EBV (71/80, 88.8%) were detected in our study population. There was no statistically significant difference in the frequency of these viruses across different diagnostic groups. Quantification of EBV load demonstrated no differences between the PTA and the elective tonsillectomy group, nor between the abscessed and non-abscessed tonsil of PTA patients. In summary, our data do not support a significant role for the examined viruses in the pathogenesis of PTA.


Thermo-Triggered In Situ Chitosan-Based Gelation System for Repeated and Enhanced Sonodynamic Therapy Post a Single Injection.
Sonodynamic therapy (SDT) by utilizing ultrasonic waves triggers the generation of reactive oxygen species (ROS) with the help of sonosensitizers to destruct deep-seated tumors has attracted great attention. However, the efficacy of SDT may not be robust enough due to the insufficient oxygen supply within solid tumors. Additionally, repeated injections and treatments, which are often required to achieve the optimal therapeutic responses, may cause additional side effects and patient incompliance. Herein, a thermo-triggered in situ hydrogel system is developed in which catalase (CAT) conjugated with sonosensitizer meso-tetra (4-carboxyphenyl) porphine (TCPP) is mixed into chitosan (CS) and beta-glycerol phosphate disodium (GP) to form the precursor solution. After injection of the precursor solution into tumors, the in situ sol-gel transformation will occur as triggered by the body temperature, resulting in the localized tumor retention of TCPP-CAT. The locally restrained TCPP-CAT not only produces ROS under ultrasonic treatment, but also sustainably reverses the oxygen-deficient status in solid tumors by triggering the O2 generation from the decomposition of endogenous H2 O2 , further promoting the efficacy of SDT. As a result, the repeated SDT after a single dose injection of such a hydrogel can offer robust treatment effects to effectively eradicate tumors.


Organoselenides as potential immunostimulants and inducers of interferon gamma and other cytokines in human peripheral blood leukocytes.
A number of organoselenium compounds have been described as anti-inflammatory, antioxidant, glutathione peroxidase-like agents and inhibitors of prostaglandin synthesis. Here we report that bis [2-(N-phenyl-carboxamido)]phenyl diselenide, 2-phenyl-1,2-benzisoselenazol-3(2H)-one (Ebselen) and related compounds are inducers of interferon gamma (IFN-gamma) and tumor necrosis factor (TNF) in human peripheral blood leukocytes. The IFN and TNF response was rapid, occurring within 20 h, and high--up to 1000 and 2000 units ml-1--and was clearly related to the dosage and the structure of the compounds. The action of the compounds and phytohemagglutinin was synergistic. The IFN gamma and TNF production was reduced after removing adherent cells. Although the mode of action of the compounds is not known, they appear to interact directly or indirectly with both adherent and non-adherent leukocytes, and stimulate the synthesis of a set of different cytokines including factors controlling the cell proliferation. Therefore, organoselenides may be regarded as the biological response modifiers.


Chronic exposure to agmatine results in the selection of agmatine-resistant hepatoma cells.
During our study of the cytostatic effect of agmatine, we were able to isolate an agmatine resistant clone from a parental hepatoma cell line, HTC. These cells, called Agres, had slower growth rate than the parental cells when cultured in normal medium. The modification in polyamine content induced by agmatine was much lower in these cells and ornithine decarboxylase, S-adenosylmethionine decarboxylase and spermidine/spermine acetyltransferase activities were much less affected. By investigating the mechanism responsible for these modifications, it was shown that agmatine and polyamines were not taken up by Agres cells. Their resistance to the antiproliferative effects of agmatine may thus arise from a lack of the polyamine transport system. Moreover, Agres cells were able to take up both glutamic acid and arginine at a rate significantly higher than that detected for HTC cells, most likely to provide components for compensatory increase of PA synthesis. These results emphasize the importance of polyamine transport for cell growth.


Efficacy of chemical and biological slug control measures in response to watering and earthworms.
The Spanish Slug (Arion vulgaris, formerly known as Arion lusitanicus) is an invasive agricultural and horticultural pest species that causes great damages all over Europe. Numerous options to control this slug are on the market; among the most commonly used are slug pellets containing the active ingredients metaldehyde or iron-III-phosphate and the application of parasitic nematodes (Phasmarhabditis hermaphrodita). These control measures potentially also affect non-target organisms like earthworms (Lumbricidae), which themselves can directly and/or indirectly alter a plant's susceptibility against slug herbivory. Also, the efficacy of slug control treatments is expected to be influenced by watering. In a greenhouse experiment we investigated the influence of daily watering vs. every third day watering on slug control efficacy and potential interactions with earthworms. We found significant interactions between watering and slug control efficacy. Slug herbivory and biomass decreased after application of slug pellets; metaldehyde was more effective under less frequent watering while iron-III-phosphate was unaffected by watering. Parasitic nematodes had no effect on slug herbivory and biomass production. Earthworm activity was reduced with less frequent watering but did not interact with slug control. We conclude that watering patterns should be considered when choosing slug control measures.


Stimulation-dependent uptake of an extracellular marker to subcellular fractions of isolated neurohypophysial tissue.
Slices of ox neurohypophyses and groups of isolated rat neurointermediate lobes were incubated in a medium containing horseradish peroxidase (HRP) and stimulated by high K+ concentrations in the medium. After washing, the tissue was homogenized and subjected to subcellular fractionation in a Percoll/sucrose gradient. HRP was exclusively taken up by particles banding at a low density of the gradient. The HRP containing particles located to this region included vacuoles of a size comparable to secretory vesicles.


Purification of choline acetyltransferase from the locust Schistocerca gregaria and production of serum antibodies to this enzyme.
Choline acetyltransferase (ChAT; EC 22.214.171.124) was purified from the heads of Schistocerca gregaria to a final specific activity of 1.61 mumol acetylcholine (ACh) formed min-1 mg-1 protein. The molecular mass of the enzyme as determined by gel filtration is 66,800 daltons. The final enzyme preparation showed one major band at 65,000 daltons on sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis, which corresponds with the native molecular mass of the enzyme, a band at 56,000 daltons, and two bands at 40,500 and 38,000 daltons. Antibodies raised against ChAT in rabbit react only with the active band on native gel after Western blotting. They strongly react with the 65,000-dalton polypeptide band on Western blots of SDS gel separation of pure preparation of enzyme and with both the 65,000- and 56,000-dalton bands after SDS gel separation of crude extract.


C isotopomer analysis of glutamate by heteronuclear multiple quantum coherence-total correlation spectroscopy (HMQC-TOCSY).
13C has become an important tracer isotope for studies of intermediary metabolism. Information about relative flux through pathways is encoded by the distribution of 13C isotopomers in an intermediate pool such as glutamate. This information is commonly decoded either by mass spectrometry or by measuring relative multiplet areas in a 13C NMR spectrum. We demonstrate here that groups of glutamate 13C isotopomers may be quantified by indirect detection of protons in a 2D HMQC-TOCSY NMR spectrum and that fitting of these data to a metabolic model provides an identical measure of the 13C fractional enrichment of acetyl-CoA and relative anaplerotic flux to that given by direct 13C NMR analysis. The sensitivity gain provided by HMQC-TOCSY spectroscopy will allow an extension of 13C isotopomer analysis to tissue samples not amenable to direct 13C detection (approximately 10 mg soleus muscle) and to tissue metabolites other than glutamate that are typically present at lower concentrations.


Therapeutic potential of neurotrophins for treatment of hearing loss.
Degeneration of spiral ganglion neurons (SGNs) and hair cells in the cochlea induced by aging, injury, ototoxic drugs, acoustic trauma, and various diseases is the major cause of hearing loss. Discovery of growth factors that can either prevent SGN and hair-cell death or stimulate hair-cell regeneration would be of great interest. Studies over the past several years have provided evidence that specific neurotrophins are potent survival factors for SGNs and protect these neurons from ototoxic drugs in vitro and in vivo. Current research focuses more on understanding the mechanism of hair-cell regeneration/differentiation and identification of growth factors that can stimulate hair-cell regeneration. SGNs are required to relay the signal to the central nervous system even when a cochlear implant is used to replace hair-cell function or in the case that cochlear sensory epithelium can be stimulated to regenerate new hair cells successfully. Therefore, neurotrophins may have their therapeutic value in prevention and treatment of hearing impairment.