Patterns of somatic distress among internally displaced persons in Ukraine: analysis of a cross-sectional survey.
There are often high rates of mental disorders in low- and middle-income countries during humanitarian crises, but the prevalence of somatic distress (SD) is underreported in the existing health service research. We aim to examine the patterns of SD among internally displaced persons (IDPs) in Ukraine, who were forcibly displaced due to the ongoing conflict in the country's eastern region. The study design was a cross-sectional survey of 2203 adult IDPs throughout Ukraine. The survey collected data on sociodemographic characteristics, traumatic life events (Life Events Checklist), utilisation of mental health care services, and self-reported outcomes of SD (Patient Health Questionnaire 15), anxiety (Generalised Anxiety Disorder 7), depression (Patient Health Questionnaire 9), and post-traumatic stress (PTSD Checklist). Descriptive and multivariate regression analyses were used. Over half of respondents (n = 1142, 55%) were identified as being at risk of SD (PHQ-15 score ≥ 6), and the prevalence of moderate (n = 377, 18%) and high severity SD risk (n = 275, 13%) was substantial. There were significant associations (p < 0.05) between SD and age, female gender, economic status, self-reported depression and post-traumatic stress, and multiple trauma exposures. Being at risk of SD was also significantly associated with increased functional disability. Use of mental health care services was low across this population and only high SD risk seemed to be a reliable predictor of care-seeking behaviour. There is a significant risk of SD among IDPs in Ukraine. Our results illustrate the need for targeted health service research and regional programs to ensure that mental health needs are appropriately met.


Plasticity of the responses to chronic hypoxia and dietary restriction in an aged organism: evidence from the Drosophila model.
Major cardiovascular diseases arise as consequences of a reduced blood flow to oxygen consuming organs such as the brain and the heart. Their incidence and consequences increase with ageing and inappropriate nutrition conditions. In this study we compared the responses of young (1 day old) or aged (1 month old) Drosophila to dietary restriction and chronic hypoxia. Changing the two major diet components (sucrose and yeast) had complex and non linear consequences on longevity. Ageing and hypoxia completely remodelled the longevity/nutrient reaction norm. Aged flies required more sucrose and less yeast than young flies and became insensitive to dietary restriction by food dilution. The responses to chronic hypoxia were largely age independent and strongly diet dependent. For instance rich diets sensitized Drosophila to chronic hypoxia and hypoxia increased the life span of starving flies (aged or young). The results highlight the importance of nutrition conditions when assessing ageing and hypoxic tolerance in the Drosophila system.


The frequency of shifts between alternative equilibria.
We derive a formula giving the frequency with which random drift shifts a population between alternative equilibria. This formula is valid when such shifts are rare (Ns much greater than 1), and applies over a wide range of mutation rates. When the number of mutations entering the population is low (4 N mu much less than 1), the rate of stochastic shifts reduces to the product of the mutation rate and the probability of fixation of a single mutation. However, when many mutations enter the population in each generation (4 N mu much greater than 1), the rate is higher than would be expected if mutations were established independently, and converges to that given by a gaussian approximation. We apply recent results on bistable systems to extend this formula to the general multidimensional case. This gives an explicit expression for the frequency of stochastic shifts, which depends only on the equilibrium probability distribution near the saddle point separating the alternative stable states. The plausibility of theories of speciation through random drift are discussed in the light of these results.


New insights on the Early Cretaceous (Hauterivian-Barremian) Urgonian lithostratigraphic units in the Jura Mountains (France and Switzerland): the Gorges de l'Orbe and the Rocher des Hirondelles formations.
The Hauterivian-Barremian series of the Jura Mountains were measured over more than 60 sections along a 200 km long transect between Aix-les-Bains (Savoie Department, France) and Bienne (Bern Canton, Switzerland), which prompted the need for a revision and improvement of the current lithostratigraphic scheme for this stratigraphic interval. A new formation, the Rocher des Hirondelles Formation, is proposed in replacement of the unsuitable Vallorbe Formation, while the Gorges de l'Orbe Formation is formally described. The Gorges de l'Orbe Formation, equivalent to the well-known "Urgonien jaune" facies, consists of two members, namely Montcherand Member and Bôle Member. The Rocher des Hirondelles Formation, equivalent to the "Urgonien blanc" facies, consists of three members, i.e. Fort de l'Écluse Member, Rivière Member and Vallorbe Member. The marly Rivière and Bôle members appear to present time-equivalent lithostratigraphic units, recording a major sedimentological event affecting contemporarily both formations. This study proposes a new sedimentary model opening a new point of view on the long-living controversies about the age of the Urgonian series from the Jura Mountains. The data point to strong diachronic ages of lithostratigraphic units with a late Hauterivian to early Barremian occurrence of the "Urgonian blanc" facies in the Meridional Jura area versus a latest Barremian age in the Central Jura area, reflecting a general progradation of the Urgonian shallow-water carbonate platform from the present-day Meridional Jura area toward external deeper-water shelf environments of the present-day Central Jura area and Molasse basin.


Ultrastructural study of medullomyoblastoma.
A case of cerebellar medullomyoblastoma in a young boy was investigated by electron microscopy. The neuroectodermal component shows the characteristics of a desmoplastic medulloblastoma. The mesodermal component consists of more or less differentiated cross-striated muscle cells. Undifferentiated muscle cells are very similar to proliferated endothelial cells of blood vessels within the muscular component, so that an origin of this component from pluripotential endothelial cells of the vessel wall is suggested. This tumor is considered a malignant teratoid because of the derivation from two blastodermic layers and because of the midline localization in children suggesting a malformative origin.


Capillary zone electrophoresis-MS.
Coupling the separation capabilities of capillary zone electrophoresis with the analytical specificity of mass spectrometry yields a tool for detecting levels of substances down to 10 attomoles.


A familial paracentric inv(1)(q42q44) resulting in a child with a del(1)(q42) karyotype.
The derivation of a 46,XY,del(1)(q42) chromosome complement in a mentally retarded child from a maternal paracentric inv(1)(q42q44) is discussed and the clinical findings are compared to previously reported cases of the same deletion syndrome.


In 1969 and 1970 calling and chorusing of the tree frog, Hyla a. arborea, was recorded daily, together with air temperature and light intensity. The onset of calling occured during the first days of May at 7.45 p.m. and shifted to about 9 p.m. during June and July. The treefrogs began calling at a light intensity of lower than 260 Lux and chorused at less than 60 Lux, provided the air temperature was above 8°C, which is the lower limit for calling activity. The start of the daily calling activity is controlled by the light intensity and by an annual endogenous rhythm. The effect of the rhythm is 6 to 10 times greater than that of the light intensity.


Parent assessment in research on the vulnerability of children and families to mental disorder.
The research methodology for a current study of the assessment of family factors as they relate to the development of psychopathology in high-risk children is described. Factor analysis of preliminary data from 83 families led to the construction of 6 rating scales on the emotional health of the patient, spouse, and child; the family; and the marriage; these should prove valuable in predicting the outcome of the index child and his family.


Knowledge, attitudes, and practices associated with zoonotic disease transmission risk in North Sulawesi, Indonesia.
Hunters, vendors, and consumers are key actors in the wildlife trade value chain in North Sulawesi, Indonesia, and potentially face an elevated risk of exposure to zoonotic diseases. Understanding the knowledge, attitudes, and practices (KAP) associated with the risk of zoonotic disease transmission in these communities is therefore critical for developing recommendations to prevent or mitigate zoonotic outbreaks in the future. Qualitative and quantitative methods were combined to understand KAP associated zoonotic diseases transmission risk in communities involved in the wildlife trade in North Sulawesi. Qualitative data were collected through semi-structured ethnographic interviews and focus group discussions (FGDs) while quantitative data were collected using questionnaires. We conducted 46 ethnographic interviews and 2 FGDs in 2016, and 477 questionnaire administrations in 2017-2018 in communities from five districts in North Sulawesi. We also collected biological specimens, including nasal swab, oropharyngeal swab, and blood, from 254 participants. The study sites were targeted based on known wildlife consumption and trade activities. The participants for qualitative data collection were purposively selected while participants for quantitative data collection were randomly selected. Biological samples were tested for five viral families including Coronaviridae, Filoviridae, Flaviviridae, Orthomyxoviridae and Paramyxoviridae. Knowledge regarding disease transmission from animals to humans was similar across the participants in qualitative focus groups, including knowledge of rabies and bird flu as zoonotic diseases. However, only a small fraction of the participants from the quantitative group (1%) considered that contact with wild animals could cause sickness. Our biological specimen testing identified a single individual (1/254, 0.004%) who was sampled in 2018 with serological evidence of sarbecovirus exposure. Overall, participants were aware of some level of risk in working with open wounds while slaughtering or butchering an animal (71%) but most did not know what the specific risks were. However, significant differences in the attitudes or beliefs around zoonotic disease risk and health seeking behaviors were observed across our study sites in North Sulawesi. Our study showed variable levels of knowledge, attitudes, and practices associated with the risk of zoonotic disease transmission among study participants. These findings can be used to develop locally responsive recommendations to mitigate zoonotic disease transmission.


DNER promotes epithelial-mesenchymal transition and prevents chemosensitivity through the Wnt/β-catenin pathway in breast cancer.
Breast cancer (BC) is the most common malignant tumour in women worldwide, and one of the most common fatal tumours in women. Delta/Notch-like epidermal growth factor (EGF)-related receptor (DNER) is a transmembrane protein involved in the development of tumours. The role and potential mechanism of DNER in epithelial-mesenchymal transition (EMT) and apoptosis in BC are not fully understood. We find that DNER is overexpressed in BC tissue, especially triple-negative breast cancer (TNBC) tissue, and related to the survival of BC and TNBC patients. In addition, DNER regulates cell EMT to enhance the proliferation and metastasis of BC cells via the Wnt/β-catenin pathway in vitro and in vivo. Moreover, the expression levels of β-catenin and DNER in BD tissue are positively correlated. The simultaneously high expression of DNER and β-catenin contributes to poor prognosis in BC patients. Finally, DNER protects BC cells from epirubicin-induced growth inhibition and apoptosis via the Wnt/β-catenin pathway. In conclusion, these results suggest that DNER induces EMT and prevents apoptosis by the Wnt/β-catenin pathway, ultimately promoting the malignant progression of BC. In conclusion, our study demonstrates that DNER functions as an oncogene and potentially valuable therapeutic target for BC.


How women with advanced cancer pray: a report from two focus groups.
To explore the meaning, function, and focus of prayer for patients with advanced cancer, and to identify the effects of prayer on their coping. Qualitative, descriptive design using focus groups. Three cancer centers that are part of a university-affiliated comprehensive cancer network in the northeastern United States. 13 adult, female outpatients receiving active treatment for ovarian or lung cancer. Two semistructured, focus group interviews were conducted. Audiotapes were transcribed verbatim. Data were coded and analyzed using standard content analysis procedures. Prayer and coping. Four themes emerged: finding one's own way, renewed appreciation for life, provision of strength and courage, and gaining a stronger spiritual connection. In addition, praying for others, conversational prayer, petitionary prayer, ritual prayer, and thanksgiving prayer were used most often by participants to cope. The findings support prayer as a positive coping mechanism for women with advanced ovarian or lung cancer. The study provides knowledge about prayer as a source of spiritual and psychological support. Oncology nurses should consider the use of prayer for patients coping with advanced cancer.


Performance evaluation of an 85-cm-bore X-ray computed tomography scanner designed for radiation oncology and comparison with current diagnostic CT scanners.
The demand for computed tomography (CT) virtual simulation is constantly increasing with the wider adoption of three-dimensional conformal and intensity-modulated radiation therapy. Virtual simulation CT studies are typically acquired on conventional diagnostic scanners equipped with an external patient positioning laser system and specialized planning and visualization software. Virtual simulation technology has matured to a point where conventional simulators may be replaced with CT scanners. However, diagnostic CT scanner gantry bores (typically 65-70 cm) can present an obstacle to the CT simulation process by limiting patient positions, compared to those that can be attained in a conventional simulator. For example, breast cancer patients cannot always be scanned in the treatment position without compromising reproducibility and appropriateness of setup. Extremely large patients or patients requiring special immobilization or large setup devices are often unable to enter the limited-bore gantry. A dedicated 85-cm-bore radiation oncology CT scanner has the potential to eliminate these problems. The scanner should provide diagnostic-quality images at diagnostic-comparable dose levels. The purpose of this study was to independently evaluate the performance of a novel 85-cm-bore CT X-ray scanner designed specifically for radiation oncology and compare it against diagnostic-type, 70-cm-bore scanners that may be used in the same setting. We performed image quality and dosimetric measurements on an 85-cm-bore CT scanner (AcQSim CT, Marconi Medical Systems, Inc., Cleveland, OH) and a 70-cm-bore, diagnostic-type scanner (UltraZ CT, Marconi Medical Systems, Inc.). Image quality measurements were performed using a manufacturer-supplied phantom (Performance Phantom, Marconi Medical Systems, Inc.), following the manufacturer's suggested testing procedures, and an independent image quality phantom (CATPHAN 500, The Phantom Laboratory, New York, NY). The standard image quality parameters evaluated for the purpose of comparison were as follows: slice thickness accuracy, high-contrast resolution (limiting spatial resolution), low-contrast resolution, uniformity and noise, and CT number accuracy and linearity. Standard head and body protocols were employed throughout most of our measurements and were kept equal between the two scanners. The computed tomography dose index was measured for standard head and body imaging protocols using accepted methods and procedures. For comparison purposes, data for a diagnostic-type, 70-cm-bore scanner (GE HighSpeed CT/i) were extracted from the literature. The results obtained for the 85-cm-bore scanner are compared with the following: (1) manufacturer-provided autoperformance phantom test results (validating its use for routine quality assurance), (2) a similar set of measurements performed on a conventional 70-cm-bore, diagnostic-type CT scanner (UltraZ CT, Marconi Medical Systems, Inc.), and (3) current available data on other diagnostic-type CT scanners (GE HighSpeed CT/i). Head and body doses seem on average to be slightly (1-2 cGy) higher for the 85-cm-bore unit than for conventional 70-cm units. Measured slice thickness was within acceptable criteria, +/-0.5 mm. There does not seem to be any significant difference in high-contrast resolution. Both units render a limiting value of approximately 7-8 lp/cm for slice thickness 8-10 mm. Both units exhibit comparable CT number uniformity, accuracy, and linearity. Noise levels seem to be slightly increased (by approximately 0.05-0.2%) for the large-bore geometry. Low-contrast resolution for both units was comparable (4.5-5.5 mm @ 0.35%). All image quality parameters are well within diagnostic acceptable levels. The overall imaging performance and mechanical integrity of the 85-cm-bore scanner are comparable to those of conventional diagnostic scanners that may be employed in a radiation oncology setting.


The cytochrome ba complex from the thermoacidophilic crenarchaeote Acidianus ambivalens is an analog of bc(1) complexes.
A novel cytochrome ba complex was isolated from aerobically grown cells of the thermoacidophilic archaeon Acidianus ambivalens. The complex was purified with two subunits, which are encoded by the cbsA and soxN genes. These genes are part of the pentacistronic cbsAB-soxLN-odsN locus. The spectroscopic characterization revealed the presence of three low-spin hemes, two of the b and one of the a(s)-type with reduction potentials of +200, +400 and +160 mV, respectively. The SoxN protein is proposed to harbor the heme b of lower reduction potential and the heme a(s), and CbsA the other heme b. The soxL gene encodes a Rieske protein, which was expressed in E. coli; its reduction potential was determined to be +320 mV. Topology predictions showed that SoxN, CbsB and CbsA should contain 12, 9 and one transmembrane alpha-helices, respectively, with SoxN having a predicted fold very similar to those of the cytochromes b in bc(1) complexes. The presence of two quinol binding motifs was also predicted in SoxN. Based on these findings, we propose that the A. ambivalens cytochrome ba complex is analogous to the bc(1) complexes of bacteria and mitochondria, however with distinct subunits and heme types.


Acute fatigue, and perceptual responses to resistance exercise.
Despite assumptions, there is an absence of research on acute fatigue responses to high- and low-load and advanced technique resistance exercise. Trained males (n = 8; age 27.2 ± 7.4 years, height 180.0 ± 6.6 cm, weight: 86.6 ± 10.3 kg) were assessed for decrement in maximal voluntary isometric torque (MVIT) and perceived effort and discomfort after heavier load (HL; 80% MVIT), lighter load (LL; 30% MVIT), forced repetition (FR), and breakdown set (BD) training protocols. Analyses revealed a significant reduction in MVIT (P < 0.05) with a significant between-condition effect, and significant post-hoc pairwise comparisons between LL and both HL (P = 0.044) and FR (P = 0.013). There were no significant between-condition effects for effort or discomfort (P > 0.05). Fatigue as a decrement in force production appears to follow a more complex relationship than simply 100% minus the force requirements of the task relative to a maximal voluntary contraction. Muscle Nerve 56: E141-E146, 2017.


Structural determination and antitumor activities of a water-soluble polysaccharide from Mortierella hepiali.
A water-soluble polysaccharide (MHP-1) isolated from cultured Mortierella hepiali was obtained by hot-water extraction, DEAE-cellulose 52 anion-exchange, and Sephadex G-25 gel permeation chromatography. Its structural characteristics were investigated by PMP pre-column derivation, partial hydrolysis with acid, methylation analysis, as well as FTIR and NMR spectroscopy. Data revealed that MHP-1 possessed a backbone consisting of the repeating unit→2)-β-d-Manp-(1, 6)-β-d-Glcp-(1→and 3)-β-d-Manp-(1→, branching at O-4 of→2)-β-d-Manp-(1, and terminated with β-d-Manp. The antitumor effects of MHP-1 on H22 tumor-bearing mice were studied. Results showed that MHP-1 significantly inhibited the growth of implanted H22 tumors in mice in vivo, but not on H22, A549, and Hep-G2 cells in vitro. Serum and spleen cells were separated to evaluate the concentrations of TNF-α by ELISA kit. The release of TNF-α was markedly induced by MHP-1 in a dose-dependent manner.


A novel fluorescence sensor based on a tripodal carboxylic acid for detection and measurement of Cu2+ in tomato: Experimental and computational studies.
A tripod organic compound, (4,4',4''-[1,3,5-Triazine-2,4,6-triyltris(oxy)] tribenzoic acid, TCPT), with donor triazine core and multiple fluorophore carboxylic motives, was prepared as an efficient ligand with high emission properties. The TCPT fluorescence emission properties as a chemical sensor were studied (λex = 370 nm) upon the addition of an appropriately diverse set of metal cations. The obtained results revealed the highly selective and efficient role of Cu2+ in quenching of TCPT, even with relevant interfering metal ions. The emission of TCPT was independent of the pH. The interaction of the sensor with Cu2+ and followed by absorption spectra and linear trend of the Stern-Volmer diagram, suggested a static quenching process. The density functional theory calculations were carried out to explore the identity of the electronic transition levels, HOMO-LUMO, and bandgap energies of TCPT. The linear range 1.00 × 10-7-1.00 × 10-6 M was obtained by fluorescence titration of a TCPT solution with Cu2+ ions at optimum conditions. The detection limit was calculated as 5.45 × 10-8 M from the established calibration of titration data. The effect of various ions was studied, and there was no significant interference from the studied metal ions. For the real sample analysis, trace levels of Cu2+ ions were successfully determined in the tomato.


MnCo2O4/Ni3S4 nanocomposite for hybrid supercapacitor with superior energy density and long-term cycling stability.
MnCo2O4 is regarded as a good electrode material for supercapacitor due to its high specific capacity and good structural stability. However, its poor electrical conductivity limits its wide-range applications. To solve this issue, we integrated the MnCo2O4 with Ni3S4, which has a good electrical conductivity, and synthesized a MnCo2O4/Ni3S4 nanocomposite using a two-step hydrothermal process. Comparing with individual MnCo2O4 and Ni3S4, the MnCo2O4/Ni3S4 nanocomposite showed a higher specific capacity and a better cycling stability as the electrode for the supercapacitor. The specific capacity value of the MnCo2O4/Ni3S4 electrode was 904.7 C g-1 at 1 A g-1 with a potential window of 0-0.55 V. A hybrid supercapacitor (HSC), assembled using MnCo2O4/Ni3S4 and active carbon as the cathode and anode, respectively, showed a capacitance of 116.4 F g-1 at 1 A g-1, and a high energy density of 50.7 Wh kg-1 at 405.8 W kg-1. Long-term electrochemical stability tests showed an obvious increase of the HSC's capacitance after 5500 charge/discharge cycles, reached a maximum value of ∼162.7% of its initial value after 25,000 cycles, and then remained a stable value up to 64,000 cycles. Simultaneously, its energy density was increased to 54.2 Wh kg-1 at 380.3 W kg-1 after 64,000 cycles.


Fine-tuning robot-assisted radical prostatectomy planning with MRI.
Robot-assisted radical prostatectomy (RARP) has now become the most common surgical treatment option for prostate cancer (CaP). Clinicopathologic data (i.e., biopsy, digital rectal exam, prostate specific antigen level) and patient-specific factors (e.g., age, erectile function, co-morbidities) are the primary sources of information that urologists use for counseling and treatment decision making. Magnetic resonance imaging (MRI) has evolved along a similar temporal arc to RARP, with increased utilization and precision over the past decade. MRI prior to RARP provides multifaceted adjunctive information, including enhancement of locoregional staging, delineation of spatial anatomic information, and identification of aberrant anatomy, all of which aid in patient treatment counseling and operative planning. This article is designed for urologic surgeons who perform RARP, with the aim of providing a review of prostate MRI imaging and highlighting findings which may specifically alter the operation. A review of the literature was performed, focusing on the most recent publications. MRI imaging of the prostate has become increasing accurate for the identification, localization, and characterization of CaP lesions. In addition to tumor-specific information, a number of intra- and extra-prostatic findings are consistently identified on MRI which may impact RARP. MRI provides important information which may alter RARP.


Narcoleptic-like Episodes in a Patient Receiving Pegylated Interferon-alpha 2b: A Case Report and Review of Literature.
A 26-year-old male developed narcoleptic-like episodes while on pegylated interferon-alpha 2b (peg-IFN-α2b) therapy for stage IIIB melanoma. Once peg-IFN-α2b was discontinued, the narcoleptic-like episodes eradicated. A case report and review of the literature are presented in this article.


An in vitro workflow to create and modify infectious clones using replication cycle reaction.
Reverse genetics systems are critical tools in combating emerging viruses which enable a better understanding of the genetic mechanisms by which viruses cause disease. Traditional cloning approaches using bacteria are fraught with difficulties due to the bacterial toxicity of many viral sequences, resulting in unwanted mutations within the viral genome. Here, we describe a novel in vitro workflow that leverages gene synthesis and replication cycle reaction to produce a supercoiled infectious clone plasmid that is easy to distribute and manipulate. We developed two infectious clones as proof of concept: a low passage dengue virus serotype 2 isolate (PUO-218) and the USA-WA1/2020 strain of SARS-CoV-2, which replicated similarly to their respective parental viruses. Furthermore, we generated a medically relevant mutant of SARS-CoV-2, Spike D614G. Results indicate that our workflow is a viable method to generate and manipulate infectious clones for viruses that are notoriously difficult for traditional bacterial-based cloning methods.


Behavioral characterization of pentylenetetrazol-induced seizures in the marmoset.
This study was designed to characterize seizures induced with pentylenetetrazol (PTZ) in marmosets. Thirteen adult marmosets (Callithrix sp.) received 20, 30, or 40 mg/kg of PTZ intraperitoneally. PTZ caused all animals to switch their natural behavioral repertoire to early convulsive behavior. Seizure scores were low at lower PTZ doses, whereas the highest dose of PTZ led to seizure scores IV and V (according to Racine's scale) in 69% of animals. To further characterize the model we performed a preliminary evaluation of the efficacy of three antiepileptic drugs: phenobarbital, phenytoin, and carbamazepine. Phenobarbital prevented PTZ-induced seizures in 100% of trials. As expected, phenytoin and carbamazepine were not effective against PTZ-induced seizures. The present study describes the PTZ model of seizures in marmosets with a drug-response profile similar to that of the rodent model, thus bringing to a well-known model (PTZ in rodents) the complexity of a nonhuman primate brain.


Phase I, two-way, crossover study to demonstrate bioequivalence and to compare safety and tolerability of single-dose XM17 vs Gonal-f® in healthy women after follicle-stimulating hormone downregulation.
XM17 is a recombinant human follicle-stimulating hormone (rhFSH) intended mainly for use in controlled ovarian hyperstimulation and the treatment of anovulation. The purpose of the current study was to establish bioequivalence, safety and tolerability of single 300-IU subcutaneous (sc) doses of XM17 to that of the reference follitropin alfa (Gonal-f(®)) in healthy young women. This open-label, Phase I, single-dose, single-center, two-way crossover study was conducted from February to May 2009. Thirty-six women aged 18-39 years were included, with a study duration of ~27 days per participant. After endogenous FSH downregulation with goserelin (3.6 mg) on study Day 0, XM17 and Gonal-f(®) were administered on Days 11 and 19 in random sequence. Frequent serum samples were drawn for standard pharmacokinetics until 168 h postdosing. Laboratory values, adverse events (AEs) and local tolerability were assessed throughout the study period. Primary endpoints included Cmax and AUC0-t. Secondary endpoints included additional pharmacokinetic (PK) parameters, safety and tolerability. Ratios of XM17 to Gonal-f(®) for Cmax and AUC0-t equaled 1.017 (90 % confidence interval [CI]: 0.958, 1.080) and 1.028 (90 % CI: 0.931, 1.134), respectively, with the CIs contained within the predefined interval (0.8, 1.25). Ratios for AUC0-168h, AUC0-∞ and t1/2 were also ~1, and no difference in tmax was detected. Both XM17 and Gonal-f(®) were well tolerated, with no detectable anti-FSH antibodies, serious AEs or AEs leading to discontinuation or dose reduction. PK bioequivalence of single 300-IU sc doses of XM17 to the reference product Gonal-f® was statistically demonstrated. XM17 was well tolerated both systemically and locally. ClinicalTrials.gov: NCT02592031 ; date of registration: 28 October, 2015.


Heat shock protein 90 is a new potential target of anti-rejection therapy in allotransplantation.
The critical roles of heat shock protein 90 (HSP90) in immune reactions associated with viral infection and autoimmune disease are well known. To date, however, its roles in the alloimmune response and the immunosuppressive effect of HSP90 inhibitors in allotransplantation have remained unknown. The purpose of this study was to examine the therapeutic efficacy of the HSP90 inhibitor 17-DMAG in allotransplantation models. C57BL/6 (H-2b) and BALB/c (H-2d) mice were used as donors for and recipients of skin and heart transplantation, respectively. Treatment with 17-DMAG (daily i.p.) or a vehicle was initiated 3 days before transplantation. Immunological outcomes were assessed by histopathological examinations, flow cytometric analysis, quantitative RT-PCR, ELISA, ELISPOT assay, and MLR. 17-DMAG treatment significantly prolonged the survival of both skin and heart allografts. In 17-DMAG-treated mice, donor-reactive splenocytes producing IFN-γ were significantly reduced along with the intragraft mRNA expression level and serum concentration of IFN-γ. Intragraft mRNA expression of cytokines and chemokines associated with both innate and adaptive immunity was suppressed in 17-DMAG-treated group. MLR showed suppression of the donor-specific proliferation of CD4 + T and CD19 + B cells in the spleens of 17-DMAG-treated mice. 17-DMAG treatment also reduced the number of activated NK cells. Furthermore, the treatment lowered the titers of donor-specific antibodies in the serum and prolonged a second skin allograft in mice sensitized by previous skin transplantation. HSP90 inhibition by 17-DMAG can affect various immune responses, including innate immunity, adaptive immunity, and humoral immunity, suggesting its therapeutic potential against acute rejection in allotransplantation.


Molecular dynamics simulations on the aggregation behavior of indole type organic dye molecules in dye-sensitized solar cells.
In Ti0(2) nanostructured dye-sensitized solar cells indole based organic dyes D149, D205 exhibits greater power conversion efficiency. Such organic dye molecules are easily undergone for aggregation. Aggregation in dye molecules leads to reduce electron transfer process in dye-sensitized solar cells. Therefore, anti-aggregating agents such as chenodeoxycholic acid are commonly added to organic dye solution in DSSCs. Studying aggregation of such dye molecules in the absence of semiconductors gives a detailed influence of anti-aggregating agents on dye molecules. Atomistic level of molecular dynamics (MD) simulations were performed on aggregation of indole type dye molecules D149, D205 and D205-F with anti-aggregating agent chenodeoxy cholic acid using AMBER program. The trajectories of the MD simulations were analyzed with order parameters such as radial atom pair distribution functions g(r), diffusion coefficients and root mean square deviations values. MD results suggest that addition of chenodeoxy cholic acid to dyes significantly reduces structural arrangement and increases conformational flexibility and mobility of dye molecules. The influence of semi-perfluorinated alkyl chains in indole dye molecules was analyzed. The parameters such as open-circuit voltage (V(oc)) and power conversion efficiency (η) of dye-sensitized solar cells are corroborated with flexibility and diffusion values of dye molecules.


Generation of Shox2-Cre allele for tissue specific manipulation of genes in the developing heart, palate, and limb.
Shox2 is expressed in several developing organs in a tissue specific manner in both mice and humans, including the heart, palate, limb, and nervous system. To better understand the spatial and temporal expression patterns of Shox2 and to systematically dissect the genetic cascade regulated by Shox2, we created Shox2-LacZ and Shox2-Cre knock-in mouse lines. We show that the Shox2-LacZ allele expresses beta-galactosidase reporter gene in a fashion that recapitulates the endogenous Shox2 expression pattern in developing organs, including the sinoatrial node (SAN), the anterior portion of the palate, and the proximal region of the limb bud. Conditional deletion of Shox2 in mice carrying the Shox2-Cre allele yielded SAN phenotypes that resemble conventional Shox2 knockout mice. Our results indicate that the Shox2-Cre allele offer a useful tool for tissue specific manipulation of genes in a number of developing organs, particularly in the developing SAN.


Ribulose diphosphate carboxylase/oxygenase. III. Isolation and properties.
Similarities in properties of ribulose diphosphate carboxylase and oxygenase activities further substantiate the hypothesis that the same protein catalyzes both reactions. The Km (ribulose diphosphate) is 0.33 mM for the ribulose diphosphate oxygenase, when assayed in air with an oxygen electrode. Maximum activity is obtained with 10 to 35 mM MgCl2. Higher MgCl2 concentrations are inhibitory, but they shift the pH optimum from 9.3 or 9.4 to 8.7 or 9.0. MnCl2 is an effective cofactor of the oxygenase and some activity is obtained with CoCl2. Both the ribulose diphosphate carboxylase and oxygenase activity of the purified protein from spinach leaves are slowly inactivated by storage at 0 degrees and reactivated in 10 min at 50 degrees, provided both 25 mM MgCl2 and 1 mM dithiothreitol are present. The sulfhydryl groups of the enzyme which react rapidly with 5,5'-dithiobis(2-nitrobenzoic acid) are approximately 4 at pH 7.8 and 11 at pH 9.4. At both pH values ribulose diphosphate prevents two of these sulfhydryl groups from reacting with this reagent. About 50% inhibition of the oxygenase activity at pH 9.0 occurs with 50 mM bicarbonate in the presence of 3 mM ribulose diphosphate, and from variations in these parameters the inhibition is attributed to the CO2 species. The purified enzyme of acrylamide gels prevented the reduction of nitroblue tetrazolium in the presence of the superoxide radical, but the enzyme in solution did not react as a superoxide dismutase.


Noninvasive thermometer for HIFU and its scaling.
Acoustic-inversion method for a noninvasive temperature measurement in tissue is presented. A set of B-scan operating in M-mode was used as a signal-equipment. The echoes reflected from an assigned surface in tissue were acquired before and after heating, and the corresponding spectra were then obtained by FFT. In order to conduct the acoustic-inversion method, a theoretical formula given by authors in another paper was invoked. The optimization algorithm was implemented to fit the spectra to the measured data and calculate changes in temperature.


A systematic review to evaluate the efficacy of azelaic acid in the management of acne, rosacea, melasma and skin aging.
Topical azelaic acid (AA) is indicated for acne and rosacea, but there is some evidence for its use for other dermatological conditions. To assess the effectiveness and safety of topical AA for acne vulgaris, rosacea, hyperpigmentation/melasma, and skin aging. RCTs of at least 6 weeks' treatment duration were eligible for inclusion. Databases including MEDLINE, Embase, CINAHL, and ClinicalTrials.gov were searched up to December 2022. Two reviewers were involved in all stages of the systematic review process. Forty-three RCTs met the inclusion criteria. Meta-analyses within 20 rosacea studies demonstrated that erythema severity, inflammatory lesion counts, overall improvement, and treatment success (achieving skin clarity) were significantly improved with AA compared with vehicle after 12 weeks. AA was more effective than metronidazole 0.75% for improved erythema severity, overall improvement, and inflammatory lesion counts. Sixteen acne studies suggest that AA is more effective than vehicle for improving global assessments and reducing acne severity. AA 20% also significantly reduced more lesions than erythromycin gel. Within seven melasma studies, AA 20% was significantly better than vehicle for both severity and global improvement. AA 20% demonstrated significantly better results compared with hydroquinone 2% for global improvement. Very few significant differences between AA and comparators were observed for commonly reported adverse events. No eligible RCTs were found that evaluated skin aging. AA is more effective than vehicle for rosacea, acne and melasma. Comparisons between AA and other treatments were often equivalent. Where there is equivalence, AA may be a good option for some clinical situations. RCT evidence is needed to evaluate the effectiveness of AA on skin aging.


Tablet PC use directly affects children's perception and attention.
Children currently grow up with a marked increase in interactive digital mobile media. To what extent digital media directly modulate children's perception and attention is largely unknown. We investigated the processing of task-irrelevant auditory information while 37 children aged 6;8-9;1-years played the identical card game on a tablet PC or with the experimenter in reality. The sound sequence included repeated standard sounds and occasionally novel sounds. Event-related potentials in the EEG, that reflect sound-related processes of perception and attention, were measured. Sounds evoked increased amplitudes of the ERP components P1, P2 and P3a during the interaction with the tablet PC compared to the human interaction. This indicates enhanced early processing of task-irrelevant information and increased allocation of attention to sounds throughout the interaction with a tablet PC compared to a human partner. Results suggest direct effects of typical situations, where children interact with a tablet PC, on neuronal mechanisms that drive perception and attention in the developing brain. More research into this phenomena is required to make specific suggestions for developing digital interactive learning programs.


Trichostrongylus colubriformis: epithelial cell migration in the proximal and distal small intestine of infected rabbits.
In Trichostrongylus colubriformis-infected rabbits, epithelial cell migration rates and cell transit times along the villi were compared by radioautography on histological slides to normal values from noninfected small intestine. Regions of gut with high (upper jejunum) and low (ileum) burdens of worms were both examined. In the control rabbits, the estimated values for the cell migration rates in the proximal and distal parts of gut were respectively 5.8 and 2.8 microns/hr. Seventy-two hours after the thymidine injection, the labeled epithelial cells were near the tip of the villi in the jejunum whereas only 60% of the villous length was labeled in the ileum. In the infected rabbits, the presence of T. colubriformis was associated with a two-fold increase of the cell velocity, in the main site of infection. Although less prominent than in the proximal region, a significant acceleration in the cell migration was also noticed in the ileum. The cell transit time was markedly reduced in the parasitized jejunum, but no variation of this parameter was found in the distal part of gut. These changes in the dynamics of epithelial cells in both regions of the gut appeared to underlie the morphological and enzymological changes of the parasitized mucosa. They particularly contribute to create an adaptive region in the small intestine beyond the main site of infection.


Analyzing stimulus-stimulus pairing effects on preferences for speech sounds.
Several studies have demonstrated effects of stimulus-stimulus pairing (SSP) on children's vocalizations, but numerous treatment failures have also been reported. The present study attempted to isolate procedural variables related to failures of SSP to condition speech sounds as reinforcers. Three boys diagnosed with autism-spectrum disorders participated. Phase 1 was designed to assess SSP effects on production of auditory stimuli via button pressing. When SSP failed to produce a preference for the target stimulus, we instituted a series of procedural manipulations intended to address potential reasons for failure. One participant preferred the target stimulus when given the opportunity to select preferred items for pairing prior to each session, but a subsequent reversal attempt produced ambiguous results. Two participants showed no consistent preference in Phase 1 and underwent a within-session reinforcer evaluation in Phase 2, in which alternative controlling variables were demonstrated by delivering preferred stimuli contingent on button pressing.


Computed tomography-based radiomics prediction of CTLA4 expression and prognosis in clear cell renal cell carcinoma.
To predict CTLA4 expression levels and prognosis of clear cell renal cell carcinoma (ccRCC) by constructing a computed tomography-based radiomics model and establishing a nomogram using clinicopathologic factors. The clinicopathologic parameters and genomic data were extracted from 493 ccRCC cases of the Cancer Genome Atlas (TCGA)-KIRC database. Univariate and multivariate Cox regression and Kaplan-Meier analysis were performed for prognosis analysis. Cibersortx was applied to evaluate the immune cell composition. Radiomic features were extracted from the TCGA/the Cancer Imaging Archive (TCIA) (n = 102) datasets. The support vector machine (SVM) was employed to establish the radiomics signature for predicting CTLA4 expression. Receiver operating characteristic curve (ROC), decision curve analysis (DCA), and precision-recall curve were utilized to assess the predictive performance of the radiomics signature. Correlations between radiomics score (RS) and selected features were also evaluated. An RS-based nomogram was constructed to predict prognosis. CTLA4 was significantly overexpressed in ccRCC tissues and was related to lower overall survival. A higher CTLA4 expression was independently linked to the poor prognosis (HR = 1.458, 95% CI 1.13-1.881, p = 0.004). The radiomics model for the prediction of CTLA4 expression levels (AUC = 0.769 in the training set, AUC = 0.724 in the validation set) was established using seven radiomic features. A significant elevation in infiltrating M2 macrophages was observed in the RS high group (p < 0.001). The predictive efficiencies of the RS-based nomogram measured by AUC were 0.826 at 12 months, 0.805 at 36 months, and 0.76 at 60 months. CTLA4 mRNA expression status in ccRCC could be predicted noninvasively using a radiomics model based on nephrographic phase contrast-enhanced CT images. The nomogram established by combining RS and clinicopathologic factors could predict overall survival for ccRCC patients. Our findings may help stratify prognosis of ccRCC patients and identify those who may respond best to ICI-based treatments.


Single-subject design and interaction analysis in the behavioral treatment of a child with a feeding problem.
A research paradigm, including an AB1AB2 single-subject design was developed and used in conjunction with an adult-child interaction analysis methodology to evaluate the effectiveness of a behavioral treatment approach to a feeding problem in a 2 1/2-year-old male. The results indicate that after nine treatment sessions, the child's diet was appropriate and the undesirable mother-child interaction pattern was changed. In addition, the interaction analysis methodology was used to evaluate the therapist's behavior modification techniques so that these could be taught to the mother. This study continued the previous endeavors to delineate feeding problems in children and subsequently to treat these problems with a behavioral approach. This kind of systematic research, with functional analysis of presenting problems and specification of the therapist's treatment behavior, is offered as a clinically appropriate paradigm for psychotherapy and behavior modification research.


Effects of antioxidants on the aging inner ear.
Age-related cochlear structural changes include the degeneration of sensory, neural cells and the stria vascularis. The hypothesis that cellular degeneration results from exposure to oxidative products of respiration was tested by supplementing aged dogs with a diet high in antioxidants and mitochondrial metabolites and by genetically modifying the expression level of the antioxidant, manganese superoxide dismutase (SOD2) in mice. Aged dogs received either a high antioxidant diet or a normal, control diet for the last 3 years of their life. Cellular measures were compared among the two aged groups (10-15 years) and young dogs. Both aged groups had cellular degeneration relative to young dogs, but the animals fed the antioxidant diet showed less degeneration at the base and apex than the control-diet group. Transgenic mice, heterozygous null for SOD2, produce only half as much enzyme as a normal mouse. These mice showed no increase in the amount of hearing loss relative to the background strain. A diet containing antioxidants reduced the magnitude of cochlear degeneration. Genetic reduction of one antioxidant, however, did not increase the magnitude of hearing loss in aging mice. A reduction in one enzyme seems to be compensated while the addition of a complex of factors is effective.


Reconstitution of SEC gene product-dependent intercompartmental protein transport.
Transport of alpha-factor precursor from the endoplasmic reticulum to the Golgi apparatus has been reconstituted in gently lysed yeast spheroplasts. Transport is measured through the coupled addition of outer-chain carbohydrate to [35S]methionine-labeled alpha-factor precursor translocated into the endoplasmic reticulum of broken spheroplasts. The reaction is absolutely dependent on ATP, stimulated 6-fold by cytosol, and occurs between physically separable sealed compartments. Transport is inhibited by the guanine nucleotide analog GTP gamma S. sec23 mutant cells have a temperature-sensitive defect in endoplasmic reticulum-to-Golgi transport in vivo. This defect has been reproduced in vitro using sec23 membranes and cytosol. Transport at 30 degrees C with sec23 membranes requires addition of cytosol containing the SEC23 (wild-type) gene product. This demonstrates that an in vitro inter-organelle transport reaction depends on a factor required for transport in vivo. Complementation of sec mutations in vitro provides a functional assay for the purification of individual intercompartmental transport factors.


On the role of extraretinal signals for saccade generation.
We investigated the accuracy of sequential saccadic eye movements, executed without visual feed-back. We found evidence that the final error of one saccade is corrected during the next, which supports the existence of extraretinal inputs to the saccadic generator. The corrections, however, were incomplete, which suggests that extraretinal signals are only partially effective.


Parallels between tuberous sclerosis complex and neurofibromatosis 1: common threads in the same tapestry.
Neurofibromatosis type 1 (NF1) and tuberous sclerosis complex (TSC) represent two neurocutaneous disorders in which affected individuals develop tumors at an increased frequency. Although the clinical manifestations of these disorders are distinctive, the identification of the genes responsible for these disorders has demonstrated remarkable similarities on a molecular level between the NF1 and TSC tumor suppressor gene products. The NF1 and TSC2 gene products are hypothesized to function as growth regulators by modulating the activities of small GTPase molecules. The overlap between the functions of these tumor suppressor genes has yielded important insights into the molecular pathogenesis underlying each of these disorders and suggested possible pharmacological therapies specifically targeted for affected individuals.


Genome-wide association studies and heritability analysis reveal the involvement of host genetics in the Japanese gut microbiota.
Numerous host extrinsic and intrinsic factors affect the gut microbiota composition, but their cumulative effects do not sufficiently explain the variation in the microbiota, suggesting contributions of missing factors. The Japanese population possesses homogeneous genetic features suitable for genome-wide association study (GWAS). Here, we performed GWASs for human gut microbiota using 1068 healthy Japanese adults. To precisely evaluate genetic effects, we corrected for the impacts of numerous host extrinsic and demographic factors by introducing them as covariates, enabling us to discover five loci significantly associated with microbiome diversity measures: HS3ST4, C2CD2, 2p16.1, 10p15.1, and 18q12.2. Nevertheless, these five variants explain only a small fraction of the variation in the gut microbiota. We subsequently investigated the heritability of each of the 21 core genera and found that the abundances of six genera are heritable. We propose that the gut microbiota composition is affected by a highly polygenic architecture rather than several strongly associated variants in the Japanese population.


A sequential approach to risk assessment of transgenic plants expressing protease inhibitors: effects on nontarget herbivorous insects.
Protease inhibitors expressed in transgenic plants can provide enhanced levels of resistance to important pest species. A sequential approach for testing the effects of protease inhibitor-expressing crops on nontarget herbivorous insects has been developed. The approach consists of five tiers. The first two tiers comprise the selection phase. In tier one, field surveys are used to characterise the nontarget invertebrate fauna of a crop. In tier 2, histochemical assays are used to identify the subset of herbivores with a particular class of digestive proteolytic enzymes. In the assessment phase a combination of laboratory 'worst-case scenario' studies (tier 3) and controlled environment or small-scale field trials (tier 4) are used to evaluate the impact of the protease inhibitor-expressing plants on the selected nontarget species. In the final tier, field trials are used to compare the relative effect of transgenic plants and current management practices, such as pesticide use, on selected species. The first four tiers of the approach are described using potatoes expressing cystatins, a family of cysteine proteinase inhibitors, as an example. Although the plants have enhanced levels of resistance to potato cyst nematodes (PCN), Globodera pallida and Globodera rostochiensis, the results establish that they have negligible impact on the nontarget herbivorous insect, Eupteryx aurata.


Anti-infectious phytotherapies of the tree-savannah of Senegal (West-Africa) II. Antimicrobial activity of 33 species.
The screening of the antimicrobial activity of 33 medicinal plants from Senegal is reported. None of these plants showed activity against the gram-negative test bacteria and against Candida albicans. Extracts of Cnestis ferruginea and Voacanga africana showed strong activity against Aspergillus niger. The former plant was also active against dermatophytes. Twenty-five of the plants tested showed activity against gram-positive bacteria.


COVID-19 Mortality by Usual Occupation and Industry:46 States and New York City, United States, 2020.
Objectives-This report describes COVID-19 mortality in 2020 among U.S. residents in 46 states and New York City by usual occupation and industry.


Membrane extraction for detoxification of biomass hydrolysates.
Membrane extraction was used for the removal of sulfuric acid, acetic acid, 5-hydroxymethyl furfural and furfural from corn stover hydrolyzed with dilute sulfuric acid. Microporous polypropylene hollow fiber membranes were used. The organic extractant consisted of 15% Alamine 336 in: octanol, a 50:50 mixture of oleyl alcohol:octanol or oleyl alcohol. Rapid removal of sulfuric acid, 5-hydroxymethyl and furfural was observed. The rate of acetic acid removal decreased as the pH of the hydrolysate increased. Regeneration of the organic extractant was achieved by back extraction into an aqueous phase containing NaOH and ethanol. A cleaning protocol consisting of flushing the hydrolysate compartment with NaOH and the organic phase compartment with pure organic phase enabled regeneration and reuse of the module. Ethanol yields from hydrolysates detoxified by membrane extraction using 15% Alamine 336 in oleyl alcohol were about 10% higher than those from hydrolysates detoxified using ammonium hydroxide treatment.


A survey of deployed foot problems in a desert environment.
A casual comment made regarding the amount of "mole skin" being dispensed to airmen to handle blisters, pressure points, and foot pain led to the development of an impromptu voluntary survey in an attempt to quantify the number of personnel with foot care concerns and the spectrum of those problems. With only a small number of sick call visits related to foot and ankle problems, the amount of mole skin being dispensed was surprising. This survey represents the results of a comprehensive evaluation of a base population involved in support of the first 2 months of Operation Iraqi Freedom.


Snapping scapular syndrome secondary to rib intramedullary fixation device.
Scapulo-thoracic joint disorders, including bursitis and crepitus, are commonly misdiagnosed problems and can be a source of persistent pain and dysfunction This article describes an unusual case of a snapping scapula syndrome secondary to a migration through the lateral cortex of a rib splint intramedullary fixation device into the scapulothoracic joint. Recently, the operative fixation of multiple ribs fractures with intramedullary fixation devices has become popular. Despite the good outcomes with new rib splint designs, concern remains about the potential complications related to potential loss of fracture reduction with migration of the wire resulting in pain or additional injury to the surrounding tissues. Surgeons should pay attention to any protrusion of intramedullary rib implants, especially in the evaluation of routine X-rays following surgical treatment. We should be aware of the possibility of this rare cause of snapping scapula syndrome to avoid delayed diagnosis and consider removing the implant will resolve the pain.


Forming connections in the homeopathic consultation.
A previous study which explored homeopathic practitioners' in depth understanding and experiences of homeopathic consultations identified "connecting" as a key component of the consultation. This paper reports on "connecting" and its role in the consultation. Using a qualitative grounded theory approach data was collected from homeopaths using in-depth interviews, observations of homeopathic consultations and solicited practitioner reflective diaries. Constant comparison assisted code, concept and category formation to form a model of the UK classical homeopathic consultation. "Connecting", describes a complex notion of relationship in the homeopathic consultation consisting of four dimensions, and performs several roles within the consultation that enable practitioners to elicit symptoms, identify expectations, assist with prescribing, help patients engage with homeopathic principles and stimulate healing. This study shows the homeopath as an important component of the therapeutic context forming complex relationships and using communication that is skills based and inductively shaped to interpret and respond to each individual patient and their narrative in the consultation. This study could have implications for teachers, students and practitioners of homeopathy by influencing training needs, and could prove instructive for other clinicians as homeopaths' communication style could be used to augment other consultations.


Pharmacokinetics of 8-methoxypsoralen in the dog.
The pharmacokinetics of 8-MOP were studied in six dogs following intravenous administration of 2 mg kg-1. In most animals a bi-exponential decline of the plasma level profile was observed. The calculated pharmacokinetic parameters varied considerably between the different dogs. The mean half-lives of distribution and of elimination were 0.20 and 2.17 h, respectively. The average total plasma clearance was 0.51 l kg-1 h-. Following both oral and intravenous administration of doses of 1, 3, and 10 mg kg-1, non-linear kinetics were found. Non-linearity was confirmed following administration of the substance at increasing infusion rates. Finally in four dogs, extraction by the liver was calculated by measuring 8-MOP concentration in the femoral artery and in a hepatic vein after intravenous administration of 1 mg kg-1. The extraction varied from animal to animal (18 per cent to nearly 100 per cent). Administration of an additional dose of 3 mg kg-1 in two of the dogs led to a decreased extraction.


A peripheral nervous system actin-binding protein regulates neurite outgrowth.
Difference cloning has identified a Villin-like mRNA transcript expressed selectively in peripheral sensory and sympathetic neurons. Pervin, the encoded 820-amino acid protein, has 60% identity with Villin and is the rat homologue of Advillin. Coimmunoprecipitation studies demonstrate that Pervin and actin interact in vivo. Transfection of COS-7 epithelial cell lines demonstrates colocalization of epitope-tagged Pervin with green fluorescent protein-actin and results in an increase in process formation. This effect is abolished when the putative actin-bundling headpiece of Pervin is deleted. Biolistic transfection of primary cultures of rat dorsal root ganglion sensory neurons also results in increased neurite outgrowth with FLAG-tagged Pervin. Deletion of the actin-bundling headpiece inhibits normal neurite growth. These data suggest that Pervin may play a significant role in regulating process outgrowth in peripheral neurons through a mechanism that involves the activity of an actin-bundling domain.


A quality assurance exercise to evaluate the accuracy and reproducibility of chromogenic in situ hybridisation for HER2 analysis in breast cancer.
Chromogenic in situ hybridisation (CISH) is an alternative to immunohistochemistry or FISH for the assessment of HER2 oncogene status in breast cancer. Although CISH is being used increasingly in routine diagnostics, there are no established inter-laboratory quality assurance programmes for this test. The reproducibility of HER2 CISH analysis was assessed when performed by seven different centres that use the test routinely in diagnostic service. The results from 28 cases showed overall concordance of 98.5% (192/195 tests; kappa coefficient 0.91). One of the discrepancies was due to the invasive carcinoma having been cut out in the sections received by two of the centres, and the other two were in the non-amplified/equivocal/low-amplified category. This is believed to be the first report of a quality assurance study assessing laboratories that use HER2 CISH routinely in clinical diagnostics. The results show that CISH is a robust technique providing a suitable assay for the frontline testing of HER2 status in breast cancer.


Everolimus after hepatic arterial embolisation therapy of metastases from gastrointestinal neuroendocrine tumours: The FFCD 1104-EVACEL-GTE phase II study.
Hepatic arterial embolisation therapy (HAET) is a treatment of liver metastases of gastrointestinal neuroendocrine tumours (GI-NETs). HAET increases circulating vascular endothelial growth factor levels. Everolimus is a treatment in NETs that may have antiangiogenic activity. This phase II study was conducted in patients with predominant and progressive liver metastases from GI-NETs. Everolimus was initiated 7-30 days after HAET. The hypothesis was that everolimus after HAET would increase hepatic progression-free survival (hPFS) rate at 24 months from 35% to 50%. Among the 74 patients included, 88% had small-bowel primary tumour, 43% had grade I and 57% grade II tumour, and 51% had extrahepatic metastases. Patients underwent one (n = 19), two (n = 54), or three (n = 1) HAET procedures. hPFS at 24 months was 33% (95% confidence interval [CI], 22.5-43.7); 40 (54%) patients had objective response. Median (95% CI) hPFS, PFS, and overall survival were 19 (14-23), 17 (13-22), and 51 (33-60) months. The most common grade III-IV toxicities (>5%) in patients receiving both HAET and everolimus (n = 67) were elevated liver enzymes (55%), fatigue (18%), diarrhoea (16%), anaemia (12%), hypertriglyceridaemia (7%) and mucositis (6%). The primary end-point was not reached. This sequence allows high liver response with HAET, and everolimus controls the extrahepatic disease. NCT01678664 (clinicaltrials.gov).


Crystallization and preliminary X-ray analysis of a novel Trichoderma reesei xylanase IV belonging to glycoside hydrolase family 5.
Xylanase IV (XYN IV) is a new recently characterized xylanase from Trichoderma reesei. It is able to degrade several different xylans, mainly producing xylose. XYN IV has been crystallized by the hanging-drop vapour-diffusion method, using PEG 6000 as a precipitant. The crystals belong to the orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a = 86.3, b = 137.5, c = 196.1 A, alpha = beta = gamma = 90 degrees. Assuming a molecular weight of 50.3 kDa, the V(M) values indicate there to be four XYN IV monomers in an asymmetric unit and the solvent content of the crystals to be 57%. Based on dynamic light-scattering measurements, XYN IV is a dimer in solution. A native data set to 2.8 A resolution has been collected at a home laboratory and a data set to 2.2 A resolution has been collected using synchrotron radiation.


Functional effects of the hypertrophic cardiomyopathy R403Q mutation are different in an alpha- or beta-myosin heavy chain backbone.
The R403Q mutation in the beta-myosin heavy chain (MHC) was the first mutation to be linked to familial hypertrophic cardiomyopathy (FHC), a primary disease of heart muscle. The initial studies with R403Q myosin, isolated from biopsies of patients, showed a large decrease in myosin motor function, leading to the hypothesis that hypertrophy was a compensatory response. The introduction of the mouse model for FHC (the mouse expresses predominantly alpha-MHC as opposed to the beta-isoform in larger mammals) created a new paradigm for FHC based on finding enhanced motor function for R403Q alpha-MHC. To help resolve these conflicting mechanisms, we used a transgenic mouse model in which the endogenous alpha-MHC was largely replaced with transgenically encoded beta-MHC. A His(6) tag was cloned at the N terminus of the alpha-and beta-MHC to facilitate protein isolation by Ni(2+)-chelating chromatography. Characterization of the R403Q alpha-MHC by the in vitro motility assay showed a 30-40% increase in actin filament velocity compared with wild type, consistent with published studies. In contrast, the R403Q mutation in a beta-MHC backbone showed no enhancement in velocity. Cleavage of the His-tagged myosin by chymotrypsin made it possible to isolate homogeneous myosin subfragment 1 (S1), uncontaminated by endogenous myosin. We find that the actin-activated MgATPase activity for R403Q alpha-S1 is approximately 30% higher than for wild type, whereas the enzymatic activity for R403Q beta-S1 is reduced by approximately 10%. Thus, the functional consequences of the mutation are fundamentally changed depending upon the context of the cardiac MHC isoform.


Effects of daily artificial gravity training on orthostatic tolerance following 60-day strict head-down tilt bedrest.
Orthostatic intolerance commonly occurs following immobilization or space flight. We hypothesized that daily artificial gravity training through short-arm centrifugation could help to maintain orthostatic tolerance following head-down tilt bedrest, which is an established terrestrial model for weightlessness. We studied 24 healthy persons (eight women; age 33.3 ± 9.0 years; BMI 24.3 ± 2.1 kg/m2) who participated in the 60-days head-down tilt bedrest (AGBRESA) study. They were assigned to 30 min/day continuous or 6 × 5 min intermittent short-arm centrifugation with 1Gz at the center of mass or a control group. We performed head-up tilt testing with incremental lower-body negative pressure until presyncope before and after bedrest. We recorded an electrocardiogram, beat-to-beat finger blood pressure, and brachial blood pressure and obtained blood samples from an antecubital venous catheter. Orthostatic tolerance was defined as time to presyncope. We related changes in orthostatic tolerance to changes in plasma volume determined by carbon dioxide rebreathing. Compared with baseline measurements, supine and upright heart rate increased in all three groups following head-down tilt bedrest. Compared with baseline measurements, time to presyncope decreased by 323 ± 235 s with continuous centrifugation, by 296 ± 508 s with intermittent centrifugation, and by 801 ± 354 s in the control group (p = 0.0249 between interventions). The change in orthostatic tolerance was not correlated with changes in plasma volume. Daily artificial gravity training on a short-arm centrifuge attenuated the reduction in orthostatic tolerance after 60 days of head-down tilt bedrest.


Preparation, development, and scale-up of standardized pentacyclic triterpenoid-rich extract from Centella asiatica (L.) Urb. and study of its wound healing activity.
This pilot-scale study of an innovative green extraction method shows increased biomarker content in plant extracts. Moreover, green extraction methods decrease the effects on the environment and human health and promote industrial growth. This study optimized the process conditions to obtain a pentacyclic triterpenoid-rich extract (PRE) from Centella asiatica (L.) Urb., which contains asiatic acid, madecassic acid, asiaticoside, and madecassoside, and evaluated its biological activities. PRE preparation was scaled up from laboratory to pilot scale. In the pilot scale, a combination of microwave-assisted extraction with an irradiation power of 4 kW and an ultrasonic-assisted extraction at 0.55 kW was used for C. asiatica extraction. The total pentacyclic triterpene content was 106.02 mg/g of crude extract. Then, the C. asiatica extract was fractionated by a macroporous resin (Diaion® HP-20). The PRE preparation method used 50% and 75% EtOH fractions. This PRE produced a high content of pentacyclic triterpenoids at 681.12 mg/g of crude extract. It presented a high anti-inflammatory effect with an IC50 value of 23.88 μg/mL for nitric oxide inhibition and induced wound healing processes (proliferation, migration, and collagen synthesis) in human dermal fibroblast cells. The information gained from this study can advance the industrial extraction of physiologically active substances from various plant sources for use as medicines or components of supplemental food and cosmeceutical products.


ERG Channels Regulate Excitability in Stellate and Bushy Cells of Mice Ventral Cochlear Nucleus.
ERG (ether-a-go-go-related gene) channels are the members of the voltage-dependent potassium channel family, which have three subtypes, as ERG1 (Kv 11.1), ERG2 (Kv 11.2), and ERG3 (Kv11.3). There is no information on ERG channels in the cochlear nucleus (CN) neurons, which is the first relay station of the auditory pathway. As occur in some of congenital long QT Syndromes (LQTS), mutation of the KCNQ11 genes for ERG channel has been reported to be accompanied by hearing loss. For that reason, we aimed to study biophysical properties and physiological importance, and contribution of ERG K+ currents to the formation of action potentials in the stellate and bushy neurons of the ventral cochlear nucleus (VCN). A total of 70 mice at 14-17 days old were used for this study. Electrophysiological characterization of ERG channels was performed using patch-clamp technique in the CN slices. In current clamp, ERG channel blockers, terfenadine (10 µM) and E-4031 (10 µM), were applied in both cell types. The activation, inactivation, and deactivation kinetics of the ERG channels were determined by voltage clamp. In conclusion, the findings obtained in the present study suggest that stellate and bushy neurons express ERG channels and ERG channels appear to contribute to setting action potential (AP) frequency, threshold for AP induction, and, possibly, resting membrane potentials in this cells.


Resistance mechanism of Acinetobacter spp. strains resistant to DW-116, a new quinolone.
DW-116 is a new fluoroquinolone antimicrobial agent with a broad spectrum. In order to elucidate the resistance mechanism to DW-116 in Acinetobacter spp. bacteria, total chromosomal DNA was isolated from 10 strains of Acinetobacter spp. resistant to DW-116. Quinolone resistance determinant region (QRDR) of DNA gyrase gene was amplified by PCR. The 345 bp nucleotide fragment yielded was inserted into pKF 3 which was used as the vector. Comparisons of the DNA sequences of 8 strains with that of the wild type strain revealed a Ser-83 to Leu mutation in mutants and all ten strains contained one silent mutation(T-->G) in QRDR. From Acinetobacter MB4-8 strain, DNA gyrase was isolated and purified, through no-vobiocin-sepharose, heparin-sepharose affinity column chromatography. The enzyme was composed of two subunits and the molecular mass of subunits A and B were 75.6 and 51.9 kDa, respectively. The supercoiling activity of the reconstituted DNA gyrase composed of subunit A from Acinetobacter MB4-8 and subunit B from E. coli was not inhibited by 128 micrograms/ml of ciprofloxacin. It might be said that one of the resistance mechanisms to DW-116 in A-cinetobacter MB4-8 was subunit A alteration of DNA gyrase.


Consultants cutting in. Healthcare consulting is seen as a burgeoning business for those who know the steps and can find willing partners.
Business is flourishing for healthcare consultants, and that's driving an acquisition trend by firms that are already well-known in the market. How has it turned into such a growth industry? While healthcare is booming, it's a dysfunctional and highly fragmented industry that's been slow to adopt IT and has to cope with spiraling inflation. "There's always some trouble spot," says David Auchterlonie, left.


Assessment the impact of different fuels used in cement industry on pollutant emissions and ambient air quality: a case study in Egypt.
This study aims to assess the impact of using different fuels in Egyptian Titan Alexandria Portland Cement Company on emissions and concentrations of pollutants (Total suspended particles (TSP), nitrogen dioxide (NO2), and sulfur dioxide (SO2)) and their influence on ambient air quality during the period 2014-2020 using AERMOD dispersion model. The results showed that changing the fuel from natural gas in 2014 to coal mixed with alternative fuels (Tire-Derived Fuel (TDF), Dried Sewage Sludge (DSS), and Refuse Derived Fuels (RDF)) in 2015-2020 caused fluctuating variations in pollutant emissions and concentrations. The highest and lowest maximum concentrations of TSP occurred in 2017 and 2014 respectively, where the TSP is positively correlated with coal, RDF, and DSS and negatively correlated with natural gas, diesel, and TDF. Also, the lowest and highest maximum NO2 concentrations were detected in 2020 and 2016 followed by 2017 respectively, where NO2 is positively correlated with DSS and negatively correlated with TDF and varies with diesel, coal, and RDF. Moreover, the maximum concentrations of SO2 were the lowest in 2018 and highest in 2016 followed by 2017 because of its considerable positive correlation with natural gas and DSS and negative correlation with RDF, TDF, and coal. Generally, it was found that increasing the percentage of TDF and RDF with decreasing the percentage of DSS, diesel, and coal will reduce pollutant emissions and concentrations and enhance ambient air quality.


Radiosensitization of mammary carcinoma cells by telomere homolog oligonucleotide pretreatment.
Ionizing radiation (IR) is a widely used approach to cancer therapy, ranking second only to surgery in rate of utilization. Responses of cancer patients to radiotherapy depend in part on the intrinsic radiosensitivity of the tumor cells. Thus, promoting tumor cell sensitivity to IR could significantly enhance the treatment outcome and quality of life for patients. Mammary tumor cells were treated by a 16-base phosphodiester-linked oligonucleotide homologous to the telomere G-rich sequence TTAGGG (T-oligo: GGTTAGGTGTAGGTTT) or a control-oligo (the partial complement, TAACCCTAACCCTAAC) followed by IR. The inhibition of tumor cell growth in vitro was assessed by cell counting and clonogenic cell survival assay. The tumorigenesis of tumor cells after various treatments was measured by tumor growth in mice. The mechanism underlying the radiosensitization by T-oligo was explored by immunouorescent determination of phosphorylated histone H2AX (γH2AX) foci, β-galactosidase staining, comet and Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) assays. The efficacy of the combined treatment was assessed in a spontaneous murine mammary tumor model. Pretreatment of tumor cells with T-oligo for 24 hours in vitro enhanced both senescence and apoptosis of irradiated tumor cells and reduced clonogenic potential. Radiosensitization by T-oligo was associated with increased formation and/or delayed resolution of γH2AX DNA damage foci and fragmented DNA. T-oligo also caused radiosensitization in two in vivo mammary tumor models. Indeed, combined T-oligo and IR-treatment in vivo led to a substantial reduction in tumor growth. Of further significance, treatment with T-oligo and IR led to synergistic inhibition of the growth of spontaneous mammary carcinomas. Despite these profound antitumor properties, T-oligo and IR caused no detectable side effects under our experimental conditions. Pretreatment with T-oligo sensitizes mammary tumor cells to radiation in both in vitro and in vivo settings with minimal or no normal tissue side effects.


In vitro cytokine release from rat type II pneumocytes and alveolar macrophages following exposure to JP-8 jet fuel in co-culture.
Alveolar type II epithelial cells (AIIE) and pulmonary alveolar macrophages (PAM) are involved in pulmonary toxicity of JP-8 jet fuel exposure. To further elucidate their inflammatory mechanisms, the effect(s) of JP-8 jet fuel on cytokine secretion were examined in a transformed rat AIIE cell line (RLE-6TN) culture alone, primary PAM (from Fischer 344 rats) culture alone, and the co-culture of AIIE and primary PAM. A series of JP-8 jet fuel concentrations (0-0.8 microg/ml), which may actually be encountered in alveolar space of lungs exposed in vivo, were placed in cell culture for 24 h. Cultured AIIE alone secreted spontaneously interleukin (IL)-1beta and -6 [below detectable limits for IL-10 and tumor necrosis factor-alpha (TNF-alpha)], whereas cultured PAM alone secreted IL-1beta, -10, and TNF-alpha, in a concentration-dependent manner. These data suggest that the release of cytokines, not only from PAM but also from AIIE cells, may contribute to JP-8 jet fuel-induced inflammatory response in the alveolar space. However, the co-cultures of AIIE and PAM showed no significant changes in IL-1beta, -6, and TNF-alpha at any JP-8 jet fuel concentration compared to control values. These cytokine levels in co-cultures of AIIE and PAM were inversely related to these of cultured AIIE or PAM alone. Interestingly, IL-10 levels in the co-culture system were concentration-dependently increased up to 1058% at JP-8 concentrations of 0.8 microg/ml, although under detectable limits in cultured AIIE alone and no significant concentration change in cultured PAM alone. It appears that PAM may possibly act via paracrine and/or autocrine pathways to signal AIIE cells to regulate cytokine release.


Self-reported vaccination-related behavior patterns among healthcare workers and the association with self-directed learning frequency: A nationwide cross-sectional survey.
Healthcare workers play an essential role in improving the public's vaccination uptake, but the full picture of such workers' engagement in vaccination-related behaviors has not been appropriately identified. According to the Integrated Theory of Health Behavior Change, self-directed learning may be a promising intervention for fostering engagement in vaccination-related behaviors, but the association between self-directed learning and such behaviors remains unclear. This study aimed to determine Chinese healthcare workers' level of engagement in behaviors for combatting vaccine-preventable diseases and assess the association between frequency of performing vaccine-focused SDL and engagement in vaccination-related behaviors. An online cross-sectional survey was conducted from January 27 to February 21, 2022, using the survey platform "wjx." Respondents were restricted to healthcare workers aged 18-65 years. A Sankey diagram and bar plots were constructed to determine patterns of engagement in a vaccination-related-behavior chain. Unconditional binary logistic regression models were fitted to determine the association between frequency of performing vaccine-focused self-directed learning and engagement in vaccination-related behaviors. Of the 2,248 survey respondents, data for 2,065 were analyzed. Participants who had received influenza or pneumococcal vaccination, routinely recommended vaccination to patients, tracked patients' vaccination status, and recommended efficiently accounted for 43.2%, 50.8%, 40.3%, and 36.4% of the total participants, respectively. When only considering those who routinely made such recommendations, the proportion of those who performed tracking and efficient recommendation was 28.8% and 26.2%, respectively. When compared to performing self-directed learning "never to less than once/six months," performing self-directed learning "more than once/week" was positively associated with being vaccinated (OR, 95% CI: 2.30, 1.74-3.03), routinely recommending vaccination (OR, 95% CI: 4.46, 3.30-6.04), and tracking the status of patients so recommended (OR, 95% CI: 6.18, 4.35-8.76). Chinese healthcare workers' pattern of engagement in vaccination-related behaviors must be improved. Higher frequencies of engagement in self-directed learning are associated with more active engagement in vaccination-related behaviors, meaning raising such frequencies could be a promising intervention for fostering behavior changes in this regard and ultimately increasing vaccination coverage.


Maternal, Perinatal, and Postnatal Predisposing Factors of Hearing Loss in Full-Term Children: A Matched Case-Control Study.
Studies on risk factors for childhood hearing loss (HL) are usually based on questionnaires or small sample sizes. We conducted a nationwide population-based case-control study to comprehensively analyze the maternal, perinatal, and postnatal risk factors for HL in full-term children. We retrieved data from three nationwide databases related to maternal characteristics, perinatal comorbidities, and postnatal characteristics and adverse events. We used 1:5 propensity score matching to include 12,873 full-term children with HL and 64,365 age-, sex-, and enrolled year-matched controls. Conditional logistic regression was used to evaluate the risk factors for HL. Among the various maternal factors, maternal HL (adjusted odds ratio [aOR]: 8.09, 95% confidence interval [95% CI]: 7.16-9.16) and type 1 diabetes (aOR: 3.79, 95% CI: 1.98-7.24) had the highest odds of childhood hearing impairment. The major perinatal risk factors for childhood hearing impairment included ear malformations (aOR: 58.78, 95% CI: 37.5-92.0) and chromosomal anomalies (aOR: 6.70, 95% CI: 5.25-8.55), and the major postnatal risk factors included meningitis (aOR: 2.08, 95% CI: 1.18-3.67) and seizure (aOR: 3.71, 95% CI: 2.88-4.77). Other factors included acute otitis media, postnatal ototoxic drug use, and congenital infections. Many risk factors for childhood HL identified in our study are preventable, such as congenital infection, meningitis, ototoxic drug use, and some maternal comorbidities. Accordingly, more effort is required to prevent and control the severity of maternal comorbidities during pregnancy, initiate genetic diagnostic evaluation for high-risk children, and aggressive screening for neonatal infections.


Mode of distribution of aminergic fibers in the cerebellar cortex of the chicken.
The cerebellar cortex of adult hens contains a dense plexus of thin varicose nerve fibers which display a formaldehyde-induced green fluorescence. This plexus is not distributed at random in the cortical layers. Within the granular layer the plexus forms a netlike pattern. The fiber branches, which have numerous varicosities, are predominantly oriented in the traverse plane of the folium. In the molecular layer the fluorescent plexus shows some variations in the convex, flat and concave portions of the folia. Many of the fluorescent branches are oriented parallel to the course of the folium. They arise from a T-division of radially oriented axons resembling parallel fibers in Golgi sections. The meshes of the fluorescent plexus in the granular layer measure 10-60 mu. In the molecular layer (top of the folia) there are about 30 fluorescent fibers per 100 mu2. The fluorescent fibers originate from the locus coeruleus and form a rostral and a caudal bundle in the cerebellar peduncle. The mode of distribution of the fluorescent fibers in the cortical layers seems to depend on the organization of the innervated tissue. Light microscopy suggests that the aminergic fibers innervate more than one class of cerebellar neurons.


Novel ctxB variants of Vibrio cholerae O1 isolates, China.
We screened 650 isolates from historical collection of Vibrio cholerae O1 during the 7th cholera pandemic in China, by amplifying and sequencing the cholera toxin subunit gene ctxB. Ten isolates were identified as harboring three novel ctxB genotypes based on amino acid residue substitutions. Within them one isolate from a patient in 1964 was similar to the El Tor genotype, except for an 11 amino acid repeat sequence (LAGKREMAIIT) that was inserted after position 62. Six environmental isolates from different regions and years were identified as the Australia El Tor genotype, except at positions 36(T→A), 39(H→Y), and 55(K→N), while three environmental isolates were similar to genotype 5, except at position 24(Q→H). Sequencing of rstR, the marker gene for the CTXΦ allele typing, revealed that two isolates carried the rstR gene of the El Tor type, five carried the classical type rstR, while other isolates carried the rstR232 type. All 10 isolates contained the repeat in the toxin gene rtxC, an El Tor biotype-specific marker, and the El Tor toxin-coregulated pili subunit A gene tcpA, showing the El Tor traits of these isolates. Additionally, by phenotypic biotyping (susceptibility to polymyxin B, positive for chicken erythrocyte agglutination, and Voges-Proskauer test), all isolates except two were typical of the prototype El Tor isolate, while these two isolates had mixed classical phenotypes (hybrid biotype). Furthermore, pulsed-field gel electrophoresis analysis suggested that the new ctxB altered isolates possessed potential transmissibility and thatthey propagated in the local region(s). Taken together, these novel ctxB variants of V. cholerae O1 experienced complex hybrid and genetic exchange but belong to the El Tor lineage, and the pathogenic and epidemic potential of these lineages should be monitored.


Bone marrow coagulated and low-level laser therapy accelerate bone healing by enhancing angiogenesis, cell proliferation, osteoblast differentiation, and mineralization.
The present study evaluated bone marrow aspirate (BMA) and low-level laser therapy (LLLT) on bone healing. It was created critical-size defects (CSD) of 5 mm diameter in rat calvaria of 64 rats. Animals were randomly divided into four groups: Control (blood clot), BMA (coagulated BMA), LLLT (laser irradiation and blood clot), and BMA/LLLT (laser irradiation and coagulated BMA). Euthanasia was performed at 15 or 30 days postoperative. Immunohistochemical reactions were performed to identify vascular endothelial growth factor (VEGF), proliferating cell nuclear antigen (PCNA), runt-related transcription factor-2 (Runx2), bone morphogenetic protein-2 (BMP-2), osteocalcin (OCN), and osteopontin (OPN). The markers were quantified, and data were statistically analyzed. Groups BMA/LLLT and LLLT presented significantly higher VEGF expression than group control. Group BMA/LLLT presented a significantly higher expression of PCNA than all experimental groups. Groups BMA and BMA/LLLT presented significantly higher expression of BMP-2 than all experimental groups. Groups LLLT and BMA/LLLT presented significantly higher expression of OPN than groups control and BMA. Groups LLLT, BMA, and BMA/LLLT presented a significantly higher expression of OCN than group control. It can be concluded that the association of BMA and LLLT enhanced bone healing by improving expression of VEGF, PCNA, Runx2, BMP-2, OPN, and OCN.


Erratum: Fixed combination of lercanidipine and enalapril in the management of hypertension; focus on patient preference and adherence [Corrigendum].
[This corrects the article on p. 449 in vol. 6, PMID: 22791982.].


Light-triggered multifunctional nanoplatform for efficient cancer photo-immunotherapy.
Cancer immunotherapy is limited by the immune escape of tumor cells and adverse effects. Photo-immunotherapy, the combination of immunotherapy and phototherapy (such as photodynamic therapy (PDT) and photothermal therapy (PTT)), can improve the effectiveness of immunotherapy in cancer treatment. Here, we first explored mesoporous hexagonal core-shell zinc porphyrin-silica nanoparticles (MPSNs), which are composed of a zinc porphyrin core and a mesoporous silica shell, and exhibit high laser-triggered photodynamic and photothermal activity, as well as outstanding drug loading capacity. In other words, MPSNs can be used not only as excellent photosensitizers for photo-immunotherapy, but also as an ideal drug carrier to achieve more efficient synergy. After loading with R837 (imiquimod, a toll-like receptor-7 agonist), MPSNs@R837 will elicit high-efficiency immunogenic cell death via PDT and PTT, and promote dendritic cell maturation after the PH-responsive release of R837, thereby, inducing tumor-specific immune responses. When combined with a programmed death ligand-1 checkpoint blockade, the photo-immunotherapy system markedly restrains primary tumors and metastatic tumors with negligible systemic toxicity. Therefore, the therapeutic strategy of integrating PTT, PDT and checkpoint blockade, shows great potential for suppressing cancer metastasis.


Research progress in nanozyme-based composite materials for fighting against bacteria and biofilms.
Nanozyme belonging to artificial enzyme is a term describing nanomaterial with enzyme-like characteristics. Great research advances have been acquired in the field of nanozymes due to their striking merits. Inspired by natural enzymes that disrupt the structural integrity of cells or interfere with metabolism, nanozymes which can effectively avoid generation of bacterial resistance may become potential alternatives for antibiotics in the context of the continuous emergence and rapid spread of drug-resistant bacteria and the slow development of new antibiotics. Naturally, nanozymes inevitably have some inherent defects, which need to be compensated by forming composite materials with other components to play a synergistic effect. What's more, nanozyme-based composite materials retain the advantages of nanozymes and integrate multiple functions into a single system to achieve an intelligent and multi-functional therapeutic model. This is a new strategy for combating bacteria/biofilms in the future. In this review, firstly we cover the general mechanisms and design principles of nanozyme-based composite materials for fighting against bacteria/biofilms and the typical types of nanozymes for resisting bacteria/biofilms. Meanwhile the applications and the advantages of nanozyme-based composite materials for anti-bacteria and anti-biofilms are emphasized. Finally, the challenges and prospects of nanozyme-based composite materials for combating bacteria/biofilms are discussed for future research in this field.


Mitochondria and neuroprotection in stroke: Cationic arginine-rich peptides (CARPs) as a novel class of mitochondria-targeted neuroprotective therapeutics.
Stroke is the second leading cause of death globally and represents a major cause of devastating long-term disability. Despite sustained efforts to develop clinically effective neuroprotective therapies, presently there is no clinically available neuroprotective agent for stroke. As a central mediator of neurodamaging events in stroke, mitochondria are recognised as a critical neuroprotective target, and as such, provide a focus for developing mitochondrial-targeted therapeutics. In recent years, cationic arginine-rich peptides (CARPs) have been identified as a novel class of neuroprotective agent with several demonstrated mechanisms of action, including their ability to target mitochondria and exert positive effects on the organelle. This review provides an overview on neuronal mitochondrial dysfunction in ischaemic stroke pathophysiology and highlights the potential beneficial effects of CARPs on mitochondria in the ischaemic brain following stroke.


Accumulation of DSBs in gamma-H2AX domains fuel chromosomal aberrations.
DNA double strand breaks (DSBs) pose a severe hazard to the genome as erroneous rejoining of DSBs can lead to mutation and cancer. Here, we have investigated the correlation between X irradiation-induced gamma-H2AX foci, theoretically induced DSBs, and the minimal number of mis-rejoined DNA breaks (MNB) in irradiated lymphocytes obtained from two healthy humans by painting of the whole chromosome complement by spectral karyotyping. There were less gamma-H2AX foci/dose than theoretically expected, while misrepair, as expressed by MNB/gamma-H2AX focus, was similar at 0.5 and 1Gy but 3.6-fold up at 3Gy. Hence, our results suggest that X-ray-induced gamma-H2AX foci in G0 lymphocyte nuclei contain more than one DSB and that the increasing number of DSBs per gamma-H2AX repair factory lead to an increased rate of misrepair.


The nature of L8 and L8S8 forms of ribulose bisphosphate carboxylase/oxygenase from Chromatium vinosum.
L8 and L8S8 forms of ribulose bisphosphate carboxylase/oxygenase (RubisCO) have been prepared from Chromatium vinosum by the extremely mild method of centrifugal fractionation. Only the L8S8 form is detectable in crude extracts of this organism. Both forms show immunological identify in double diffusion studies using antibody to L subunits of the L8S8 form. L subunits from both L8 and L8S8 enzymes are identical by the criteria of peptides observed after limited proteolysis and N-terminal sequence analysis. In addition, these subunits show regions of homology with L subunits from Rhodospirillum rubrum, Anacystis nidulans, and spinach. S subunits of the C. vinosum enzyme are completely homologous to those from A. nidulans and higher plants from the 18th through 25th residue, a stretch preceded in all cases by two basic amino acids.


Utility of the Enhanced Liver Fibrosis score as a blood biomarker of pulmonary fibrosis secondary to SARS-CoV-2 pneumonia.
SARS-CoV-2 pneumonia can lead to several sequelae, among them, pulmonary fibrosis. The Enhanced Liver Fibrosis (ELF) score is a panel of serum markers of liver fibrosis. We aimed to describe the utility of the ELF score as a biomarker of pulmonary fibrosis secondary to COVID-19 pneumonia. Chest computed tomography (CT) scan, lung function tests (LFT) and blood analysis were obtained at three months after discharge. Data were analysed according to ELF scores and posteriorly divided into ELF tertiles. One hundred twenty-nine patients were recruited; of these, 85.7% presented bilateral pneumonia at diagnosis of SARS-CoV2 infection. At 3 months after discharge, CT scan was available in 123 patients, 73 (59.3%) of whom presented parenchymal lung abnormalities (PLA) and LFT showed impairment in 28 (22.7%) patients. Globally, the most frequent PLA was ground glass opacities (50%), followed by bronchial thickening (26.8%), reticular pattern (19.5%), consolidation (10.5%) and air bronchogram sign (7.3%). Radiological findings were only significant in the higher tertile of ELF, with a reticular pattern as the predominant PLA (p = 0.002). Moreover, patients with both PLA and LFT impairment, presented a trend towards higher levels of ELF compared with patients with only PLA or LFT impairment, or no impairment (9.9 (0.7) vs 9.6 (0.8), 9.1 (1.1) and 9.3 (0.7); p = 0.054). Patients with both PLA and LFT alteration at 3 months after SARS-CoV-2 pneumonia had higher ELF scores. The ELF score may be useful to identify patients with risk of fibrotic changes after SARS-CoV-2 pneumonia.


Does menopausal transition really influence mental health? Findings from the prospective long-term Zurich study.
In the prospective long-term Zurich study, we re-examined the hypothesized association between mental health problems in women and the transition through menopausal stages. One hundred sixty-eight women from a population-based Swiss community cohort were prospectively followed up from age 21 to 50. At age 50, the occurrence of hot flushes/night sweats and sleep disturbances was significantly more frequent in peri- and post-menopausal women. Irritability/nervousness was increased only in peri-menopausal women, but that association was accounted for by neuroticism trait scores at age 30. Transitions to peri- or post-menopause were not related to changes in either the prevalence rates of DSM major depressive episode or anxiety disorders, or the course of psychopathological syndromes as assessed by the Symptom Checklist 90 - Revised. The null associations held when adjusting for duration of reproductive period or age at menopause. Preceding mental health problems between ages 21 and 41, increased neuroticism trait scores at age 30, and concurrent psychosocial distress were significantly related to mental health problems occurring between ages 41 and 50. Depending upon the cut-off point that was chosen, the arbitrary dichotomization of a continuous depression outcome produced spurious associations with the menopausal transition. We conclude that mental health problems between ages 41 and 50 are probably not directly related to the menopausal transition, and that previously reported associations could be false positives due to inadequate dichotomizations, reporting bias, undisclosed multiple adjustments or overfitting.


Pharmacokinetic Drug Interaction Studies with Enzalutamide.
Two phase I drug interaction studies were performed with oral enzalutamide, which is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). A parallel-treatment design (n = 41) was used to evaluate the effects of a strong cytochrome P450 (CYP) 2C8 inhibitor (oral gemfibrozil 600 mg twice daily) or strong CYP3A4 inhibitor (oral itraconazole 200 mg once daily) on the pharmacokinetics of enzalutamide and its active metabolite N-desmethyl enzalutamide after a single dose of enzalutamide (160 mg). A single-sequence crossover design (n = 14) was used to determine the effects of enzalutamide 160 mg/day on the pharmacokinetics of a single oral dose of sensitive substrates for CYP2C8 (pioglitazone 30 mg), CYP2C9 (warfarin 10 mg), CYP2C19 (omeprazole 20 mg), or CYP3A4 (midazolam 2 mg). Coadministration of gemfibrozil increased the composite area under the plasma concentration-time curve from time zero to infinity (AUC∞) of enzalutamide plus active metabolite by 2.2-fold, and coadministration of itraconazole increased the composite AUC∞ by 1.3-fold. Enzalutamide did not affect exposure to oral pioglitazone. Enzalutamide reduced the AUC∞ of oral S-warfarin, omeprazole, and midazolam by 56, 70, and 86 %, respectively; therefore, enzalutamide is a moderate inducer of CYP2C9 and CYP2C19 and a strong inducer of CYP3A4. If a patient requires coadministration of a strong CYP2C8 inhibitor with enzalutamide, then the enzalutamide dose should be reduced to 80 mg/day. It is recommended to avoid concomitant use of enzalutamide with narrow therapeutic index drugs metabolized by CYP2C9, CYP2C19, or CYP3A4, as enzalutamide may decrease their exposure.