Nuclear RNA metabolism in rat hippocampal slices incubated in vitro.
Rat hippocampal slices were incubated with [3H]uridine in vitro to analyze the metabolism of nuclear RNA and the RNA precursor fractions. Labeling of total nuclear RNA was linear for 4 h of incubation and proportional to the concentration of labeled uridine in the incubation medium. Addition of 3.5 X 10(-8) M corticosterone to the incubation medium produced an enhancement of nuclear RNA labeling with no significant effect on the labeling of the RNA precursor fraction. Progesterone and dexamethasone, at the same concentration, had no effect on either variable. Labeling of RNA by cerebellar slices under the same conditions was approximately one-half the value obtained using hippocampal slices and the cerebellar RNA precursor fraction accumulated only 65% of the radioactivity from [3H]uridine found in the hippocampal pool. Corticosterone had no effect on the labeling of total nuclear RNA in cerebellar slices. Nuclear poly(A)-containing RNA constituted 19% of the total labeled nuclear RNA in these incubations, as estimated by oligo (dT)-cellulose chromatography. Cordycepin (3'-deoxyadenosine) at a concentration of 25 micrograms/ml inhibited to some extent the labeling of total nuclear RNA and the RNA precursor fraction, but preferentially diminished the amount of labeled RNA bound to oligo (dT)-cellulose. Corticosterone increased the amount of [3H]RNA which bound to oligo (dT)-cellulose, while progesterone had no effect. These results show that hippocampal slices maintained in vitro, can be used to analyze nuclear RNA metabolism, one positive regulator of which in the rat hippocampus is the adrenal steroid, corticosterone.


3,3'-Diselenodipropionic acid (DSePA) forms 1:1 complex with Hg (II) and prevents oxidative stress in cultured cells and mice model.
Mercury is one of the most toxic heavy metal for mammals particularly in inorganic form. In present study, 3,3'-diselenodipropionic acid (DSePA), a well-known pharmacological diselenide was evaluated for its interaction with HgCl2 and ability to prevent HgCl2-induced toxicity in experimental cellular and mice models. UV-visible, stopped flow, Fourier-transform infrared spectroscopy and 1H nuclear magnetic resonance spectroscopy studies confirmed that DSePA sequestered Hg (II) ions with stoichiometry of 1:1 and binding constant of ~104 M-1. X-ray photoelectron spectroscopy and X-ray powder diffraction analysis suggested that diselenide group of DSePA was involved in the complexation with Hg (II) ions. Further, Hg-DSePA complex degraded within 10 days to form excretable HgSe. The binding constant of DSePA and Hg (II) was comparable with that of dihydrolipoic acid, a standard disulfide compound used in heavy metal detoxification. Corroborating these observations, pre-treatment of DSePA (10 μM) significantly prevented the HgCl2 (50 μM)-induced glutathione oxidation (GSH/GSSG), decrease of thioredoxin reductase (TrxR) and glutathione peroxidase (GPx) activities and cell death in Chinese Hamster Ovary (CHO) cells. Similarly, intraperitoneal administration of DSePA at a dosage of 2 mg/kg for 5 consecutive days prior to exposure of HgCl2 (1 mg/kg) significantly suppressed oxidative stress in renal and hepatic tissues of C57BL/6 mice. In conclusion, the protective effect of DSePA against Hg induced oxidative stress is attributed to its ability to rescue the activities of GPx, TrxR and GSH by sequestering Hg (II) ions. DSePA being a relatively safer selenium-compound for in vivo administration can be explored for mercury detoxification.


The importance of sustained compliance with physical distancing during COVID-19 vaccination rollout.
Increasing vaccination coverage against SARS-CoV-2 enabled relaxation of lockdowns in many countries in Europe. As the vaccination rollouts progressed, the public health authorities were seeking recommendations on the continuation of physical distancing measures during ongoing vaccination rollouts. Compliance with these measures was declining while more transmissible virus variants have emerged. We used a SARS-CoV-2 transmission model to investigate the feedback between compliance, infection incidence, and vaccination coverage. We quantified our findings in terms of cumulative number of new hospitalisations three and six months after the start of vaccination. Our results suggest that the combination of fast waning compliance in non-vaccinated individuals, low compliance in vaccinated individuals, low vaccine efficacy against infection and more transmissible virus variants may result in a higher cumulative number of new hospitalisations than in a situation without vaccination. These adverse effects can be alleviated by deploying behavioural interventions that should preferably target both vaccinated and non-vaccinated individuals. The choice of the most appropriate intervention depends on vaccination rate and vaccine efficacy against infection. Supplementary behavioural interventions aiming to boost compliance to physical distancing measures can improve the outcome of vaccination programmes, until vaccination coverage is sufficiently high. For optimal results, these interventions should be selected based on the vaccine efficacy against infection and expected vaccination rate. While we considered the dynamics of SARS-CoV-2, the qualitative effects of the interplay between infectious disease spread and behavior on the outcomes of a vaccination programme can be used as guidance in a future similar pandemic.


Characterization of a Timepix detector for use in SEM acceleration voltage range.
Hybrid pixel direct electron detectors are gaining popularity in electron microscopy due to their excellent properties. Some commercial cameras based on this technology are relatively affordable which makes them attractive tools for experimentation especially in combination with an SEM setup. To support this, a detector characterization (Modulation Transfer Function, Detective Quantum Efficiency) of an Advacam Minipix and Advacam Advapix detector in the 15-30 keV range was made. In the current work we present images of Point Spread Function, plots of MTF/DQE curves and values of DQE(0) for these detectors. At low beam currents, the silicon detector layer behaviour should be dominant, which could make these findings transferable to any other available detector based on either Medipix2, Timepix or Timepix3 provided the same detector layer is used.


Enhanced photodynamic antimicrobial activity of surface modified SiNPs doped with zinc(II) phthalocyanines: The effect of antimicrobial ampicillin and extra charges from a sultone.
1-(2-Methoxyethyl)piperidine sustituted Zn phthalocyanine complex (2) is synthesised and quartenised (3). These complexes are loaded into silica nanoparticles (SiNPs) that are futher surface modified with ampicillin and 1.3-propanesultone. The photophysical and photochemical properties of the complexes and their doped conjugates were investigated in dimethylsulfoxide. The cationic complex (3) is used for photodynamic antimicrobial activity. Log reduction values of above 9 are obtained towards the photoiactivation of Staphyloccocus aureus.


Complete Genome Sequence of Bartonella alsatica Strain IBS 382 (CIP 105477).
Bartonella alsatica causes bacteremia in rabbits and, rarely, human infections. Here, we announce the complete and closed genome of B. alsatica IBS 382 (CIP 105477), generated by long-read Pacific Biosciences single-molecule real-time (SMRT) sequencing. The availability of this genome sequence allows future work on understanding the zoonotic potential of this pathogen.


Nanobodies, the potent agents to detect and treat the Coronavirus infections: A systematic review.
The newly emerged coronavirus (SARS-CoV-2) continues to infect humans, and no effective treatment has yet been found. Antibody therapy is one way to control infection caused by COVID-19. However, the use of classical antibodies raises complex issues. Heavy chain antibodies (HCAbs) are single-domain antibodies derived from the Camelidae family. The variable part of these antibodies (Nanobodies or VHH) has interesting properties such as small size, cost-effective production, and good tissue permeability, causing VHH to be regarded as an antiviral therapeutics. However, the small size of nanobodies may lead to low antigen binding affinity and rapid renal clearance. In this systematic review, the application of nanobodies in the treatment of COVID-19 infection and other similar infections (MERS and SARS) was reviewed.


Underlying determinants of maternal mortality in a rural South African population with high HIV prevalence (2000-2014): A population-based cohort analysis.
Maternal mortality is one of the significant health indicators of any country and it's a frequent subject in many global heath discussions. Even though the global trends have shown a decrease on maternal mortality, many countries in sub-Saharan Africa failed to achieve the MDG 5 target in 2015.There is no specific single solution for reducing maternal mortality but there is unanimity that a reliable health system with skilled personal is vital for addressing maternal mortality. This study therefore seeks to identify the risk factors for maternal mortality in typical rural sub-Saharan African countries. A longitudinal population based cohort study was conducted using data from 2000-2014 in Africa Health Research Institute (AHRI).The Cox regression method was used to assess the influence of selected risk factors using the Mosley-Chen model on maternal mortality. A total of 20701 women aged 15-49 years were included in the study. The study found 212 maternal deaths from 32,620 live births with a maternal mortality ratio (MMR) of 650 per 100,000 live births. The main causes of death were Communicable diseases (38.2%), Aids and TB (31%) and Unknown causes (11.8%). An increased risk of death was identified on, poor wealth index (HR 3.92[1.01, 15.3]), period of death 2000-2006(HR32.1 [3.79, 71.5]) and number of deliveries (6.76[2.70, 16.9]) were associated with a high risk of maternal mortality after adjusting for other independent variables included in the study. Socio-economic status, number of deliveries and period of death were found to be associated with maternal death in rural South Africa.


Thromboprophylaxis for Coagulopathy Related to COVID-19 in Pediatrics: A Narrative Review.
In addition to harming the respiratory system, COVID-19 can affect multiple organs. Children may develop a specific complication of COVID-19 called multisystem inflammatory syndrome in children (MIS-C) which could influence the vascular system of children and cause multiple coagulopathies in the body. Information on the use of thromboprophylaxis in this condition was collected via the review of various articles. In general, different factors in immune system responses can trigger the initiation of thrombotic events. Studies have shown that starting anticoagulant prophylaxis, which contributes to decreased thrombotic events, is dependent on the patient's condition and D-dimer levels. However, further studies on pediatric populations are needed to establish the role of anticoagulants in children with this condition.


Effects of concurrent canine Cushing's syndrome and diabetes Mellitus on insulin requirements, trilostane dose, and survival time.
Trilostane and insulin requirements and survival time of dogs with concurrent naturally-occurring Cushing's syndrome (CS) and diabetes mellitus (DM) has not been fully investigated. This retrospective study evaluated trilostane and insulin doses in dogs with concurrent CS and DM compared to dogs with only CS or DM. Additionally, a survival analysis was performed using a Kaplan-Meier survival curve. Survival time was compared through Log-rank test. Cox proportional regression method was used to screen predictor factors of death in dogs with CS, DM or concurrent CS and DM. A total of 95 dogs were included, 47 dogs had CS, 31 dogs had DM and 17 dogs had concurrent CS and DM. After long-term follow-up, dogs with concurrent CS and DM required higher final median doses of insulin than dogs with DM [0.90 (0.73-1.1) vs 0.67 (0.55-0.73) u/kg/12 h; P = 0,002]. Conversely, the median trilostane requirements in dogs with concurrent CS and DM did not differ from the median trilostane requirements of dogs with CS [1.52 (0.76-2.80) vs 1.64 (1.19-4.95) mg/kg/day; P = 0.283]. No statistical difference was found for the median survival time between dogs with CS and dogs with concurrent CS and DM (1245 vs 892 days; p = 0.152). Although, median survival time of dogs with DM was not reached, it was longer than median survival time of dogs with CS and DM (892 days; P = 0.002). In conclusion, diabetic dogs with concurrent CS need higher insulin doses and have a shorter survival time compared to diabetic dogs without CS.


[Depolarization of primary afferents during fictitious scratching of thalamic cats].
The cord dorsum and dorsal root potentials were recorded during fictious scratching in L6 segment of the thalamic cats. It is shown that primary afferent depolrization (PAD) can be modulated by the central generator of scratching. In some afferent fibres antidromic spikes appear on the top of PAD-waves. Antidromic spikes can be also evoked in the period of "rest" by mechanical stimulation of hindlimb receptors. It is supposed that PAD and resulting antidromic spikes which appear during real scratching may effectively control the level of afferent inflow to the spinal neurons.


Sequential changes in pathophysiology of systemic inflammatory response in a disseminated neonatal herpes simplex virus (HSV) infection.
Disseminated neonatal herpes simplex virus (HSV) infection causes a typical systemic inflammatory response syndrome and has a high mortality rate. However, the validity of anti-inflammatory intervention against this condition remains unknown. We sought to demonstrate the sequential changes in the pathophysiology of disseminated neonatal HSV infections. The HSV serum copy number as well as high-mobility group box 1 (HMGB1) and cytochrome c concentrations, which predict the severity and mortality rate of sepsis, were sequentially evaluated in a patient with disseminated neonatal HSV infection caused by HSV-2. As the patient presented with evidence of hyper-inflammation and severe illness, we empirically undertook anti-inflammatory intervention that included the administration of prednisolone, high-dose immunoglobulin, and blood exchange therapy in addition to high-dose acyclovir (ACV) therapy. The patient survived without significant neurological sequela. We found that (1) the serum concentrations of both HMGB1 and cytochrome c were extremely high, (2) temporal increases in these biomarkers were observed after admission, and (3) interestingly, the increase in HMGB1 level preceded that of cytochrome c. These results suggested that the pathophysiology of this condition changed sequentially in a dramatic manner, and the timing of our anti-inflammatory intervention was prior to the transition of pathological status from hyper-inflammation to massive apoptosis. Anti-inflammatory intervention may only be effective if it is undertaken during the early phase of disseminated neonatal HSV infections.


A pilot study of topiramate in the treatment of infantile spasms.
West syndrome is a rare epileptic syndrome associated with infantile spasms, a specific abnormal electroencephalographic pattern (termed hypsarrhythmia), and mental retardation. Management of this disorder is difficult because current treatment regimens, including many anticonvulsants and hormones, are often ineffective. Topiramate (TPM) is a new antiepileptic drug that may be effective in pediatric epilepsies. We conducted a pilot study to test the effects of rapid TPM dosing in patients with refractory infantile spasms. Eleven children with refractory infantile spasms were given an initial dose of 25 mg TPM per day in addition to their current therapy. Dosage was increased by 25 mg every 2-3 days until spasms were controlled, the maximal tolerated dose was reached, or the maximal dose of 24 mg/kg/day was achieved. Efficacy was primarily assessed by video EEG and secondarily by parental count of spasm frequency. Five (45%) subjects became spasm free during the study, with absence of infantile spasms and hypsarrhythmia (either classic or modified) proven by video EEG. Nine subjects, including the five spasm free, achieved a spasm reduction of > or =50%. Spasm frequency decreased from 25.6+/-19.3 to 6.9+/-5.9 spasms/day. Sixty-four percent of the subjects were able to achieve TPM monotherapy. Results in this cohort of 11 patients with refractory disease show TPM to be a promising new agent for the treatment of infantile spasms.


Virulent Newcastle disease virus in Nigeria: identification of a new clade of sub-lineage 5f from livebird markets.
Newcastle disease (ND), caused by Avian Paramyxovirus Type 1, is a highly contagious and devastating viral disease of poultry of worldwide distribution with an enormous economic impact. Although ND is reported to be endemic in Nigeria, little information exists on the molecular epidemiology and the lineage distribution of the Newcastle disease viruses (NDVs) in the country, especially in the live bird markets (LBMs). Recent studies reported the identification of three unique sub-lineages. namely; 5f, 5g and 5h in West Africa, and sub-lineages 5f and 5g in particular in non-commercial farms in Nigeria. In this study, 33 NDV isolates, which included NDVs recovered from LBMs in Nigeria, during active surveillance from 2007 to 2008 and viruses recovered from outbreaks in backyard and commercial chicken farms within the same period were analysed. Based on determination of the F(0) cleavage site amino acid sequence and phylogenetic analysis, the isolates were classified as virulent; 16 strains were identified as sub-lineage 5g and 17 as sub-lineage 5f. Interestingly, 13 strains from the 5f group formed a distinct cluster that was not identified by other groups in similar studies. The close genetic similarities identified, provided evidence for the first time of the epidemiological link between the viruses circulating in the LBMs and those recovered from outbreaks in backyard and commercial chicken farms in Nigeria between 2007 and 2008. The emergence and identification of new sub-lineages provide an insight into the high rate of genetic drift occurring in NDV strains in Nigeria, and raises a lot of concerns about the efficacy of current ND control measures in the country.


TREM-1 exacerbates bleomycin-induced pulmonary fibrosis by aggravating alveolar epithelial cell senescence in mice.
Our previous study showed that triggering receptors expressed on myeloid cell-1 (TREM-1) was upregulated in bleomycin (BLM)-induced pulmonary fibrosis (PF) mouse model. However, the role of TREM-1 in the development of PF and its underlying mechanism remain unclear. Herein, we report that the prophylactical blockade of TREM-1 using a decoy peptide dodecapeptide (LR12) exerted protective effects against BLM-induced PF in mice, with a higher survival rate, attenuated tissue injury, and less extracellular matrix deposition. Interestingly, therapeutic blockade of TREM-1 at the early stage of fibrosis also attenuated BLM-induced PF, suggesting a non-inflammatory effect. More importantly, we observed that TREM-1 blockade with LR12 significantly reduced the expression of the senescence-relative protein, including p16, p21, p53, and γ-H2AX in the lungs of PF mice. Notably, TREM-1 was upregulated in alveolar epithelial cells (AECs) and correlated with the levels of senescence markers in BLM-treated mice. In vitro, activating TREM-1 with an agonistic antibody exacerbated BLM-induced senescence in MLE12 cells, a murine AEC cell line. Furthermore, prophylactic or therapeutic blockade of TREM-1 protected MLE12 cells from senescence induced by BLM or H2O2. In conclusion, our findings elucidate a pro-fibrotic effect of TREM-1 by inducing AECs senescence in PF, providing a potential strategy for fibrotic disease treatment.


Vascular cell signaling by membrane estrogen receptors.
The definition of estrogen's actions has expanded from transcriptional regulation to the rapid, membrane-initiated activation of numerous signal transduction cascades. Multiple biological effects of estrogen have been shown in numerous animals, cellular and molecular studies, which support the favorable effects of estrogen on vascular structure, function, and cell signaling. Work from several laboratories has shown that these effects are mediated by distinct forms of estrogen receptor (ER) alpha. This includes estrogen-stimulated rapid activation of endothelial nitric oxide synthase (eNOS), resulting in the elaboration of the athero-protective, angiogenesis-promoting product nitric oxide (NO). We have described the expression of ER46, an N-terminus truncated isoform of the ERalpha, in human endothelial cells (EC), and its critical role in membrane-initiated, rapid responses to 17beta-estradiol (E2). We have proposed an ER46-centered, eNOS activating molecular complex in human EC caveolar membranes, containing c-Src, phosphatidylinositol 3-kinase (PI3K), Akt and eNOS. Our previous studies support estrogen-induced rapid eNOS activation via a sequential c-Src/PI3K/Akt cascade in EC. In this review, we describe estrogen-induced, rapid, non-genomic actions in endothelium, driven by c-Src-ER46-caveolin-1 interactions, with consequent activation of eNOS. Amidst ongoing controversies in hormone replacement therapy, these molecular and cellular data, defining favorable estrogenic effects on the endothelium, provide a strong impetus to resolve these clinical questions.


Purification and characterization of beta-galactoside-binding lectin from chick embryonic skin.
Lectin activity was found in tarsometatarsal skin of chick embryo. It was specific for beta-linked galactosyl residues and required a thiol-reducing agent for hemagglutination activity. The lectin was extracted from dermis and epidermis (skin) with lactose and purified to apparent homogeneity by affinity chromatography on asialofetuin-Sepharose. Examination of their biochemical properties showed that although dermis and epidermis develop from different origins, they contain the same lectin. The apparent subunit Mr of lectin was 14000 and its isoelectric point was 7.0. Under non-dissociating conditions, the lectin exists mainly as a dimer. Radioimmunoassay showed that this skin-type lectin is present in many tissues including skin, muscle, bone, eye, heart, liver and brain at various developmental stages. A wide distribution and a marked change in its content during development strongly suggest that the lectin might have a fundamental role in cellular function, embryonic development and tissue differentiation.


In vivo migration and function of transferred HIV-1-specific cytotoxic T cells.
The persistence of HIV replication in infected individuals may reflect an inadequate host HIV-specific CD8+ cytotoxic T lymphocyte (CTL) response. The functional activity of HIV-specific CTLs and the ability of these effector cells to migrate in vivo to sites of infection was directly assessed by expanding autologous HIV-1 Gag-specific CD8+ CTL clones in vitro and adoptively transferring these CTLs to HIV-infected individuals. The transferred CTLs retained lytic function in vivo, accumulated adjacent to HIV-infected cells in lymph nodes and transiently reduced the levels of circulating productively infected CD4+ T cells. These results provide direct evidence that HIV-specific CTLs target sites of HIV replication and mediate antiviral activity, and indicate that the development of immunotherapeutic approaches to sustain a strong CTL response to HIV may be a useful adjunct to treatment of HIV infection.


Guinea worm disease--the final chapter?
The global campaign for the eradication of dracunculiasis has succeeded in reducing the incidence of guinea worm disease by >99% in the past 20 years. This has been accomplished by the provision of safe drinking water supplies, filtration of drinking water, chemical control of intermediate hosts, case containment and, crucially, local health-education initiatives.


Autologous cultivated conjunctival transplantation for recurrent viral papillomata.
To describe the use of an autologous serum-free derived cultivated conjunctival epithelial equivalent in the treatment of extensive recurrent viral papillomata. Interventional case report. A 10-year-old child with extensive recurrent viral papillomata involving the superior and inferior tarsal, forniceal, and bulbar conjunctiva underwent surgical excision of all diseased areas and double freeze-thaw cryotherapy. Autologous serum-free cultivated conjunctival equivalents were used to reconstruct the ocular surface and conjunctival fornices. Almost complete epithelialization was achieved within 5 days postoperatively. A good cosmetic and functional result was obtained, and no recurrences or cicatricial complications developed during 12-month follow-up. Transplantation of autologous cultivated conjunctiva was effectively used in the reconstruction of the ocular surface after extensive excision of recurrent viral papillomata. This modality of treatment may be useful in the treatment of ocular surface disorders in which extensive conjunctival and fornix reconstruction is required.


The parvalbumin/somatostatin ratio is increased in Pten mutant mice and by human PTEN ASD alleles.
Mutations in the phosphatase PTEN are strongly implicated in autism spectrum disorder (ASD). Here, we investigate the function of Pten in cortical GABAergic neurons using conditional mutagenesis in mice. Loss of Pten results in a preferential loss of SST(+) interneurons, which increases the ratio of parvalbumin/somatostatin (PV/SST) interneurons, ectopic PV(+) projections in layer I, and inhibition onto glutamatergic cortical neurons. Pten mutant mice exhibit deficits in social behavior and changes in electroencephalogram (EEG) power. Using medial ganglionic eminence (MGE) transplantation, we test for cell-autonomous functional differences between human PTEN wild-type (WT) and ASD alleles. The PTEN ASD alleles are hypomorphic in regulating cell size and the PV/SST ratio in comparison to WT PTEN. This MGE transplantation/complementation assay is efficient and is generally applicable for functional testing of ASD alleles in vivo.


Impact of ultrasonic pretreatment under different operational conditions on the mesophilic anaerobic digestion of sunflower oil cake in batch mode.
In this study ultrasonic (US) pretreatment was investigated with the aim of improving the anaerobic digestion of sunflower oil cake (SuOC), the solid waste derived from the extraction process of sunflower oil. Five ultrasonic pretreatment assays were conducted at specific energy (SE) and sonication times in a range from 24,000 kJ/kg TS and 16.6 min (assay 1: US1) to 597,600 kJ/kg TS and 331.2 min (assay 5: US5), respectively, all operating at a constant sonication frequency (20 kHz) and ultrasonic power (120 W). As regards ultrasonic pretreatment, the working conditions of the first assay (US1) using samples of SuOC at 2% (w/v) showed to be the most appropriate in terms of both lignin and hemicellulose degradation (57.7% and 66.7%, respectively) and cellulose increase (54% increase with respect to its initial concentration). The percentage of COD solubilization increased from only 14% to 21% when SE was 25 times higher. Results obtained in batch anaerobic digestion experiments (biochemical methane potential - BMP - tests) conducted at 35°C of the solid and liquid fractions released from the different ultrasonic conditions tested, indicated that for the first experiment (US1) the average ultimate methane yield obtained was 53.8% higher than that achieved for untreated SuOC. Finally, the kinetic constants of the anaerobic digestion of the solid and liquid fractions released after the ultrasonic pretreatment were virtually independent of the operation conditions assayed.


Interheteromolecular Hyperconjugation Boosts (De)hydrogenation for Reversible H2 Storage.
Interheteromolecular hyperconjugation is ubiquitous in organic systems, affecting bond length, dipole moments, conformations and so on, while its effect on (de)hydrogenation reactivity in a heterogeneous thermo-catalytic system has rarely been explored. Herein, the N-heterocycles containing a benzene ring and aliphatic chain [N-ethylcarbazole (NEC) and N-propylcarbazole (NPC)] were utilized to study the correlation between interheteromolecular hyperconjugation and catalytic (de)hydrogenation. Density functional theory calculations, variable-temperature 1 H nuclear magnetic resonance spectroscopy, and catalytic experiments showed that the presented hyperconjugation between NEC and NPC weakened the electron cloud density of aromatic rings and thus facilitated the reactivity with hydrogen featuring unpaired electrons. Therefore, an extremely low temperature of 80 °C was enough for the hydrogenation. Moreover, this interheteromolecular hyperconjugation was general in other N-heterocycles (e. g., N-methyindole and NPC) and was also effective to (de)deuterate as revealed by isotope experiments. This work expands the application of interheteromolecular hyperconjugation to heterogeneous thermocatalysis for reversible H2 storage.


The circadian transcription factor ARNTL2 is regulated by weight-loss interventions in human white adipose tissue and inhibits adipogenesis.
Misalignment of physiological circadian rhythms promotes obesity which is characterized by white adipose tissue (WAT) expansion. Differentiation of Adipose stem/progenitor cells (ASCs) contributes to WAT increase but the importance of the cellular clock in this process is incompletely understood. In the present study, we reveal the role of the circadian transcription factor Aryl hydrocarbon receptor nuclear translocator-like 2 (ARNTL2) in human ASCs, isolated from subcutaneous (s)WAT samples of patients undergoing routine elective plastic abdominal surgery. We show that circadian synchronization by serum-shock or stimulation with adipogenic stimuli leads to a different expression pattern of ARNTL2 relative to its well-studied paralogue ARNTL1. We demonstrate that ARNTL2 mRNA is downregulated in ASCs upon weight-loss (WL) whereas ARNTL2 protein is rapidly induced in the course of adipogenic differentiation and highly abundant in adipocytes. ARNTL2 protein is maintained in ASCs cooperatively by mechanistic Target of Rapamycin (mTOR) and Mitogen-activated Protein Kinase (MAPK) signalling pathways while ARNTL2 functions as an inhibitor on both circuits, leading to a feedback mechanism. Consistently, ectopic overexpression of ARNTL2 repressed adipogenesis by facilitating the degradation of ARNTL1, inhibition of Kruppel-Like Factor 15 (KLF15) gene expression and down-regulation of the MAPK-CCAAT/enhancer-binding protein β (C/EBPβ) axis. Western blot analysis of sWAT samples from normal-weight, obese and WL donors revealed that ARNTL2 protein was solely elevated by WL compared to ARNTL1 which underscores unique functions of both transcription factors. In conclusion, our study reveals ARNTL2 to be a WL-regulated inhibitor of adipogenesis which might provide opportunities to develop strategies to ameliorate obesity.


Transforming preconceptional, prenatal, and interconceptional care into a comprehensive commitment to women's health.
Preconception and interconception care respond to the growing body of evidence that many of the most important determinants of birth outcomes may exist before pregnancy occurs. In this sense, the strategy of extending prenatal care into the preconception and interconception periods marks a useful step in reforming the public health approach to improving birth outcomes. However, although helpful in underscoring the continuity of risk that can ultimately find expression in adverse birth outcomes, the concern is that without greater critical attention these relatively new care constructs have the potential to undermine rather than strengthen a comprehensive system of women's health care.


[Robot-assisted laparoscopic radical prostatectomy].
The advantage of minimally invasive surgery in the form of laproscopic radical prostatectomy compared with open retropubic radical prostatectomy is indisputable. But a long learning curve seems to be a clear disadvantage. Robotic surgery devices such as the da Vinci system could be very helpful here. The aim of this study was to demonstrate our own experience with da Vinci prostatectomy in consideration of the learning curve. Since implementation of the da Vinci system 23 months ago, we have done over 300 operating procedures with the system. Despite of having great know how in laparoscopic surgery the conversion rate was only 1.7%. The oncological outcome was satisfactory and comparable with the results reported in the literature. A complication rate of only 5.1% also seems acceptable. With the da Vinci system, we can combine the advantages of a minimally invasive procedure with those of open surgery but without the disadvantage of a long learning curve. At the moment, the expense factor remains a handicap.


A highly accurate protein structural class prediction approach using auto cross covariance transformation and recursive feature elimination.
Structural class characterizes the overall folding type of a protein or its domain. Many methods have been proposed to improve the prediction accuracy of protein structural class in recent years, but it is still a challenge for the low-similarity sequences. In this study, we introduce a feature extraction technique based on auto cross covariance (ACC) transformation of position-specific score matrix (PSSM) to represent a protein sequence. Then support vector machine-recursive feature elimination (SVM-RFE) is adopted to select top K features according to their importance and these features are input to a support vector machine (SVM) to conduct the prediction. Performance evaluation of the proposed method is performed using the jackknife test on three low-similarity datasets, i.e., D640, 1189 and 25PDB. By means of this method, the overall accuracies of 97.2%, 96.2%, and 93.3% are achieved on these three datasets, which are higher than those of most existing methods. This suggests that the proposed method could serve as a very cost-effective tool for predicting protein structural class especially for low-similarity datasets.


Long-term follow-up for efficacy and safety of treatment of retinitis pigmentosa with valproic acid.
The purpose of this study was to determine the long-term efficacy and safety of valproic acid (VPA) treatment in patients with pigmentary retinal dystrophies. A retrospective chart review was conducted on 31 patients with a diagnosis of pigmentary retinal dystrophy prescribed VPA at a single centre. Visual field (VF), visual acuity (VA), length of treatment, liver enzymes and side effects were analysed. VF areas were defined using Goldmann VF (GVF) tracings recorded before, during and after VPA treatment using the V4e isopter for each eye. Using custom software, planimetric areas of VF were calculated. Five of the patients (10 eyes) had two Goldmann VF tracings, allowing comparison between baseline and follow-up VF. After 9.8 months of VPA, VF decreased by 0.145 cm(2) (26.478%) (p=0.432). For 22 of the patients (41 eyes), VA data was available, and logarithm of the minimum angle of resolution (logMAR) score changed by 0.056 log units (representing a decline in VA) after 14.9 months on VPA (p=0.002). Twelve patients (38.7%) reported negative side effects related to VPA use. VPA plays a complex role in patients with pigmentary retinal dystrophies and may be associated with VA and field decline as well as adverse side effects. Physicians should use caution with using VPA for pigmentary retinal dystrophies.


Phosphorylated modification and in vitro antioxidant activity of Radix Hedysari polysaccharide.
Phosphorylated modification of a polysaccharide obtained from Radix Hedysari (RHP) was studied. Three phosphorylated polysaccharides (RHPP) with variable degrees of substitution (DS(p)) were obtained with 4-dimethylaminopyridine (DMAP) and N, N' Dicyclocarbodiimide (DCC) as catalyst. The structures of RHPP were characterized by FT-IR spectra and (13)C NMR spectra. Depending on different reaction time, RHPP showed different DS(p) ranging from 0.30 to 0.66, and different Mw ranging from 86.6 to 89.7 KDa. Compared with RHP, RHPP exhibited superior antioxidant activities in vitro, which indicated that phosphorylated modification could enhance antioxidant activities of RHP. Furthermore, it was obvious that the DS(p) had a significant effect on the antioxidant activity.


Investigation of the non-size-determined T4N0-2M0 non-small-cell lung cancer: what is the proper T category for the tumour with additional nodules in different lobes of ipsilateral lung?
This study aimed to explore the prognostic disparity among T4N0-2M0 non-small-cell lung cancer (NSCLC) patients with different T4 descriptors. T3-4N0-2M0 NSCLC patients were included. Patients were assigned to 7 subgroups: T3, T4 tumours with size larger than 70 mm (T4-size), T4 tumours with aorta/vena cava/heart invasion (T4-blood vessels), T4 tumours with vertebra invasion (T4-vertebra), T4 tumours with carina/trachea invasion (T4-carina/trachea), T4 tumours with additional tumour nodules in different lobes of ipsilateral lung (T4-add) and T4 tumours had at least 2 T4 descriptors (T4-multiple). Univariable and multivariable Cox analyses were used to explore the effect of T4 category on overall survival. Kaplan-Meier method with log-rank test was used to compare survival differences among subgroups. Propensity score matching was used to minimize the bias caused by imbalanced covariates between groups. A total of 41 303 eligible T3-4N0-2M0 NSCLC cases were included (17 057 T3 cases and 24 246 T4 cases). There were 10 682 cases, 573 cases, 557 cases, 64 cases, 2888 cases and 9482 cases in the T4-size, T4-blood vessels, T4-vertebra, T4-carina/trachea, T4-add and T4-multiple subgroups, respectively. Multivariable Cox analyses revealed that T4-add patients had the best prognosis in the entire cohort and in several subgroups. In the matched cohort of T4-add and T4-size and T4-add and T3, the survival of T4-add patients was superior to that of T4-size patients (P < 0.001) but was comparable to that of T3 patients (P = 0.115). Among NSCLC patients with different T4 descriptors, T4-add patients had the best prognosis. T4-add patients and T3 patients had similar survivals. Herein, we proposed that T4-add patients should be downstaged from T4 to T3 category. Our results served as a novel supplement to the proposals for the T category revision.


A way to explore the existence of "immortals" in cancer registry data - An illustration using data from ICBP SURVMARK-2.
Accurately recorded vital status of individuals is essential when estimating cancer patient survival. When deaths are ascertained by linkage with vital statistics registers, some may be missed, and such individuals will wrongly appear to be long-term survivors, and survival will be overestimated. Interval-specific relative survival that levels off above one indicates that the survival among the cancer patients is better than expected, which could be due to the presence of immortals. We included colon cancer cases diagnosed in 1995-1999 within the 19 jurisdictions in seven countries participating in ICBP SURVMARK-2, with follow-up information available until end-2015. Interval-specific relative survival was estimated for each year following diagnosis, by country and age group at diagnosis. The interval-specific relative survival levels off at 1 for all countries and age groups, with two exceptions: for the age group diagnosed at age 75 years and above in Ireland, and, to a lesser extent, in New Zealand. Overall, a subset of immortals are not apparent in the early years within the ICBP SURVMARK-2 study, except for possibly in Ireland. We suggest this approach as one strategy of exploring the existence of immortals, and to be part of routine checks of cancer registry data.


Repeatability and reproducibility of phase analysis of gated single-photon emission computed tomography myocardial perfusion imaging used to quantify cardiac dyssynchrony.
A novel method to quantify dyssynchrony has been developed using phase analysis of gated single-photon emission computed tomography perfusion imaging. We report on the effect of variability in image reconstruction on the phase analysis results (repeatability) and on the interobserver and intraobserver reproducibility of the technique. Phase standard deviation (SD) and bandwidth are phase indices that quantify dyssynchrony. To evaluate repeatability, raw data sets were processed twice in 50 patients with left ventricular dysfunction and 50 normal controls. To determine the optimal processing method, two replicated phase analysis results were obtained using automated and manual base parameter placement. Reproducibility of the phase analysis was determined using the data from 20 patients. In normal controls, manual base parameter placement improves repeatability of the phase analysis as measured by the mean absolute difference between two reads for phase SD (12.0 degrees vs. 1.2 degrees , P<0.0001) and bandwidth (33.7 degrees vs. 3.6 degrees , P<0.0001). Repeatability is better for normal controls than for patients with left ventricular dysfunction for phase SD (1.2 degrees vs. 6.0 degrees , P<0.0001) and bandwidth (3.6 degrees vs. 26.5 degrees , P<0.0001). Reproducibility of the phase analysis is high as measured by the intraclass correlation coefficients for phase SD and bandwidth of 0.99 and 0.99 for the interobserver comparisons and 1.00 and 1.00 for the intraobserver comparisons. A novel method to quantify dyssynchrony has been developed using gated single-photon emission computed tomography perfusion imaging. Manual base parameter placement reduces the effect that variability in image reconstruction has on phase analysis. A high degree of reproducibility of phase analysis is observed.


Mechanisms underlying the limited injectability of hydraulic calcium phosphate paste.
Calcium phosphate (CaP) cements are being increasingly used for minimally invasive hard tissue implantation. Possible approaches to improve the bad injectability of hydraulic calcium phosphate pastes have been discussed and investigated in a number of recent publications. However, the liquid-phase separation mechanism leading to the limited injectability has not yet been addressed. Liquid-phase separation means that the liquid-to-powder ratio (LPR) of the extruded paste is higher than the LPR of the paste left in the syringe. The goal of this paper was to remedy this situation by looking at the liquid-phase migration occurring during the injection of a paste from a syringe through a cannula. Experimentally, it was seen that the liquid content of both the syringe paste and the extrudate decreased during the paste injection. Moreover, a high extrusion velocity, small syringe size, short cannula and high LPR favored a good injectability. These results could be partly explained in light of rheological measurements performed with the investigated paste.


Extend an Embrace: The Availability of Hugs Is an Associate of Higher Self-Rated Health in Later Life.
This study examined the relationship between the "availability of hugs" and self-rated health (SRH) in later life. Data of 20,258 older adults, aged 65 years and greater, were analyzed from the Canadian Community Health Survey. Logistic regression techniques were used to estimate the association between the availability of hugs and reporting higher SRH. Results demonstrated that participants who had hugs available to them "all," "most," and "some" of the time had significantly greater odds of reporting higher SRH than those who reported hugs available to them "none of the time" (ORrange = 1.31-1.46, 95% CIrange = [1.10-1.74], prange = .01-.001). The availability of hugs was a stronger or more reliable associate of SRH than other established associates. As such, the potential health promoting role of hugs can be supported. Future research should examine the appropriate contexts, settings, and implementation practices for hugging interventions among consenting older adults.


Special presentation of bronchobiliary fistula after transcatheter arterial chemoembolization: A case report.
Transcatheter arterial chemoembolization (TACE) is a widely adopted treatment for advanced stage hepatocellular carcinoma (HCC). Nevertheless, several complications may occur, such as hepatic artery injury, nontarget embolization, pulmonary embolism, hepatic abscess, biloma, biliary strictures, and hepatic failure. However, bronchobiliary fistula is rarely mentioned before. A 65-year-old man with HCC underwent the TACE procedure, and then he encountered fever, dyspnea, abdominal pain, and abundant yellowish purulent bronchorrhea. Bronchobiliary fistula was diagnosed based on the computed tomography (CT) scan of his chest, which revealed the right lower lobe of his lung was connected to a hepatic cystic lesion. Percutaneous transhepatic cystic drainage was performed, and we obtained yellowish bile, showing the same characteristics as the patient's bronchorrhea. We kept drainage of his biloma and provided supportive care as the patient wished. Unfortunately, the patient passed away due to progressive right lower lobe pneumonia 2 weeks later. This case exhibits a typical CT scan image that was helpful for the diagnosis of post-TACE bronchobiliary fistula. Post-TACE bronchobiliary fistula formation hypothesis includes biliary tree injuries with subsequent biloma formation and diaphragmatic injuries. Moreover, the treatment of bronchobiliary fistula should be prompt to cease pneumonia progression. Therefore, we introduce this rare complication of post-TACE bronchobiliary fistula in hopes that future clinicians will keep earlier intervention in mind.


Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes.
Polycystic ovary syndrome (PCOS) is the most prevalent endocrinopathy in women. A common symptom of PCOS is hyperandrogenism (AE); however, the source of these androgens is uncertain. Aldo-keto reductase family 1 member C3 (AKR1C3) catalyzes the formation of testosterone (T) and 5α-dihydrotestosterone (DHT) in peripheral tissues, which activate the androgen receptor (AR). AKR1C3 is induced by insulin in adipocytes and may be central in driving the AE in PCOS. We elucidated the conversion of both classical and 11-oxygenated androgens to potent androgens in a model of PCOS adipocytes. Using high-performance liquid chromatography (HPLC) discontinuous kinetic assays to measure product formation by recombinant AKR1C3, we found that the conversion of 11-keto-Δ4-androstene-3,17-dione (11K-4AD) to 11-ketotestosterone (11K-T) and 11-keto-5α-androstane-3,17-dione (11K-5AD) to 11-keto-5α-dihydrotestosterone (11K-DHT) were superior to the formation of T and DHT. We utilized a stable isotope dilution liquid chromatography high resolution mass spectrometric (SID-LC-HRMS) assay for the quantification of both classical and 11-oxygenated androgens in differentiated Simpson-Golabi-Behmel syndrome adipocytes in which AKR1C3 was induced by insulin. Adipocytes were treated with adrenal derived 11β-hydroxy-Δ4-androstene-3,17-dione (11β-OH-4AD), 11K-4AD, or Δ4-androstene-3,17-dione (4AD). The conversion of 11β-OH-4AD and 11K-4AD to 11K-T required AKR1C3. We also found that once 11K-T is formed, it is inactivated to 11β-hydroxy-testosterone (11β-OH-T) by 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1). Our data reveal a unique role for HSD11B1 in protecting the AR from AE. We conclude that the 11-oxygenated androgens formed in adipocytes may contribute to the hyperandrogenic profile of PCOS women and that AKR1C3 is a potential therapeutic target to mitigate the AE of PCOS.


Expression and potential roles of IL-33/ST2 in the immune regulation during Clonorchis sinensis infection.
During clonorchiasis, immune responses of hosts are responsible for the removal of the worms and also are involved in the progress of the pathological damage caused by Clonorchis sinensis. Interleukin-33 (IL-33), a recently described cytokine signaling through the ST2 receptor, has emerged as a potent inducer to bile duct proliferation and fibrosis; however, little is known of this signaling in the pathogen-caused periductal inflammation and fibrosis. In the present study, using immunohistochemistry, real-time PCR, enzyme-linked immunosorbent assay (ELISA), and flow cytometry, we studied the expression of IL-33/ST2 during C. sinensis infection, as well as their potential roles in C. sinensis-induced host immune responses. The results showed that a higher level of IL-33 was detected in the sera of patients of clonorchiasis (n = 45), compared with in those of healthy donors (n = 16). Similarly, in FVB mice experimentally infected with C. sinensis, a higher level of IL-33 was detected at latent stage both in the serum and in the liver, as well as the up-regulated expression of ST2 receptor on the inflammatory cells, especially on CD4(+) T cells in the liver of infected mice. Our results, for the first time, indicated that the increased IL-33/ST2 may be involved in the regulation of immunopathology induced by C. sinensis.


Impact of multiple firings on fracture load of veneered zirconia restorations.
This investigation evaluated the impact of multiple firings during the veneering process of anterior all-ceramic restorations on the fracture load (FL) of zirconia crowns veneered with different ceramics (ZRT, ZRO, HFZ, STR). All-ceramic crowns with anatomically reduced zirconia frameworks were prepared using four different veneering ceramics (N = 192/n = 48 per veneering ceramic). The crowns were fired 2 and 10 times. Half of them were thermocycled (5000 cycles, 5 °C/55 °C, 20s). FL using Voss shear test was measured. Data was analyzed using ANOVA with partial eta squared and post-hoc Scheffé-test as well as t-test and Weibull analysis. Regarding FL, greatest differences were among the number of firings (p<0.001, ηp2 = 0.369). FL was not influenced by the interaction of both number of firings and aging level (p = 0.231) and the interaction of number of firings and veneering ceramic (p = 0.222). Differences were found comparing FL values of ZRT and STR (p<0.001) and of HFZ and STR (p<0.001). No differences occurred among the veneering ceramics after 2 (p = 0.430) and after 10 firings (p = 0.057) in respect to initial FL. For all initially tested veneering ceramics, FL showed higher values after 10 firings (p≤0.001-0.014). When aged, ZRO, HFZ, and STR also provided higher FL values after 10 firings (p≤0.001). For ZRT, FL values differed between initial and aged testing after 2 firings (p = 0.001) with aged specimens providing higher FL values. After 10 firings, none of the veneering ceramics showed differences regarding FL values between initial and aged testing. Weibull modulus was higher for ZRT specimens after 10 firings when tested initially (m = 10.1) and for aged ZRT specimens after 2 firings (m = 11.1). Failures occurred either with chipping of the veneer or total fracture. Veneered zirconia restorations tested presented higher FL after 10 firings compared to 2 firings. Aging via thermocycling showed a positive effect on the FL.


Noncardiac findings in cardiac imaging with multidetector computed tomography.
We investigated the frequency of the noncardiac findings in cardiac imaging with multidetector computed tomography (MDCT). Multidetector computed tomography is an accepted new tool to evaluate the heart. In cardiac MDCT scans, organs other than the heart are also irradiated, but usually not assessed. A total of 503 patients underwent cardiac imaging with 16- or 64-slice MDCT. Cardiologists assessed the heart, while radiologists reviewed the other organs. A total of 346 new, noncardiac findings were identified in 292 patients (58.1%). A total of 114 patients (22.7%) had clinically significant findings including 4 cases of malignancy (0.8%). There were a significant number of noncardiac findings in cardiac MDCT. To avoid missing clinically important findings, physicians who analyze cardiac MDCT scan--either radiologists or cardiologists--should carefully evaluate all the organs irradiated in the scan.


Preferential sensing and response to microenvironment stiffness of human dermal fibroblast cultured on protein micropatterns fabricated by 3D multiphoton biofabrication.
While cells are known to sense and respond to their niche including the matrix and the mechanical microenvironment, whether they preferentially sense and react to the stiffness of their microenvironment regardless of its intrinsic material properties is unknown. In this work, protein micropillar arrays with independently controllable stiffness via alterations in pillar height and elastic modulus via laser power used during photochemical cross-linking, were fabricated using a recently developed multiphoton-based 3D protein micro-patterning technology. Human dermal fibroblasts were cultured on these micropillar arrays and the specific interactions between cells and the protein micropatterns particularly on the formation and maturation of the cell-matrix adhesions, were investigated via immunofluorescence staining of the major molecular markers of the adhesions and the measurement of their cluster size, respectively. Our results showed that the cluster size of focal adhesions increased as the stiffness of the micropillar arrays increased, but it was insensitive to the elastic modulus of the protein micropillars that is one of the intrinsic material properties. This finding provides evidence to the notion that cells preferentially sense and react to the stiffness, but not the elastic modulus of their microenvironment.


Ovarian Toxicity Induced by Aluminum Chloride: Alteration of Cyp19a1, Pcna, Puma, and Map1lc3b genes Expression.
Aluminum (Al) is an abundant metal with wide application in our daily lives including medicine, industry, cosmetics, and packaging. After entrance to the body, aluminum binds to transferrin and reaches different tissues. Al is a metalloestrogen that can lead to oxidative stress (OxS) and endocrine disruption. No detailed study can be found addressing the effect of Al on the ovary and granulosa cells (GCs). In this study, the focus is on the treated ovaries and GCs of NMRI mice exposed to low, middle, and high doses of aluminum chloride (AlCl3) via in vitro and in vivo assays. The steroidogenic, proliferative, apoptotic, and autophagic-related genes were examined. Up-regulated expression of steroidogenic and proliferative genes was detected. The observed apoptotic and autophagic genes had variable expression. Interrupted ovarian structure, disrupted folliculogenesis, presence of Call-Exner bodies, overexpression of steroidogenic gene, and unbalanced apoptosis/autophagy and proliferation resembled features of granulosa cell tumor (GCT).


CLL immunotoxins.
Immunotoxins composed of cell-selective ligands covalently linked to peptide toxins have been developed for the treatment of chemotherapy relapsed or refractory malignancies including chronic lymphocytic leukemia (CLL). A number of CLL immunotoxins have been clinically tested including T101-ricin A, H65-ricin A, DAB(486)IL2, DAB(389)IL2, RFB4 (dsFv)-PE38 and anti-Tac(Fv)-PE38. Remissions have occurred in some patients without significant myelosuppression, but novel agents continue to be needed. Kay and co-workers in this issue of Leukemia Research have targeted interleukin-4 receptors (IL4R) on CLL B cells with a recombinant IL4 pseudomonas exotoxin fusion protein (IL-4(38--37)-PE38KDEL). A fraction of patients (19%) had CLL cells that were extremely sensitive to the immunotoxin. This novel agent may provide an important new therapeutic for use in the treatment of CLL.


Treatment of lung large cell neuroendocrine carcinoma.
Lung large cell neuroendocrine carcinoma (L-LCNEC) is a rare, aggressive, and difficult-to-treat tumor. It is classified as a neuroendocrine subtype of large cell lung carcinoma (LCLC) belonging to the non-small cell lung cancer (NSCLC) group, but it is also included in the neuroendocrine tumor (NET) group. Most of the available data related to its treatment derive from retrospective analyses or small case series. For patients with L-LCNEC, prognosis is generally very poor. In early stages (I-II-III), surgery is recommended but does not seem to be sufficient. Platinum-based adjuvant chemotherapy may be useful while the role of neoadjuvant chemotherapy is still not well defined. In patients with advanced L-LCNEC, the chemotherapy regimens used in SCLC still remain the standard of treatment, but results are not satisfactory. Due to their peculiar clinical and biological features and the lack of literature data, there is an emerging need for a consensus on the best treatment strategy for L-LCNEC and for the identification of new therapeutic options. In this review, we will discuss the key aspects of L-LCNEC management with the aim to clarify the most controversial issues.


Calcium influx, but not intracellular calcium release, supports PACAP-mediated ERK activation in HEK PAC1 receptor cells.
In HEK cells expressing GFP-tagged PAC1Hop1 receptors, PACAP augments ERK phosphorylation through two parallel pathways: one through PACAP/PAC1 receptor internalization/endosome MEK/ERK signaling and the other through PLC/DAG/PKC activation. We examined whether elevation of intracellular calcium ([Ca(2+)]i) was required for either of the PACAP/PAC1 receptor-mediated ERK activation mechanisms. The PACAP (25 nM)-induced elevation of [Ca(2+)]i was greater with cells maintained in Ca(2+)-containing than in Ca(2+)-deficient solution, suggesting that both calcium release from internal stores and calcium influx contributed to the rise in [Ca(2+)]i. A thapsigargin-induced increase in [Ca(2+)]i also was greater with calcium in the external solution. OAG, the cell permeable analogue of DAG, increased [Ca(2+)]i, but only in Ca(2+)-containing solution. Decreasing external calcium or depleting internal calcium stores did not block PACAP-induced PAC1 receptor internalization. Omission of calcium from the external solution, but not thapsigargin pretreatment, significantly blunted PACAP-stimulated ERK phosphorylation. The PKC inhibitor BimI decreased PACAP-mediated ERK activation in both Ca(2+)-containing or Ca(2+)-deficient solutions. In contrast, following Pitstop 2 pretreatment to block endocytic mechanisms, PACAP activated ERK only when calcium was present in the external solution. We conclude that the endosome signaling pathway is largely calcium-independent whereas calcium influx appears necessary for the PLC/DAG/PKC component of PACAP-induced ERK activation.


Establishment of trimester-specific reference intervals for thyroid stimulating hormone and free thyroxine during pregnancy in southwest China by indirect method.
A series of physiological changes in thyroid function occur during pregnancy and differ from those non-pregnant women. This study aimed to establish the pregnancy-specific reference intervals of TSH and FT4 using an indirect method based on the healthy pregnant women from southwest China population. Thyroid function test results which available on the Laboratory Information System (LIS) were collected from the pregnancies who visited the Obstetric Clinic or the Department of Gynecology between 1 January 2015, and 30 December 2020. We grouped the data by trimesters to establish the reference intervals (RIs) based on the clinical consensus of different levels of TSH and FT4 at different weeks of gestation. All arrangements were referenced to the document CLSI EP28-A3C. A total of 33,040 thyroid function test results of pregnant women, aged 31 (28,33) years were statistical analyzed. Estimated RIs for TSH and FT4 in the first, second and third trimesters corresponding to the 2.5th and 97.5th percentiles in TPOAb negative were 0.02-5.23, 0.03-5.24, 0.37-5.68 mIU/L, 11.66-20.69, 10.1-18.59, 9.85-16.86pmol/L, respectively. This study provides trimester-specific RIs for TSH and FT4 among healthy pregnant women in southwest China which guides clinicians to diagnosis and screen for thyroid disorders in this region.


Modeling and Stiffness-based Continuous Torque Control of Lightweight Quasi-Direct-Drive Knee Exoskeletons for Versatile Walking Assistance.
State-of-the-art exoskeletons are typically limited by low control bandwidth and small range stiffness of actuators which are based on high gear ratios and elastic components (e.g., series elastic actuators). Furthermore, most exoskeletons are based on discrete gait phase detection and/or discrete stiffness control resulting in discontinuous torque profiles. To fill these two gaps, we developed a portable lightweight knee exoskeleton using quasi-direct drive (QDD) actuation that provides 14 Nm torque (36.8% biological joint moment for overground walking). This paper presents 1) stiffness modeling of torque-controlled QDD exoskeletons and 2) stiffness-based continuous torque controller that estimates knee joint moment in real-time. Experimental tests found the exoskeleton had high bandwidth of stiffness control (16 Hz under 100 Nm/rad) and high torque tracking accuracy with 0.34 Nm Root Mean Square (RMS) error (6.22%) across 0-350 Nm/rad large range stiffness. The continuous controller was able to estimate knee moments accurately and smoothly for three walking speeds and their transitions. Experimental results with 8 able-bodied subjects demonstrated that our exoskeleton was able to reduce the muscle activities of all 8 measured knee and ankle muscles by 8.60%-15.22% relative to unpowered condition, and two knee flexors and one ankle plantar flexor by 1.92%-10.24% relative to baseline (no exoskeleton) condition.


[Influenza outbreak in weaners with involvement of Mycoplasma hyorhinis and Haemophilus parasuis. A case report].
In a closed farrow-to-finish piglet producing farm 80% of 7-week-old piglets displayed respiratory disease with a 5% mortality rate. In addition to purulent bronchopneumonia in combination with interstitial pneumonia predominantly in the apical and middle lobes, fibrinous serositis was present in the thoracic and abdominal cavities. Further investigations succeeded in confirming the non-pandemic strain of porcine influenza A virus (FLUAVsw) subtype H1avN1. The molecular genetic studies on Mycoplasma (M.) hyopneumoniae and porcine reproductive and respiratory syndrome virus were negative, whereas M. hyorhinis and Haemophilus parasuis were isolated from serous membranes. The possible importance of the underrated M. hyorhinis as a cofactor for viral infections should be emphasized and we demonstrated that the cause of apical lobe pneumonia is not restricted to M. hyopneumoniae. Mother pigs had been vaccinated with an influenza vaccine covering the subtype H1avN1. Only 33% of the examined piglets had maternal antibodies in the 7th week of life. The difficulty of prophylaxis of infections by FLUAVsw in weaners due to lack of vaccine authorization for piglets before their 56th day is reflected by this observation.


Is neonatal uterine bleeding responsible for early-onset endometriosis?
It has been hypothesized that the origin of early-onset endometriosis could be from endometrial mesenchymal stem cells (eMSCs) in neonatal uterine blood (NUB). There is no information on the possible mechanistic basis linking an association between NUB/neonatal endometrium and development of early-onset endometriosis. In this study we performed a series of experiments to clarify the mechanistic link between NUB and/or neonatal endometrium and development of early-onset endometriosis. We retrospectively collected postmortem neonatal endometria (n = 15) and prospectively collected NUB (n = 18) of female babies for the analysis of different biological markers including eMSCs. Immunohistochemical analysis of neonatal endometria was performed to examine the expression patterns of ovarian steroid receptors (ER/PGR), decidualization (prolactin, IGFBP1), pre-decidualization (Glycodelin A, α-SMA), proliferation (Ki-67 index), vascularity (CD31 + cells), immunocompetent CD68+, CD45+, CD56 + cells and some putative markers of eMSCs. Cell transfer method and immunocytochemistry were used to investigate the eMSCs and/or endometrial cells in NUB. Immunohistochemical analysis of postmortem neonatal endometria revealed variable staining response to ER/PGR, decidual markers, and substantial proliferative and angiogenic activity. A moderate to strong immunoexpression of Glycodelin-A was found in both neonatal and adult endometria. The tissue infiltration of CD56+, CD45 + and CD68 + immunocompetent cells was significantly low in neonatal endometria than that in adult endometria (p = 0.0003, p < 0.0001, p = 0.034, respectively). No eMSCs or even endometrial cells were detected in NUB. However, a variable expression of some phenotypes of eMSCs (CD90/CD105) was found in neonatal endometria. Based on our serial experiments we did not find any supporting evidence for the role of NUB in early-onset endometriosis. Neonatal endometria showed variable expression of ovarian steroid receptors, decidualization, and a substantial amount of proliferative and angiogenic activity. As an alternative mechanism, a significantly less tissue accumulation of immunocompetent cells in neonatal endometria may explain the survival of ER + and PGR + cells should they make entry into the pelvis and consequent development of early endometriosis with the onset of ovarian function. Future study with large sample size and application of modified technological tools is warranted to test the NUB hypothesis and to clarify their biological or clinical significance. not applicable.


Do not forget the brachial plexus-prevalence of distal brachial plexus pathology on routine shoulder MRI.
Most of the shoulder magnetic resonance imaging (MRI) examination focuses on internal joint structures but disregarding other structures like the distal brachial plexus, which may miss important findings. Hereby, we attempt to evaluate the prevalence of distal brachial plexus abnormalities and/or muscular denervation changes seen on routine shoulder MRI examinations and discuss common pathologies affecting the distal brachial plexus. A total of 701 routine shoulder MRI studies were evaluated. The evaluation of each exam was focused on the visualized brachial plexus elements and musculature abnormalities in each case. If any abnormalities of plexus and/or musculature were found, potential underlying etiologies such as paralabral or spinoglenoid notch cysts, infiltrative/primary masses on imaging, history of prior viral illness, and radiation therapy were searched. It was then confirmed whether the abnormal findings were mentioned in the exam reports or not. Thirty-four cases (4.85%) demonstrated abnormal findings of the visualized brachial plexus cords or branches and/or musculature. It was observed that in 35.3% of exam reports these findings were not mentioned, mainly missing subtle nerve abnormalities, but correctly reporting and interpreting the encountered muscle abnormalities. The distal brachial plexus and its branches should be included in the search pattern for shoulder MRI examinations. • Normal T2 signal of the brachial plexus is iso- to slightly hyperintense to muscle but less signal intense than fluid. • Diffuse, geographic muscle edema is an indirect sign of brachial plexus pathology. • Increased T2-weighted nerve signal with or without caliber or course change should be reported and followed up to find the underlying etiology.


Proline-rich Akt substrate of 40kDa (PRAS40): a novel downstream target of PI3k/Akt signaling pathway.
Modifications in signaling of the proline-rich Akt substrate of 40-kDa (PRAS40) pathway is implicated in type 2 diabetes and melanoma. PRAS40 is known for its ability to regulate the mammalian target of rapamycin complex 1 (mTORC1) kinase activity, possessing a key regulatory role at the cross point of signal transduction pathways activated by growth factor receptors. Recently it has been found that PRAS40 is regulated by its upstream phosphatidylinositol 3-kinase/Akt (PI3K/Akt) which is activated by many tyrosine kinase receptors growth factors including insulin-like growth factor 1. Also, PRAS40 functions downstream of mTORC1 and upstream from its effectors ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1). Phosphorylation of PRAS40 by Akt and mTORC1 disrupts the binding between mTORC1 and PRAS40, and relieves the inhibitory constraint of PRAS40 on mTORC1 activity. This review summarizes the signaling regulating PRAS40 phosphorylation, as well as the dual function of PRAS40 as substrate and inhibitor of mTORC1 upon growth factor stimulation and under pathophysiological conditions.


Interaction of benzo- and naphthoquinones with soluble glutathione S-transferases from rat liver.
The in vitro interaction of 1,4-benzoquinone, 1,2- and 1,4-naphthoquinone, and 2-methyl-1,4-naphthoquinone with rat liver glutathione S-transferases (GST) was studied, using reduced glutathione and 1-chloro-2,4-dinitrobenzene (CDNB) as substrates. The inhibition of the GST activity by quinones in crude extracts was dose dependent. While most of the dihydroxynaphtalenes investigated also inhibited the GST activity, dihydroxybenzenes and catecholamines did not. The quinones inhibited all the GST isoenzymes, albeit at different degrees. Kinetic studies revealed mixed type function inhibition towards glutathione and competitive inhibition towards CDNB, implicating that quinones are GST substrates. This was further confirmed by titration of remaining glutathione in appropriate incubation mixtures. These results indicate that GST could have a protective function against quinones, and that catecholamines are conjugated with glutathione via a reactive quinone intermediate.


A longitudinal study of the association between domestic contact with livestock and contamination of household point-of-use stored drinking water in rural Siaya County (Kenya).
Emerging evidence suggests close domestic proximity of livestock and humans may lead to microbiological contamination of hands, objects, food and water supplies within domestic environments, adversely impacting public health. However, evidence quantifying the relationship between livestock, domestic animals, humans and microbiological contamination of household stored water remains limited. This longitudinal study aimed to examine the relationship between domestic contact with livestock and domestic animals on microbiological contamination of household Point-of-Use (POU) stored drinking water in rural Kenya and assess the influence of choice of faecal indicator on such associations. A survey was performed in 234 households in Siaya county, Kenya, to observe presence of livestock (cattle, goats, poultry) and domestic animals (cats, dogs) in household compounds, alongside other risk factors for contamination of POU stored drinking water such as sanitation, storage conditions and hygiene practices. Samples from water sources (e.g. piped, spring/wells, boreholes, surface and rainwater) and from POU storage containers were tested for E. coli and intestinal enterococci. Livestock-related risk factors for water contamination were examined through multinomial regression, controlling for confounders. Rainwater was the main POU water source and was found to be highly susceptible to contamination. Multivariate analysis showed greater risk of gross (>100 CFU/100 mL) water contamination (with E. coli) for households where goats were observed, and/or where poultry roosted in proximity to stored household water (relative risk RR = 2.71; p = 0.001 and RR = 2.02; p = 0.012 respectively). Presence of a poultry coop was also associated with elevated intestinal enterococci densities (RR = 4.46; p = 0.001). Associations between contamination and livestock risk factors were thus similar for both bacteria groups, but E. coli counts declined more rapidly following collection from surface waters than enterococci counts (p = 0.024). The presence of livestock (particularly goats) and poultry within household compounds increases POU water contamination risk, suggesting the need for improved interventions to address cross-contamination within rural domestic settings. Within Siaya county, more effective community education is needed to raise awareness of POU water quality protection, particularly of rainwater.


The subunit structure of Saccharomyces cerevisiae transcription factor IIIC probed with a novel photocrosslinking reagent.
A photocrosslinking nucleotide, 5-[N-(p-azidobenzoyl)-3-aminoallyl]-deoxyuridine monophosphate (N3Rd-UMP), has been used to identify four polypeptides that are associated with the large Saccharomyces cerevisiae RNA polymerase III transcription factor TFIIIC, and to map the locations of these subunits along DNA when TFIIIC binds to the S.cerevisiae SUP4 tRNA(Tyr) gene. The 145 kd subunit of TFIIIC is primarily accessible to photocrosslinking from the vicinity of the box B + internal promoter element; 95 and 55 kd subunits are located on opposite sides of the DNA helix in the vicinity of the box A internal promoter element; a 135 kd subunit is less strongly crosslinked to the box A region and to a DNA segment between boxes B and A. DNA probes containing more than one N3RdUMP residue can form crosslinks between polypeptide chains. The specific circumstances of formation and the apparent mol. wts of two of these products lead to the tentative suggestion that a protomer of TFIIIC may contain two 95 kd subunits.


Analysis of the difference in the behavioral effects of apomorphine in C57BL/6 and DBA/2 mice.
The influence of pimozide on the effects of apomorphine on locomotor activity and stereotypy was studied in two inbred strains of mice. In C57BL/6 mice, in which apomorphine did not produce stereotypy of gnawing, the biphasic effect of apomorphine on locomotor activity (hypomotility followed by hypermotility) was unaffected by pimozide. In DBA/2 mice, in which high doses of apomorphine produce hypomotility and compulsive gnawing, both these effects (but not hypomotility produced by low doses of apomorphine) were counteracted by pimozide. The results are consistent with the assumption that both strains of mice have separate inhibitory and stimulatory dopamine receptors mediating locomotor activity. In addition, DBA/2 but not C57BL/6 mice have dopamine receptors which mediate stereotypy and are sensitive to pimozide.


A ZEB1-miR-375-YAP1 pathway regulates epithelial plasticity in prostate cancer.
MicroRNA-375 (miR-375) is frequently elevated in prostate tumors and cell-free fractions of patient blood, but its role in genesis and progression of prostate cancer is poorly understood. In this study, we demonstrated that miR-375 is inversely correlated with epithelial-mesenchymal transition signatures (EMT) in clinical samples and can drive mesenchymal-epithelial transition (MET) in model systems. Indeed, miR-375 potently inhibited invasion and migration of multiple prostate cancer lines. The transcription factor YAP1 was found to be a direct target of miR-375 in prostate cancer. Knockdown of YAP1 phenocopied miR-375 overexpression, and overexpression of YAP1 rescued anti-invasive effects mediated by miR-375. Furthermore, transcription of the miR-375 gene was shown to be directly repressed by the EMT transcription factor, ZEB1. Analysis of multiple patient cohorts provided evidence for this ZEB1-miR-375-YAP1 regulatory circuit in clinical samples. Despite its anti-invasive and anti-EMT capacities, plasma miR-375 was found to be correlated with circulating tumor cells in men with metastatic disease. Collectively, this study provides new insight into the function of miR-375 in prostate cancer, and more broadly identifies a novel pathway controlling epithelial plasticity and tumor cell invasion in this disease.


Effect of culture temperature on the heterologous expression of Pleurotus eryngii versatile peroxidase in Aspergillus hosts.
Production of recombinant versatile peroxidase in Aspergillus hosts was optimized through the modification of temperature during bioreactor cultivations. To further this purpose, the cDNA encoding a versatile peroxidase of Pleurotus eryngii was expressed under control of the alcohol dehydrogenase (alcA) promoter of Aspergillus nidulans. A dependence of recombinant peroxidase production on cultivation temperature was found. Lowering the culture temperature from 28 to 19 degrees C enhanced the level of active peroxidase 5.8-fold and reduced the effective proteolytic activity twofold. Thus, a maximum peroxidase activity of 466 U L(-1) was reached. The same optimization scheme was applied to a recombinant Aspergillus niger that bore the alcohol dehydrogenase regulator (alcR), enabling transformation with the peroxidase cDNA under the same alcA promoter. However, with this strain, the peroxidase activity was not improved, while the effective proteolytic activity was increased between 3- and 11-fold compared to that obtained with A. nidulans.


Biochemical changes under the effect of carbon tetrachloride intoxication.
The present study deals with investigations on the general features of protein and iron metabolism under several conditions of chronic and acute liver damage induced by carbon tetrachloride. Data revealed a drop in the levels of serum total protein and albumin. The levels of alpha1, alpha2 and beta globulins were found to be increased. Gamma fraction was found to be proportionate with dosage accumulation and to varying extent. There were changes in haematocrit and haemoglobin values in all groups of chronic and acute carbon tetrachloride intoxicated rats. Also, there were no changes in reticulocyte count, plasma iron and total iron binding capacity levels in chronic intoxicated animals. However, in acute carbon tetrachloride plasma iron and total iron-binding capacity were significantly elevated.


The moderating role of physical fitness in the relationship between sugar-sweetened beverage consumption and adiposity in schoolchildren.
The mediating and moderating associations of cardiorespiratory fitness (CRF) and handgrip strength on the association between dietary patterns and several health outcomes have been previously studied. For instance, handgrip strength has been found as a moderator of the relationship between excess weight and cardiometabolic risk factors in young adults. Similarly, CRF has been shown as a mediator of the association between diet and obesity in children. However, to our knowledge, the role of CRF and handgrip strength on the association between sugar-sweetened beverage (SSB) consumption and adiposity is still unclear. The aim of this study was to determine whether CRF and handgrip strength moderate the association between SSB consumption and adiposity in a population-based sample of Spanish schoolchildren. This cross-sectional study involved 475 schoolchildren (52.0% girls), aged 8-12, from ten schools in Cuenca (Spain). Adiposity was determined as body fat (in kg), which was measured using a bioimpedance analysis system. Data on SSB consumption were gathered by using the Children's Eating Habits Questionnaire, which was completed by parents. The CRF level was determined by the 20-m Shuttle Run test and Nevill's curvilinear allometric model. Handgrip strength was determined using a digital dynamometer with adjustable grip. For each unit (in ml/kg/min) of CRF increased, the association between SSB consumption and adiposity was moderated (B = - 0.09, CI 95% - 0.14 to - 0.04). This significant moderation was also found for each 0.01 unit of increased normalized handgrip strength (B = - 0.07; CI 95% - 0.11 to - 0.02). Similarly, the Johnson-Neymann technique established three different regions. The first region shows that the association of SSB consumption on adiposity in participants who had levels of CRF < 43.4 ml/kg/min or handgrip strength < 0.34 was greater and statistically significant. The second region (43.4-57.4 ml/kg/min for CRF; 0.34-0.58 for normalized handgrip strength) depicted that the association between SSB consumption and adiposity was not statistically significant in those with a CRF level or normalized handgrip strength between the lower and upper thresholds. The third region was found at > 57.4 ml/kg/min (for CRF level) and > 0.58 (for normalized handgrip strength), indicating that the association between SSB consumption and adiposity was lower and statistically significant in children above these moderator values. Our results showed that certain levels of CRF and normalized handgrip strength moderate the association between SSB consumption and adiposity in a sample of Spanish schoolchildren. It might be possible that higher physical fitness level in childhood may contribute to reducing the association between SSB consumption and adiposity.


Assessment of ocular microcirculation in patients with end-stage kidney disease.
To determine the impact that end-stage kidney disease (ESKD) has on ocular microcirculation in the optic nerve head (ONH) and choroid area shown by laser speckle flowgraphy (LSFG). We studied 24 consecutive Japanese patients with ESKD who visited the department of Nephrology at our hospital and 55 age- and gender-matched subjects who had undergone polysomnography. The mean blur rates (MBRs) in vessels (MBR-Vessel), in the tissue (MBR-Tissue), throughout the ONH (MBR-All), and throughout the choroid (MBR-Choroid) were analyzed. We divided the MBR-Tissue into four sections (superior, temporal, inferior, and nasal). The results of systemic and ocular parameters were compared between the ESKD patients and control subjects. We performed single and multiple regression analyses to determine the MBR section(s) that correlated most strongly with serum creatinine and the estimated glomerular filtration rate (eGFR) and to identify the independent factors for selected MBR sections in the ESKD patients. All sections of the ONH in the ESKD patients were significantly lower than those in the control subjects. MBR-Choroid was not significantly different between the control and ESKD groups. The single regression analyses revealed that MBR-Tissue had the strongest correlations with creatinine and the eGFR. The multiple regression analyses revealed hematocrit, creatinine, and eGFR as factors independently contributing to the MBR-Tissue. The inferior section of MBR-Tissue was most strongly correlated with creatinine and the eGFR. The MBRs in the ONH of the ESKD patients decrease compared with control subjects and the inferior section of MBR-Tissue is correlated with serum creatinine and eGFR.


Production of Gynogenic Plants of Red Beet (Beta vulgaris L.) in Unpollinated Ovule Culture In Vitro.
The unique and balanced components of the biochemical composition, together with high antioxidant activity, make the red beet necessary a dietary vegetable crop, much contributing to healthy food ration. The application of the technology for producing gynogenic plants in vitro increases the genetic diversity and significantly reduces the period of time required to obtain the appropriate homozygous lines used to create the F1 hybrids that are demanded in the market. For induction of gynogenesis, we used IMB medium developed by us with the addition of 55 g/L sucrose, 3 g/L phytogel, 200 mg/L ampicillin, and 0.4 mg/L thidiazuron (TDZ) and cultured at 28 °C in the dark for 4-6 weeks. Shoot regeneration from embryoids and callus was performed on MS medium with 20 g/L sucrose, 3 g/L phytogel, 1 mg/L 6-benzylaminopurine (BAP), and 0.1 mg/L gibberellic acid (GA3). Immersion of the obtained microshoots with 5-7 well-developed leaves for 10-15 s into concentrated sterile indole-3-butyric acid (IBA) solution (50 mg/L) followed by their cultivation on solid medium ½ IMB with 2% sucrose and 3 g/L phytogel was the most efficient method for root formation. The addition of silver nitrate (22 mg/L) to the nutrient medium provoked an increase in the number of induced ovules up to nine per Petri dish (up to 25% of induced ovules). Gynogenic development was produced in six out of 11 genotypes studied, and the plants that were then acclimatized to ex vitro conditions were obtained in three genotypes (Nezhnost', Dobrynya, b/a 128). The evaluation of ploidy of gynogenic plants that was carried out by flow cytometry and direct counting of chromosomes stained with propion-lacmoide revealed that all obtained gynogenic plants were haploids (2n = x = 9).


Photodynamic therapy for primary tracheobronchial malignancy in Northwestern China.
Photodynamic therapy (PDT) has been routinely performed to treat tracheobronchial malignancy. However, the experience in tracheobronchial adenoid cystic carcinoma (ACC) and peripheral lung cancer is still insufficient. This study aimed to share the experience of PDT for patients with primary tracheobronchial malignancy, especially the adenoid cystic carcinoma and peripheral lung cancer, and evaluated the efficacy and safety of PDT in Northwestern Chinese patients. This study retrospectively analyzed the clinical data of 23 patients with primary tracheobronchial malignancy receiving PDT in our center. The short-term effect was evaluated by the objective tumor response and the clinical response. The long-term effect was estimated by recurrence-free survival (RFS). Of 23 patients, SR was achieved in 18 patients and MR in 3 patients. The clinical symptoms and the quality of life were significantly improved after PDT (P<0.05). And the mean RFS was 8.9 ± 1.9 months. SR for 6 cases of ACC were achieved with significant improvement of clinical symptoms and quality of life. No procedure-related complications appeared. And PDT was successfully performed for the peripheral lung cancer with the guidance of electromagnetic navigation bronchoscopy (ENB). This study demonstrated that PDT achieved satisfactory efficacy and safety for Northwestern Chinese patients with primary tracheobronchial malignancy. Patients with ACC can benefit from PDT. And ENB-guided PDT is a novel and available option for the peripheral lung cancer. In short, this study accumulated valuable experience for the application of PDT in Chinese patients with primary tracheobronchial malignancy.


Painful os styloideum in a child.
Os styloideum is an immobile bone protrusion, located on the dorsum of the wrist between the trapezoid, capitate, and the second and third metacarpals, which may be associated with wrist pain. It usually presents in adults after degenerative changes occur. We report a case of a 12-year-old girl who presented with os styloideum. She was evaluated with plain radiographs, bone scintigraphy, and wrist CT. Plain radiographs were initially interpreted as normal. Bone scintigraphy demonstrated focal tracer uptake in the right trapezoid. CT demonstrated an os styloideum fused to the right trapezoid associated with secondary degenerative changes. Os styloideum is a rare cause of wrist pain in children.


Human adrenocortical NCI-H295 cells express VIP receptors. Steroidogenic effect of vasoactive intestinal peptide (VIP).
VIP receptors are frequently overexpressed by various endocrine tumors. In this study the expression of VIP receptors in the human adrenocortical carcinoma cell line NCI-H295 and their involvement in the regulation of steroidogenesis was investigated. NCI-H295 cells express VIP1 and VIP2 receptors as demonstrated by RT-PCR, whereas they do not express VIP itself. The receptors are functionally coupled to steroidogenesis since VIP (10(-9) M to 10(-6) M) exerted a dose-dependent stimulatory effect on the release of aldosterone, cortisol, and DHEA. VIP increased ACTH-stimulated releases of aldosterone and cortisol. The proliferation rate of NCI-H295 cells was not affected by VIP. These data show that NCI-H295 cells express both forms of the VIP receptor and that VIP is involved in an ACTH-independent regulation of steroidogenesis in the adrenal tumor cells.


Adrenocorticotropic hormone secretion in response to anticipatory stress and venepuncture: The role of menstrual phase and oral contraceptive use.
Oral contraceptives (OCs) are primarily known for their effects on the reproductive system, but they can also impact the hypothalamic-pituitary-adrenal (HPA) axis. The present study aimed to compare plasma adrenocorticotropic hormone (ACTH) responses to the anticipatory stress of participating in a scientific experiment and venepuncture in OC users versus naturally cycling (NC) women, with a focus on variations throughout the menstrual cycle. We recruited 131 young women (average age 20.5) and obtained blood samples to measure plasma ACTH concentrations immediately after venepuncture and again after 15 min of group activities designed to facilitate interpersonal attachment and stress-buffering. ACTH levels decreased in 70% of all participants throughout the group activities. A two-way repeated measures ANOVA highlighted a significant interaction between time and OC use, indicating differential changes in ACTH levels during social interaction between OC users and NC women. Further, the post-hoc analysis revealed that a period of stress-buffering group activities significantly decreased ACTH levels in NC women during menstrual and secretory phases, but not during the proliferative phase. In contrast, OC users did not display a decrease during group activities, regardless of the phase. This study underscores the influence of OC use on stress regulation, demonstrating that OCs not only modulate reproductive functions but also impact ACTH stress reactivity. Additionally, it emphasizes the importance of considering hormonal contraceptive use and menstrual cycle phases when assessing female stress responses.


The multidisciplinary approach to ovarian tumours in children and adolescents.
Ovarian tumours in children and adolescents are rare diseases. Although the majority of tumours are benign, the diagnosis and management present various challenges that require a wide range of expertise. The multidisciplinary team ensures not only accurate diagnosis and correct and minimally invasive management, but also minimal psychological impact and the preservation of fertility. This article outlines the multidisciplinary team approach to ovarian masses in children and adolescents. The team includes paediatric oncologists, gynaecological surgeons, pathologists, radiologists, fertility experts, geneticists and psycho-social services.


Hemostatic effectiveness of fibrin glue derived from single-donor fresh frozen plasma.
Fibrin glue derived from pooled human blood is an effective sealant for high-porosity vascular grafts and a valuable topical hemostatic agent in heparinized patients. Use of this agent in the United States is prohibited because of potential transmission of hepatitis B, acquired immunodeficiency syndrome, and other serologically transmitted illnesses. We have developed a cryoprecipitation technique that allows preparation of fibrin glue from single-donor fresh frozen plasma. Use of this agent presumably entails no greater risk of disease transmission than intravenous administration of single-unit fresh frozen plasma. This report describes our early clinical experience with this material. Fibrin glue was used as a sealant for porous woven Dacron tubular prostheses and cardiovascular patches in 19 patients. The fibrin glue sealant has also been employed to control bleeding from needle holes and small anastomotic tears in 22 patients. No patient in this series had a bleeding complication from a suture line or graft treated with fibrin glue. This experience indicates that like fibrin glue from pooled blood, fibrin glue from single-donor plasma is effective as a graft sealant and topical hemostatic agent. Preparation of fibrin glue from single-donor plasma is simple and economical, and may provide cardiothoracic surgeons in the United States with a widely available, valuable hemostatic adjunct.


Physiologically based pharmacokinetic model to predict drug-drug interactions with the antibody-drug conjugate enfortumab vedotin.
Enfortumab vedotin is an antibody-drug conjugate (ADC) comprised of a Nectin-4-directed antibody and monomethyl auristatin E (MMAE), which is primarily eliminated through P-glycoprotein (P-gp)-mediated excretion and cytochrome P450 3A4 (CYP3A4)-mediated metabolism. A physiologically based pharmacokinetic (PBPK) model was developed to predict effects of combined P-gp with CYP3A4 inhibitor/inducer (ketoconazole/rifampin) on MMAE exposure when coadministered with enfortumab vedotin and study enfortumab vedotin with CYP3A4 (midazolam) and P-gp (digoxin) substrate exposure. A PBPK model was built for enfortumab vedotin and unconjugated MMAE using the PBPK simulator ADC module. A similar model was developed with brentuximab vedotin, an ADC with the same valine-citrulline-MMAE linker as enfortumab vedotin, for MMAE drug-drug interaction (DDI) verification using clinical data. The DDI simulation predicted a less-than-2-fold increase in MMAE exposure with enfortumab vedotin plus ketoconazole (MMAE geometric mean ratio [GMR] for maximum concentration [Cmax], 1.15; GMR for area under the time-concentration curve from time 0 to last quantifiable concentration [AUClast], 1.38). Decreased MMAE exposure above 50% but below 80% was observed with enfortumab vedotin plus rifampin (MMAE GMR Cmax, 0.72; GMR AUClast, 0.47). No effect of enfortumab vedotin on midazolam or digoxin systemic exposure was predicted. Results suggest that combination enfortumab vedotin, P-gp, and a CYP3A4 inhibitor may result in increased MMAE exposure and patients should be monitored for potential adverse effects. Combination P-gp and a CYP3A4 inducer may result in decreased MMAE exposure. No exposure change is expected for CYP3A4 or P-gp substrates when combined with enfortumab vedotin.ClinicalTrials.gov identifier Not applicable.


Anti-angiogenic effect of α-mangostin.
Eleven known prenyl xanthones, isolated from the pericarp of Garcinia mangostana, were tested for their ability to inhibit the phosphorylation of kinase domain receptor (KDR) tyrosine kinase. α-Mangostin was found to inhibit phosphorylation of KDR. α-Mangostin also showed to inhibit phosphorylation of the Y1175 residue of KDR (10 μM). This is the first report that α-mangostin inhibited the phosphorylation of KDR tyrosine kinase and also the Y1175 residue of KDR. α-Mangostin also showed inhibitory effects on proliferation of human umbilical vein endothelial cells (HUVECs) (IC(50) 1.2 μM) and human umbilical artery endothelial cells (IC(50) 2.4 μM), as well as the migration (IC(50) 0.034 μM) and tubule formation (at the concentrations of 0.6 and 1.2 μM) of HUVECs. These results suggest that the inhibition of the phosphorylation of KDR tyrosine kinase is concerned in the anti-angiogenic activity of α-mangostin.


Effects of guinea pig vasoactive intestinal peptide on the isolated perfused guinea pig heart.
The pharmacological effects of guinea pig vasoactive intestinal peptide (VIP) were studied in isolated perfused guinea pig hearts. Bolus injections of VIP produced a dose-dependent tachycardia that was not affected by atenolol. A decrease in amplitude of ventricular contractions occurred in response to all doses of VIP. This response was preceded by a small increase in amplitude in 3 of 6 hearts at the highest dose. VIP produced a decrease in perfusion pressure which was prominent after coronary tone was elevated with [Arg8]-vasopressin. The present findings support speculation that VIP may have a role in the regulation of heart rate and coronary blood flow.


Regional remodeling strain and its association with myocardial apoptosis after myocardial infarction in an ovine model.
Progressive left ventricular remodeling after myocardial infarction has been viewed as an important contributor to progressive heart failure. The objective of this study was to investigate the relationship between myocardial apoptosis and strain during progressive cardiac remodeling. Before creation of an anterolateral left ventricular infarction by ligation of diagonal arteries, 16 sonomicrometry transducers were placed in the left ventricular free wall of 8 sheep to assess regional deformation in the infarct, adjacent, and normally perfused remote myocardial regions over 8 weeks' duration. Hemodynamic, echocardiographic and sonomicrometric data were collected before infarction and then 30 minutes and 2, 6, and 8 weeks after infarction. At the end of the study, regional myocardial tissues were collected for apoptotic signaling proteins. At terminal study, an increase in left ventricular end-diastolic pressure of 8.1 +/- 0.1 mm Hg, a decrease in ejection fraction from 54.19% +/- 5.68% to 30.55% +/- 2.72%, and an end-diastolic volume increase of 46.08 +/- 5.02 mL as compared with the preinfarct values were observed. The fractional contraction at terminal study correlated with the relative abundance of apoptotic protein expressions: cytochrome c (r(2) = 0.02, P < .05), mitochondrial Bax (r(2) = 0.27, P < .05), caspase-3 (r(2) = 0.31, P < .05), and poly (adenosine diphosphate-ribose) polymerase (r(2) = 0.30, P < .05). These myocardial apoptotic activities also correlated with remodeling strain: cytochrome c (r(2) = 0.02, P < .05), mitochondrial Bax (r(2) = 0.28, P < .05), caspase-3 (r(2) = 0.43, P < .05), and poly (adenosine diphosphate-ribose) polymerase (r(2) = 0.37, P < .05). Increase in regional remodeling strain led to an increase in myocardial apoptosis and regional contractile dysfunction in heart failure.


A method for the determination of organically bound tritium in marine biota based on an improved tubular-combustion system.
A method for the measurement of organically bound tritium (OBT) in marine biota has been developed using a combustion device designed with three independent temperature control zones and a two-stage intake mode to ensure full combustion of samples. The versatility of the combustion device and combustion water recoveries were tested on nine different types of marine biota, with recoveries varying from 85.15% to 92.67%, with an average of 89.4 ± 11.34%. This indicates that our developed combustion method (combustion program and apparatus) provides stable results. Finally, the OBT activity of the marine samples measured varied from 1.88 to 12.9 Bq/L, with an average of 5.61 ± 3.21 Bq/L.