Gamma interferon augments macrophage activation by lipopolysaccharide by two distinct mechanisms, at the signal transduction level and via an autocrine mechanism involving tumor necrosis factor alpha and interleukin-1.
When given in the presence of gamma interferon (IFN-gamma), otherwise nontoxic doses of lipopolysaccharide (LPS or endotoxin) become highly lethal for mice. The mechanisms of this synergistic toxicity are not known. We considered the possibility that an interaction between the LPS-induced NF-kappaB and IFN-gamma-induced JAK-STAT pathways at the pretranscriptional level may enhance the LPS-induced signals. To test this hypothesis, we incubated murine macrophage RAW 264.7 cells with IFN-gamma for 2 h before addition of different doses of LPS. Consistent with the synergistic induction of inducible nitric oxide synthase mRNA and nitric oxide production by a combination of LPS and IFN-gamma, IFN-gamma strongly augmented LPS-induced NF-kappaB activation and accelerated the binding of NF-kappaB to DNA to as early as 5 min. In agreement with this, IFN-gamma pretreatment promoted rapid degradation of IkappaB-alpha but not that of IkappaB-beta. Inhibition of protein synthesis during IFN-gamma treatment suppressed LPS-initiated NF-kappaB binding. A rapidly induced protein appeared to be involved in IFN-gamma priming. Preincubation of cells with antibodies to tumor necrosis factor alpha or the interleukin-1 receptor partially reduced the priming effect of IFN-gamma. In a complementary manner, LPS enhanced the activation of signal-transducing activator of transcription 1 by IFN-gamma. These data suggest novel mechanisms for the synergy between IFN-gamma and LPS by which they cross-regulate the signal-transducing molecules. Through this mechanism, IFN-gamma may transform a given dose of LPS into a lethal stimulus capable of causing sepsis. It may also serve a beneficial purpose by enabling the host to respond quickly to relatively low doses of LPS and thereby activating antibacterial defenses.


Identification of key biomarkers and related immune cell infiltration in cervical cancer tissue based on bioinformatics analysis.
Cervical cancer (CC) is the most common gynecological malignant tumor. Immunotherapy has become a new model for the treatment of CC, especially advanced and recurrent cancer. At present, many studies are exploring the safety and efficacy of immunotherapy for advanced or recurrent CC. In this study, CIBERSORT was used to analyze the immune cell infiltration in CC patients, to evaluate the proportion of immune cell types in CC samples, to quantify the cell composition of the immune response, and to analyze its prognostic value. The expression profile datasets of CC were downloaded from the GEO. The differentially expressed genes (DEGs) between CC and normal cervical tissues were identified via R software (version 4.1.1), and their functions and pathways were enriched and analyzed. A protein-protein interaction network was constructed to screen the hub gene. Immune cell infiltration in CC was analyzed via scientific reverse convolution algorithm (CIBERSORT), and the hub gene was analyzed via survival analysis to screen the diagnostic biomarkers of CC. A total of 144 DEGs and 12 hub genes were identified. DEGs are mainly involved in molecular functions such as serine-peptidase activity, serine-hydrolase activity, and chemokine activity. The enrichment pathway is closely related to the interaction between viral proteins and cytokines and cytokine receptors, the interleukin 17 signaling pathway, and chemokine signaling pathway. The immune cell infiltration analysis showed that T cells were the main infiltrating immune cells in CC, especially T cells CD8+ and CD4+ . The survival analysis of the hub gene showed that CEP55, MCM2, RFC4, and RRM2 had high diagnostic value. CEP55, MCM2, RFC4, and RRM2 can be used as diagnostic markers for CC. CD8+ and CD4+ T cells are closely related to the occurrence and development of CC.


Chicken hematopoietic cells transformed by seven strains of defective avian leukemia viruses display three distinct phenotypes of differentiation.
Chicken hematopoietic cells transformed in vitro and in vivo by seven strains of replication-defective avian leukemia viruses were assayed for the expression of six erythroid and five myeloid differentiation parameters, including differentiation-specific surface antigens as detected by newly developed antisera. The transformed cells were found to display three distinct phenotypes of differentiation. First, cells transformed by AEV resemble erythroblasts. They express heme, globin, carbonic anhydrase and erythrocyte cell surface antigen at low levels, and histone H5 and erythroblast cell surface antigen at high levels. Second, cells transformed by MC29, CMII, OK10 and MH2 viruses have macrophage-like properties. They strongly express Fc receptors, phagocytic capacity and macrophage cell surface antigen, but only weakly express myeloblast cell surface antigen and are negative for ATPase activity. Third, cells transformed by AMV and E26 viruses resemble myeloblasts in that they weakly express Fc receptors, phagocytic capacity and macrophage cell surface antigen but strongly express myeloblast cell surface antigen and ATPase activity. No difference was found between in vitro- and in vivo-transformed cells in the parameters tested. In light of recent genetic and biochemical evidence, we believe that these phenotypes reflect the action of three new types of viral-transforming genes, designated erb (erythroblast), mac (macrophage) and myb (myeloblast).


Oxidant denuder sampling for analysis of polycyclic aromatic hydrocarbons and their oxygenated derivates in ambient aerosol: evaluation of sampling artefact.
The concentrations of some polycyclic aromatic hydrocarbons (PAH) and oxygenated PAH (O-PAH) can be changed by oxidation reactions during sampling. This can lead to an over- or underestimation of the corresponding adverse health effects. The aim of this study was the evaluation of these sampling artefacts. The potential of using an oxidant denuder was shown by parallel low-volume sampling with and without MnO(2) ozone denuder. Twenty-three PAH and 11 O-PAH in ambient air were analysed, both in the vapour and particulate phase. The denuder was proven to be highly efficient for stripping ozone from air while causing no significant particle losses. In general, the concentrations of 5- to 7-ring PAH, which are predominantly associated with particles, were underestimated in non-denuded samples. The highest losses due to reaction with ozone and other atmospheric oxidants were observed for benzo[a]pyrene and perylene. Concurrently, the concentrations of most of the mainly particle-associated 4- to 5-ring O-PAH were higher in the non-denuded samples. The denuder did not only remove ozone, moreover other gaseous species such as more volatile PAH and O-PAH were partially oxidized on the catalytic surface, too. Degradation of PAH and concurrent degradation/formation reactions of O-PAH occurred. The corresponding reactivities of selected PAH and O-PAH are discussed.


Amorphous solid dispersions of lidocaine and lidocaine HCl produced by ball milling with well-defined RAFT-synthesised methacrylic acid polymers.
This study focuses on the use of methacrylic acid polymers synthesised via the Reversible Addition Fragmentation chain Transfer (RAFT) polymerisation method for the production of amorphous solid dispersions (ASDs) by ball milling, to kinetically solubilize a poorly water-soluble model drug. The solid-state characteristics and the physical stability of the formulations were investigated using X-ray diffraction, differential scanning calorimetry, and infrared spectroscopy. This was followed by dissolution studies in different media. It was discovered that the acidic polymers of methacrylic acid were capable of interacting with the weakly basic drug lidocaine and its hydrochloride salt form to produce ASDs when a polymer to drug ratio of 70:30 w/w was used. The ASDs remained amorphous following storage under accelerated aging conditions (40 °C and 75% relative humidity) over 8 months. Fast dissolution and increased lidocaine solubility in different media were obtained from the ASDs owing to the reduced microenvironment pH and enhanced solubilization of the drug caused by the presence of the acidic polymer in the formulation. Production of ASDs using well-defined RAFT-synthesised acidic polymers is a promising formulation strategy to enhance the pharmaceutical properties of basic poorly water-soluble drugs.


A comparative evaluation of dot immunobinding assay (Dot-Iba) and polymerase chain reaction (PCR) for the laboratory diagnosis of tuberculous meningitis.
The results of a Dot immunobinding assay (Dot Iba) for the detection of mycobacterial antigen in the cerebrospinal fluid (CSF) of 45 patients with tuberculous meningitis (TBM) were compared with the results of a polymerase chain reaction (PCR) for the detection of Mycobacterium tuberculosis. In eight patients with culture proven TBM, Dot-Iba gave positive results, while PCR yielded positive results only in six patients. The overall sensitivities of Dot-Iba and PCR in 37 patients with culture negative (probable) TBM were 75.67% and 40.5% respectively. Dot-Iba, in contrast to PCR is a rapid and relatively easier method. More importantly, Dot-Iba is suitable for the routine application for the laboratory diagnosis of TBM and therefore best suited to laboratories in the developing world.


An observational study of once-daily modified-release methylphenidate in ADHD: quality of life, satisfaction with treatment and adherence.
Attention deficit hyperactivity disorder (ADHD) impacts significantly on the quality of life (QoL) of patients and their families. Choice of therapy is increasingly influenced by treatment satisfaction and patient preference, with once-daily modified-release methylphenidate (MPH-MR) formulations offering clear benefits compared with immediate-release (IR) dosage forms. The effects of MPH-MR on QoL in ADHD have not been widely investigated and need more clarity in practice. The open-label OBSEER study evaluated the effectiveness and tolerability of Equasym XL(®), a MPH-MR formulation, in routine practice. Children and adolescents (aged 6-17 years) with ADHD and attending school were included if Equasym XL(®) treatment was planned by the treating physician. Physicians, parents and patients completed questionnaires assessing QoL (KINDL; parent, child or adolescent versions), satisfaction with medication, adherence and treatment tolerability at baseline (Visit 1), 1-3 weeks (Visit 2) and 6-12 weeks (Visit 3) over a maximum 3-month observation period. Data from 822 consecutively referred patients were analysed. QoL and medication satisfaction increased from Visit 1 to Visit 3, with both patients and parents rating therapy with Equasym XL(®) as better than previous drug therapy. KINDL total score effect sizes were 0.67 (parents' ratings), 0.52 (children's ratings) and 0.51 (adolescents' ratings; all p < 0.001). All KINDL subscores also increased: both parents and patients had the greatest improvement for school. Adherence to Equasym XL(®) was frequently rated as superior to prior treatment, particularly compared with MPH-IR repeated dosing. Treatment was generally well tolerated; approximately 3% of the patients discontinued treatment due to adverse events. Equasym XL(®) improved QoL compared with prior therapy, and resulted in good medication satisfaction and adherence in drug-naïve and previously treated patients.


An RNA Aptamer Inhibits a Mutation-Induced Inactivating Misfolding of a Serpin.
Most serpins are fast and specific inhibitors of extracellular serine proteases controlling biological processes such as blood coagulation, fibrinolysis, tissue remodeling, and inflammation. The inhibitory activity of serpins is based on a conserved metastable structure and their conversion to a more stable state during reaction with the target protease. However, the metastable state also makes serpins vulnerable to mutations, resulting in disease caused by inactive and misfolded monomeric or polymeric forms ("serpinopathy"). Misfolding can occur either intracellularly (type-I serpinopathies) or extracellularly (type-II serpinopathies). We have isolated a 2'-fluoropyrimidine-modified RNA aptamer, which inhibits a mutation-induced inactivating misfolding of the serpin α1-antichymotrypsin. It is the first agent able to stabilize a type-II mutation of a serpin without interfering with the inhibitory mechanism, thereby presenting a solution for the long-standing challenge of preventing pathogenic misfolding without compromising the inhibitory function.


Results of Pulmonary Resection: Sarcoma and Germ Cell Tumors.
Pulmonary metastasis occurs in as many as 88% and 80% of stage IV patients with sarcoma and germ cell tumors, respectively. Pulmonary metastatectomy may be the only means of rendering a patient disease free. Sublobar resection (wedge or segmentectomy), lobectomy, and pneumonectomy achieve complete resection. Bilateral disease can be resected via staged thoracoscopy/thoracotomy, median sternotomy, or clamshell thoracotomy. Multiple resections and re-resections have resulted in improved survival. Five-year survival rates as high as 35% to 52% for sarcoma and 80% for germ cell tumor can be realized.


Pinealectomy and constant illumination increase the density of melatonin binding sites in the pars tuberalis of rodents.
We report here the effects of pinealectomy and light exposure on the melatonin receptor density in the pars tuberalis of the rat and the European hamster using quantitative autoradiography. Scatchard analysis revealed that 24 and 72 h of constant light exposure (LL) before sacrifice did not modify the Kd value of melatonin for its receptors in rats and European hamsters (about 70 pM). In contrast, the Bmax value was significantly increased in both species when the animals were kept in constant illumination for 72 h before sacrifice (50%-70% compared with the controls). A similar increase was also observed in rats pinealectomized 3 days before sacrifice and then kept in either constant illumination or in 12L/12D. Pinealectomy or constant light exposure are known to result in a clear decrease in the concentration of circulating melatonin. We demonstrate here that they also result in an increase in the density of melatonin receptors. This could suggest a direct effect of melatonin on its own receptors.


MHC antigens in urine as olfactory recognition cues.
The classical class I antigens of the major histocompatibility complex (MHC) are cell-surface glycoproteins which were originally discovered because they cause rapid rejection of cells or tissues grafted between unrelated individuals. These molecules are encoded by the K, D and L loci of the mouse MHC (and analogous loci in other species) which show extreme species polymorphism and a large number of alleles. In an outbreeding population 3.6 X 10(9) unique MHC class I phenotypes can be encoded by the 100 alleles at each of the K and D loci and the 6 alleles at the L locus. This level of polymorphism ensures that the cells and tissues of each unrelated individual are uniquely identified by their class I membrane-bound antigens. Like other membrane bound proteins, these class I molecules are anchored in the lipid bilayer by a hydrophobic domain encoded by exon 5. However, there have been reports of the occurrence of classical class I molecules in true solution in the blood of humans, mice, and rats. We report here that classical polymorphic class I molecules in normal rats are constitutively excreted in the urine and that untrained rats can distinguish the smell of urine samples taken from normal donors that differ only at the class I MHC locus and therefore excrete different allelomorphs of class I molecules in their urine.


Effect of hot flushes on cardiovascular autonomic responsiveness: a randomized controlled trial on hormone therapy.
To compare the responses of heart rate and blood pressure to various autonomic tests in women with and without pre-treatment hot flushes during estradiol and estradiol+medroxyprogesterone acetate (MPA) use. Hundred and fifty recently postmenopausal women (72 with and 78 without hot flushes) were randomized to receive transdermal estradiol (1mg/day), oral estradiol (2 mg/day) alone or in combination with MPA (5mg/day), or placebo for six months. Cardiovascular responsiveness was comprehensively assessed with controlled and deep breathing, active orthostatic test, Valsalva maneuver and handgrip test. Hot flushes were accompanied with a significant reduction (-2.2±0.7 vs. 1.3±1.1 beats/min, p=0.03) in resting heart rate during estradiol-only treatment; the route of estradiol administration was no factor in this regard. This effect was attenuated by the addition of MPA to oral estradiol. Hot flushes were also associated with reduced maximal heart rate in response to handgrip during the use of estradiol-only therapy (-2.2±1.3 vs. 2.8±1.5 beats/min, p=0.038); again, the MPA addition eliminated this effect. Hot flushes were accompanied with lowered resting but augmented blood pressure responses to handgrip test during all hormone regimens, whereas in women without hot flushes estradiol-only regimen tended to elevate diastolic resting blood pressure. Hot flushes appear as determinants for cardiovascular responses to hormone therapy. Estradiol-only therapy causes beneficial changes in cardiovascular regulation in flushing women, and these are blunted, in part, by the addition of MPA.


Sex differences in amphetamine-induced locomotor activity in adult rats: role of testosterone exposure in the neonatal period.
The present studies assessed the extent to which adult sex differences in responsiveness to both acute and repeated amphetamine (AMPH) treatment can be attributed to differential exposure to testosterone (T) during the early critical period for sexual differentiation. At birth, male pups were sham-operated or gonadectomized, whereas female pups were given T or an oil injection. In adulthood, all animals were gonadectomized or sham-operated. Locomotor activity in response to either 1.5 mg/kg AMPH (IP) or the saline vehicle was measured for 2 h every third day, on five occasions. On the sixth occasion, all animals received 0.75 mg/kg AMPH (IP) in a test for sensitization. In Experiment 1, animals were tested in the absence of circulating gonadal hormones, whereas in Experiment 2, all animals received 5.0 micrograms estradiol benzoate (SC), 30-35 min prior to each behavioral test. Results indicate that neonatal exposure to T suppresses responsiveness to AMPH in adulthood. The differences between neonatal T-exposure groups were magnified in the presence of circulating estradiol. The fact that female animals were more responsive to AMPH regardless of neonatal T exposure suggests that lifetime exposure to estradiol alters responsiveness to this hormone, and to AMPH, in adult animals and/or that exposure to T both pre- and postnatally is necessary for the full suppression of responsiveness seen in adult male animals.


Autopsy: moribund art or vital science?
The autopsy rate in the United States has fallen dramatically in the past 40 years. Factors contributing to its decline include diagnostic over-confidence among clinicians, competing demands upon pathologists, difficulties obtaining consent from families, and its costs. The benefits of autopsy are clear: confirmation, clarification, and correction of antemortem diagnoses; discovery and definition of new diseases; evaluation of new diagnostic tests, new surgical techniques, and new drugs; investigation of environmental and occupational diseases; reassurance of family members; and contributions to medical and epidemiologic research. Proposals to revive the autopsy are reviewed, including altering the method of obtaining consent, altering autopsy procedures, structuring teaching around the autopsy, training autopsy pathologists in anatomic subspecialties, reinstating minimal autopsy requirements for hospital accreditation, providing financial support, and educating the public and the medical profession about its values. Accomplishing these changes quickly will prevent loss of its many benefits to the clinician, family, hospital, and society.


Autophagy: A new concept in autoimmunity regulation and a novel therapeutic option.
Nowadays, pharmacologic treatments of autoinflammatory diseases are largely palliative rather than curative. Most of them result in non-specific immunosuppression, which can be associated with broad disruption of natural and induced immunity with significant and sometimes serious unwanted injuries. Among the novel strategies that are under development, tools that modulate the immune system to restore normal tolerance mechanisms are central. In these approaches, peptide therapeutics constitute a class of agents that display many physicochemical advantages. Within this class of potent drugs, the phosphopeptide P140 is very promising for treating patients with lupus, and likely also patients with other chronic inflammatory diseases. We discovered that P140 targets autophagy, a finely orchestrated catabolic process, involved in the regulation of inflammation and in the biology of immune cells. In vitro, P140 acts directly on a particular form of autophagy called chaperone-mediated autophagy, which seems to be hyperactivated in certain subsets of lymphocytes in lupus and in other autoinflammatory settings. In lupus, the "correcting" effect of P140 on autophagy results in a weaker signaling of autoreactive T cells, leading to a significant improvement of pathophysiological status of treated mice. These findings also demonstrated ex vivo in human cells, open novel avenues of therapeutic intervention in pathological conditions, in which specific and not general targeting is highly pursued in the context of the new action plans for personalized medicines.


Epidermal DNA vaccine for influenza is immunogenic in humans.
A phase I clinical trial was conducted to evaluate a monovalent influenza DNA vaccine containing the HA gene from A/Panama/2007/99 delivered by particle-mediated epidermal delivery (PMED). Three groups of 12 healthy adult subjects received a single dose on day 0 of either 1, 2 or 4 microg of DNA vaccine, delivered as 1, 2 or 4 PMED administrations. The PMED influenza DNA vaccine elicited serum hemagglutination-inhibition (HAI) antibody responses at all three dose levels, with the highest and most consistent responses in subjects vaccinated with the highest dose level. Antibody responses were greatest at the last time point tested, day 56. Treatment-related reactions were mild to moderate, and included skin reactions at the vaccine site. These results provide a preliminary indication of the safety and immunogenicity of a prototype epidermal DNA vaccine for influenza.


County incidence and geospatial trends of early-onset hypertensive disorders of pregnancy in Kentucky, 2008-2017.
Early-onset hypertensive disorders of pregnancy (eHDP) are associated with more severe maternal and infant outcomes than later-onset disease. However, little has been done to evaluate population-level trends. Therefore, in this paper, we seek to address this understudied area by describing the geospatial and temporal patterns of county-level incidence of eHDP and assessing county-level demographics that may be associated with an increased incidence of eHDP. Employing Kentucky certificates of live and stillbirth from 2008-2017, this ecological study detected county-level clusters of early-onset hypertensive disorders of pregnancy using SaTScan, calculated average annual percent change (AAPC) with a join point analysis, and identified county-level covariates (% of births to women ≥ 35 years of age, % with BMI ≥ 30 kg/m2, % currently smoking, % married, and % experienced eHDP) with a fixed-effects negative binomial regression model for longitudinal data with an autoregressive (AR) correlation structure offset with the natural log of the number of births in each county and year. County-level incidence of eHDP had a non-statistically significant increase of almost 3% (AAPC: 2.84, 95% CI: -4.26, 10.46), while maternal smoking decreased by almost 6% over the study period (AAPC:-5.8%, 95%CI: -7.5, -4.1), Risk factors for eHDP such as pre-pregnancy BMI ≥ 30 and proportion of births to women ≥ 35 years of age increased by 2.3% and 3.4% respectively (BMI AAPC:2.3, 95% CI: 0.94, 3.7; ≥ 35 years AAPC:3.4, 95% CI: 0.66, 6.3). After adjusting for race, county-level proportions of college attainment, and maternal smoking throughout pregnancy, counties with the highest proportion of births to women with BMI ≥ 30 kg/m2 reported an eHDP incidence 20% higher than counties with a lower proportion of births to mothers with a BMI ≥ 30 kg/m2 and a 20% increase in eHDP incidence (aRR = 1.20, 95% CI: 1.00, 1.44). We also observed that counties with the highest proportion vs. the lowest of mothers ≥ 35 years old (> 6.1%) had a 26% higher incidence of eHDP (RR = 1.26, 95%CI: 1.04, 1.50) compared to counties with the lowest incidence (< 2.5%). We further identified two county-level clusters of elevated eHDP rates. We also observed that counties with the highest vs. lowest proportion of mothers ≥ 34 years old (> 6.1% vs. < 2.5%) had a 26% increase in the incidence of eHDP (RR = 1.26, 95% CI: 1.04, 1.50). We further identified two county-level clusters of elevated incidence of eHDP. This study identified two county-level clusters of eHDP, county-level covariates associated with eHDP, and that while increasing, the average rate of increase for eHDP was not statistically significant. This study also identified the reduction in maternal smoking over the study period and the concerning increase in rates of elevated pre-pregnancy BMI among mothers. Further work to explore the population-level trends in this understudied pregnancy complication is needed to identify community factors that may contribute to disease and inform prevention strategies.


Renal mitochondrial toxicity: effects of thymidine analogues and tenofovir disoproxil fumarate in African people with HIV.
We investigated the contributions of thymidine analogue and tenofovir disoproxil fumarate (TDF) antiretroviral therapy on renal mitochondrial toxicity in Ghanaian people with HIV (PWH). Similar levels of renal biochemical and mitochondrial dysfunction were seen, and there was no increased risk in PWH who had sequenced from thymidine analogue to TDF. However, mild renal impairment was associated with mitochondrial DNA damage in TDF but not thymidine analogue-treated PWH. These data support the continued use of TDF in resource-limited settings.


The World Health Organization (WHO) dataset for guiding suicide prevention policies: A 3-decade French national survey.
Public health policies aim to prevent suicide in the general population. Assessing their effectiveness is required to further guide public health policies. The present article focuses on the French paradox. The French health care system was classified as the best in the world according the World Health Organization (WHO). However, suicide rates in France remain high compared to other European countries. The aim of the present article was to analyze (i) the evolution of suicide Age-Standardized Death (ASDRs) in France during the last three decades and the associations with socio-economic parameters and (ii) to understand which populations may specifically benefit from further targeted suicide prevention policies. The database of the World Health Organization (WHO), freely available, was explored in April 2015. ASDRs were calculated each year by ratio between the number of deaths by suicide and the total population (per 100,000 inhabitants). Number of deaths by gender and age were also analyzed. Overall, ASDR suicide has decreased since 1987 in France (-32.8% between 1987 and 2010). However, France kept the same rank (10/26) when compared to other European countries between 1987 and 2010. The relative burden of suicide in all-causes mortality increased during the same period (+28.2%) while the total number of deaths by suicide increased only slightly (+3.9%). More specifically, the number of deaths by suicide increased substantially in [35-54] years old (+40%) and 75+ years old (+27%) males, and in [35-54] (+41%) years old females. Between 2000 and 2010, suicide rates significantly decreased when yearly mean income increased, and when general and psychiatric care beds decreased. Although ASDR suicide has decreased in France since 1987, this decline is quite modest when considering its universal access to care, the prevention of depression and suicide public policies. Suicide prevention public policies should focus on evaluation and improvement of prevention and care in the [35-54] years old population, and in the males aged 75+.


Pathophysiology of type 1 and type 2 diabetes mellitus: a 90-year perspective.
Diabetes mellitus is a complex metabolic disorder associated with an increased risk of microvascular and macrovascular disease; its main clinical characteristic is hyperglycaemia. The last century has been characterised by remarkable advances in our understanding of the mechanisms leading to hyperglycaemia. The central role of insulin in glucose metabolism regulation was clearly demonstrated during the early 1920s, when Banting, Best, Collip and Macleod successfully reduced blood glucose levels and glycosuria in a patient treated with a substance purified from bovine pancreata. Later, during the mid-1930s, clinical observations suggested a possible distinction between 'insulin-sensitive' and 'insulin-insensitive' diabetes. Only during the 1950s, when a reliable measure of circulating insulin was available, was it possible to translate these clinical observations into pathophysiological and biochemical differences, and the terms 'insulin-dependent' (indicating undetectable insulin levels) and 'non-insulin-dependent' (normal or high insulin levels) started to emerge. The next 30 years were characterised by pivotal progress in the field of immunology that were instrumental in demonstrating an immune-mediated loss of insulin-secreting β-cells in subjects with 'insulin-dependent' diabetes. At the same time, new experimental techniques allowing measurement of insulin 'impedance' showed a reduced peripheral effect of insulin in subjects with 'non-insulin-dependent' diabetes (insulin resistance). The difference between the two types of diabetes emerging from decades of observations and experiments was further formally recognised in 1979, when the definitions 'type I' and 'type II' diabetes were introduced to replace the former 'insulin-dependent' and 'non-insulin-dependent' terms. In the following years, many studies elucidated the natural history and temporal contribution of insulin resistance and β-cell insulin secretion in 'type II' diabetes. Furthermore, a central role for insulin resistance in the development of a cluster of cardiometabolic alterations (dyslipidaemia, inflammation, high blood pressure) was suggested. Possibly as a consequence of the secular changes in diabetes risk factors, in the last 10 years the limitation of a simple distinction between 'type I' and 'type II' diabetes has been increasingly recognised, with subjects showing the coexistence of insulin resistance and immune activation against β-cells. With the advancement of our cellular and molecular understanding of diabetes, a more pathophysiological classification that overcomes the historical and simple 'glucocentric' view could result in a better patient phenotyping and therapeutic approach.


Suppressed nuclear envelope proteins activate autophagy of vascular smooth muscle cells during cyclic stretch application.
Dysfunctions of vascular smooth muscle cells (VSMCs) play crucial roles in vascular remodeling in hypertension, which correlates with pathologically elevated cyclic stretch due to increased arterial pressure. Recent researches reported that autophagy, a life-sustaining process, was increased in hypertension. However, the mechanobiological mechanism of VSMC autophagy and its potential roles in vascular remodeling are still unclear. Using renal hypertensive rats in vivo and FX5000 stretch application Unit in vitro, the autophagy of VSMCs was detected. The results showed that LC3II remarkably enhanced in hypertensive rats and 15% cyclic stretch (mimic the pathologically increased mechanical stretch in hypertension), and the activity of mammalian target of rapamycin (mTOR) was suppressed in 15% cyclic stretch. Administration of autophagy inhibitors, bafilomycin A1 and chloroquine, repressed VSMC proliferation efficiently, but did not affect the degradation of two important nuclear envelope (NE) proteins, lamin A/C and emerin. Using RNA interference to decline the expression of lamin A/C and emerin, respectively, we discovered that autophagy was upregulated under both static and 5% cyclic stretch conditions, accompanying with the decreased mTOR activity. During 15% cyclic stretch application, mTOR inhibition was responsible for autophagy elevation. Chloroquine administration in vivo inhibited the expression of PCNA (marker of proliferation) of abdominal aorta in hypertensive rats. Altogether, these results demonstrated that pathological cyclic stretch suppresses the expression of lamin A/C and emerin which subsequently represses mTOR pathway so as to induce autophagy activation. Blocking autophagic flux may be a practicable way to relieve the pathological vascular remodeling in hypertensive.


Investigation of variable lymphocyte receptors in the alternative adaptive immune response of hagfish.
Jawless vertebrates have an alternative adaptive immune system mediated by variable lymphocyte receptors (VLRs), VLRA, VLRC and VLRB. In investigation on the adaptive immunity of hagfish, avian influenza virus hemagglutinin (H9N2-HA1) was used as a model antigen, with mRNA expression levels of VLRA, VLRC and Ikaros were up-regulated in the first week post-immunization. CD45 was up-regulated after the first week; and expression of VLRB progressively increased over the course of the trial. The transcriptional/translational activation of VLRB in blood was verified. The VLRBs cloned from these transcripts showed diversity in their leucine-rich repeats (LRRs). The production of specific VLRB increased in a time- and dose-dependent manner, detected by an anti-VLRB antibody (11G5). The plasma VLRB could distinguish H9N2-HA1 from unrelated proteins, but not from other HA1 subtypes. Together, our findings show that VLRs play a major role in the alternative adaptive immune system of hagfish by responding to specific foreign substances, such as H9N2-HA1.


Anti-Mycobacterium tuberculosis activity of antituberculosis drugs and amoxicillin/clavulanate combination.
We report the in vitro drugs interaction by the resazurin drugs combination microtiter assay (REDCA) of amoxicillin (AMO)/clavulanate (CLAV) with isoniazid (INH), ethambutol (EMB), and rifampicin (RIF) against susceptible and resistant Mycobacterium tuberculosis isolates. The addition of AMO/CLAV to classical antituberculosis drugs should be explored as a promising alternative for the treatment of resistant tuberculosis (TB).


Rapid Clearing CT-001 Restored Hemostasis in Mice with Coagulopathy Induced by Activated Protein C.
Activated protein C (APC) is one of the mechanisms contributing to coagulopathy, which is associated with high mortality. The counteraction of the APC pathway could help ameliorate bleeding. However, patients also transform frequently from a hemorrhagic state to a prothrombotic state at a later time. Therefore, a pro-hemostatic therapeutic intervention should take this thrombotic risk into consideration. CT-001 is a novel factor VIIa (FVIIa) with enhanced activity and desialylated N-glycans for rapid clearance. We assessed CT-001 clearance in multiple species and its ability to reverse APC-mediated coagulopathic blood loss. The N-glycans on CT-001 were characterized by liquid chromatography-mass spectrometry. Three species were used to evaluate the pharmacokinetics of the molecule. The potency and efficacy of CT-001 under APC-pathway induced coagulopathic conditions were assessed by coagulation assays and bleeding models. The N-glycosylation sites of CT-001 had high occupancy of desialylated N-glycans. CT-001 exhibited 5 to 16 times higher plasma clearance in human tissue factor knockin mice, rats, and cynomolgus monkeys than wildtype (WT) FVIIa. CT-001 corrected the activated partial thromboplastin time (APTT) and thrombin generation of coagulopathic plasma to normal in in vitro studies. In an APC-mediated saphenous vein bleeding model, 3 mg/kg CT-001 reduced bleeding time in comparison to WT FVIIa. The correction of bleeding by CT-001 was also observed in a coagulopathic tail amputation severe hemorrhage mouse model. The efficacy of CT-001 is independent of the presence of tranexamic acid and the combination of CT-001 and tranexamic acid does not lead to increased thrombogenicity. CT-001 corrected APC pathway-mediated coagulopathic conditions in preclinical studies and could be a potentially safe and effective pro-coagulant agent for addressing APC-mediated bleeding. Basic science research. Not applicable.


Hibernoma presenting as an asymptomatic neck mass.
Hibernomas are rare benign tumors of brown fat tissue origin. These tumors are generally found in locations where fetal fat persists (back, axilla, thorax and retroperitoneum). We report a case of a patient with an asymptomatic neck mass that initially presented for evaluation of hoarseness. Imaging and complete surgical excision of the mass were performed and revealed hibernoma. Review of the literature for the presentation of hibernoma in the neck is performed. Hibernomas are rare benign tumors that infrequently present in the neck. Complete surgical removal is curative. To date no malignant transformation or metastasis has been described.


A new ent-clerodane diterpene from Detarium microcarpum Guill. & Perr. and its protective potential for osteoporosis.
A new clerodane diterpene, named 6α-hydroxy-3,13E-clerodien-15-oic acid (1), together with a known clerodane diterpene (2), four known labdane diterpenes (3-6), a triterpenoid (7), a known steroid (8), and two benzenoid compounds (9 and 10) were isolated from Detarium microcarpum Guill. & Perr. The structures of all obtained compounds were determined by chemical properties and spectroscopic evidence, accompanied by comparisons with data in the literature. Electronic circular dichroism (ECD) was performed for compounds 1-4 to confirm the absolute configuration. Compounds 1-3 and 8-10 were evaluated for the protective effect on osteoblasts. Compound 1 was observed to increase the proliferation of dexamethasone (DEX)-treated MC3T3-E1 cells significantly at 1 μM, which was comparable with the positive control geniposide at 10 μM. The results were further confirmed by flow cytometry analysis. In addition, compound 1 increased the level of alkaline phosphatase (ALP) and mineralization in osteoblasts inhibited by DEX. Moreover, Compound 9 (vanillic acid) showed a pronounced inhibition (IC50 6.5 ± 0.6 μM) on reactive oxygen species (ROS) production, and 10 (4-O-methyl gallic acid) showed a good inhibition with IC50 as 103.3 ± 2.2 μM, compared with the standard drug ibuprofen (IC50 54.2 ± 9.2 μM). Besides, compounds 1-3 and 8-10 were non-cytotoxic against MCF-7, NCI-H460, Hela, and BJ cell lines.


Characterisation of pragmatic postoperative PAin Trajectories over seven days and their association with CHronicity after 3 months: a prospective, pilot cohort study (PATCH study).
Reliable outcome measurement providing information both on early and late postoperative pain outcomes are still lacking. The purpose of this study was: 1) to characterise postoperative pain trajectories according to an innovative pragmatic concept: ideal pain trajectory (rapid and sustained pain relief) vs non-ideal pain trajectories (late, transient, or no pain relief); and 2) to assess the incidence of persistent post-surgical pain (PPSP) and the potential association between non-ideal pain trajectories and PPSP. This prospective observational pilot cohort study was performed from March until June 2016. A total of 344 patients undergoing major general surgery were invited to complete a self-assessment of pain intensity using numerical rating scale (NRS; 0 = no pain to 10 = worst pain) from day 1 until day 7 after surgery, in order to establish their pain trajectory. Three months after surgery, patients were screened for PPSP. Rest pain score was analysed in 308 participants. Among them, 210 (68% - 95% CI: 63-73) had an "ideal" pain trajectory, while 98 (32% - 95% CI: 27-37) had "non-ideal" pain trajectories. Three months after surgery, 31% (95% CI: 26-37) reported PPSP. Multivariable analysis showed that "non-ideal" pain trajectories [OR 2.25; (95% CI: 1.26-4.01) P = 0.006] were significantly associated with PPSP. The present study proposes an innovative pragmatic concept of postoperative pain trajectories: ideal vs non-ideal pain trajectories, providing information both on acute postoperative pain resolution and early identification patients at risk for developing PPSP. NCT02599233; November, 6, 2015, with clinicaltrials.gov.


Distribution and sources of organic carbon, nitrogen and their isotopic composition in surface sediments from the southern Yellow Sea, China.
The southern Yellow Sea (SYS) is a significant repository of sedimentary organic matter (SOM) and has been impacted by green tides since 2007; however, data on the distribution and quantitative contributions of different SOM sources has been scarce. TOC, TN and their δ13C and δ15N values were determined in 38 surface sediments. TOC and TN were high in central mud area and low in sand area. TOC was positively correlated with the abundance of fine-grained sediments, indicating that controlling factors of SOM were the sediment types and circulation system. The SOM included marine and terrestrial organic matter and anthropogenic nutrient inputs according to TOC/TN (5.8-14.3), δ13C (-25.1‰ to -21.0‰) and δ15N (2.6‰-6.4‰). High terrestrial contributions in northern and western parts of SYS, were influenced by terrestrial materials and eroded substances of the abandoned Yellow River delta, respectively. In the central mud area of SYS, marine organic matter was dominant.


Solubilization and purification of the Ni-stimulated arginine-vasopressin binding site of rat brain membranes.
Arginine vasopressin binding sites on rat brain membranes were solubilized and purified by affinity chromatography. Membrane protein solubilized with CHAPS bound arginine vasopressin (AVP) only in the presence of divalent cations. Specific binding to the solubilized tissue was maximally stimulated by Ni2+, and markedly stimulated by Co2+ (30% of maximal binding with Ni2+), Zn2+ (18%), and Fe2+ (11%), parallel to the effects of these ions on the binding of AVP to neural membranes. Binding to solubilized tissue was not stimulated by Mg2+, Cu2+, Mn2+, or Ca2+. In the presence of Ni2+, binding of AVP to solubilized tissue was reversible, and the dissociation constant (10.5 nM), pH optimum, and time course were virtually identical to those of the membrane-bound AVP binding site. Purification of solubilized AVP-binding proteins by affinity chromatography on AVP-sepharose followed by gel electrophoresis yielded a major band of 55 kdalton molecular weight when purified in the presence of 5 mM Mg2+, or a major band of 62 kdaltons when purified in the presence of 1-5 mM Ni2+ or 10 microM Zn2+. By means of a new binding assay involving conjugation of the 62 kdalton fraction to brain membranes, the extent of purification of AVP binding activity was 150-fold in the presence of Ni2+. We suggest that the 62 kdalton protein is a component of the Ni-stimulated AVP binding site.


The eIF1A C-terminal domain promotes initiation complex assembly, scanning and AUG selection in vivo.
Translation initiation factor 1A stimulates 40S-binding of the eukaryotic initiation factor 2 (eIF2)/GTP/Met-tRNA(iMet) ternary complex (TC) and promotes scanning in vitro. eIF1A contains an OB-fold present in bacterial IF1 plus N- and C-terminal extensions. Truncating the C-terminus (deltaC) or mutating OB-fold residues (66-70) of eIF1A reduced general translation in vivo but increased GCN4 translation (Gcd- phenotype) in a manner suppressed by overexpressing TC. Consistent with this, both mutations diminished 40S-bound TC, eIF5 and eIF3 in vivo, and deltaC impaired TC recruitment in vitro. The assembly defects of the OB-fold mutation can be attributed to reduced 40S-binding of eIF1A, whereas deltaC impairs eIF1A function on the ribosome. A substitution in the C-terminal helix (98-101) also reduced 43S assembly in vivo. Rather than producing a Gcd- phenotype, however, 98-101 impairs GCN4 derepression in a manner consistent with defective scanning by reinitiating ribosomes. Indeed, 98-101 allows formation of aberrant 48S complexes in vitro and increases utilization of non-AUG codons in vivo. Thus, the OB-fold is crucial for ribosome-binding and the C-terminal domain of eIF1A has eukaryotic-specific functions in TC recruitment and scanning.


Potential of turmeric-derived compounds against RNA-dependent RNA polymerase of SARS-CoV-2: An in-silico approach.
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of the COVID-19 pandemic. Currently, there are no particular antivirals available to battle with COVID-19. The RNA-dependent RNA polymerase (RdRp) has emerged as a novel drug target due to its essential role in virus replication. In this study, turmeric-derived compounds were chosen and subjected to in-silico analysis to evaluate their binding affinity against the RdRp-RNA complex of SARS-CoV-2. Our in-silico approach included the analysis of protein-ligand interactions by molecular docking and molecular dynamics simulations, followed by free energy calculations by molecular mechanics Poisson-Boltzmann surface area analysis. Curcumin and diacetylcurcumin showed stability and good binding affinity at the active site of the SARS-CoV-2 RdRp-RNA complex. Furthermore, to validate the potency of selected compounds, we compared them with Favipiravir and Remdesivir antiviral drugs from our previous analysis on targeting tea bioactive molecules to inhibit RdRp-RNA complex. The comparative analysis revealed that the selected compounds showed higher potential to be developed as RdRp-RNA inhibitors than antiviral medicines Remdesivir and Favipiravir. However, these compounds need to be further validated by in-vitro and in-vivo investigations.


Biorefinery Byproducts and Epoxy Biorenewable Monomers: A Structural Elucidation of Humins and Triglycidyl Ether of Phloroglucinol Cross-Linking.
The need for thermosets from renewable resources is continuously increasing to find eco-friendly alternatives to petroleum-derived materials. Products obtained from biomass have shown to play an important role in this challenge. Here, we present the structural characterization of new biobased thermosets made of humins, a byproduct of lignocellulosic biorefinery, and glycidylated phloroglucinol coming from the biomass phenolic fraction. By employing attenuated total reflection-Fourier transform infrared and NMR spectroscopies, we elucidated the connections between these two systems, contributing to clarify their molecular structures and their reactivities. We demonstrated that the resin curing takes place through ether bond formation between humin hydroxyl functions and phloroglucinol epoxides. Besides cross-linking, humins show a complex rearrangement of their furanic structure through different concomitant chemical pathways depending on the reaction conditions.


The suitability of sunglasses used by patients following ingestion of psoralen.
We have investigated the types of eyewear which patients on photochemotherapy have obtained, and determined their suitability for providing adequate protection. Fifty-eight pairs of sunglasses from 53 patients were assessed. Spectral transmission was measured between 200 nm and 800 nm at 10 nm intervals. Thirty-eight pairs of glasses (66%) were found to be satisfactory. Particularly high UV transmission was recorded in 11 cases (19%), highlighting the need for increased awareness of the problem of ensuring that suitable protective eyewear is used.


Psychophysiological effects and dose equivalence of zopiclone and triazolam administered to healthy volunteers. Methodological considerations.
1. Dose-equivalence studies of zopiclone and triazolam were carried out. 2. Zopiclone (6.25, 8.75 and 11.25 mg), triazolam (0.1875, 0.375 and 0.5 mg) and placebo were given in the morning to 14 healthy male volunteers aged 20-25 years under double-blind conditions according to an incomplete block design. Each patient received three of the seven possible treatments at intervals of at least 1 week. Subjects were evaluated using physiological measures, rating scales and memory tasks before and 1.5 and 4.5 h after drug administration. 3. The sedative and amnestic effects of zopiclone were qualitatively similar to those of triazolam, with the highest dose of each having the greatest effect. 4. On the basis of the digit symbol substitution test, 10 mg of zopiclone is equivalent to 0.5 mg of triazolam. Methodological problems of the experimental design of dose-equivalence studies are discussed.


Proposal of Thermoactinomyces mirandus sp. nov., a filamentous, anaerobic bacterium isolated from a biogas plant.
We isolated a filamentous, thermophilic, and first anaerobic representative of the genus Thermoactinomyces, designated strain AMNI-1T, from a biogas plant in Tyrol, Austria and report the results of a phenotypic, genetic, and phylogenetic investigation. Strain AMNI-1T was observed to form a white branching mycelium that aggregates into pellets when grown in liquid medium. Cells could primarily utilize lactose, glucose, and mannose as carbon and energy sources, with acetate accelerating and yeast extract being mandatory for growth. The optimum growth temperature and pH turned out to be 55 °C and pH 7.0, respectively, with an optimum NaCl concentration of 0-2% (w/v). 16S rRNA gene sequence comparison indicated that the genetic relatedness between strain AMNI-1T and Thermoactinomyces intermedius, Thermoactinomyces khenchelensis, and Thermoactinomyces vulgaris was less than 97%. The G + C content of the genomic DNA was 44.7 mol%. The data obtained suggest that the isolate represents a novel and first anaerobic species of the genus Thermoactinomyces, for which the name Thermoactinomyces mirandus is proposed. The type strain is AMNI-1T (= DSM 110094T = LMG 31503T). The description of the genus Thermoactinomyces is emended accordingly.


Immunomodulatory activity of extracellular Hsp70 mediated via paired receptors Siglec-5 and Siglec-14.
The intracellular chaperone heat-shock protein 70 (Hsp70) can be secreted from cells, but its extracellular role is unclear, as the protein has been reported to both activate and suppress the innate immune response. Potential immunomodulatory receptors on myelomonocytic lineage cells that bind extracellular Hsp70 are not well defined. Siglecs are Ig-superfamily lectins on mammalian leukocytes that recognize sialic acid-bearing glycans and thereby modulate immune responses. Siglec-5 and Siglec-14, expressed on monocytes and neutrophils, share identical ligand-binding domains but have opposing signaling functions. Based on phylogenetic analyses of these receptors, we predicted that endogenous sialic acid-independent ligands should exist. An unbiased screen revealed Hsp70 as a ligand for Siglec-5 and Siglec-14. Hsp70 stimulation through Siglec-5 delivers an anti-inflammatory signal, while stimulation through Siglec-14 is pro-inflammatory. The functional consequences of this interaction are also addressed in relation to a SIGLEC14 polymorphism found in humans. Our results demonstrate that an endogenous non-sialic acid-bearing molecule can be either a danger-associated or self-associated signal through paired Siglecs, and may explain seemingly contradictory prior reports on extracellular Hsp70 action.


Thalidomide and its impact in dermatology.
Thalidomide, originally marketed as a sedative, was introduced in West Germany in 1956 and in numerous other countries soon thereafter. In part because it did not impair coordination or respiratory function, the drug rapidly became extremely popular. By 1961, however, there were mounting reports of phocomelia and other severe congenital abnormalities associated with maternal use of thalidomide, and the drug was withdrawn from the market and its availability highly restricted. A few years later, thalidomide would find use in dermatology after it was reported that leprosy patients with erythema nodosum leprosum (ENL) experienced rapid and dramatic improvement after taking the drug as a sedative. Additional data quickly confirmed thalidomide's efficacy in ENL, and today it is the drug of choice in the condition. In subsequent decades, the drug has been successfully tried in treatment of a variety of apparently unrelated dermatologic disorders. Meanwhile, thalidomide has been shown to possess a range of biologic actions, including inhibition of tumor necrosis factor alpha, possibly relevant to its clinical efficacy. Dermatologic disorders in addition to ENL in which thalidomide's effectiveness is well documented include aphthous stomatitis, discoid lupus erythematosus, actinic prurigo, Behçet's disease, and prurigo nodularis. More recently, the drug has been employed in dermatologic conditions associated with HIV infection. When used with safeguards to prevent teratogenicity and the drug's other major adverse effect, peripheral neuropathy, thalidomide may offer a good therapeutic option for many patients in whom other drug therapies have proven inadequate.


Organization and spatial arrangement of fluorescein-labeled native actin microinjected into normal locomoting and experimentally influenced Amoeba proteus.
Fully polymerization-competent fluorescein-labeled actin from skeletal muscle was microinjected into both normal moving and experimentally treated Amoeba proteus. Its intracellular distribution was followed by integral image intensification of the fluorescence on a television screen and compared with controls injected with rhodamine-labeled serum albumin. The labeled actin was incorporated into the endogenous actin pool and exhibited a characteristic redistribution depending on the cellular morphology. Increased amounts of labeled actin could be detected within a thin layer separating the hyalo- and granuloplasm or running immediately beneath the plasma membrane when hyaloplasmic regions were absent. The topography of the fluorescent layer demonstrated in living cells is in agreement with the cortical microfilament layer described ultrastructurally recently in corresponding cells. The combined results emphasize the important role of the cortical filament layer in both morphogenetic processes (e.g., hyalo-granuloplasm separation or changes in cell shape) and motive force generation for cytoplasmic streaming and amoeboid movement.


Treatment initiation for parkinson's disease in Australia 2013-2018: a nation-wide study.
Guidelines highlight the importance of an individualized approach to treatment initiation for Parkinson's disease. Our aim was to investigate initiation of anti-Parkinson medication in Australia from 2013-2018, and to determine factors predicting choice of initial treatment. Cohort of new-users (N = 4,887) of anti-Parkinson medication aged ≥ 40 years were identified from a 10% random representative sample of national medication dispensing data from July-2013 to June-2018. Changes in treatment initiation were examined across the whole cohort and stratified by age and sex. Treatment initiation was most frequent with levodopa followed by non-ergot dopamine agonists (DAs) and anticholinergics. Two thirds initiated with levodopa across the study period. Initiation with non-ergot DAs increased from 22 to 27% (rate ratio, RR 1.23, 95% confidence interval, CI 1.02-1.47) and initiation with anticholinergics decreased from 6.9% to 2.4% (RR 0.34, 95% CI 0.21-0.55) from 2013-2018. Among persons aged ≥ 65 years, one third of women and one fourth of men initiated on levodopa. Among women aged < 65 years, rates of treatment initiation with DAs (37%) and levodopa (37%) were similar in 2013/2014 but initiation with DA exceeded levodopa thereafter. Among men aged < 65 years, treatment initiation with levodopa (44%-49%) remained more frequent than initiation with DAs (29%-32%) throughout the study period. Treatment initiation with levodopa was most frequent among persons aged ≥ 65 years, consistent with current guidelines. Whilst the value of levodopa sparing strategies is unclear, treatment initiation with DA has become increasingly common relative to levodopa among women but not among men aged < 65 years.


Lambing rate and prolificacy in inseminated hair sheep treated with bovine somatotropin.
This study evaluated whether the administration of 50 and 100 mg bovine somatotropin (bST) at the start of estrous synchronization and at the time of artificial insemination improves lambing rate and prolificacy in hair sheep. Four hundred eighty adult hair ewes (Pelibuey, Blackbelly, Dorper, Katahdin, and their crosses) were synchronized with intravaginal sponge containing 40 mg of fluorogestone acetate. On the day of sponge insertion, ewes were assigned to three treatments: the bST-100 treatment (n = 156) received 100 mg bST at the start of synchronization (d 0) and at the time of insemination (d 14), the bST-50 treatment (n = 159) received 50 mg bST in the same schedule as the previous group, and the control (n = 165) did not receive any bST. Lambing rate and percentage of multiple births were analyzed using the GENMOD procedure of SAS. Prolificacy data were analyzed using the MIXED procedure of SAS. The IGF-1 and insulin concentrations were analyzed with ANOVA for repeated measures. The bST application did not affect the lambing rate (P = 0.06). The proportion of ewes with multiple births (P = 0.01) and prolificacy (P = 0.04) were higher in the bST-50 (54.3% and 1.57 ± 0.1) than the bST-100 (18.2% and 1.25 ± 0.1) and control (33.3% and 1.28 ± 0.1) groups. The IGF-1 and insulin concentrations were higher (P < 0.05) in the bST-treated groups, but the insulin concentration was higher (P = 0.001) in the bST-100 group than in the bST-50 group. The administration of 50 or 100 mg bST at the start of synchronization and at the time of artificial insemination does not increase lambing rate. However, the dose of 50 mg increased the proportion of multiple births and prolificacy.


Categorizing a Face and Facing a Category: The Constructive Impacts of Ambiguity and Uncertainty in Racial Categorization.
The past generation has seen a dramatic rise in multiracial populations and a consequent increase in exposure to individuals who challenge monolithic racial categories. We examine and compare two potential outcomes of the multiracial population growth that may impact people's racial categorization experience: (a) exposure to racially ambiguous faces that visually challenge the existing categories, and (b) a category that conceptually challenges existing categories (including "biracial" as an option in addition to the monolithic "Black" and "White" categories). Across four studies (N = 1,810), we found that multiple exposures to faces that are racially ambiguous directly lower essentialist views of race. Moreover, we found that when people consider a category that blurs the line between racial categories (i.e., "biracial"), they become less certain in their racial categorization, which is associated with less race essentialism, as well. Importantly, we found that these two effects happen independently from one another and represent two distinct cognitive processes.


Inter- and intraindividual reproducibility of anorectal manometry.
This study investigates the inter- and intraindividual variability of normal values and, thus, the reproducibility of anorectal manometry. Following a standardized protocol, three anorectal manometries were performed 4 h apart on 2 days of investigation, with an interval of 4 weeks, in ten healthy volunteers. Measured parameters in all 60 manometries were: sphincter length (SL), resting pressure (RP), maximum squeeze pressure (MSP), relaxation of the internal anal sphincter (RIAS), and rectal compliance (RC). Interindividual variability was expressed as standard deviation from calculated mean values and intraindividual variability was tested with Wilcoxon's test for tied samples and Spearman's rank correlation test. A large interindividual variability was found for all measured parameters, except for SL, reflecting the extensive absolute range of measured values. Median intraindividual variability among the six individual measurements and between both measurement days revealed that MSP, RIAS and RC are parameters which were not reproducible in this volunteer study. A significant correlation between the results of the repetitive measurements and, thus, a good reproducibility was only found for the parameters SL and RP. Anorectal manometry has only limited diagnostic value; although rather exact quantifications of individual parameters can be achieved, the impact of these measurements should be regarded rather critically, since only SL and RP appeared to be reproducible parameters.


To feed or let eat! A scale of independence, exploration, and family to measure baby-led weaning as a complementary feeding approach.
This article reports the development and validation of a measure of parents' use of baby-led weaning (BLW). BLW is a child-centred approach to complementary feeding where the infant is allowed to eat whole foods (rather than purees) and explore a variety of foods and textures. To date, parents' use of BLW has been assessed using either single items or a wide variety of measures. In this study, exploratory and confirmatory factor analyses on independent samples supported three BLW subscales: independence, exploration, and family. The final 13-item scale showed adequate fit statistics and good reliability (χ2 (62) = 115.02, p < 0.001; CFI = 0.98; TLI = 0.98; RMSEA = 0.05; SRMR = 0.06; exploration a = 0.738; family a = 0.715; independence a = 0.809). In addition, the scale demonstrated good external validity and related in theoretically expected ways to an infant feeding-style measure and parent report of complementary feeding approach. This study was limited as it was mostly white parents, and the scale should be validated on a more diverse sample. Future research can use this scale to examine if BLW relates to infant taste preferences, parenting styles, and child eating behaviours to improve child nutrition and health outcomes.


Discharge and aftercare in chronic lung disease of the newborn.
This article deals with the discharge planning and continuing care of babies with chronic lung disease of the newborn (CLD), especially those with a continuing oxygen requirement, with some reference to longer term outcome. The pattern of CLD has changed since early descriptions, and the most useful definition for persisting morbidity in a baby with lung disease is a continuing oxygen requirement beyond 36 weeks post-menstrual age. Long-term oxygen therapy to maintain oxygen saturation at a mean of 95% or more and prevent levels below 90% is the cornerstone of management, and with adequate oxygen therapy the excess mortality previously reported in CLD can largely be avoided. Care must be given to the method of assessing oxygen saturation: overnight monitoring using appropriate recording devices is recommended. Exposure to respiratory viruses should be minimized where possible. Metabolic requirements are increased, but if efforts are made to maintain adequate energy input the long-term outlook for catch-up growth in height is good. Respiratory morbidity is increased in early life, but this improves in later childhood, along with lung function and exercise tolerance. Although respiratory symptoms should be treated as they arise, there is no evidence for long-term benefit from any pharmacological intervention in CLD.


CrustyBase: an interactive online database for crustacean transcriptomes.
Transcriptome sequencing has opened the field of genomics to a wide variety of researchers, owing to its efficiency, applicability across species and ability to quantify gene expression. The resulting datasets are a rich source of information that can be mined for many years into the future, with each dataset providing a unique angle on a specific context in biology. Maintaining accessibility to this accumulation of data presents quite a challenge for researchers.The primary focus of conventional genomics databases is the storage, navigation and interpretation of sequence data, which is typically classified down to the level of a species or individual. The addition of expression data adds a new dimension to this paradigm - the sampling context. Does gene expression describe different tissues, a temporal distribution or an experimental treatment? These data not only describe an individual, but the biological context surrounding that individual. The structure and utility of a transcriptome database must therefore reflect these attributes. We present an online database which has been designed to maximise the accessibility of crustacean transcriptome data by providing intuitive navigation within and between datasets and instant visualization of gene expression and protein structure.The site is accessible at https://crustybase.org and currently holds 10 datasets from a range of crustacean species. It also allows for upload of novel transcriptome datasets through a simple web interface, allowing the research community to contribute their own data to a pool of shared knowledge.


Technologic Evolution of Navigation and Robotics in Spine Surgery: A Historical Perspective.
Spine surgery is continuously evolving. The synergy between medical imaging and advances in computation has allowed for stereotactic neuronavigation and its integration with robotic technology to assist in spine surgery. The discovery of x-rays in 1895, the development of image intensifiers in 1940, and then advancements in computational science and integration have allowed for the development of computed tomography. In combination with the advancements of stereotaxy in the late 1980s, and manipulation of volumetric and special data for 3-dimensional reconstruction in 1998, computed tomography has revolutionized neuronavigational systems. Integrating all these technologies, robotics in spine surgery was introduced in 2004. Since then, it has become a safe modality that can reproducibly place accurate pedicle screws. Robotics may have the added benefits of improving the surgical workflow and optimizing surgeon ergonomics. Growing at a rapid rate, the second-generation spinal robotics have overcome preliminary limitations and errors. However, comparatively, robotics in spine surgery remains in its infancy. By leveraging technologic advancements in medical imaging, computation, and stereotactic navigation, robotics in spine surgery will continue to mature and expand in utility.


A Mobile Alert System for Preparing the Delivery of Radiation Mitigators.
A mobile system allowing hospital medical personnel to prepare for the administration of radiation mitigators prior to receiving casualties is desirable. We evaluated a portable spectroscopic personal radiation detector for use as an ambulance-based unit for early detection and identification of gamma radiation. We tested the sensitivity, time-to-identification, and radionuclide identification accuracy rates, change in detector response to vehicle operation, interference from cardiac equipment, and internal versus external radiation source location. We detected radiation sources in each of 119 trials using a humanoid phantom in a moving ambulance with a primary radionuclide identification accuracy of 96%. Typical identification time was around two minutes (149±95 s). Our observations suggest this mobile system is a potential pre-hospital arrival tool allowing for rapid preparation of radiation mitigators.


Immunosuppression in broilers under experimental aflatoxicosis.
The effects of purified aflatoxin B1 on cell mediated immunity in broilers were carried out using 0.3 p.p.m. and 1 p.p.m. dose level. The percentage of acid alpha-naphthyl acetate esterase reacting lymphocytes was significantly (P less than 0.05) decreased in chicks fed 0.3 p.p.m. and 1 p.p.m. level of aflatoxin B1. The albumin and globulin values were also significantly decreased (P less than 0.05) at both dose levels.


To prevent the allergic disease: the dream of the allergist.
Allergen avoidance, allergen immunotherapy, IgE antagonists, biological medications, prevention and treatment of respiratory infections, probiotics, adapted formula, vitamins, and oligo-elements have been investigated as strategies in the prevention of allergic diseases. Promising findings were obtained. To prevent allergic diseases could be a dream that will be soon realized in clinical practice.


Soluble Fas/FasLare elevated in the serum and cerebrospinal fluid of patients with neurocysticercosis.
Neurocysticercosis (NCC) caused by Taeniasolium is one of the most common parasitic diseases of the central nervous system. Inflammation and apoptosis are two main responses involved in NCC pathogenesis. We aimed to examine apoptosis by the TUNEL assay and apoptosis-associated sFas and sFasL levels in the cerebrospinal fluid (CSF) and serum of patients with NCC. Brain biopsy (n = 1), CSF (n = 14), and serum (n = 36) of patients with NCC and uninfected controls (n = 14 and 24 for CSF and serum, respectively) were collected together with clinical data. Residual brain tissue was analyzed by the TUNEL assay. sFas and sFasL in CSF samples and sFas, sFasL, and p53 in serum samples were measured by ELISA. Immunohistochemistry of the biopsy indicated the presence of vimentin-positive arachnoid tissue in the TUNEL-positive region. Compared to controls, sFas was significantly reduced in CSF samples of patients with NCC (P = 0.018), especially among those without inflammation, but significantly increased in the serum samples of the vesicular(P = 0.011), moderate(P = 0.025), and non-epilepsy(P = 0.049) subgroups of patients with NCC. sFasL was elevated in the CSF (P < 0.0001), as well as in the calcified subgroup (P = 0.031), but sFasL levels in CSF were similar among patients with NCC with and without inflammation. These findings support a role of sFas and sFasL in the induction of apoptosis in patients with NCC, with sFas probably being involved in the inflammation phase of NCC and depending on host factors such as parasite stage, disease severity, and symptoms, and sFasL being involved in the inflammation, non-inflammation, and calcification phase of the disease.


Study on the mechanism of puerarin against osteoarthritis from ferroptosis based on network pharmacology and bioinformatics.
Network pharmacology and bioinformatics were used to study puerarin's molecular mechanism in treating osteoarthritis from the perspective of ferroptosis, revealing a new treatment target. Ferroptosis-related targets were obtained from FerrDb. Puerarin action targets were retrieved from TCMSP, Pharmmappe, SwissTargetPrediction, and Targetnet databases, and supplemented with PubMed. The gene expression profiles of GSE12021, GSE55235, and GSE82107 were obtained using "Osteoarthritis" as the search term in the GEO database, and the differential expression gene screening analysis was performed for osteoarthritis. The intersection targets between puerarin, iron death, and osteoarthritis were obtained using Venn diagrams. GO and KEGG analyses were conducted with R software. Molecular docking and visualization of puerarin and core targets were performed using Autodock Vina and PyMol software. The effects of puerarin on the cell viability and the TNFα, IL6, and Ilβ levels of human inflammation articular chondrocytes were tested in vitro experiments. Puerarin, ferroptosis, and osteoarthritis share four targets: PLIN2, PTGS2, VEGFA, and IL6. GO enrichment analysis showed that puerarin maintained the blood-brain barrier, regulated peptide serine phosphorylation, and had anti-inflammatory effects. KEGG analysis showed that puerarin's anti-inflammatory effects were mainly through VEGF, IL-17, C-type lectin receptor, HIF-1, TNF, and other signaling pathways. Puerarin closely bound PLIN2, PTGS2, VEGFA, and IL6 targets in molecular docking. In vitro, puerarin prevented osteoarthritis. Network pharmacology and bioinformatics explained puerarin's multi-target and multi-pathway treatment of OA, which may be related to ferroptosis, and confirmed its anti-inflammatory effect.


Urapidil, but not dihydropyridine calcium channel inhibitors, preserves the hypoxic pulmonary vasoconstriction: an experimental study in pig arteries.
Hypoxic pulmonary vasoconstriction (HPV) is a protective mechanism maintaining blood oxygenation by redirecting blood flow from poorly ventilated to well-ventilated areas in the lung. Such a beneficial effect is blunted by antihypertensive treatment with dihydropyridine calcium channel inhibitors. The aim of the present study was to evaluate the effect of urapidil, an antihypertensive agent acting as an α1 adrenergic antagonist and a partial 5-HT1A agonist, on HPV in porcine proximal and distal pulmonary artery rings, and to characterize underlying mechanisms. Rings from proximal and distal porcine pulmonary artery were suspended in organ chambers and aerated with a 95% O2 + 5% CO2 gas mixture. HPV was induced by changing the gas to a 95% N2 + 5% CO2 mixture following a low level of pre-contraction with U46619. Hypoxia induced a contractile response in both proximal and distal pulmonary artery rings. This effect is observed in the presence of a functional endothelium and is inhibited by a soluble guanylyl cyclase inhibitor (ODQ), a NO scavenger (carboxy-PTIO), and by catalase in proximal pulmonary artery rings. The endothelium-dependent HPV is prevented by nicardipine and clevidipine but remained unaffected by urapidil in both proximal and distal pulmonary artery rings. These findings indicate that urapidil, in contrast to nicardipine and clevidipine, preserves the hypoxia-triggered vasoconstriction in isolated pulmonary arteries. They further indicate the involvement of the NO-guanylyl cyclase pathway and H2 O2 in HPV. Further research is warranted to determine the potential clinical relevance of the preserved hypoxia-induced pulmonary vasoconstriction by urapidil.


The results of total hip arthroplasty for fractured neck of femur in octogenarians.
The role of total hip arthroplasty (THA) for fracture in octogenarians remains unclear. Over a two-year period, 354 patients aged > 80 years were admitted with a displaced intracapsular hip fracture. Using defined clinical guidelines, 38 patients underwent THA with a median age of 84 years, mean follow-up of 20 months. Primary outcomes were dislocation, 30-day and one-year mortality, revision surgery and periprosthetic fracture. There were no dislocations or periprosthetic fractures and patient survival was 97% at 30 days and 87% at one year. There was one revision for deep infection. This study demonstrates that THA for selected octogenarians can be performed safely, allows the majority of patients to return to independent living and has a low complication rate.


Insuppressibility of plasma glucagon by orally or intravenously administered glucose in diabetes mellitus.
In order to study the response of pancreatic alpha cells to the change blood glucose, plasma pancreatic glucagon levels were measured after glucose loading given orally (50g) or intravenously (25g) in twenty-two normal controls and eighty untreated diabetics. Basal plasma pancreatic glucagon levels did not differ significantly in the two groups. However, oral or intravenous glucose administration caused a decrease in plasma pancreatic glucagon in normal subjects but not in diabetics. In "moderate" or "severe" diabetics, plasma pancreatic glucagon tended to increase paradoxically following oral glucose loading. To evaluate the sensitivity of pancreatic alpha cells to glucose, we calculated the index, -sigma delta IRG/sigma delta BS, after oral glucose loading. It was 1.96 +/- 0.57 in normal subjects, and significantly higher than in "mild" (0.11 +/- 0.05), "moderate" (-0.002 +/- 0.06) and "severe" (-0.09 +/- 0.07) diabetics. These results demonstrate the insensitivity of alpha cells to hyperglycemia in patients with diabetes mellitus as compared with normal subjects.


Physicians' attitudes about referring their type 2 diabetes patients for bariatric surgery.
Despite increasing evidence about the beneficial effects of bariatric surgery, little is known about physicians' attitudes toward it as a treatment of type 2 diabetes. Our objective was to investigate physicians' attitudes about referring patients with type 2 diabetes for bariatric surgery. Physicians were identified from the Pennsylvania Integrated Clinical and Administrative Research Database and other databases. Physicians at an academic medical center (n = 142) and community-based physicians (n = 197) in the Philadelphia area in specialties likely to treat type 2 diabetes were sent a survey about their perceptions of the safety and efficacy of bariatric surgery as a treatment for obesity and type 2 diabetes. Of the physicians, 93 returned the survey, for a combined response rate of 27.4%. Respondents reported having positive impressions of bariatric surgery as a treatment for obesity and type 2 diabetes (79.6% and 67.4%, respectively). Only 20.8% of respondents indicated that they would be likely to refer their patients with type 2 diabetes with a body mass index of 30-34.9 kg/m(2) to a randomized research trial of bariatric surgery. In general, physicians who treat patients with type 2 diabetes had favorable impressions about bariatric surgery as a treatment for obesity and type 2 diabetes. However, only a few were willing to refer their patients with type 2 diabetes and a body mass index of 30-34.9 kg/m(2) to randomized research trials of bariatric surgery. This reluctance to refer patients represents an important barrier to the successful completion of studies of the efficacy of bariatric surgery for those with type 2 diabetes and a body mass index <35 kg/m(2).


Mechanisms for tamoxifen resistance in breast cancer: possible role of tamoxifen metabolism.
Potential mechanisms for tamoxifen resistance include loss or alteration in estrogen receptor or other transcription factors and altered tamoxifen pharmacology. Using an experimental model, we have previously demonstrated that one form of tamoxifen resistance is related to the acquired ability of tamoxifen to stimulate tumor growth. These tamoxifen-stimulated tumors contain a reduced tamoxifen concentration and an altered metabolite profile suggesting that accumulation of more estrogenic metabolites could explain this phenomenon. However, in vivo treatment of nude mice carrying tamoxifen-stimulated tumors with fixed ring non-isomerizable analogs, or other analogs resistant to conversion to metabolite E (a full estrogen), still resulted in tumor growth stimulation. Growth of these tamoxifen-stimulated tumors was inhibited by a pure steroidal antiestrogen, ICI 182,780, suggesting that this drug should be investigated in patients with tamoxifen resistance. These tamoxifen-stimulated tumors could be further stimulated by estrogen replenishment, and estrogen stimulation was blocked by tamoxifen, indicating that tamoxifen has both agonist and antagonist properties in these tumors. Our data suggest that although tamoxifen-stimulated tumors display a markedly altered metabolite profile, isomerization or metabolism of tamoxifen does not fully explain the development of tamoxifen-stimulated growth. The mechanisms by which tamoxifen acquires more potent in vivo agonist properties over time remains to be defined.


Discussion of "Carbon benefits of wolfberry plantation on secondary saline land in Jingtai oasis, Gansu - A case study on application of the CBP model" by Yaolin Wang, Chuanyan Zhao, Quanlin Ma, Yingke Li, Hujia Jing, Tao Sun, Eleanor Milne, Mark Easter, Keith Paustian, Hoi Wen Au Yong, John McDonagh (2015) [Journal of Environmental Management 157, 303-310].
Wang et al. (2015) employed driving force-pressure-state-impact-response (DPSIR) framework to provide a robust decision-making structure for carbon emission reduction by use of wolfberry plantation in the Jingtai oasis, China. DPSIR appropriately identified the causes of problem along with adopting the responses to the barriers associated with wolfberry plantation. However, the discusser argues that, the paper could have prepared more viable outcomes, if the authors had used causal network rather than causal chains through the DPSIR framework. Furthermore, they could have quantified the mutual relationship among the relevant factors to provide a detailed economic assessment. With this knowledge in hand, the current discussion letter suggests eDPSIR and meDPSIR to address drawbacks regarding conventional DPSIR framework. Due to proper performance of eDPSIR and meDPSIR, they are recommended as practical tools in the future environmental studies.


Alteration of Basal Ganglia and Right Frontoparietal Network in Early Drug-Naïve Parkinson's Disease during Heat Pain Stimuli and Resting State.
The symptoms and pathogenesis of Parkinson's disease (PD) are complicated and an accurate diagnosis of PD is difficult, particularly in early-stage. Because functional magnetic resonance imaging (fMRI) is non-invasive and is characterized by the integration of different brain areas in terms of functional connectivity (FC), fMRI has been widely used in PD research. Non-motor symptom (NMS) features are also frequently present in PD before the onset of classical motor symptoms with pain as the primary NMS. Considering that PD could affect the pain process at multiple levels, we hypothesized that pain is one of the earliest symptoms in PD and investigated whether FC of the pain network was disrupted in PD without pain. To better understand the pathogenesis of pain in PD, we combined resting state and pain-stimuli-induced task state fMRI to identify alterations in FC related to pain in PD. Fourteen early drug-naïve PD without pain and 17 age- and sex-matched healthy controls (HC) participated in our testing task. We used independent component analysis to select seven functional networks related to PD and pain. We focused on abnormalities in FC and in functional network connectivity (FNC) in PD compared with HC during the task (51°C heat pain stimuli) and at rest. Compared with HC, PD showed decreased FC in putamen within basal ganglia network (BGN) in task state and decreased FC in putamen of salience network (SN) and mid-cingulate cortex of sensorimotor network in rest state. FNC between the BGN and the SN are reduced during both states in PD compared with HC. In addition, right frontoparietal network (RFPN), which is considered as a bridge between the SN and default-mode network, was significantly disturbed during the task. These findings suggest that BGN plays a role in the pathological mechanisms of pain underlying PD, and RFPN likely contributes greatly to harmonization between intrinsic brain activity and external stimuli.


Topographical and functional anatomy of trapezius muscle innervation by spinal accessory nerve and C2 to C4 nerves of cervical plexus.
The aim of this study was to determine the existence and the frequency of communicating branches between the spinal accessory nerve (SAN) and the C2, C3 and C4 roots of the cervical plexus. The present study also aimed to elucidate whether these branches contain motor fibers or not. Dissection of the cervical region was performed on twelve adult cadavers. A powered operating microscope was necessary to dissect the SAN and its branches and also to dissect C2, C3 and C4 nerve branches. In a second step, data from 13 patients who underwent 25 modified neck dissections under trapezius muscle's monitoring were collected. At the end of surgery, intraoperative stimulation on the SAN, C2, C3 and C4 nerve branches was performed. Registered potentials in the three parts of the trapezius muscle, using the NIM Medtronic system, were analyzed. During cadaver dissection, 18 (78 %) communicating branches were identified between the SAN and C2, 11 (48 %) between the SAN and C3, 12 (52 %) between the SAN and C4. Intraoperative stimulation of the SAN and its branch for the trapezius muscle provided a significant electroneurographic response in the three parts of the trapezius muscle in all subjects. Intraoperative stimulation of C3 led to recordable contractions of the trapezius muscle in 5 (20 %) modified neck surgeries, stimulation of C4 led to recordable contractions during 5 (20 %) modified neck dissections. One case of contraction was recorded after intraoperative stimulation of C2 (7 %). Although we were able to identify at least one communicating branch between the SAN and the roots of the cervical plexus in each cadaver dissection, the cervical plexus is not always involved in trapezius motor innervation. Intraoperative electroneurography demonstrated that a motor input from the cervical plexus to the trapezius muscle was provided in only 32 % of cases. Therefore, SAN trunk and C3-C4 roots should be carefully preserved during modified neck dissection to protect trapezius and shoulder functions.


The m6A-methylase complex recruits TREX and regulates mRNA export.
N6-methyladenosine (m6A) is the most abundant internal modification of eukaryotic mRNA. This modification has previously been shown to alter the export kinetics for mRNAs though the molecular details surrounding this phenomenon remain poorly understood. Recruitment of the TREX mRNA export complex to mRNA is driven by transcription, 5' capping and pre-mRNA splicing. Here we identify a fourth mechanism in human cells driving the association of TREX with mRNA involving the m6A methylase complex. We show that the m6A complex recruits TREX to m6A modified mRNAs and this process is essential for their efficient export. TREX also stimulates recruitment of the m6A reader protein YTHDC1 to the mRNA and the m6A complex influences the interaction of TREX with YTHDC1. Together our studies reveal a key role for TREX in the export of m6A modified mRNAs.


[Subglottic tracheal stenosis].
To assess the results of endoscopic CO(2) laser resections combined with mitomycin-C and/or triamcinolone acetonide therapy in the treatment of patients with symptomatic subglottic tracheal stenosis. Eleven patients (all female) with subglottic tracheal stenosis were divided into two groups: six patients with idiopathic subglottic tracheal stenosis and five with subglottic tracheal stenosis of known etiology (four with Wegener's disease and one with polychondritis of the trachea). Three patients showed signs of reflux. The primary outcome measure was improvement of the clinical symptoms and the secondary the postoperative reduction of airway resistance. All patients were treated with CO(2) laser resections combined with mitomycin-C and/or triamcinolone acetonide therapy. Postoperative examinations during a period of 7 to 72 months demonstrated a reduction of symptoms and of airway resistance in all patients. One or more endoscopic CO(2) laser resections combined with mitomycin-C and/or triamcinolone acetonide therapy are effective in the treatment of subglottic tracheal stenoses. Long-term oral steroid and immunosuppressive therapy as well as the use of proton pump inhibitors positively influences the postoperative outcome.


Nanozyme-based guanidinium peptides mediate surface reactive oxygen species for multidrug resistant bacterial infection management.
Nanozymes are effective novel antibacterial agents. However, they still have some shortcomings such as low catalytic efficiency, poor specificity, and non-negligible toxic side effects. Here, we synthesized iridium oxide nanozymes (IrOx NPs) by a one-pot hydrothermal method and used guanidinium peptide-betaine (SNLP/BS-12) to modify the surface of IrOx NPs (SBI NPs) to obtain a high-efficiency and low-toxicity antibacterial agent. In vitro experiments showed that SBI NPs with SNLP/BS12 could enhance IrOx NPs to target bacteria, mediate bacterial surface catalysis and reduce the cytotoxicity of IrOx NPs to mammalian cells. Importantly, SBI NPs were able to effectively alleviate MRSA acute lung infection and effectively promote diabetic wound healing. Accordingly, iridium oxide nanozymes functionalized with guanidinium peptides are expected to be an effective antibiotic candidate in the postantibiotic era.


Corrigendum: Identification of Signature Genes Associated With Invasiveness and the Construction of a Prognostic Model That Predicts the Overall Survival of Bladder Cancer.
[This corrects the article DOI: 10.3389/fgene.2021.694777.].


The effect of controlled halothane anaesthesia on splanchnic oxygen consumption in the dog.
The influence of halothane ansesthesia on splanchnic oxygen flow and oxygen uptake was studied in seven dogs. Mean oxygen supply to the liver and the portally-drained tissues decreased significantly to 44% and 53% of control values, respectively, while mena oxygen consumption diminished insignificantly to 68% and 82% of control values, respectively. There was a fall in the oxygen flow/oxygen consumption ratio in all animals following halothane. The relatively unimpaired oxygen uptake, in spite of a diminished oxygen supply, led to an increased extraction of oxygen by the tissues. Some factors affecting oxygen utilisation during halothane anaesthesia are discussed.


Preoperative clinical symptomatology and stroke burden in pediatric moyamoya angiopathy: Defining associated risk variables.
To evaluate the preoperative clinical and magnetic resonance imaging and angiography (MRI-MRA) characteristics in pediatric moyamoya patients. Analysis included 100 children with moyamoya angiopathy referred to our moyamoya center for preoperative evaluation. Clinical symptoms, neurological status using Pediatric Stroke Outcome Measurement (PSOM) and degree of disability on modified Rankin scale score (mRS) were evaluated. MRI-MRA evaluation included the assessment of ischemic lesions and involvement of posterior circulation. Data were analyzed for moyamoya disease (MMD), moyamoya syndrome (MMS) and age at disease onset. Stroke was a common presentation in both MMD and MMS patients. TIAs and headaches/migraine were more frequent in MMD. There was no evidence of a difference in stroke burden on MRI as well as in PCA involvement between the two subgroups. Children <2 years had higher odds of having a stroke (OR 15.5, 95% CI 3.8-62.4, p < 0.001), recurrent stroke (OR 11.8, 95%CI 2.9-46.7, p < 0.001) and unfavorable mRS (≥2) (OR 4.2, 95% CI 1.3-13.7, p = 0.01) when compared to those >5 years of age. There was some evidence of association of PCA involvement with recurrent strokes (OR 3.1, CI 1.0-9.6, p = 0.05), a poor PSOM (OR 3.0, 95% CI 1.1-8.2, p = 0.04) and mRS (OR 3.1, 95% CI 1.2-8.3, p = 0.02). Stroke seems to be a common presentation in both MMD and MMS patients. Early age at symptom onset and involvement of posterior circulation seem to be important risk factors for a high stroke burden and an unfavorable PSOM and mRS.


Reversed phase liquid chromatography method with fluorescence detection of gemifloxacin in rat plasma and its application to the pharmacokinetic study.
A simple, accurate and precise high-performance liquid chromatographic method with fluorescence detection was developed and validated for the determination of gemifloxacin (GEM) in rat plasma using furosemide as internal standard (I.S.). Plasma samples were pretreated by direct deproteinization and all samples and standard solutions were chromatographed at 45°C using triethylamine solution (0.5%, v/v, pH 3.0±0.1), methanol and acetonitrile (63:30:7, v/v/v) as the mobile phase. Chromatographic resolution was achieved using a RP-C(18) column (Atlantis, Waters, 150 mm × 4.6 mm, 5 μm) at a flow rate of 1.0 mL min(-1) and an injection volume of 30 μL. The analytes were measured by fluorescence detection with excitation and emission wavelengths of 344 nm and 399 nm, respectively. The retention times for GEM and I.S. were approximately 7.5 and 12.6 min, respectively. The lower limit of quantitation (LLOQ) was 20 ng mL(-1) and the calibration curves were linear over a concentration range of 20-5000 ng mL(-1). The intra- and inter-day precisions, expressed by relative standard deviation (R.S.D.) were lower than 6.24% and 4.49%, respectively. The accuracy ranged from 91.3% to 112% and from 98.8% to 106% for the lower and upper limit of quantitation of the calibration curve, respectively. Ratio of peak area of analyte to I.S. was used for quantification of plasma samples. No interferences from endogenous substances were found. The recovery of GEM and I.S. from plasma was greater than 90%. Drug stability in plasma was shown at room temperature for 4h, after three freeze-thaw cycles for 24h, in freezer at -80°C for 60 days, and in the autosampler after processing for 12h. The utility of the assay was confirmed by the successful analysis of plasma samples from GEM pharmacokinetics studies in the rats after intravenous administration.


Organochlorines and mercury in blood of a fish-eating population at the River Elbe in Schleswig-Holstein, FRG.
The blood of people living near the River Elbe who eat contaminated fish from the river was checked for organochlorines (n = 136): Hexachlorobenzene, HCB, the Hexachlorocyclohexanes beta-HCH, gamma-HCH, Octachlorostyrene, OCS, p,p-DDE and Mercury, Hg (n = 43). The concentrations (ng/ml blood) of OCS (less than 0.5-9.2) and Hg (1.1-79.2) can be attributed to fish consumption, those of the organochlorines--exept gamma-HCH--are related to age.


Surface functional groups and biofilm formation on microplastics: Environmental implications.
Microplastics (MPs) contamination is becoming a significant environmental issue, as the widespread omnipresence of MPs can cause many adverse consequences for both ecological systems and humans. Contrary to what is commonly thought, the toxicity-inducing MPs are not the original pristine plastics; rather, they are completely transformed through various surface functional groups and aggressive biofilm formation on MPs via aging or weathering processes. Therefore, understanding the impacts of MPs' surface functional groups and biofilm formation on biogeochemical processes, such as environmental fate, transport, and toxicity, is crucial. In this review, we present a comprehensive summary of the distinctive impact that surface functional groups and biofilm formation of MPs have on their significant biogeochemical behavior in various environmental media, as well as their toxicity and biological effects. We place emphasis on the role of surface functional groups and biofilm formation as a means of influencing the biogeochemical processes of MPs. This includes their effects on pollutant fate and element cycling, which in turn impacts the aggregation, transport, and toxicity of MPs. Ultimately, future research studies and tactics are needed to improve our understanding of the biogeochemical processes that are influenced by the surface functional groups and biofilm formation of MPs.


Prediction of overall survival after re-irradiation with stereotactic body radiation therapy for pancreatic cancer with a novel prognostic model (the SCAD score).
To develop a predictive model for stratification of patients with pancreatic cancer who may achieve survival benefits from re-irradiation with stereotactic body radiation therapy (SBRT). The score was developed based on clinical predictors of OS in 31 patients receiving two courses of SBRT with Cox proportional hazards model. Results were then validated in another cohort with 11 participants to assess the performance of the score. In the training cohort, the median BED10 of the first and second SBRT was 59.5 Gy (48-85.5 Gy) and 50.2 Gy (43.7-66.9 Gy) in 5-8 fractions, while in the validation cohort, the median BED10 of the first and second SBRT was 59.5 Gy (52.5-66.9 Gy) and 47.7 Gy (40.6-54.8 Gy) in 5-8 fractions. The interval between the first and second SBRT of the training cohort and validation cohort was 10.5 months (6.1-24.3 months) and 12.8 months (6.5-29.1 months), respectively. Multivariable analysis showed that tumor stage (P = 0.005), BED10 (P = 0.006) and CA19-9 response (P = 0.04) were significantly predictive of overall survival, which formed SCAD score (named after the initials of factors). Patients with the score < 3 points had a superior OS compared with those with the score ≥ 3 points in the validation cohort (median OS has not been reached vs. 15.9 months, P = 0.032). The SCAD score may have the potential to identify individuals benefiting from re-SBRT and be a step toward more personalized medicine.


Profiling of iridoid glycosides in Vaccinium species by UHPLC-MS.
The iridoid profile of four Vaccinium species was investigated using UHPLC-MS to obtain further information about this group of species for phytochemical characterization. Fruits of bog bilberry (Vaccinium uliginosum L.) showed 14 different iridoid glycosides with a total amount of 20mg/kg fresh weight (FW), whereas bilberry (Vaccinium myrtillus L.) contained 11 iridoid glycosides and a total amount of 127mg/kg FW. Highbush blueberry (Vaccinium corymbosum L.) and lowbush blueberry (Vaccinium angustifolium L.) contained none of the investigated iridoid glycosides. Among the different iridoids, the isomers scandoside and deacetylasperulosidic acid as well as a dihydro derivative thereof were described for the first time in the Ericaceae family. The p-coumaroyl isomers of scandoside, deacetylasperulosidic acid and dihydromonotropein are reported for the first time in V. myrtillus and V. uliginosum. Monotropein and its p-coumaroyl isomers were found for the first time in V. uliginosum. The comparison of iridoid profiles in bilberry fruit and juice samples revealed constant proportions throughout the juice processing. Quantification and profile determination of iridoids may be used for species differentiation and thus for authentication purposes.