SARS-CoV-2 (COVID-19) as a Predictor of Neuroinflammation and Neurodegeneration: Potential Treatment Strategies.
The SARS-CoV-2 (COVID-19) pandemic has attracted attention to the challenge of neuroinflammation as an unavoidable component of viral infections. Acute neuroinflammatory responses include activation of resident tissue macrophages in the CNS followed by release of a variety of cytokines and chemokines associated with activation of oxidative stress and delayed neuron damage. This makes the search for treatments with indirect anti-inflammatory properties relevant. From this point of view, attention is focused on further study of the treatment of patients with COVID-19 with dipyridamole (Curantil) which, having antiviral and anti-inflammatory effects, can inhibit acute inflammatory activity and progression of fibrosis, is a drug with potential, especially among patients with early increases in the D-dimer concentration and severe signs of microangiopathy.


Rapid versus intermediate health impact assessment of foreshore development plans.
To describe the main differences between conducting a rapid health impact assessment (HIA) and an intermediate HIA on foreshore development plans and their feasibility from a health service perspective. A rapid HIA and an intermediate HIA were undertaken on two foreshore development plans. The main differences between the two HIAs were in the identification, assessment and decision-making stages of the HIA. While the rapid HIA was less resource intensive than the intermediate HIA, there are several factors that affect the feasibility of conducting this type of HIA within a short time period.


Long-Term Recipient Health-Related Quality of Life and Donor-Recipient Relationship following Sibling Pediatric Hematopoietic Stem Cell Transplantation.
Despite the fact that the choice of donors and the number of sources of hematopoietic stem cells have increased, a sibling remains a preferred donor for allogeneic hematopoietic stem cell transplantation (HSCT). Transplant donation between siblings is a unique life experience that may have an impact on their future relationship. The aim of the study was to quantitatively measure the quality of life (QoL) in patients who underwent transplant and to describe the relationship between a recipient and a sibling donor after HSCT. We identified and invited 82 adults aged 18.0 to 38.7 years (median, 23.6) who underwent HSCT in our center and their sibling donors to participate in this survey. Forty-five patients (54.9%) and their siblings consented to take part in the study. The studied group consisted of 45 matched siblings donor (MSD)-HSCT recipients (19 women and 26 men) aged 18.0 to 36.2 (median, 28.5) years, who underwent MSD-HSCT at the age of 5.8 to 16.3 (median, 11.9) years, and their sibling donors aged 21.0 to 36.0 (median, 31.0) years, who were aged 11.2 to 20.2 (median, 15.5) years at bone marrow harvesting. For QoL and sibling relationship assessment, we used the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) and the Adult Sibling Relationship Questionnaire (ASQR). Higher scores indicate better quality of life in each scale of the FACT-BMT and the more significant is the factor in a sibling relationship measured by the ASQR. The questionnaires were given to both subgroups, HSCT recipients and donors, and the results were compared with each other. The overall result of the FACT-BMT questionnaire was 117 ± 35.0. The highest QoL was found in the functional (25.0 ± 3.5) and social well-being (25.0 ± 3.5) subscales, whereas the worst was in the emotional well-being (18.0 ± 9.5) subscale. Statistically, the QoL score was not influenced by current age (P = .378), age at the moment of HSCT (P = .256), and sex (P = .117). Being a recipient or a donor of HSCT was not a significant factor associated with warmth (2.6 ± 0.5 versus 3.1 ± 0.5; P = .830) and conflict (2.0 ± 0.7 versus 2.1 ± 1.2; P = .886) within the sibling relationship, whereas recipients scored significantly lower in rivalry within the sibling relationship compared with HSCT donors (0.8 ± 0.3 versus 1.2 ± 0.2; P = .012). The FACT Treatment Outcome Index remained the only significant predictor of warmth in the sibling relationship between HSCT recipient and donor. QoL in adult patients after HSCT in childhood was good. Sibling donor-recipient relationship is unbalanced, with a higher level of rivalry presented among donors. Further multicenter studies based on a larger cohort of patients are necessary to assess all aspects of the sibling relationship after transplantation experience.


Are prescribing patterns of diuretics in general practice good enough? A report from the Møre & Romsdal Prescription Study.
To examine general practitioners' (GPs) prescribing patterns of diuretics with respect to indications, drugs and doses to reveal possible needs for prescribing audits. Observational, cross-sectional study. The Norwegian county Møre & Romsdal. 1896 prescriptions for diuretics prescribed by GPs during two months. Prescriptions (drugs, strength of tablets, volume prescribed, directions for use). Diagnoses for prescribing. Furosemide was prescribed most frequently (48.7%) followed by the compound diuretic of hydrochlorothiazide and amiloride (26.4%), thiazides and related drugs (13.0%), and spironolactone (5.8%). Diuretics were mainly prescribed for hypertension (48.4%), congestive heart failure (35.6%), and oedemas (e.g. orthostatic) (6.1%). The patients' mean age was 69.2 years; two of three were females. When thiazides and related drugs were prescribed for hypertension, we found that the daily dose was excessive in 37.2% of the cases. In congestive heart failure, furosemide was prescribed in about four of five cases, while bumetanide was prescribed in 1.5% of the cases. Our findings indicate that GPs need more knowledge about low-dose diuretic therapy in hypertension, about different diuretic regimens in heart failure, and about non drug treatment for orthostatic oedema. Clinical pharmacology regarding diuretics should be given priority in the vocational training and continuing education for GPs.


Ploidy status rarely changes in myeloma patients at disease progression.
Hyperdiploid and non-hyperdiploid multiple myeloma represents distinct biological entities characterized by different patterns of genetic changes. We sought to determine whether ploidy category (non-hyperdiploid versus hyperdiploid) remains stable over time from diagnosis to progression. Of the 43 patients studied (39 by flow cytometry DNA index and 4 by a FISH-based index), only five (12%) altered their ploidy status at progression. In three of these patients, the change may possibly be attributable to technical artifacts because of the low absolute change in DNA index. For those who retain their ploidy subtypes, the DNA index change minimally (3.75+/-4.87%). It would appear that the initiating genetic events underlying hyperdiploid and non-hyperdiploid MM that marks them out as distinct entities continue to dominate and persist during disease evolution and progression.


Kinetic study and modeling on photocatalytic degradation of para-chlorobenzoate at different light intensities.
In order to clarify the dependence of apparent adsorption constant Ks in the Langmuir-Hinshelwood (L-H) model on the incident light intensity, photocatalytic degradation kinetic characteristics were experimentally investigated at different light intensities using para-chlorobenzoate (4-CBA) as a model compound. In all cases 4-CBA initial degradation rates showed dependence on 4-CBA initial concentration, which can be described by the L-H model. However, the adsorption constant Ks and rate constant kr obviously varied with light intensity. To account for the experimental finding, slight modification of the classic kinetic model developed by Turchi and Ollis was tentatively proposed by assuming insufficiency of H2O/OH- available for photo-activated holes' scavenging. Such a kinetic model predicts that both k(r) and Ks(-1) are linearly proportional to the square root of the intensity in a rather large intensity range. The validity of the modified model was proved by fitting it to the experimental data.


Prescribing Tamoxifen in Patients With Mood Disorders: A Systematic Review of Potential Antimanic Versus Depressive Effects.
Tamoxifen is a selective estrogen receptor modulator widely used for treatment and prevention of estrogenic receptor-positive breast cancer. Tamoxifen is an object of growing interest in psychopharmacology as an antimanic drug, because it inhibits the protein kinase C, a molecular target of bipolar disorder. Consistently, the potential depressive effect of tamoxifen has been repeatedly reported. This article systematically reviews studies examining tamoxifen impact on mood, exploring either its potential therapeutic use as antimanic agent or its potential depressive effect. Eight studies explored tamoxifen antimanic properties, all, but one, reported a rapid and efficacious antimanic action. As to the depressive effect, 9 cohort studies emerged among which 4 pointed out an increased risk of depression. Seven case reports described the onset or exacerbation of depressive episodes besides 1 case series study reported a high rate of depressive symptoms. In addition, 1 case report study described a tamoxifen-induced manic episode. The present review highlights tamoxifen treatment as a possible trigger of mood symptoms onset or exacerbation in vulnerable patients. Accordingly, patients with a history of mood disorders may require a close clinical surveillance during tamoxifen use. At the same time, the use of tamoxifen as an antimanic agent in psychiatric settings requires caution, as available evidence came from small-sample studies with short observation time. More studies are needed to define how long-term tamoxifen use may affect the course of bipolar disorder.


Pt(II) and Au(III) complexes containing Schiff-base ligands: A promising source for antitumor treatment.
The effective application of cisplatin in the clinic as an antitumor treatment has stimulated widespread interest in inorganic metal drugs. In particular, complexes containing the transition metals platinum and gold have attracted considerable attention due to their antitumor effects. The Pt(II) and Au(III) Schiff-base complexes are potential antitumor agents because of their remarkable biological activities and good stability, lipophilicity, and electroluminescent properties. These complexes act via various antitumor mechanisms that are unlike those of the classic platinum drugs, providing a feasible solution for improving the serious side effects caused by metal chemotherapy. In this review, promising antitumor agents based on Pt(II) and Au(III) complexes containing Schiff-base ligands, and their biological targets, including G-quadruplex DNA and thioredoxin reductase, are comprehensively summarized.


Combining chemometric and phytochemical tools to isolate and characterize activity of Vismia gracilis compounds against Aedes aegypti.
Vismia gracilis extracts were tested against Aedes aegypti to assess mortality and behavioural effects. The leaf hexanic extract (L-Hex) presented increased larvicidal activity with exposure period: LC50 46.48 µg/mL (24 h) and LC50 20.57 µg/mL (48 h). Eight compounds were annotated/isolated from the L-Hex active extract, 4 benzophenones and 4 anthraquinones. Considering chemometric findings, the benzophenone moiety, tested as the commercial benzophenone, promoted larval mortality (LC50 16.35 µg/mL). Both the L-Hex extract and benzophenone induced intestinal damage in larvae. Benzophenone also promoted toxicity and behavioural effects in female adults. These findings highlighted the potential use of this class of compounds for developing vector-control products.


RBM24 exacerbates bladder cancer progression by forming a Runx1t1/TCF4/miR-625-5p feedback loop.
RNA-binding motif protein 24 (RBM24) acts as a multifunctional determinant of cell fate, proliferation, apoptosis, and differentiation during development by regulating premRNA splicing and mRNA stability. It is also implicated in carcinogenesis, but the functions of RBM24 in bladder cancer (BC) remain unclear. In the present study, we revealed that RBM24 was upregulated in BC tissues. Importantly, we found that a higher level of RBM24 was correlated with poor prognosis in BC patients. Overexpression of RBM24 promoted BC cell proliferation, while depletion of RBM24 inhibited BC cell proliferation in vivo and in vitro. Mechanistically, RBM24 positively regulated Runx1t1 expression in BC cells by binding to and enhancing Runx1t1 mRNA stability. Furthermore, Runx1t1 in turn promoted RBM24 expression by interacting with the transcription factor TCF4 and suppressing the transcription of miR-625-5p, which directly targets RBM24 and suppresses RBM24 expression. RBM24-regulated BC cell proliferation was moderated via the Runx1t1/TCF4/miR-625-5p feedback loop. These results indicate that the RBM24/Runx1t1/TCF4/miR-625-5p positive feedback loop participates in BC progression. Disruption of this pathway may be a potential therapeutic strategy for BC treatment.


Mechanisms involved in the hypotensive effect of a kappa-opioid receptor agonist in hypertensive rats.
It remains unclear whether the activation of kappa-opioid receptors has strong hypotensive effects under hypertensive condition, and the underlying mechanisms have not yet been investigated. Therefore, the present study is designed to use spontaneously hypertensive rats (SHR) to investigate the effects of a kappa-opioid receptor agonist on the regulation of urinary formation in hypertensive conditions and to identify its underlying mechanism. The hemodynamics, urine flow rate, vasodilatation of isolated renal artery, and plasma hormones were determined by physiological in vivo experimental technique, isolated artery perfusion technique and radioimmunoassay. Intravenous administration of U50, 448H significantly decreased mean arterial blood pressure in both Wistar-Kyoto (WKY) rats and SHR. However, the blood pressure vasodepressor effect of U50, 448H was much more profound in SHR than in WKY rats. Administration of U50, 448H in SHR not only caused significantly greater effects in increasing urine volume and decreasing plasma anti-diuretic hormone than in WKY rats, but also caused significant reduction in plasma angiotensin. Moreover, vasodilatory effect of U50, 488H was significantly exhibited in the renal artery segments isolated from SHR. All effects described above were abolished by nor-binaltorphimine. These data indicate that the depressor effect of U50, 488H in SHR is significantly stronger than that in WKY rats, and the effect is mediated or modulated by a kappa-opioid receptor sensitive mechanism. The sensitized hypotensive effect of U50, 488H in SHR may be attributed, in part, to its vasodilatory effect, enhanced beneficial effect on plasma humoral factors, and stronger diuretic effect in these hypertensive animals.


16S rRNA gene sequence analysis of drinking water using RNA and DNA extracts as targets for clone library development.
The bacterial composition of chlorinated drinking water was analyzed using 16S rRNA gene clone libraries derived from DNA extracts of 12 samples and compared to clone libraries previously generated using RNA extracts from the same samples. Phylogenetic analysis of 761 DNA-based clone sequences showed that unclassified bacteria were the most abundant group, representing nearly 62% of all DNA sequences analyzed. Other phylogenetic groups identified included Proteobacteria (20%), Actinobacteria (9%), Cyanobacteria (4%), and Bacteroidetes (2%). The composition of RNA-based libraries (1122 sequences) was similar to the DNA-based libraries with a few notable exceptions: Proteobacteria were more dominant in the RNA clone libraries (i.e., 35% RNA; 20% DNA). Differences in the Proteobacteria composition were also observed; alpha-Proteobacteria was 22 times more abundant in the RNA-based clones while beta-Proteobacteria was eight times more abundant in the DNA libraries. Nearly twice as many DNA operational taxonomic units (OTUs) than RNA OTUs were observed at distance 0.03 (101 DNA; 53 RNA). Twenty-four OTUs were shared between all RNA- and DNA-based libraries (OTU0.03) representing only 18% of the total OTUs, but 81% (1527/1883) of all sequences. Such differences between clone libraries demonstrate the necessity of generating both RNA- and DNA-derived clone libraries to compare these two different molecular approaches for community analyses.


Validity of Diagnostic Criteria for Temporomandibular Joint Disorder in the Diagnosis of Disc Displacement Disorders of Temporomandibular Joint.
The objective of this study is to assess the validity Diagnostic Criteria for Temporomandibular joint Disorder (DC/TMD) in the diagnosis of disc displacement (DD) disorders of temporomandibular joint (TMJ). It was a prospective study in which total of 55 patients accounting to 110 TMJ; with clinical diagnosis of DD disorder as per DC/TMD criteria and all above age of 18 years were included. All the patients with clinical diagnosis of DD disorder were advised MRI. All the MRI scans were read by single radiologist. Clinician and Radiologist were blinded to each others findings. MRI diagnosis and clinical diagnosis were compared and results were formulated. The use of the Kappa statistic test indicated a good diagnostic agreement (k = 0.68) between the clinician and the radiologist. The DC/TMD criterion was found to have good validity and reliability in the diagnosis of DD disorders with sensitivity of 91.57% and specificity of 77.78%. The positive predictive value and negative predicted value calculated were 92.68% and 78%, respectively. The positive and negative likelihood ratio found was 4.12 and 0.11, respectively. DC/TMD is a simple, reliable, valid, cost-effective tool in the diagnosis of DD disorders.


Improved purification of the pyruvate dehydrogenase complex from Ascaris suum body wall muscle and characterization of PDHa kinase activity.
An improved purification scheme for the isolation of the Ascaris suum pyruvate dehydrogenase complex directly from body wall muscle has been developed which yields a fully activated pyruvate dehydrogenase complex with substantial PDHa kinase activity. The apparent Km for coenzyme A (CoA) is much lower than previously reported and can only be accurately measured in the presence of a CoA-regenerating system. The alpha-pyruvate dehydrogenase subunit of the ascarid complex is unique and its migration on sodium dodecylsulfate polyacrylamide gels is altered after phosphorylation. PDHa kinase activity is inhibited by ADP, thiamine pyrophosphate, and physiological levels of pyruvate and propionate. In contrast, PDHa kinase activity is stimulated by elevated NADH/NAD+ and acetyl CoA/CoA ratios, although it appears that the NADH/NAD+ ratios required for half-maximal stimulation are more than an order of magnitude greater than those reported for mammalian pyruvate dehydrogenase complexes.


Atypical echocardiographic findings of endocarditis in an immunocompromised patient.
Cardiovascular manifestations in patients infected with human immunodeficiency virus (HIV) have been altered by the introduction of highly active antiretroviral therapy regimens that allow more effective prophylactic treatment and an increased time of survival. Because of this, noninfectious cardiac conditions associated with HIV disease are being recognized with increasing frequency in these patients. Cardiac involvement in HIV-infected patients varies from clinically silent to overtly symptomatic disease. By some estimates a direct cardiac cause of mortality is between 1% and 6% of all cases. Pericardial effusion, pericarditis, myocarditis, cardiomyopathy, endocarditis, and pulmonary hypertension are well-recognized cardiac illnesses associated with HIV infection. Echocardiography has been crucial in evaluating HIV-infected patients to assess the extent of cardiac involvement. This case report illustrates atypical echocardiographic manifestations of endocarditis and paravalvular abscess in an immunocompromised patient.


Pharmacological Basis of Breast Cancer Resistance to Therapies - An Overview.
Breast Cancer (BC) is a molecular heterogeneous disease and patients with similar clinico-pathological characteristics often display different response to treatment. Cellular processes, including uncontrolled cell-cycle, constitutive activation of signalling pathways and alterations in DNA-repair mechanisms are the main altered features in breast cancer. These cellular processes play significant roles in the emergence of resistance to therapies. The introduction of target therapies and immunotherapy significantly improved the survival of breast cancer patients. The incorporation of novel biomarkers together with the introduction of new therapeutic options may help to overcome treatment resistance. Molecular profiling promises to help in refine personalized treatment decisions and catalyse the development of further strategies when resistances inevitably occurs. This review provides a summary of genetic and molecular aspects of resistance mechanisms to available treatments for BC patients, and its clinical implications.


Positional hypoxaemia following post-traumatic pulmonary insufficiency.
The effect of body position on ventilatory function was evaluated in a patient with unilateral lung disease. The patient's pulmonary dynamics were examined in the supine, right, and left decubitus positions under conditions of positive pressure ventilation with zero end-expiratory pressure (ZEEP) and 5 cm H2O (0.9 KPa) positive end expiratory pressure (PEEP). When the patient was positioned so that the "diseased" lung was dependent, there was a marked decrease in PaO2 and increase in venous admixture when compared to the values in the supine position. These changes were relatively greater in the ZEEP, than the PEEP situation. When the "diseased* lung was not dependent, there was an increase in PaO2 and a decrease in venous admixture. This was most pronounced when PEEP was applied. Changes in body position may result in clinically significant alterations in pulmonary gas exchange, especially in patients with pre-existing pulmonary dysfunction.


Study on mechanism of hepatoprotective effect of Chrysanthemum morifolium Ramat. based on metabolomics with network analysis and network pharmacology.
Hangju (HJ), the dried flower heads of Chrysanthemum morifolium Ramat., has a significant hepatoprotective effect. However, its underlying protection mechanism against acute liver injury (ALI) has been unclear. An integrated strategy based on metabolomics with network analysis and network pharmacology was developed to explore the potential molecular mechanism of HJ on ALI protection. Firstly, differential endogenous metabolites were screened and identified by metabolomics approach and metabolic pathway analysis was performed by MetaboAnalyst. Secondly, marker metabolites were used to construct metabolite-response-enzyme-gene networks and discover hub metabolites and potential gene targets in network analysis. Thirdly, hub genes through the protein-protein interaction (PPI) network were acquired by the aid of network pharmacology. Finally, the gene targets were taken to intersect with the relevant active ingredients for validation by molecular docking. In total, 48 flavonoids were identified in HJ, which were associated with 8 potential therapeutic targets in network pharmacological analysis. Biochemistry and histopathology analysis demonstrated that HJ exerted hepatoprotective effects. 28 biomarkers were successfully identified as possible biomarkers for the prevention of ALI. The sphingolipid metabolic pathway and the glycerophospholipid metabolic pathway was considered a crucial signaling pathway by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. In addition, phosphatidylcholine and sphingomyelin were considered as hub metabolites. Twelve enzymes and 38 genes were considered as potential targets in the network analysis. Based on the combined analysis above, HJ was shown to modulate 2 key upstream targets, including PLA2G2A and PLA2G4A. Molecular docking showed that active compounds of HJ had high binding affinity with these key targets. In conclusion, the flavonoid components of HJ can inhibit PLA2 and regulate glycerophospholipid and sphingolipid metabolism pathway to delay the pathological process of ALI, which may be a potential mechanism of HJ against ALI.


The effects of a novel bicarbonate loading protocol on serum bicarbonate concentration: a randomized controlled trial.
Previous studies have shown that sodium bicarbonate ingestion may enhance intense exercise performance, but may also cause severe gastrointestinal distress. The purpose of this study was to determine whether a modified sodium bicarbonate (SB) ingestion protocol would elevate serum bicarbonate concentration more than previous methods without causing gastrointestinal distress. In randomized order, seven (5 men, 2 women) elite middle-distance runners ingested either placebo, Modified SB (600 mg·kg- 1 over 19.5 h), or Acute SB (300 mg·kg- 1) in opaque gelatin capsules. Baseline and post-ingestion blood samples were analyzed for bicarbonate, pH, sodium, hematocrit, and lactate. Repeated measures ANOVA (2 time points × 3 conditions) were analyzed to determine differences in serum bicarbonate, lactate, sodium, blood pH, and hematocrit. Gastrointestinal distress was assessed via self-report on a Likert scale of 1-10. Simple (condition) and repeated (time) within-participant contrasts were used to determine the location of any statistically significant main and interaction effects (p ≤ 0.05). Both Modified SB (7.6 mmol·L- 1, p < 0.01) and Acute SB (5.8 mmol·L- 1, p < 0.01) increased serum bicarbonate concentration compared to the placebo (p ≤ 0.05). Post-ingestion serum bicarbonate concentration was significantly higher for the Modified SB (34.7 ± 2.2 mmol·L- 1, 28.0% increase) trials than the Acute SB (33.5 ± 2.0 mmol·L- 1, 20.9% increase) trials (p = 0.05). There was no reported severe GI distress in the Modified SB trials, but two cases in the Acute SB trials. Modified SB elevated serum bicarbonate concentration more than Acute SB, without any severe gastrointestinal side effects. Consequently, it is recommended that future experimentation involving SB by researchers and athletes use the novel ingestion protocol described in this study due to its potential for improved effectiveness and reduced gastrointestinal impact. ClinicalTrials.gov , NCT03813329 . Registered 23 January 2019 - Retrospectively registered.


Do mentors matter in graduating pediatrics residents' career choices?
Little is known about the association between mentorship and career choice during residency in pediatrics. This study examines graduating residents with mentors who provide career advice and the relationship between having a mentor who is a subspecialist and having a subspecialty practice goal. National, random samples of 1000 graduating pediatrics residents were surveyed each year from 2006 to 2012; 4197 (61%) responded. Responses were pooled across years to examine mentor specialty and career goal at time of residency graduation. Multivariable logistic regression was used to examine relationships between mentor specialty and career goal at the time of graduation. Most (87%) residents reported having a mentor who provided career advice during residency; the proportion linearly increased from 83% in 2006 to 87% in 2012; P < .05. Forty-five percent of those with mentors had a mentor who was a subspecialist; 55% had a generalist as a mentor. Overall, 45% of residents had a subspecialty career goal at time of graduation. After controlling for career goal at the start of residency and resident characteristics, residents with a subspecialist mentor were more likely to have a subspecialty career goal at time of graduation (adjusted odds ratio = 5.25; 95% confidence interval, 4.41-6.25). Residents who were male, without children, without debt, not married, not minority, and from larger residency programs were also more likely to have a subspecialty career goal at the time of graduation from residency. Almost 9 in 10 pediatric residents have a mentor who provides career advice. Although multiple factors shape decisions about careers, mentor specialty is one factor that might encourage residents to pursue fellowship training.


Sex separation by body color via a W-chromosome-linked transgene.
Sex separation processes are important for commercial insect production and sterile insect techniques. Here, we describe the transgenic insertion of a DsRed expression cassette driven by the enhancer HR3 and strong promoter IE1 into the silkworm W chromosome as a dominant visible marker of sex separation. The obtained transgenic lines showed female-specific body color visible to the naked eye at the second- to fifth-instar larval, pupal and adult stages, and their performance traits were comparable to those of a nontransgenic practical silkworm variety. This strategy can greatly facilitate the sex separation of silkworms for male-only rearing and to obtain hybrids while avoiding sibling mating, and it can also be applied to the sex separation of other light-colored insects.


Neuronal activity disrupts myelinated axon integrity in the absence of NKCC1b.
Through a genetic screen in zebrafish, we identified a mutant with disruption to myelin in both the CNS and PNS caused by a mutation in a previously uncharacterized gene, slc12a2b, predicted to encode a Na+, K+, and Cl- (NKCC) cotransporter, NKCC1b. slc12a2b/NKCC1b mutants exhibited a severe and progressive pathology in the PNS, characterized by dysmyelination and swelling of the periaxonal space at the axon-myelin interface. Cell-type-specific loss of slc12a2b/NKCC1b in either neurons or myelinating Schwann cells recapitulated these pathologies. Given that NKCC1 is critical for ion homeostasis, we asked whether the disruption to myelinated axons in slc12a2b/NKCC1b mutants is affected by neuronal activity. Strikingly, we found that blocking neuronal activity completely prevented and could even rescue the pathology in slc12a2b/NKCC1b mutants. Together, our data indicate that NKCC1b is required to maintain neuronal activity-related solute homeostasis at the axon-myelin interface, and the integrity of myelinated axons.


Earliest ultrasound finding of implantation?
Our purpose was to verify our earlier observation of an altered endometrial echo character during the periimplantation period, signifying the earliest detection of implantation by ultrasound. The transvaginal ultrasound study used a 7.5-MHz probe on day 6 following preembryo transfer. Of 31 embryo transfers studied. 8 (25.8%) were positive for this sign on day 6, whereas 9 patients later showed a gestational sac, giving an accuracy of this sign of 88.8% (8 of 9). The normal secretory-phase endometrium shows a typical, evenly distributed hyperechogenecity described earlier by Hackeloer (1). In some cases of proliferative phases, too, this echo pattern has been reported by others (2, 3), and observed by us in stimulated and unstimulated cycles, and has been named type A endometrium by Gonen et al. (4) Both these varieties are seen to have an even, unbroken outline at the anterior and posterior myometrial-endometrial interphase. We report what we believe to be the earliest ultrasound picture of implantation, resembling this variety of endometrial echo but having an irregular outline (Fig. 2).


Verbal instructions and top-down saccade control.
Few studies have addressed the interaction between instruction content and saccadic eye movement control. To assess the impact of instructions on top-down control, we instructed 20 healthy volunteers to deliberately delay saccade triggering, to make inaccurate saccades or to redirect saccades--i.e. to glimpse towards and then immediately opposite to the target. Regular pro- and antisaccade tasks were used for comparison. Bottom-up visual input remained unchanged and was a gap paradigm for all instructions. In the inaccuracy and delay tasks, both latencies and accuracies were detrimentally impaired by either type of instruction and the variability of latency and accuracy was increased. The intersaccadic interval (ISI) required to correct erroneous antisaccades was shorter than the ISI for instructed direction changes in the redirection task. The word-by-word instruction content interferes with top-down saccade control. Top-down control is a time consuming process, which may override bottom-up processing only during a limited time period. It is questionable whether parallel processing is possible in top-down control, since the long ISI for instructed direction changes suggests sequential planning.


Elite football on artificial turf versus natural grass: movement patterns, technical standards, and player impressions.
The aim of the present study was to examine the movement patterns, ball skills, and the impressions of Swedish elite football players during competitive games on artificial turf and natural grass. Time - motion analyses (36 observations) and technical analyses (16 team observations) were performed and 72 male and 21 female players completed a questionnaire. No differences were observed between artificial turf and natural grass in terms of total distance covered (mean 10.19 km, s = 0.19 vs. 10.33 km, s = 0.23), high-intensity running (1.86 km, s = 0.10 vs. 1.87 km, s = 0.14), number of sprints (21, s = 1 vs. 22, s = 2), standing tackles (10, s = 1 vs. 11, s = 1) or headers per game (8, s = 1 vs. 8, s = 1), whereas there were fewer sliding tackles (P < 0.05) on artificial turf than natural grass (2.1, s = 0.5 vs. 4.3, s = 0.6). There were more short passes (218, s = 14 vs. 167, s = 12) and midfield-to-midfield passes (148, s = 11 vs. 107, s = 8) (both P < 0.05) on artificial turf than natural grass. On a scale of 0-10, where 0 = "better than", 5 = "equal to", and 10 = "worse than", the male players reported a negative overall impression (8.3, s = 0.2), poorer ball control (7.3, s = 0.3), and greater physical effort (7.2, s = 0.2) on artificial turf than natural grass. In conclusion, the running activities and technical standard were similar during games on artificial turf and natural grass. However, fewer sliding tackles and more short passes were performed during games on artificial turf. The observed change in playing style could partly explain the male players' negative impression of artificial turf.


The effect of serotonergic and noradrenergic antidepressants on face emotion processing in depressed patients.
In healthy volunteers, exposure to antidepressants increases the recognition of positive face emotions and decreases recognition of negative emotions. It has been proposed that this may underlie therapeutic effects of antidepressants, but to date this has not been tested in clinical populations. Recognition of facial emotions was measured at baseline (N=108) and after 2 (N=59) and 6 weeks (N=69) of treatment in depressed primary care patients who had been randomised to treatment with either citalopram (SSRI) or reboxetine (NaRI) in an open-label study. Changes in emotional processing were compared to clinical outcome after 6 weeks of treatment. Significant increases in recognition accuracy of disgust, happiness and surprise occurred by two-weeks of treatment with both antidepressants, and did not further change at 6 weeks. There was a significant correlation between the increased accuracy in recognition of happy faces over the first two-weeks of treatment and the clinical improvement after six-weeks of treatment. There was no control group and changes over time may be due to practice effects. Antidepressants altered emotional processing in depressed patients with some similarities to the effects seen in healthy volunteers. The largest effect seen was increased recognition of disgust that may be specific to depressed patients. The correlation between increased accurate recognition of happy faces at two-weeks of treatment and clinical outcome at six-weeks of treatment suggests that early changes in emotional processing may underlie clinical response to antidepressants.


Attributable risk and economic cost of hospital admissions for depression due to short-exposure to ambient air pollution: A multi-city time-stratified case-crossover study.
Depression has become the most common mental disease globally and is a strong predictor for suicide. Studies have indicated that exposure to high levels of air pollution increased the risk of depression, but evidence in human populations is still limited. At present, a few studies estimated the impact of multi-pollutants on hospitalization for depression in multi-city in areas with severe air pollution. We aimed to examine the association between short-term exposure to common ambient air pollutants and hospital admissions (HAs) for depression based on statistics of inpatients with depression in multi-city. The 10,459 records of HAs for depression from medical institutions in nine cities/prefectures, Sichuan Province, China, between January 1, 2017 and December 31, 2018 were collected. Air pollutant data including PM2.5, PM10, SO2 and NO2 from provincial ecological environment monitoring stations were obtained. Based on a time-stratified case-crossover design, we estimated the impact on relative risk (RR) of short-term exposure to air pollutants on hospitalization for depression, with stratification by sex, age, and economic level. The cost of illness method was used to further assess hospitalization costs. The short-term exposure to air pollutants was positively associated with hospitalization for depression. The increase of air particulate matter (PM) had the strongest effect on lag 0 day (PM2.5:1.037 (95% CI:1.022,1.052), PM10:1.024 (95% CI:1.013,1.036)). The effects of SO2 reached the peak on lag 2 day (1.317 (95% CI:1.151,1.507)). Women and older people were more likely to be affected by air pollutants and prone to depression (P = 0.013, P = 0.006). During the study period, the economic cost of hospitalization for depression caused by PM pollution was US$ 8.36 million. The air pollutant concentration level of the monitoring stations in the study area was regarded as personal pollutant exposure, which may not accurately reflect the patient's exposure level, resulting in a certain measurement error. Short-term changes to ambient air pollution exposure may increase the risk of hospital admissions for depression and cause economic costs due to hospitalization.


Extracellular vesicles from human urine-derived stem cells merged in hyaluronic acid ameliorate erectile dysfunction in type 2 diabetic rats by glans administration.
The high prevalence of erectile dysfunction (ED) in patients with type 2 diabetes mellitus (DM2) is a challenging clinical problem. Researches on extracellular vesicles from urine-derived stem cells (USC-EVs) have shown that they have significant therapeutic effects in a variety of diseases by injection including ED. Hyaluronic acid (HA) is especially useful for delivering bioactive molecules. This study investigated the effects and related mechanisms of local administration of human USC-EVs combined with HA (USC-EVs-HA) on a rat model of DM2ED. UCSs were extracted from human urine samples and identified for preparation of the corresponding USC-EVs. The effects of high glucose and USC-EVs on human umbilical vein endothelial cells (HUVECs) were assessed in vitro using a CCK-8 assay to determine cell proliferation and pick the most appropriate concentration for subsequent experiments. Scratch and tube formation assays were performed to assess the function of HUVECs. Quantitative real-time polymerase chain reaction (PCR) was used to detect the expression of genes such as B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (BAX), and superoxide dismutase-2 (SOD2). HA, USC-EVs, and USC-EVs-HA were prepared at concentrations and then administered topically to DM2ED rats multiple times. Intracavernous pressure and mean arterial pressure were measured to assess erectile function in rats. Masson, Tunel, Immunohistochemistry, and Western blot analysis were performed to assess the fibrosis and endothelial function in corpus cavernosum, respectively. Compared with the control group, the proliferation, migration ability, and tube-forming ability of HUVECs decreased in high glucose environment, while USC-EVs could optimize the function of HUVECs, reverse the expression of apoptotic genes, and enhance the antioxidant capacity. USC-EVs-HA showed improvement in ED compared to the HA and USC-EVs groups, and the 10-dose group was better than the 5-dose group. Histologically, the USC-EVs-HA group significantly improved apoptosis, angiogenesis, and smooth muscle regeneration in the corpus cavernosum compared to the HA group. The topical application of USC-EVs-HA in the treatment of DM2ED rats has been proved effective. The potential mechanism might to promote the proliferation of endothelial cells and smooth muscle in the corpus cavernosum, which leads to the remodeling of erectile function. And multiple dosing at intervals may make the effect more pronounced.


The effects of traumatic experiences during transit and pushback on the mental health of refugees, asylum seekers, and migrants.
Background: There are 26 million people recognised as refugees worldwide. Many of them spent a prolonged period of time in transit - time after they leave their country of origin and before they reach the receiving country. Transit brings numerous protection and mental health risks refugees are exposed to.Objective: The aim of this study was to assess the stressful and traumatic experiences refugees are exposed to during transit, with a special focus on the experience of pushback - the denial of access to the territory to foreign nationals and forcible return to countries of origin or neighbouring countries without an assessment of their rights to international protection, as well as the impact of these experiences on refugees' mental health and well-being.Method: 201 refugees currently residing in Serbia completed the Stressful and Traumatic Experiences in Transit questionnaire - short version (SET-SF), questionnaire for assessing stressful and traumatic experiences during pushback (SET-SF PB), Refugee Health Screener (RHS-15), and Well-being index (WHO-5).Results: The results showed that refugees experience a large number of stressful and traumatic events (M = 10.27, SD = 4.85). In addition, half of the participants experience severe symptoms of depression (50.7%), while about a third of the participants experience severe symptoms of anxiety (37.8%) and post-traumatic stress disorder (PTSD) (32.3%). Refugees who experienced pushback showed overall higher levels of depression, anxiety, and PTSD. Traumatic experiences during transit and pushback were positively related to the severity of depression, anxiety, and PTSD. In addition, traumatic experiences during pushback showed an incremental contribution in predicting refugees' mental health difficulties over and above traumatic experiences in transit.Conclusions: This study provides valuable insights into the multiple risks refugees are exposed to and emphasise the need for the provision of adequate protection and support.


Did the OCT Show Progression Since the Last Visit?
Identifying progression is of fundamental importance to the management of glaucoma. It is also a challenge. The most sophisticated, and probably the most useful, commercially available clinical tool for identifying progression is the Guided Progression Analysis (GPA), which was initially developed to identify progression using 24-2 visual field tests. More recently, it has been extended to retinal nerve fiber layer (RNFL) and ganglion cell+inner plexiform layer thicknesses measured with optical coherence tomography (OCT). However, the OCT GPA requires a minimum of 3 tests to determine "possible loss (progression)" and a minimum of 4 tests to determine if the patient shows "likely loss (progression)." Thus, it is not designed to answer a fundamental question asked by both the clinician and the patient, namely: Did damage progress since the last visit? Some clinicians use changes in summary statistics, such as global/average circumpapillary RNFL thickness. However, these statistics have poor sensitivity and specificity due to segmentation and alignment errors. Instead of relying on the GPA analysis or summary statistics, one needs to evaluate RNFL and ganglion cell+inner plexiform layer probability maps and circumpapillary OCT B-scan images. In addition, we argue that the clinician can make a better decision about suspected progression between 2 test days by topographically comparing the changes in the different OCT maps and images, in addition to topographically comparing the changes in the visual field with the changes in OCT probability maps.


Impact of drought and heat stress individually and in combination on physio-biochemical parameters, antioxidant responses, and gene expression in Solanum lycopersicum.
The present study was carried out to investigate the effect of individual drought, heat, and combined drought and heat stress on tomato plants. Combined stress resulted in the higher accumulation of Proline (101.9%), MDA (38.55%), H2O2 (101.19%), and lower levels of RWC (53.84%). Individual drought and heat stress decreased photosynthetic pigments like total chlorophyll content by (45.45%) and (25.35%), respectively, higher rates of pigment reduction (79.42%) were observed under combined drought and heat stress. Combined stress decreased PSII efficiency (Fv/Fm), quantum yield (ΦPSII), and photochemical efficiency (qp) and increased non-photochemical quenching (NPQ) levels. Moreover, the gas exchange parameters E, A, and Pn decreased by 5.36%, 36.45%, and 51.00%, respectively, in comparison to control plants. Antioxidant enzymes, SOD, APX, CAT, and GR showed a two- to threefold increase under combined drought and heat stress; however, the non-enzymatic antioxidants AsA and GSH displayed one-twofold increase under combined stress. Moreover, 2- to 2.5-fold decrease was observed in MDHAR and DHAR enzyme transcripts under combined stress conditions. The transcripts corresponding to AsA-GSH pathway enzymes SOD, APX, GR, DHAR, and MDHAR were up-regulated by 8- to 12-fold under combined drought and heat. Furthermore, DREB and LEA transcripts were up-regulated under drought and combined stress and down-regulated under drought stress. In the same manner, HSP70 and HSP90 transcripts were up-regulated under heat and combined stress; however, the transcription levels got down-regulated under drought stress. Additionally, rbcL and RCA transcripts were down-regulated especially under combined stress in comparison to individual drought and heat conditions. PSIP680 relative expression levels were up-regulated under drought stress; however, the transcripts were down-regulated under heat and combined stress. Taken together, the results suggest that the combined stress has a predominant effect over individual stress.


Resistance mechanisms adopted by a Salmonella Typhimurium mutant against bacteriophage.
Bacteriophages have key roles in regulating bacterial populations in most habitats. A Salmonella Typhimurium mutant (N18) with impaired sensitivity to phage fmb-p1 was obtained and examined, the adsorption efficiency of fmb-p1 to N18 was reduced to 6%, compared to more than 97% for wild type S. Typhimurium CMCC50115. Reduced adsorption was accompanied by a reduction of 90% in the LPS content compared to wild type. Electron microscopy showed phage scattered around N18 with minimal engagement, while the phage were efficiently adsorbed to the wild type with tails oriented towards the bacterial surface. Evidence suggests fmb-p1 can slightly infect N18 and this does not give rise to an increase of phage titer. RT-qPCR data show that several Salmonella genes involved in lipopolysaccharide synthesis and five virulence related genes were down-regulated upon exposure of N18 to phage fmb-p1. In contrast, phage resistance related genes such as the SOS response, restriction-modification (RM), and Cas1 gene were up-regulated in N18. These data suggest that although inefficient adsorption and entry is the primary mechanism of resistance, transcriptional responses to phage exposure indicate that alternative resistance mechanisms against phage infection are also brought to bear, including digestion of phage nucleic acids and activation of the SOS. These findings may help develop strategies for biocontrol of Salmonella where multi-resistant bacteria are encountered or emerge in applications for food production, bioremediation or wastewater treatment.


Sexual Behaviors and HIV/STI Prevention Strategies Among Sexual Minority Men in Ecuador Who Use Geosocial Networking Apps.
Around the world, geosocial networking apps have become widely popular among sexual minority men (SMM). This research analyzed the sexual behaviors and HIV and STI prevention strategies (HIV/STI testing, HIV/STI inquiry, and HIV/STI disclosure) of an online-recruited sample of 284 SMM living in Ecuador. Sexting and oral sex were the most common sexual behaviors among SMM in the sample. Most participants had low perceptions of HIV and STI risk; 85% reported being tested for HIV and 70% for STIs. Being older predicted higher odds of being tested for either HIV or STIs at least once. Being single also predicted HIV testing. Future interventions in the country should explore apps' utility as intervention tools to spread information about sexual health and HIV prevention strategies, such as condom use and event-driven PrEP. Apps can also facilitate connections to sexual health services, including programs for PrEP initiation and linkage to HIV treatment. They should also focus on promoting sexual harm reduction conversations among potential app-met sexual partners.


In vivo ESR-CT imaging of the liver in mice receiving subcutaneous injection of nitric oxide-bound iron complex.
ESR measurements and ESR-CT imaging of subcutaneously (SC) injected nitric oxide (NO)-bound iron complexes were conducted on the upper abdomen of live mice. The use of NO-bound iron complex with N-(dithiocarboxy)sarcosine resulted in a clear ESR-CT image showing high intensity areas in the ventral regions, while other NO-bound iron complexes with N-methyl-D-glucamine dithiocarbamate or N,N-diethyl-dithiocarbamate were inappropriate because of low S/N ratios. To investigate the distributions of SC injected NO-bound iron complexes in the abdomens of mice, we measured ESR signals in resected abdominal organs. The signal amplitude was higher in the resected liver than in the resected gastrointestinal organs or the blood samples. The findings suggest that the high intensity areas in the ESR-CT images thus obtained correspond to the liver.


The use of sample genealogies for studying a selectively neutral m-loci model with recombination.
A selectively neutral m-loci model with recombination is studied. A general method is developed to calculate the variance of the number of segregating sites in samples of arbitrary size and the m-loci homozygosity. The method is based on properties of the genealogy of the sample rather than diffusion approximations. To demonstrate the scope of the method several calculations are presented.


Honesty as a trait.
The purpose of this paper is to review recent research about the possibility that some people are more honest than others and about the causes of them being so. We tackle four big questions about the consistency of honest behavior, the content and breadth of trait honesty, the mechanisms underlying trait honesty, and the measurement of trait honesty. Recent research reveals we are only at the beginning states of answering these questions about honesty. Invigorated research is needed to firmly resolve whether individuals differ in honesty and if so, integrate the determining mechanisms and develop strong measurements.


Periostin Plays a Key Role in Radioresistance of Head and Neck Cancer Cells Via Epithelial-to-Mesenchymal Transition.
Head and neck squamous cell carcinoma (HNSCC) is an aggressive head and neck malignancy. The aim of this study was to elucidate the role of periostin (POSTN) in the epithelial-to-mesenchymal transition (EMT) process mediating the acquisition of radioresistance in HNSCC. The expression levels of EMT hallmark genes including POSTN and Erk/Akt signaling pathways were compared between radiosensitive and radioresistant HNSCC cells. POSTN mRNA expression was higher in radioresistant HNSCC cells, and silencing POSTN significantly impaired their invasiveness under the effect of EMT process represented by up-regulation of mesenchymal markers and down-regulation of an epithelial marker. Expression levels of Erk and Akt were higher in radioresistant cells. POSTN in association with the Erk and Akt signaling pathways was up-regulated during the EMT process, leading to the conversion of radiosensitive to radioresistant HNSCC cells. POSTN may be a key marker for predicting the radioresistance and therapeutic target of HNSCC.


Can National Registries Contribute to Predict the Risk of Cancer? The Cancer Risk Assessment Model (CRAM).
To develop a predictive model based on Danish administrative registers to facilitate automated identification of individuals at risk of any type of cancer. A nationwide register-based cohort study covering all individuals in Denmark aged +20 years. The outcome was all-type cancer during 2017 excluding nonmelanoma skin cancer. Diagnoses, medication, and contact with general practitioners in the exposure period (2007-2016) were considered for the predictive model. We applied backward selection to all variables by logistic regression to develop a risk model for cancer. We applied the models to the validation cohort, calculated the receiver operating characteristic curves, and estimated the corresponding areas under the curve (AUC). The study population consisted of 4.2 million persons; 32,447 (0.76%) were diagnosed with cancer in 2017. We identified 39 predictive risk factors in women and 42 in men, with age above 30 as the strongest predictor for cancer. Testing the model for cancer risk showed modest accuracy, with an AUC of 0.82 (95% CI 0.81-0.82) for men and 0.75 (95% CI 0.74-0.75) for women. We have developed and tested a model for identifying the individual risk of cancer through the use of administrative data. The models need to be further investigated before being applied to clinical practice.


Fructose-induced modifications of myoglobin: Change of structure from met (Fe3+) to oxy (Fe2+) form.
We studied structural modifications of metmyoglobin (Mb) after short-term (6 days) and long-term (30 days) glycation by fructose (fructation). Fructation caused gradual changes in the structure of the protein with respect to increased absorbance at 280 nm, enhanced fluorescence emission (with excitation at 285 nm), increased surface accessible tryptophan residues and reduced α-helix content and change in tertiary structure. However, long-term fructation changed Mb to oxymyoglobin (MbO2), as demonstrated by different spectroscopic (absorption, fluorescence, circular dichroic and electron paramagnetic resonance) studies and trifluoperazine-induced oxygen release experiment. Fructation appeared to modify Arg139 to arg-pyrimidine, which exhibited antioxidative activity and might be involved in the conversion of met (Fe3+) to oxy (Fe2+) form of myoglobin.


Comorbidities and mortality risk among extensive-stage small-cell lung cancer patients in mainland China: impacts of hypertension, type 2 diabetes mellitus, and chronic hepatitis B virus infection.
The present study investigated the impact of major comorbidities, including hypertension, type 2 diabetes mellitus (T2DM), and chronic hepatitis B virus (HBV) infection, on the progression-free survival (PFS) and overall survival (OS) of extensive-stage small-cell lung cancer (ES-SCLC) patients in China. Patients having a pathologic diagnosis of ES-SCLC between 2009 and 2017 were enrolled and grouped according to their specific comorbidities. The PFS and OS for each group were evaluated using the Kaplan-Meier method and Cox proportional hazard models. In total, 632 patients were analyzed. The median PFS (mPFS) of these patients was 9 months [95% confidence interval (CI), 6-12 months]. The mPFS of patients without hypertension or T2DM was 9 months; conversely, it was significantly reduced for patients with hypertension [7 months (P < 0.0001)] or T2DM [5 months (P < 0.0001)]. However, mPFS was not significantly different between patients with and without HBV infection (P = 0.2936). A similar trend was observed for OS as well. Further multivariate analyses showed that the OS of patients with hypertension [hazard ratio (HR), 1.344; 95% CI, 1.073-1.683; P = 0.010] or T2DM (HR, 1.455; 95% CI, 1.134-1.868; P = 0.003) was significantly shorter than that of patients without these comorbidities. Accordingly, mortality risk was the highest in patients with concurrent hypertension and T2DM (HR, 1.665; 95% CI, 1.037-2.672; P = 0.00058). Our study found that hypertension and T2DM may be associated with a worse prognosis in ES-SCLC patients. Considerable attention should be paid to the accompanying anti-comorbidity therapies available for patients with ES-SCLC.


Teniposide (VM-26) in patients with non-squamous-cell carcinoma of the cervix. A phase II trial of the Gynecologic Oncology Group.
Twenty-three evaluable patients with non-squamous-cell carcinoma of the cervix were treated with teniposide 100 mg/m2 per week administered as a 30-60 min infusion. Escalations of 20 mg/m2 per week to a maximum dose of 160 mg/m2 were performed in patients without toxicity. Thirteen of the 23 patients had no prior chemotherapy. One patient had a partial response (95% confidence intervals for response less than or equal to 19%). Toxicity was minimal. Seven patients had white blood cell counts of less than 2,000/mm3 but only one had less than 1,000/mm3. No patients had platelet counts less than 50,000/mm3, and no bleeding or septic episodes were noted. Two patients had mild nausea and seven had mild nausea and vomiting. Teniposide displays no major activity in patients with non-squamous-cell cervical cancer.


Kinetic mechanism of 1-N6-etheno-2-aza-ATP and 1-N6-etheno-2-aza-ADP binding to bovine ventricular actomyosin-S1 and myofibrils.
The fluorescence emission of 1-N6-etheno-2-aza-ATP (epsilon-aza-ATP) at 410-460 nm is enhanced approximately 8-fold upon mixing substoichiometric concentrations of epsilon-aza-ATP with bovine cardiac actomyosin-S1 or myofibrils. The time course of nucleotide fluorescence measured in a front face stopped flow cell upon mixing epsilon-aza-ATP with bovine cardiac myofibrils ([Ca2+] less than 10(-7) M) is essentially the same as that with bovine cardiac actomyosin subfragment-1. In single turnover experiments, the fluorescence rapidly rises to a maximum value, then decreases with a rate constant of 0.04 s-1 at 0 degree C to a final value that is approximately twice the level of the unbound nucleotide. At concentrations of epsilon-aza-ATP greater than 40 microM the kinetics of epsilon-aza-ATP binding is clearly biphasic for both actomyosin-S1 and myofibrils. At 0 degree C, the rate of the more rapid phase is proportional to nucleotide concentration and has a second order rate constant of 1.7 X 10(5) M-1 s-1; the rate of the slower phase extrapolates to a maximum of 4-5 s-1 at high nucleotide concentration. The rate constants for dissociation of epsilon-aza-ADP from bovine cardiac actomyosin-S1 and myofibrils were measured from the decrease in epsilon-aza-ADP fluorescence enhancement observed upon displacement by ATP to be 20 and 18 s-1, respectively, at 0 degree C. These results indicate that most of the cross-bridges in cardiac myofibrils are bound to actin and that the geometric constraints imposed upon the interaction of actin and myosin by the three-dimensional structure of the myofibril do not modify the kinetics of epsilon-aza-ATP binding or epsilon-aza-ADP dissociation.


SIRPα-αCD123 fusion antibodies targeting CD123 in conjunction with CD47 blockade enhance the clearance of AML-initiating cells.
Acute myeloid leukaemia (AML) stem cells (LSCs) cause disease relapse. The CD47 "don't eat me signal" is upregulated on LSCs and contributes to immune evasion by inhibiting phagocytosis through interacting with myeloid-specific signal regulatory protein alpha (SIRPα). Activation of macrophages by blocking CD47 has been successful, but the ubiquitous expression of CD47 on healthy cells poses potential limitations for such therapies. In contrast, CD123 is a well-known LSC-specific surface marker utilized as a therapeutic target. Here, we report the development of SIRPα-αCD123 fusion antibodies that localize the disruption of CD47/SIRPα signalling to AML while specifically enhancing LSC clearance. SIRPα-αCD123 antibodies were generated by fusing the extracellular domain of SIRPα to an αCD123 antibody. The binding properties of the antibodies were analysed by flow cytometry and surface plasmon resonance. The functional characteristics of the fusion antibodies were determined by antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity assays using primary AML patient cells. Finally, an in vivo engraftment assay was utilized to assess LSC targeting. SIRPα-αCD123 fusion antibodies exhibited increased binding and preferential targeting of CD123+ CD47+ AML cells even in the presence of CD47+ healthy cells. Furthermore, SIRPα-αCD123 fusion antibodies confined disruption of the CD47-SIRPα axis locally to AML cells. In vitro experiments demonstrated that SIRPα-αCD123 antibodies greatly enhanced AML cell phagocytosis mediated by allogeneic and autologous macrophages. Moreover, SIRPα-αCD123 fusion antibodies efficiently targeted LSCs with in vivo engraftment potential. SIRPα-αCD123 antibodies combine local CD47 blockade with specific LSC targeting in a single molecule, minimize the risk of targeting healthy cells and efficiently eliminate AML LSCs. These results validate SIRPα-αCD123 antibodies as promising therapeutic interventions for AML.


A reinvestigation of the lipopolysaccharide structure of Helicobacter pylori strain Sydney (SS1).
In this study, we describe a reinvestigation of the lipopolysaccharide (LPS) structure of Helicobacter pylori strain Sydney (SS1) based on the NMR analysis of oligosaccharides obtained through the use of various degradations of the LPS as well as capillary electrophoresis-MS data. The results of the analysis indicated that the core region of a major H. pylori SS1 LPS glycoform consists of a backbone core oligosaccharide substituted at the D-glycero-D-manno-heptose (DD-Hep) residue by a linear chain composed of a trisaccharide fragment α-ddHep-3-α-L-Fuc-3-β-GlcNAc, as previously demonstrated for H. pylori strain 26695, further elongated by consecutively added α-Glc and β-Gal residues, and terminating in a novel linear chain consisting of 1,2-linked β-ribofuranosyl residues, where the last β-ribofuranosyl residue provides a point of attachment for the O-chain polysaccharide: [Formula: see text] where [2-β-Ribf-](n) is a short (three to five residues) oligomer of 1,2-linked β-ribofuranose (riban), and PS is a polysaccharide chain consisting of N-acetyllactosamine, substituted with α-Fuc to form Lewis (Le)-type structures. In addition to the previously identified LacNAc, Le(y) and Le(x) components, the O-chain polysaccharide of H. pylori SS1 LPS was found to contain a novel LacNAc unit carrying a phosphoethanolamine substituent at the O-6 position of β-GlcNAc residues.


Assessment of the knowledge level and experience of healthcare personnel concerning CPR and early defibrillation: an internal survey.
In-hospital cardiac arrest (IHCA) is a major public health problem with significant mortality. Rapid cardiopulmonary resuscitation and early defibrillation is extremely connected to patient outcome. In this study, we aimed to assess the effects of a basic life support and defibrillation course in improving knowledge in IHCA management. We performed a prospective observational study recruiting healthcare personnel working at Azienda Ospedaliero Universitaria Pisana, Pisa, Italy. Study consisted in the administration of two questionnaires before and after BLS-D course. The course was structured as an informative meeting and it was held according to European Resuscitation Council guidelines. 78 participants completed pre- and post-course questionnaires. Only 31.9% of the participants had taken part in a BLS-D before our study. After the course, we found a significative increase in the percentage of participants that evaluated their skills adequate in IHCA management (17.9% vs 42.3%; p < 0.01) and in the correct use of defibrillator (38.8% vs 67.9% p < 0.001). However, 51.3% of respondents still consider their preparation not entirely appropriate after the course. Even more, we observed a significant increase in the number of corrected responses after the course, especially about sequence performed in case of absent vital sign, CPR maneuvers and use of defibrillator. The training course resulted in significant increase in the level of knowledge about the general management of IHCA in hospital staff. Therefore, a simple intervention such as an informative meetings improved significantly the knowledge about IHCA and, consequently, can lead to a reduction of morbidity and mortality.


Burkholderia thailandensis E264 as a promising safe rhamnolipids' producer towards a sustainable valorization of grape marcs and olive mill pomace.
Within the circular economy framework, our study aims to assess the rhamnolipid production from winery and olive oil residues as low-cost carbon sources by nonpathogenic strains. After evaluating various agricultural residues from those two sectors, Burkholderia thailandensis E264 was found to use the raw soluble fraction of nonfermented (white) grape marcs (NF), as the sole carbon and energy source, and simultaneously, reducing the surface tension to around 35 mN/m. Interestingly, this strain showed a rhamnolipid production up to 1070 mg/L (13.37 mg/g of NF), with a higher purity, on those grape marcs, predominately Rha-Rha C14-C14, in MSM medium. On olive oil residues, the rhamnolipid yield of using olive mill pomace (OMP) at 2% (w/v) was around 300 mg/L (15 mg/g of OMP) with a similar CMC of 500 mg/L. To the best of our knowledge, our study indicated for the first time that a nonpathogenic bacterium is able to produce long-chain rhamnolipids in MSM medium supplemented with winery residues, as sole carbon and energy source. KEY POINTS: • Winery and olive oil residues are used for producing long-chain rhamnolipids (RLs). • Both higher RL yields and purity were obtained on nonfermented grape marcs as substrates. • Long-chain RLs revealed stabilities over a wide range of pH, temperatures, and salinities.


Relationships among trait, situational, and comparative optimism: clarifying concepts for a theoretically consistent and evidence-based intervention to maximize resilience.
Research evidence identifies trait optimism as the strongest individual predictor of adolescent resilience when framed within Lazarus's theory of stress and coping. As a precursor to the development of an intervention to maximize resilience, this study clarifies the concept of optimism. Relationships among trait, situational, and comparative optimism were explored. The sample (N = 132) consisted of rural adolescents between 14 and 18 years old who were attending public school. The results demonstrate weak correlations, suggesting that adolescents' perceptions of situations may be amenable to an intervention to maximize resilience but that adolescents also do not expect to experience health or environmental problems. Implications for developing an intervention are discussed.


Mechanisms of enhanced arrhythmogenicity of regional ischemia in the hypertrophied heart.
The coexistence of cardiac hypertrophy (H) and ischemia (I) can create a particularly arrhythmogenic substrate. Most studies investigate the effects of global I on H. However, global I is not a good surrogate model of the clinical situation. The purpose of this study was to investigate the electrophysiological effects of regional I superimposed on H using optical mapping of membrane voltage. We investigated the guinea pig model of left ventricular H (LVH) induced by suprarenal banding of abdominal aorta. Twelve hearts with or without LVH were mounted in a Langendorff preparation, and regional I was induced by 20 minutes of ligation of the left anterior descending artery. Left ventricle epicardial action potential duration (APD) was significantly prolonged in the LVH group compared with controls. I significantly shortened APD in the I risk zone in both groups, but the percentages of APD shortening (28% vs. 40%) and the magnitudes of shortening (57 +/- 18 vs. 105 +/- 32 ms) were greater in the LVH group. The greater dispersion of repolarization (DR) across the border of the I zone resulted in arcs of functional conduction block and circulating wave fronts. Tachycardia-dependent APD alternans developed more often in the LVH group, and the area of alternans versus the area of the I zone was significantly larger. Ventricular tachyarrhythmias (VTs) developed in all 12 hearts with LVH including six non-self-terminating VTs, compared with four control hearts with self-terminating VT. Regional I superimposed on LVH resulted in greater DR at the border between the I and non-I zones as well as in a greater tendency to develop APD alternans. Both arrhythmogenic mechanisms correlated with an increased incidence of VT.


Apple fruit recovery from anoxia under controlled atmosphere storage.
This study investigated the dynamic changes in the anaerobic metabolism end products (ethanol, acetaldehyde and ethyl acetate) of different apple cultivars during 84-days of regular air (RA) and controlled atmosphere (CA) storage after 0-, 3-, 7- and 14-days of anoxia. Increasing the length of exposure to anoxia increased the anaerobic metabolites concentrations (AMC) in all cultivars. Fruit could recover from anoxia, and the AMC dissipated after 84-days of storage under both storage systems when the duration of anoxia was <7-days. The rate of metabolite dissipation following 14-days of anoxia differed among cultivars and storage systems. The reduction in AMC was faster under CA than RA-storage for 'Golden Delicious' and 'Jonagold' fruit, while the opposite trend was observed for 'Kanzi'. These results indicate that storage under CA post anoxia maintains better fruit quality during 84-days of storage than RA and effectively reduces the AMC.


Vitamin E differentially affects short term exercise induced changes in oxidative stress, lipids, and inflammatory markers.
Physical activity or exercise is a proven deterrent of cardiovascular diseases. The purpose of this study was to examine whether vitamin E supplementation interfere with the potential benefits of exercise. A total of 455 apparently healthy men and women were recruited, for a 2-month aerobic/cardiovascular exercise program. Subjects were randomly assigned for soft gel vitamin E or placebo (800 IU), and required to give blood at 0, 2, 4 and 8 weeks of exercise. Levels of lipid and markers of oxidative stress and inflammation were measured along with the VO2 and duration time spent on treadmill. Statistical analysis did not show significant changes in the levels of lipids and markers of oxidative stress and inflammation. Favorable trends among both of the randomization groups were observed in lipids, and some of the oxidative stress and inflammatory markers. This study also established several interesting correlations between VO2, and lipids on one hand and markers of oxidation and inflammation on the other hand. Reduction in LDL levels positively associated with increased levels of MCP-1 (P < 0.008) among placebo group, and also decreased hCRP levels strongly correlated with the increases in VO2 (P < 0.0004) among the placebo, and vitamin E subjects (P < 0.01). Exercise training induces oxidative stress might be instrumental in favorable lipid reduction and markers of oxidative stress and inflammation. However interestingly, vitamin E didn't demonstrate favorable effects on the level of oxidative stress and inflammation associated with exercise.


Traumatic autonephrectomy due to explosion: a case report and literature review.
A 47-year-old man presented 33 years after major trauma resulting from an explosion with asymptomatic microhaematuria. An IVU, showed a completely calcified non-functioning right kidney with hypertrophic left kidney. Investigations for other causes of haematuria were negative. The results of long-term conservative management of traumatic renal infarction are reviewed.


No evidence for a common blood microbiome based on a population study of 9,770 healthy humans.
Human blood is conventionally considered sterile but recent studies suggest the presence of a blood microbiome in healthy individuals. Here we characterized the DNA signatures of microbes in the blood of 9,770 healthy individuals using sequencing data from multiple cohorts. After filtering for contaminants, we identified 117 microbial species in blood, some of which had DNA signatures of microbial replication. They were primarily commensals associated with the gut (n = 40), mouth (n = 32) and genitourinary tract (n = 18), and were distinct from pathogens detected in hospital blood cultures. No species were detected in 84% of individuals, while the remainder only had a median of one species. Less than 5% of individuals shared the same species, no co-occurrence patterns between different species were observed and no associations between host phenotypes and microbes were found. Overall, these results do not support the hypothesis of a consistent core microbiome endogenous to human blood. Rather, our findings support the transient and sporadic translocation of commensal microbes from other body sites into the bloodstream.


The novel metabotropic glutamate receptor agonist 2R,4R-APDC potentiates stimulation of phosphoinositide hydrolysis in the rat hippocampus by 3,5-dihydroxyphenylglycine: evidence for a synergistic interaction between group 1 and group 2 receptors.
The mGlu receptor subtypes and second messenger pathways that mediate 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) responses in brain tissues are not fully understood. 1S,3R-ACPD differs from 3,5-dihydroxyphenylglycine (DHPG) or quisqualate in that 1S,3R-ACPD also activates group 2 mGlu receptors (mGlu2 and mGlu3) that are negatively linked to cAMP formation. To investigate the contribution of group 2 mGlu receptor activity of 1S,3R-ACPD to the phosphoinositide response in the rat hippocampus, we examined the effects of the novel group 2 mGlu receptor agonist 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC). 2R,4R-APDC did not activate or inhibit group 1 mGlu receptors (human mGlu1 alpha and mGlu5a) or group 3 mGlu receptors (human mGlu4 and mGlu7), but potently decreased forskolin-stimulated cAMP formation in human mGlu2- and mGlu3-expressing cells. In slices of the adult rat hippocampus 2R,4R-APDC had no effect on basal phosphoinositide hydrolysis; however, it was found to greatly enhance phosphoinositide hydrolysis to DHPG or quisqualate. In the neonatal rat hippocampus, 2R,4R-APDC enhanced the potency of DHPG, while not affecting the maximal response to group 1 mGlu receptor agonists. Thus, the phosphoinositide response in the rat hippocampus to 1S,3R-ACPD is mediated by a synergistic interaction between group 1 and group 2 mGlu receptors.


Genome Sequences of Soft Rot-Causing Pectobacterium Isolates from Different Vegetables.
Eleven Pectobacterium strains were isolated from soft rot-diseased vegetables. Here, we report their genome sequences and characteristics. Five isolates were found to be Pectobacterium versatile, while the other six were determined to be Pectobacterium brasiliense.


Distention promotes platelet and leukocyte adhesion and reduces short-term patency in pig arteriovenous bypass grafts.
A pig model of autologous saphenous vein to common carotid artery bypass grafting was developed. An end-to-end anastomotic technique led to lower middle graft and distal turbulence. Saphenous veins were surgically prepared with or without distention at 600 mm Hg, implanted into the arterial circulation, and removed 2 hours later. Medial integrity was then assessed by adenosine triphosphate/adenosine diphosphate concentration ratio, and endothelial integrity, leukocyte and platelet adhesion by scanning electron microscopy. In grafts made with undistended vein adenosine triphosphate/adenosine diphosphate concentration ratio was not significantly lower (3.0 +/- 0.1, n = 32) than in freshly isolated vein (3.3 +/- 0.1, n = 26), endothelial cover was 98% +/- 1%, n = 6, and there was little platelet or leukocyte adhesion. In distended grafts adenosine triphosphate/adenosine diphosphate concentration ratio was reduced to 2.2 +/- 0.2 (n = 7, p less than 0.005), endothelial cover was reduced to 38% +/- 14% (n = 6, p less than 0.001), and there was extensive platelet and leukocyte adhesion to exposed subendothelium. In separate experiments graft patency measured at 1 to 5 weeks was significantly greater (96%, n = 25) when undistended vein was used than when distended vein was used (64%, n = 25, p less than 0.005). The data show that distention leads to medial and endothelial damage and that this is associated with increased platelet and leukocyte adhesion and with reduced early patency.


Co-expression of the calcitonin receptor gene in the hypothalamic kisspeptin neurons in female rats.
Hypothalamic kisspeptin neurons are considered to play a critical role in regulating mammalian reproduction and integrating humoral and neuronal inputs that control gonadotropin-releasing hormone (GnRH)/gonadotropin release. The present study aimed to investigate the upstream regulator candidates for kisspeptin neurons. Visualized kisspeptin neurons that were taken from the arcuate nucleus (ARC) of Kiss1-tdTomato rats were subjected to next-generation sequencing (NGS) analysis. In situ hybridization (ISH) for the calcitonin receptor gene (Calcr) was performed throughout the whole forebrain of ovariectomized wild-type female rats that had been implanted with a negative feedback level of estrogen, because the Calcr expression was evident in the ARC kisspeptin neurons from the NGS analysis. Then, a double ISH was performed for the Calcr and kisspeptin gene (Kiss1) in the brain regions, containing either the anteroventral periventricular nucleus (AVPV) or ARC of the female rats. The NGS analysis revealed that the Calcr was highly expressed in the ARC kisspeptin neurons. It was found that the Calcr was co-expressed in 12% and 22% of the Kiss1-expressing cells in the ARC and AVPV, respectively. The present study suggests that calcitonin receptor signaling could be involved in the regulation of reproductive function through the direct control of the ARC and/or AVPV kisspeptin neurons, and then GnRH/gonadotropin release.


Antichagasic activity of komaroviquinone is due to generation of reactive oxygen species catalyzed by Trypanosoma cruzi old yellow enzyme.
A novel potent trypanocidal diterpene, komaroviquinone, was reduced by Trypanosoma cruzi old yellow enzyme (TcOYE) to its semiquinone radical. The reductase activity in trypanosome lysates was completely immunoabsorbed by anti-TcOYE antibody. Since TcOYE is expressed throughout the T. cruzi life cycle, komaroviquinone is an interesting candidate for developing new antichagasic drugs.


An analysis of fatal bicycle accidents in Victoria (Australia) with a special reference to nighttime accidents.
This paper examines the fatal bicycle accidents which occurred in the period 1981-1984 in Victoria with particular emphasis on nighttime fatalities. The examination provides information on aspects of accident location, environment, problem type, time, and cyclist characteristics. The relationship between actual accidents and cyclists perceived collision danger is also investigated. The characteristics of fatal bicycle accidents are different to those of overall "casualty" accidents. A difference also exists between day and night, and between metropolitan and nonmetropolitan fatal accidents. In the metropolitan area, adult cyclists over 17 years were over-involved in fatal accidents. The proportion of cyclists involved in fatalities at night increases with increase in age. Almost 80% of nighttime accidents occurred on links on arterial roads, and the majority in the high speed limit zones (75 kph and over). A greater proportion of accidents was initiated by cyclists. In 90% of nighttime cyclist fatalities the cyclist was hit from the rear, compared with 40% in daytime. Inadequacy of bicycle and street lighting was found to be an important factor in nighttime fatalities.


A new method for processing of continuous intracranial pressure signals.
This paper describes a new method for processing of continuous pressure signals. Continuous intracranial pressure (ICP) signals were sampled at 100 Hz, converted into digital data and processed during 6s time windows. According to a new algorithm, cardiac beat-induced single ICP waves were identified; pressure waves caused by noise in the signal were rejected for further analysis. The amplitude and latency values of the accepted single ICP waves were determined. For accepted 6s time windows, the mean ICP wave was computed as mean ICP wave amplitude and mean ICP wave latency. Mean ICP for every time window was computed according to current practice as sum of pressure levels divided by number of samples. The mean ICP wave parameters provide information about the single ICP waves that is not given by mean ICP. The method has been implemented in software to be used during online ICP monitoring, revealing mean ICP wave amplitude, mean ICP wave latency and mean ICP as numerical values every 6s. The values are presented in trend plots. Verification of correct single ICP wave identification can be done during online ICP monitoring. The clinical significance of the method was illustrated in four patients by observations that mean wave amplitudes corresponded better to the acute clinical state than the mean ICP; mean wave amplitudes could be elevated despite a normal mean ICP. In one patient with ICP and arterial blood pressure (ABP) signals monitored simultaneously with identical time reference, there was a weak correlation between mean ICP and ABP wave amplitudes. It is tentatively suggested that the mean ICP wave parameters are related to intracranial pressure-volume compensatory reserve capacity (compliance).


The efficacy of endoscopic mucosal resection in the diagnosis and treatment of group III gastric lesions.
The efficacy of endoscopic mucosal resection (EMR) in diagnosing and treating group III lesions was analyzed. Forty-three patients, with group III lesions confirmed by histopathological examination of the biopsy specimens, were included. All of these patients underwent EMR. The final diagnosis after EMR broadly classified the lesions as adenocarcinoma or adenoma. The clinicopathological features and therapeutic results were analyzed. Adenocarcinoma was identified in 16 patients (37.2%) and adenoma in 27 patients (62.8%). There were no differences in gender, age, lesion site, macroscopic type, or maximum diameter between the two groups. A significant difference in the maximum diameter of elevated lesions (p<0.05) was found between adenocarcinomas and adenomas, with the elevated lesions of adenocarcinomas measuring more than 10 mm. No residual focus recurrence was found among the adenomas. We conclude that EMR is effective and useful in diagnosing and treating group III lesions.


No Home without Hormones: How Plant Hormones Control Legume Nodule Organogenesis.
The establishment of symbiotic nitrogen fixation requires the coordination of both nodule development and infection events. Despite the evolution of a variety of anatomical structures, nodule organs serve a common purpose in establishing a localized area that facilitates efficient nitrogen fixation. As in all plant developmental processes, the establishment of a new nodule organ is regulated by plant hormones. During nodule initiation, regulation of plant hormone signaling is one of the major targets of symbiotic signaling. We review the role of major developmental hormones in the initiation of the nodule organ and argue that the manipulation of plant hormones is a key requirement for engineering nitrogen fixation in non-legumes as the basis for improved food security and sustainability.


Herbo-metallic ethnomedicine 'Malla Sindoor' ameliorates lung inflammation in murine model of allergic asthma by modulating cytokines status and oxidative stress.
Asthma is the leading inflammatory disease of the airways with inadequate therapeutic options. 'Malla Sindoor' (MS) is a metal-based ethnomedicinal formulation that has been prescribed in the ancient traditional medicinal system for treating chronic inflammations. Here, we validated the anti-inflammatory and anti-asthmatic properties of traditional metallic medicine MS in asthmatic mice model and in LPS stimulated human monocytic THP-1 cells, by examining the relevant cellular, biochemical and molecular intermediates. Scanning Electron Microscope (SEM), Electron Dispersive X-ray (EDX), and X-Ray Diffraction (XRD) were performed to characterize MS particles. Allergic asthma was induced in Balb/c mice through intraperitoneal ovalbumin (OVA) injection. Experimental groups include, normal control, disease control, Dexamethasone (2 mg/kg) and three MS treated groups: 4.3 mg/kg, 13 mg/kg, and 39 mg/kg. Quantitative PCR, inflammatory cytokines and anti-oxidant enzymes, and histological analysis were performed, in the treated mice and LPS stimulated human monocytic THP-1 cells for determining the MS efficacy. SEM image analysis showed the MS to be heterogenous in shape with a particle size distribution between 100 nm-1 μm. Elemental composition showed the presence of mercury (Hg), arsenic (As), and sulphur (S) along with other elements in the forms of mercury sulfide, arsenic trioxide, and their alloy crystals. OVA-challenge of the Balb/c mice resulted in the development of overt pathological features for allergic asthma including smooth muscle thickening and collagen deposition. Mice receiving MS-exhibited alleviation of allergic asthma features. BAL fluid analysis showed a decrease in the total cell count and decreases in neutrophils, monocytes, lymphocytes, and eosinophils. Further, the stimulated levels of interleukin (IL)-1β, -6, and TNF-α cytokines and antioxidant levels were also reduced upon MS-treatment. At the molecular level, MS-treatment reduced stimulated mRNA expression levels for IL-4, -5, -10, -13, -33, and IFN-γ cytokines. Histological analysis following MS-treatment of OVA-stimulated mice lungs showed a reduction in mucus accumulation in airways, decreases in peribronchial collagen deposition, bronchial smooth muscle thickening, and attenuation of inflammatory cell infiltration. In addition, under in-vitro conditions, MS-treatment attenuated the LPS induced secretion of IL-1β, -6, and TNF-α from THP-1 cells. Collectively, the results suggest that MS acts as an effective anti-asthmatic and anti-inflammatory agent, by regulating various cellular, biochemical and molecular intermediates.


Elevated levels of preoperative circulating CD44⁺ lymphocytes and neutrophils predict poor survival for non-small cell lung cancer patients.
Certain circulating cells have been shown to predict the clinical outcome of several cancers. The objective of this study was to identify clinical, hematological and immunological predictors of prognosis in non-small cell lung cancer (NSCLC) patients. A retrospective study on a prevalent cohort of 225 NSCLC patients hospitalized at the Zhejiang Province Cancer Hospital (ZPCH) was conducted from August 1, 2006 to April 15, 2008. Circulating lymphocytes were measured by flow cytometry. WBC count and classification in peripheral blood were measured with a Coulter counter. We calculated the proportion of patients surviving after first hospital admission and hazard ratios (HR) using the Cox proportional hazards model. Elevated levels of preoperative circulating CD44(+) lymphocytes, WBCs and neutrophils indicated low cumulative survival. Clinical stage (HR: 2.292; 95% confidence interval (CI): 1.34-3.91, P=0.002), neutrophils (HR: 1.877; 95% CI: 1.34-2.62, P<0.001) and CD44(+) lymphocytes (HR: 1.018; 95% CI: 1.00-1.03, P=0.002) are independent predictors of survival in NSCLC patients, respectively. Elevated levels of CD44(+) lymphocytes and neutrophils correlated with distant metastasis and prognosis in NSCLC patients with stage III/IV, respectively. CD44(+) lymphocytes along with neutrophils could serve as an independent prognostic marker for NSCLC patients.


Plasmodium falciparum: stage specific effects of a selective inhibitor of lactate dehydrogenase.
Plasmodium falciparum lactate dehydrogenase (PfLDH) is essential for ATP generation. Based on structural differences within the active site between P. falciparum and human LDH, we have identified a series of heterocyclic azole-based inhibitors that selectively bind within the PfLDH but not the human LDH (hLDH) active site and showed anti-malarial activity in vitro and in vivo. Here we expand on an azole, OXD1, from this series and found that the anti-P. falciparum activity was retained against a panel of strains independently of their anti-malarial drug sensitivity profile. Trophozoites had relatively higher PfLDH enzyme activity and PfLDH-RNA expression levels than rings and were the most susceptible stages to OXD1 exposure. This is probably linked to their increased energy requirements and consistent with glycolysis being an essential metabolic pathway for parasite survival within the erythrocyte. Further structural elaboration of these azoles could lead to the identification of compounds that target P. falciparum through such a novel mechanism and with more potent anti-malarial activity.


Pathogenesis of and unifying hypothesis for idiopathic pouchitis.
Ileal pouch-anal anastomosis is the procedure of choice in the surgical management of refractory ulcerative colitis. Pouchitis affects up to 60% of patients following ileal pouch-anal anastomosis for ulcerative colitis. It overlaps significantly with ulcerative colitis such that improvements in our understanding of one will impact considerably on the other. The symptoms are distressing and impinge significantly on patients' quality of life. Despite 30 years of scientific and clinical investigation, the pathogenesis of pouchitis is unknown; however, recent advances in molecular and cell biology make a synergistic hypothesis possible. This hypothesis links interaction between epithelial metaplasia, changes in luminal bacteria (in particular sulfate-reducing bacteria), and altered mucosal immunity. Specifically, colonic metaplasia supports colonization by sulfate-reducing bacteria that produce hydrogen sulfide. This causes mucosal depletion and subsequent inflammation. Although in most cases antibiotics lead to bacterial clearance and symptom resolution, immunogenetic subpopulations can develop a chronic refractory variant of pouchitis. The aims of this paper are to discuss proposed pathogenic mechanisms and to describe a novel mechanism that combines many hypotheses and explains several aspects of pouchitis. The implications for the management of both pouchitis and ulcerative colitis are discussed.


Evaluation of Plasmodium vivax genotyping markers for molecular monitoring in clinical trials.
Many antimalarial interventions are accompanied by molecular monitoring of parasite infections, and a number of molecular typing techniques based on different polymorphic marker genes are used. Here, we describe a genotyping technique that provides a fast and precise approach to study Plasmodium vivax infection dynamics during circumstances in which individual clones must be followed over time. The method was tested with samples from an in vivo drug efficacy study. The sizes of polymerase chain reaction fragments were evaluated by capillary electrophoresis to determine the extent of size polymorphism for 9 potential genetic markers (5 genes of merozoite surface proteins [msp] and 4 microsatellites) in 93-108 P. vivax-positive blood samples from 3 villages in Papua New Guinea. The microsatellites MS16 and Pv3.27 showed the greatest diversity in the study area, with 66 and 31 different alleles, respectively, followed by 2 fragments of msp1 and 2 other microsatellites. msp3alpha, msp4, and msp5 revealed limited polymorphism. Even for the most diverse markers, the highest allelic frequencies reached 6% (MS16) or 13% (Pv3.27). To reduce the theoretical probability of superinfection with parasites that have the same haplotype as that detected at baseline, we propose to combine at least 2 markers for genotyping individual P. vivax infections.


Celecoxib reduces hepatic vascular resistance in portal hypertension by amelioration of endothelial oxidative stress.
The balance between endothelial nitric oxide (NO) synthase (eNOS) activation and production of reactive oxygen species (ROS) is very important for NO homeostasis in liver sinusoidal endothelial cells (LSECs). Overexpression of cyclooxygenase-2 (COX-2), a major intravascular source of ROS production, has been observed in LSECs of cirrhotic liver. However, the links between low NO bioavailability and COX-2 overexpression in LSECs are unknown. This study has confirmed the link between low NO bioavailability and COX-2 overexpression by COX-2-dependent PGE2-EP2-ERK1/2-NOX1/NOX4 signalling pathway in LSECs in vivo and in vitro. In addition, the regulation of COX-2-independent LKB1-AMPK-NRF2-HO-1 signalling pathway on NO homeostasis in LSECs was also elucidated. The combinative effects of celecoxib on diminishment of ROS via COX-2-dependent and COX-2-independent signalling pathways greatly decreased NO scavenging. As a result, LSECs capillarisation was reduced, and endothelial dysfunction was corrected. Furthermore, portal hypertension of cirrhotic liver was ameliorated with substantial decreasing hepatic vascular resistance and great increase of portal blood flow. With the advance understanding of the mechanisms of LSECs protection, celecoxib may serve as a potential therapeutic candidate for patients with cirrhotic portal hypertension.


Giant inflammatory polyposis of the descending colon associated with a Crohn's disease-like colitis.
A case of giant inflammatory polyposis associated with a localized inflammatory bowel disease of the descending colon in a 49-year-old man is presented. Lower abdominal distension rapidly appeared without any previous history of gastrointestinal disease. Two months later, he underwent a left hemicolectomy. Postoperative recovery was complete and he remains in good health more than 2 years later. The resected colon showed a giant and bizarre polyposis measuring up to 12 cm in length and 2 cm in height and covering the entire circumference of the colon. The polyposis consisted of narrow worm- or noodle-like polyps that bridged over the irregularly shaped ulcers, which sometimes extended into muscularis propria. Although longitudinal ulcers or scars, stricture, and a cobble-stone appearance were not observed, transmural inflammation and deep fissures were found in the interpolypoid area. From these findings, this case seems to be more similar to Crohn's disease than other inflammatory bowel diseases.


Neonatal hyperoxia enhances age-dependent expression of SARS-CoV-2 receptors in mice.
The severity of COVID-19 lung disease is higher in the elderly and people with pre-existing co-morbidities. People who were born preterm may be at greater risk for COVID-19 because their early exposure to oxygen (hyperoxia) at birth increases the severity of respiratory viral infections. Hyperoxia at birth increases the severity of influenza A virus infections in adult mice by reducing the number of alveolar epithelial type 2 (AT2) cells. Since AT2 cells express the SARS-CoV-2 receptors angiotensin converting enzyme (ACE2) and transmembrane protease/serine subfamily member 2 (TMPRSS2), their expression should decline as AT2 cells are depleted by hyperoxia. Instead, ACE2 was detected in airway Club cells and endothelial cells at birth, and then AT2 cells at one year of age. Neonatal hyperoxia stimulated expression of ACE2 in Club cells and in AT2 cells by 2 months of age. It also stimulated expression of TMPRSS2 in the lung. Increased expression of SARS-CoV-2 receptors was blocked by mitoTEMPO, a mitochondrial superoxide scavenger that reduced oxidative stress and DNA damage seen in oxygen-exposed mice. Our finding that hyperoxia enhances the age-dependent expression of SARS-CoV-2 receptors in mice helps explain why COVID-19 lung disease is greater in the elderly and people with pre-existing co-morbidities.


Adult male northern elephant seals maintain high rates of glucose production during extended breeding fasts.
Many species undergo natural fasts as part of their life histories. Extended fasting is associated with increased β-oxidation of fatty acids and reduced oxidation of glucose to minimize commitment of body protein to gluconeogenesis. However, the metabolic strategies used to sustain extended fasts simultaneous with high rates of energy expenditure are not well understood. Studies in fasting adult female and weanling northern elephant seals (NES) have revealed high rates of endogenous glucose production (EGP) under constraints of high nutrient demand for lactation or development but relatively low rates of metabolism. These studies revealed low rates of glucose oxidation and high rates of glucose recycling through the Cori cycle. We measured rates of glucose flux in fasting adult male NES to assess how significantly longer fasting durations, higher metabolic rates, and greater rates of muscular activity affect glucose kinetics. We measured glucose turnover in 18 adult males using the clearance of [6-H3] glucose during breeding and molting. Adult male NES maintain high rates of EGP across extended fasts. EGP greatly exceeded estimated needs for glucose-dependent tissues, varied directly with plasma insulin and lactate concentrations, and was inversely related to plasma ketoacid concentrations. Together, these findings suggest that high rates of glucose production and recycling during breeding maintain high blood glucose levels to support glucose-dependent tissues while minimizing production of ketoacids and commitment of protein stores to glucose production.