Morphological analysis of the antimicrobial action of nitric oxide on gram-negative pathogens using atomic force microscopy.
Atomic force microscopy (AFM) was used to study the morphological changes of two gram-negative pathogens, Pseudomonas aeruginosa and Escherichia coli, after exposure to nitric oxide (NO). The time-dependent effects of NO released from a xerogel coating and the concentration-dependent effects rendered by a small molecule that releases NO in a bolus were examined and compared. Bacteria exhibited irregular and degraded exteriors. With NO-releasing surfaces, an increase in surface debris and disorganized adhesion patterns were observed compared to controls. Analysis of cell surface topography revealed that increasing membrane roughness correlated with higher doses of NO. At a lower total dose, NO delivered via a bolus resulted in greater membrane roughness than NO released from a surface via a sustained flux. At sub-inhibitory levels, treatment with amoxicillin, an antibiotic known to compromise the integrity of the cell wall, led to morphologies resembling those resulting from NO treatment. Our observations indicate that cell envelope deterioration is a visible consequence of NO-exposure for both gram-negative species studied.


Dermatologic medication adherence.
Human behavior is directly related to the development of various skin disease conditions and to the effectiveness of skin disease treatment regimens. Adherence research studies have demonstrated abysmal adherence to topical treatment of common skin disorders, opening new opportunities for improving skin disease treatment outcomes. The treatment of skin raises unique issues in environmental exposures, psychosocial human interactions, biology, and pharmacology. The resulting human behaviors and the potential to understand and modify those behaviors through behavioral research studies are exciting and promising.


Tumor Resection May Improve Survival in Patients With Soft Tissue Sarcoma Aged 75 Years and Older.
This study aimed to analyze the decision-making process of treatment and the clinical outcomes of patients with STS aged 75 years and older. Overall, 72 patients were reviewed. The mean and median ages were 82 and 81 years, respectively. Of the 72 patients, 17 did not undergo surgical resection. Age was related to the decision to pursue surgical treatment. Resection was performed in 55 patients. The 5-year overall survival was 51.8%. Patients with an American Society of Anesthesiologists physical status (ASA-PS) score of 3 had a worse survival. Twenty-five patients developed metastasis. The median survival time after metastasis in 12 patients who received metastasectomy and/or lung radiofrequency ablation was superior (18.2 months) to that of the remaining 13 patients without any treatment (3.2 months). Surgical treatment should be considered in elderly patients if their physical condition is not poor. ASA-PS score may be a tool to indicate physical condition.


The molecular genetics of pediatric lipid disorders: recent progress and future research directions.
Over the last 10 years, the explosion of molecular biology and molecular genetic techniques have allowed major advances in the diagnosis and management of a wide variety of human disorders. These range from accurate and simple screening for carriers of thalassemia (Old JM, Varawalla NY, Weatherall DJ: Lancet 2:834-837, 1990) to the use of preimplantation diagnosis of embryos at risk for untreatable congenital defects (Monk M, Holding C: Lancet 1:985-988, 1990) and the development of gene therapy for treatment of disorders such as adenosine deaminase deficiency (Sharp D: Lancet 1:1277-1278, 1991). These same molecular techniques have also been applied to pediatric lipid disorders with some notable successes, both in their diagnosis and understanding the mechanisms of the resulting pathology, including the recent experiments (Wilson JM, Grossman M, Wu CH, Chowdhury NR, Wu GY, Chowdhury JR: J Biol Chem 267:963-967, 1992) that have led to proposals to treat homozygous familial hypercholesterolemia by gene therapy. The purpose of this review is to detail this molecular genetic progress for two of the disorders that result in disturbed triglyceride metabolism in infants, lipoprotein lipase deficiency and apo CII deficiency, and four disorders that lead to disturbed cholesterol levels in infancy, abetalipoproteinemia, hypobetalipoproteinemia, familial defective apo B, and familial hypercholesterolemia. We will also address the question of how knowledge of the mutation causing the defect in a particular patient could be clinically useful and highlight areas of research for the future.


Apixaban, concomitant medicines and spontaneous reports of haemorrhagic events.
Little is known about the potential safety issues associated with apixaban in clinical practice and their reporting in spontaneous adverse event (SAE) databases. To describe SAE reports associated with the oral anticoagulant apixaban from Australia, Canada and USA and to examine associated concomitant medicine use. SAE report databases from Australia, Canada and the USA were examined for all reports of adverse events associated with apixaban and concomitant medicines from 1 January 2012 to 30 September 2014. Disproportionality analysis (proportional reporting ratio (PRR) and reporting odds ratio (ROR)) was conducted for the quantitative detection of signals using the USA database. There were 97 SAE reports associated with apixaban from Australia, 77 from Canada and 2877 from the USA. Reporting of haemorrhage (any type) was common, ranging from 18% for USA to 31% for Australia. Gastrointestinal (GI) haemorrhage was the most commonly reported haemorrhage, accounting for approximately 10% of adverse event reports across all countries. Positive signals were confirmed in the USA data (haemorrhage (any type) PRR, 12.1; χ2, 5582.2 and ROR, 13.4; 95% CI: 12.13-14.6; GI haemorrhage PRR, 11.8; χ2, 2325.4 and ROR, 12.3; 95% CI, 10.8-14.0). Reporting of concomitant use of medicines with the potential to increase bleeding risk ranged from 47.6% in Canada to 65.5% in Australia. A large proportion of adverse event reports for apixaban were associated with use of concomitant medicines which may have increased the risk of haemorrhage.


Carbohydrate and glycoprotein specificity of two endogenous cerebellar lectins.
Two endogenous cerebellar mannose binding lectins have been isolated in an active form by immunoaffinity chromatography employing their respective immobilized antibodies. One of them, termed cerebellar soluble lectin (CSL), was extracted in the absence of detergents, whereas the other, called Receptor 1 (R1), was soluble only in the presence of detergents. Tests of inhibition of agglutination of erythrocytes were performed with mono-, oligo and polysaccharides, as well as glycoconjugates of known structures. On the basis of agglutinating activities these 2 lectins are different from the previously reported lectins in brain, since they were not inhibited by galactosides and lactosides and were only marginally inhibited by glycosaminoglycans. CSL and R1 were better inhibited by mannose-rich glycopeptides as compared to the corresponding oligosaccharides. The different inhibition patterns obtained with glycans of known structures indicated that these lectins are very discriminative. Although CSL and R1 have similar specificities, they differed in their binding properties towards glycopeptides of ovalbumin. Both lectins showed considerable affinity for endogenous cerebellar glycopeptides, also rich in mannose. These glycopeptides belong to a few endogenous Con A-binding cerebellar glycoprotein subunits and are not present on other endogenous Con A-binding glycoproteins. In the forebrain, where CSL and R1 were also present, at least some of the glycoproteins interacting with the lectins were different from that observed in the cerebellum. Our data overall suggest that specific cell recognition in the nervous system could be invoked via the interactions between widely distributed lectins and cell-specific glycoproteins.


Papillomavirus vaccination and Guillain-Barre Syndrome among girls: A cohort study in Spain.
Studies of the association of Guillain-Barré Syndrome (GBS) with papillomavirus vaccination (HPVv; scheduled from 2007) have provided contradicting results, probably due to the low frequency of this disease. We aimed at estimating that risk relative to non-vaccination among girls, by using the Spanish Primary Care Database for Pharmacoepidemiological Research (BIFAP). A cohort study of girls aged 9-18 years during 2007-2016 free of GBS or HPVv was selected and followed up to GBS diagnosis. Follow-up time was divided by time-varying HPVv exposure and confounders. Crude Incidence rates (IR per 1,000,000 person-years (py)) and adjusted Hazard Ratios (HR) of GBS were estimated anytime after vaccination compared to non-exposed periods. HRs were also estimated for the first 90 days after HPVv (risk-window) and thereafter. Out of 388,849 girls, of which 154,255 were vaccinated, 6 'confirmed' GBS cases occurred during non-exposure periods (IR of 5.83 per million person-years; 95% CI: 2.62-12.97) and 3 'confirmed' cases anytime after vaccination (IR of 7.87; 95% CI: 2.54-24.39). The resulting adjusted HR anytime after vaccination was 1.24 (95% CI: 0.19-8.00). All three cases occurred after the risk window of 90 days with an HR of 1.77 (95% CI: 0.25-12.54) for post-exposure periods as compared with non-exposure. Since zero cases occurred during the risk window, no HR could be estimated for exposed periods. Incidences of GBS were in line with the range previously reported for young people, supporting the potential of BIFAP for performing studies on GBS. However, a lack of power may be present for quantifying the relative risk of such a rare disease after the vaccination among the study cohort, where we can only exclude an increased risk of 8-times relative to no vaccination.


The role of endothelial and non-endothelial prostaglandins in the relaxation of isolated blood vessels of the rabbit induced by acetylcholine and bradykinin.
Strips of rabbit extrapulmonary, coeliac and mesenteric arteries were mounted in organ baths for isotonic recording of changes in tissue length. The formation by the strips of the vasodilator prostaglandins PGI2 (measured as 6-keto-PGF1 alpha) and PGE2 was determined by specific radioimmunoassays. Removal of vascular endothelium initially increased and then permanently decreased the basal prostaglandin release of the tissues. Acetylcholine (ACh) relaxed strips of all three arteries if the endothelium was intact. ACh also stimulated the formation of PGI2 and PGE2 from all three tissues; about 60% of these prostaglandins originated from endothelial cells. Indomethacin caused complete inhibition of prostaglandins formation and a slight inhibition of the ACh-relaxation (not statistically significant). Complete inhibition of the ACh relaxation was achieved with nordihydroguaiaretic acid (NDGA). NDGA also partially inhibited prostaglandin formation. These data suggest that in blood vessels that are also prostaglandin-sensitive, the ACh relaxation is predominantly mediated by a non-prostaglandin endothelium-derived relaxing factor. Bradykinin was more potent that ACh in releasing prostaglandins from the same arteries. This release was activated in subendothelial components of the vascular wall. Neither this prostaglandin release nor the bradykinin-induced relaxations were significantly reduced in endothelium-denuded arteries. Indomethacin completely blocked the bradykinin-induced prostaglandin release and the bradykinin relaxation. NDGA caused a moderate inhibition of the bradykinin-induced prostaglandin release and slightly attenuated the bradykinin relaxation (neither effect of NDGA was statistically significant). Under all experimental conditions (control, indomethacin, NDGA) and with all three arteries there was a good correlation between the bradykinin-induced prostaglandin release and the respective mechanical response. No such correlation could be found for ACh. Prostaglandin-dependent relaxations of the coeliac and mesenteric artery are probably mediated by endogenous PGI2. The extrapulmonary artery is rather insensitive to PGI2 and is probably relaxed mainly by endogenous PGE2.


Disability Rating Scale in the First Few Weeks After a Severe Traumatic Brain Injury as a Predictor of 6-Month Functional Outcome.
An early acute marker of long-term neurological outcome would be useful to help guide clinical decision making and therapeutic effectiveness after severe traumatic brain injury (TBI). We investigated the utility of the Disability Rating Scale (DRS) as early as 1 wk after TBI as a predictor of favorable 6-mo Glasgow Outcome Scale extended (GOS-E). To determine the predictability of a favorable 6-mo GOS-E using the DRS measured during weeks 1 to 4 of injury. The study is a sub analysis of patients enrolled in the Epo Severe TBI Trial (n = 200) to train and validate L1-regularized logistic regression models. DRS was collected at weeks 1 to 4 and GOS-E at 6 mo. The average area under the receiver operating characteristic curve was 0.82 for the model with baseline demographic and injury severity variables and week 1 DRS and increased to 0.88 when including weekly DRS until week 4. This study suggests that week 1 to 4 DRS may be predictors of favorable 6-mo outcome in severe TBI patients and thus useful both for clinical prognostication as well as surrogate endpoints for adaptive clinical trials.


Nomenclature: Naming Your Gene-Modified Mouse.
For many of us, if we are honest, nomenclature is a tedious, incomprehensible jargon that interferes with presenting and reading research data. While understanding the rules governing nomenclature involves a steep learning curve, the curve is short, and the basics, with a little effort, are grasped relatively quickly.Like a language, nomenclature is a communication tool that provides a common ground for a disparate group of people. Standardized names provide universally recognized identifiers that can be used by technicians, researchers, purchasing agents, and facility managers, in fact, anyone who uses mice. The formal nomenclature conveys information on the genetics, the technology involved in making the mutation, who created and maintained the strain, and its relationship to other strains. Using a standardized nomenclature for genes, alleles, and strains assists in the goal of reproducible science and helps to bridge the vast amount of data generated by multi-species genome projects.


Marine microbial diversity.
Invisible to the naked eye, yet dominating life with some 1030 cells, bacteria and archaea (referred to herein as 'microbes') play key roles in the global cycling of nutrients, matter and energy in our oceans. Having experimented for over 3.5 billion years since their first appearance, they are true master chemists that are capable of carrying out the most diverse and complex of chemical reactions. One of the most abundant groups, cyanobacteria, converts light into chemical energy by fixing carbon dioxide into organic matter. Part of this fixed carbon is consumed by higher trophic levels, while another fraction sinks to the deep sediments where, over geological time scales, it fossilizes into the natural resources that we tap into for our everyday lives. Despite our knowledge of their global importance and significant recent advances in marine microbiome research (Figure 1), some of the most fundamental questions still remain unanswered, and serve as active drivers of current research in this field: How many microbes are out there, and how many different types? What are they? What are their functional roles? How are they globally distributed? How do they adapt to varying environmental conditions and how will they respond to future environmental changes? This Primer provides a brief overview on how these questions have been addressed in the context of developing technologies. We discuss new insights, as well as new concepts and more refined questions, and we highlight some of the future promises and challenges that lie ahead.


Mannan oligosaccharides alleviate oxidative injury in the head kidney and spleen in grass carp (Ctenopharyngodon idella) via the Nrf2 signaling pathway after Aeromonas hydrophila infection.
Mannan oligosaccharides (MOS) are recommended as aquaculture additives owing to their excellent antioxidant properties. In the present study, we examined the effects of dietary MOS on the head kidney and spleen of grass carp (Ctenopharyngodon idella) with Aeromonas hydrophila infection. A total of 540 grass carp were used for the study. They were administered six gradient dosages of the MOS diet (0, 200, 400, 600, 800, and 1,000 mg/kg) for 60 d. Subsequently, we performed a 14-day Aeromonas hydrophila challenge experiment. The antioxidant capacity of the head kidney and spleen were examined using spectrophotometry, DNA fragmentation, qRT-PCR, and Western blotting. After infection with Aeromonas hydrophila, 400-600 mg/kg MOS supplementation decreased the levels of reactive oxygen species, protein carbonyl, and malonaldehyde and increased the levels of anti-superoxide anion, anti-hydroxyl radical, and glutathione in the head kidney and spleen of grass carp. The activities of copper-zinc superoxide dismutase, manganese superoxide dismutase, catalase, glutathione S-transferase, glutathione reductase, and glutathione peroxidase were also enhanced by supplementation with 400-600 mg/kg MOS. Furthermore, the expression of most antioxidant enzymes and their corresponding genes increased significantly with supplementation of 200-800 mg/kg MOS. mRNA and protein levels of nuclear factor erythroid 2-related factor 2 also increased following supplementation with 400-600 mg/kg MOS. In addition, supplementation with 400-600 mg/kg MOS reduced excessive apoptosis by inhibiting the death receptor pathway and mitochondrial pathway processes. Based on the quadratic regression analysis of the above biomarkers (reactive oxygen species, malondialdehyde, and protein carbonyl) of oxidative damage in the head kidney and spleen of on-growing grass carp, the recommended MOS supplementation is 575.21, 557.58, 531.86, 597.35, 570.16, and 553.80 mg/kg, respectively. Collectively, MOS supplementation could alleviate oxidative injury in the head kidney and spleen of grass carp infected with Aeromonas hydrophila.


Genome-wide gene-diet interaction analysis in the UK Biobank identifies novel effects on hemoglobin A1c.
Diet is a significant modifiable risk factor for type 2 diabetes (T2D), and its effect on disease risk is under partial genetic control. Identification of specific gene-diet interactions (GDIs) influencing risk biomarkers such as glycated hemoglobin (HbA1c) is a critical step towards precision nutrition for T2D prevention, but progress has been slow due to limitations in sample size and accuracy of dietary exposure measurement. We leveraged the large UK Biobank (UKB) cohort and a diverse group of dietary exposures, including 30 individual dietary traits and 8 empirical dietary patterns, to conduct genome-wide interaction studies in ~340 000 European-ancestry participants to identify novel GDIs influencing HbA1c. We identified five variant-dietary trait pairs reaching genome-wide significance (P < 5 × 10-8): two involved dietary patterns (meat pattern with rs147678157 and a fruit & vegetable-based pattern with rs3010439) and three involved individual dietary traits (bread consumption with rs62218803, dried fruit consumption with rs140270534 and milk type [dairy vs. other] with 4:131148078_TAGAA_T). These were affected minimally by adjustment for geographical and lifestyle-related confounders, and four of the five variants lacked genetic main effects that would have allowed their detection in a traditional genome-wide association study for HbA1c. Notably, multiple loci near transient receptor potential subfamily M genes (TRPM2 and TRPM3) interacted with carbohydrate-containing food groups. These interactions were further characterized using non-European UKB subsets and alternative measures of glycaemia (fasting glucose and follow-up HbA1c measurements). Our results highlight GDIs influencing HbA1c for future investigation, while reinforcing known challenges in detecting and replicating GDIs.


SLC17A9 protein functions as a lysosomal ATP transporter and regulates cell viability.
Lysosomes contain abundant ATP, which is released through lysosomal exocytosis following exposure to various stimuli. However, the molecular mechanisms underlying lysosomal ATP accumulation remain unknown. The vesicular nucleotide transporter, also known as solute carrier family 17 member 9 (SLC17A9), has been shown to function in ATP transport across secretory vesicles/granules membrane in adrenal chromaffin cells, T cells, and pancreatic cells. Here, using mammalian cell lines, we report that SLC17A9 is highly enriched in lysosomes and functions as an ATP transporter in those organelles. SLC17A9 deficiency reduced lysosome ATP accumulation and compromised lysosome function, resulting in cell death. Our data suggest that SLC17A9 activity mediates lysosomal ATP accumulation and plays an important role in lysosomal physiology and cell viability.


Primary drug resistance of mycobacterium tuberculosis in Shandong, China, 2004-2018.
Primary drug-resistant tuberculosis (DR-TB) has contributed to a significant health and economic burden on a global scale, especially in China. we sought to estimate epidemiological characteristics of primary DR-TB in China from 2004 to 2018. Eleven thousand four hundred sixty-seven newly diagnosed and 1981 retreated TB cases with drug susceptibility data were included. Chi-Square test for trends, linear regression, a joinpoint regression model and temporal trend in proportions of the different resistance patterns were carried out. The proportion of primary DR-TB and mono-resistant TB (MR-TB) in China had reduced by more than 12% since 2004, and were 21.38%, 13.35% in 2018 respectively. Among primary DR-TB cases (2173,18.95%), the percentage of multiresistant TB (MDR-TB, from 5.41 to 17.46%), male (from 77.03 to 84.13%), cavity (from 13.51 to 43.92%), rifampicin(RFP)-resistant TB (from 8.11 to 26.98%), streptomycin(SM)-resistant TB (from 50.00 to 71.43%) increased significantly (P < 0.05). On the contrary, the proportion of female, non-cavity, isoniazide(INH)-resistant TB (from 55.41 to 48.15%) and MR-TB (from 82.43 to 62.43%) decreased significant (P < 0.05). The primary drug resistance rate among female, cavity, smoking, drinking, 15 to 44 year-old TB subgroups increased by 0.16, 6.24, 20.95, 158.85, 31.49%, respectively. The percentage of primary DR-TB, RFP-resistant TB dropped significantly during 2004-2007 in Joinpoint regression model. The total rate of drug resistance among new TB cases showed a downward trend in Shandong, China, from 2004 to 2018. Primary drug resistance patterns were shifting from female, non-cavity, INH-resistant TB, and MR-TB groups to male, cavity, RFP/SM-resistant TB, and MDR-TB groups. Considering the rising drug resistance rate among some special population, future control of primary DR-TB in China may require an increased focus on female, cavity, smoking, drinking, or 15 to 44 year-old TB subgroups.


Proteomic analysis of the effects of simulated microgravity in human gastric mucosal cells.
Microgravity is an ecological factor that affects the environment of the body. In this study, quantitative isobaric labeling (tandem mass tag) method was used to study the changes in human gastric mucosal cells under simulated microgravity for the first time. Comparative proteomic analysis identified 394 (202 upregulated and 192 downregulated) and 542 (286 upregulated and 256 downregulated) proteins differentially regulated by simulated microgravity after 3 and 7 days, respectively. Then the identified proteins were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses for further exploration. The results of the analysis showed that the ribosomes of gastric mucosal cells were significantly impacted after exposure to simulated microgravity for 3 days, and the cells appeared to be in a state of stress and inflammation. Exposure to simulated microgravity for 7 days significantly affected the mitochondria of the cells, oxidative stress became more evident, while inflammation and weakened connections were observed in the cells. The results of this study highlighted the temporal response trend of gastric mucosal cells to the stressor of microgravity at the two time points of 3 and 7 days. These findings will provide insights into the development of methods to protect the gastric mucosa during space flight.


Longitudinal change in blood pressure is associated with cardiovascular disease mortality in a Chinese cohort.
A number of studies have demonstrated a J-shaped curve between blood pressure (BP) and all-cause mortality, but few studies have used longitudinal change in BP to study mortality in the Chinese population. We performed a 30-year follow-up study to examine the association between BP (at baseline and longitudinal change) and risk of mortality in the Linxian General Population Trial Cohort. At baseline, a total of 29 584 healthy adults were enrolled in the Linxian General Population Trial in 1985 and followed through to the end of 2014. The final analysis was restricted to 29 439 participants (55% women) after exclusion of outliers. We also examined the potential effects of BP trajectory patterns during the period of 1985-1999 on sequent risk of mortality. Adjusted Cox proportional hazards models were used to estimate HRs and 95% CIs. Compared with participants with normal BP, patients with prehypertension, stage 1, stage 2 or stage 3 hypertension had an increased risk of all-cause mortality, with HRs of 1.09 (95% CI 1.05 to 1.14), 1.34 (95% CI 1.28 to 1.40), 1.69 (95% CI 1.60 to 1.79) and 2.14 (95% CI 2.01 to 2.28), respectively. Relative to stable BP of normotension, having a rise in BP from normotension to hypertension or from prehypertension to hypertension both conferred an increased risk of total and cardiovascular disease and stroke mortality (total: HRs 1.22 (95% CI 1.12 to 1.34) and 1.36 (95% CI 1.23 to 1.51); cardiovascular disease: HRs 1.42 (95% CI 1.17 to 1.73) and 1.55 (95% CI 1.24 to 1.93); stroke: HRs 2.29 (95% CI 1.88 to 2.80) and 2.61 (95% CI 2.11 to 3.24), respectively). These findings emphasise that development of incident hypertension in middle age could increase the risk of total, cardiovascular disease and stroke mortality, and suggest that current BP targets could be revised. NCT00342654;Post-results.


Nutritionally essential fatty acids and biologically indispensable cyclooxygenases.
The study of cyclooxygenases (COXs), targets of aspirin and related drugs, is rooted in the discovery of essential fatty acids (EFAs). There are two COXs that convert EFAs, primarily arachidonic acid, to prostaglandins. Each COX is involved with distinct biologies. COX-1 expression is constitutive while COX-2 is inducible. The two COXs might have evolved partly to permit prostaglandin formation at different tissue sites. However, COX-2 is sometimes induced in cells already expressing COX-1, and in these instances, COX-2 functions while COX-1 is latent. This can occur because of unique biochemical properties of COX-2 that enable cells to form prostaglandins when arachidonic acid comprises a small fraction of available fatty acids and the concentrations of peroxides that are necessary for COX to function are low.


Bone Growth Capacity of Human Umbilical Cord Mesenchymal Stem Cells and BMP-2 Seeded Into Hydroxyapatite/Chitosan/Gelatin Scaffold in Alveolar Cleft Defects: An Experimental Study in Goat.
To evaluate bone regeneration in alveolar defects treated with human umbilical cord-derived mesenchymal stem cells (hUCMSCs), hydroxyapatite/chitosan/gelatin (HA/CS/Gel) scaffold, and bone morphogenic protein-2 (BMP-2) in Capra hircus models. Randomized posttest-only control group design. Animal Hospital at Bogor Agricultural Institute. Healthy and equally treated 24 female Capra hircus/goats. Animals were randomly assigned to 3 experimental group design (iliac crest alveolar bone graft/ICABG [control], HA/Cs/Gel+BMP-2 [Novosys], and HA/Cs/Gel+BMP-2+UCMSCs). Graft materials were implanted in surgically made alveolar defects. Postoperative functional score and operating time were assessed. New bone growth, bone density, inflammatory cells recruitment, and neoangiogenesis were evaluated based on radiological and histological approach at 2 time points, week 4 and 12. Statistical analysis was done between treatment groups. Operating time was 34% faster and functional score 94.5% more superior in HA/Cs/Gel+BMP-2+hUCMSC group. Bone growth capacity in HA/Cs/Gel+BMP-2+UCMSCs mimicked ICABG, but ICABG showed possibility of bone loss between week 4 and 12. The HA/Cs/Gel+BMP-2+UCMSCs showed early bone repopulation and unseen inflammatory cells and angiogenesis on week 12. The HA/Cs/Gel+BMP-2+hUCMSCs were superior in enhancing new bone growth without donor site morbidity compared to ICABG. The presence of hUCMSCs in tissue-engineered alveolar bone graft (ABG), supported with paracrine activity of the resident stem cells, initiated earlier new bone repopulation, and completed faster bone regeneration. The HA/Cs/Gel scaffold seeded with UCMSCs+BMP-2 is a safe substitute of ICABG to close alveolar bone defects suitable for patients with cleft lip, alveolus, and palate.


The impact of fiscal transfer payments on energy conservation and emission reduction in China: Does the development stage matter?
Fiscal transfer payments (TRANS) are the institutional supplement of Chinese-style fiscal decentralization, which is of great significance to economic development. However, the relationship between TRANS and energy conservation and emission reduction (ECER) remains to be further discussed. Using panel data of 30 provinces in China from 2003 to 2020, this study empirically examines the impact of TRANS on energy-environmental performance (EEP) from the perspectives of influence mechanism, regional heterogeneity and nonlinearity. The results show that the influence of TRANS on ECER presents an obvious U-shaped relationship, and this influence has regional heterogeneity. At the same time, the investment-driven effect, infrastructure effect and industrial structure effect are important channels through which TRANS affect ECER. The partially linear functional coefficient models show that TRANS have different effects in different development stages. With the continuous improvement of economic level and urbanization level, the promotion effect of TRANS on ECER is more and more obvious. These results indicate that the government should increase fiscal investment in ECER, and pay attention to the development stage of different regions.


Phylogenetic tree construction of butyrylcholinesterase sequences in life forms.
Butyrylcholinesterase is an enzyme with few known physiological functions. It is related to acetylcholine that was shown to be expressed in a variety of life forms. We performed a search using the human butyrylcholinesterase gene (HGNC:983;MIM:177400), and found the sequence in a broad spectrum including plants, bacteria and animals. Therefore butyrylcholinesterase appears to have evolved early in evolution, and to have been conserved.


[Occupational toxic exposure and the pregnant woman. 2: results of a prospective study of 100 pregnancies].
Many women of childbearing age are occupationally exposed to chemicals and concerned with the ensuing risk when pregnant. To present the results of a prospective follow-up study of 100 pregnant women and to discuss them after a brief overview of the published data on this topic. Since January 1996 the Lyon Poison Center has been conducting a prospective follow-up of all request concerning pregnant women occupationally exposed to chemicals. A thorough evaluation of the hazards of the handled products and of the actual exposure at the workplace is done for each patient. A toxicological advice is given and the outcome of the pregnancy is followed-up. One hundred pregnant women were included between January 1996 and December 2000. Based on the nature of the handled products, two groups have been identified: the first included 73 women exposed to organic solvents and the second 27 women exposed to miscellaneous. When the exposure was considered potentially hazardous for the pregnancy, either withdrawal from the workstation (19 cases), avoidance of certain activities (9 cases) or improvement of individual protective measures (29 cases) was recommended. In 43% of the cases, the occupational exposure was not considered hazardous to the outcome of the pregnancy. No increase of adverse outcome was identified: 4 miscarriages and 96 living births were observed, with 2 major malformations and 1 minor malformation. Occupational exposure to chemicals was not found to affect adversely the outcome of these 100 pregnancies.


Biomechanical mechanism of peak braking force modulation during increased walking speed in healthy young adults.
Walking speed is an important indicator of health and function across a variety of populations. Faster walking requires both larger propulsive and braking forces, thoughof the two, propulsive force generation has been far more extensively investigated. This study seeks to develop and validatea quasi-static biomechanical model of braking forcein healthy individualsacrossself-selected and fast walking speeds. Additionally, the model was used to quantify the relative contribution of knee extension torque versus leading limb angle (LLA) to changes in braking force across walking speeds. Kinetic and kinematic data from 44 young healthy participants walking overground at 2 different speeds were analyzed. The model prediction correlated strongly with actual braking force production at the self-selected speed (r = 0.9; p < 0.01), the fast speed (r = 0.97; p < 0.01) andthe change between speeds (r = 0.95, p < 0.01). On average, increases in knee extension torque and the LLA contributed 132 % and 12 %, respectively, to increases in peak braking force (PBF). Increases in the external lever arm length operated to reduce predicted braking force by 56 %. The results highlight the importance of rapid eccentric contraction of the knee extensors during braking force modulation in healthy gait.


Visual performance in idiopathic macular holes.
Previously published reports on the clinical features of idiopathic macular holes highlight the predilection for post-menopausal women and implicate vitreomacular traction in the aetiology of these lesions. Relatively little attention, however, has been paid to the quality of visual loss in eyes with macular holes. Histological studies of full-thickness macular holes have shown loss of all retinal layers in the area of the hole, and this would be expected to produce a central absolute scotoma of the same diameter. The majority of patients with full-thickness holes in this series did not have an absolute scotoma large enough to be detected on the Amsler Chart or when reading. It is suggested that following formation of a macular hole, enlargement may occur without further loss of foveal tissue and without enlargement of the absolute scotoma, due to tangential vitreous traction or contraction of an associated epiretinal membrane.


Murine recessive hereditary spherocytosis, sph/sph, is caused by a mutation in the erythroid alpha-spectrin gene.
Spectrin, a heterodimer of alpha- and beta-subunits, is the major protein component of the red blood cell membrane skeleton. The mouse mutation, sph, causes an alpha-spectrin-deficient hereditary spherocytosis with the severe phenotype typical of recessive hereditary spherocytosis in humans. The sph mutation maps to the erythroid alpha-spectrin locus, Spna1, on Chromosome 1. Scanning electron microscopy, osmotic gradient ektacytometry, cDNA cloning, RT-PCR, nucleic acid sequencing, and Northern blot analyses were used to characterize the wild type and sph alleles of the Spna1 locus. Our results confirm the spherocytic nature of sph/sph red blood cells and document a mild spherocytic transition in the +/sph heterozygotes. Sequencing of the full length coding region of the Spna1 wild type allele from the C57BL/6J strain of mice reveals a 2414 residue deduced amino acid sequence that shows the typical 106-amino-acid repeat structure previously described for other members of the spectrin protein family. Sequence analysis of RT-PCR clones from sph/sph alpha-spectrin mRNA identified a single base deletion in repeat 5 that would cause a frame shift and premature termination of the protein. This deletion was confirmed in sph/sph genomic DNA. Northern blot analyses of the distribution of Spna1 mRNA in non-erythroid tissues detects the expression of 8, 2.5 and 2.0 kb transcripts in adult heart. These results predict the heart as an additional site where alpha-spectrin mutations may produce a phenotype and raise the possibility that a novel functional class of small alpha-spectrin isoforms may exist.


Pyrrolo[3,4-h]quinolinones a new class of photochemotherapeutic agents.
Pyrrolo[3,4-h]quinolin-2-ones were synthesized as nitrogen isosters of the angular furocoumarin angelicin, with the aim of obtaining new photochemotherapeutic agents with increased antiproliferative activity and lower undesired toxic effects. A versatile synthetic pathway was approached to allow the isolation of derivatives of the new ring system with a good substitution pattern on the pyrrole moiety. Photobiological screenings of the new compounds revealed a potent phototoxic effect and a great UVA dose dependence, reaching IC(50) values at submicromolar level. The induced cellular photocytotoxicity was related to apoptosis with the involvement of mitochondria and lysosomes, alteration of cell cycle profile and membrane lipid peroxidation.


An anatomic-based approach for the placement of implantable loop recorders.
Placement of the Reveal implantable loop recorder (ILR; Medtronic Inc., Minneapolis, MN, USA) has previously involved preoperative cutaneous mapping to determine the optimal location. We describe an anatomic-based approach to ILR placement that does not require cutaneous mapping. A total of 63 patients (40 women, 23 men, mean age 38 ± 15 years) were included in the study. Each underwent implantation of a Reveal ILR in the left upper chest area midway between the supraclavicular notch and the left breast area. Thirty-two patients received a Medtronic Reveal DX ILR and 31 received Reveal XT device. In all 62 patients, adequate electrocardiographic tracings were obtained at implant without the need for preoperative cutaneous mapping, and all were followed for a period of 10 ± 4 months afterwards. The mean P wave amplitude was 0.12 ± 0.20 mV at implant and at follow-up (6-14 months postimplant); the amplitude was 0.11 ± 0.19 mV. The peak-to-peak QRS amplitude was 0.48 ± 0.15 mV at implant and 0.44 ± 0.16 mV at a follow-up of 6-14 months. The P waves were not detected in two patients at follow-up. In one patient, decreased amplitude of QRS complex resulted in the autoactivation of the device and in one other patient noise was inappropriately oversensed and recorded. A simple anatomic approach can be used for reveal ILR placement.


Ultra-broadband reflectionless Brewster absorber protected by reciprocity.
The Brewster's law predicts zero reflection of p-polarization on a dielectric surface at a particular angle. However, when loss is introduced into the permittivity of the dielectric, the Brewster condition breaks down and reflection unavoidably appears. In this work, we found an exception to this long-standing dilemma by creating a class of nonmagnetic anisotropic metamaterials, where anomalous Brewster effects with independently tunable absorption and refraction emerge. This loss-independent Brewster effect is bestowed by the extra degrees of freedoms introduced by anisotropy and strictly protected by the reciprocity principle. The bandwidth can cover an extremely wide spectrum from dc to optical frequencies. Two examples of reflectionless Brewster absorbers with different Brewster angles are both demonstrated to achieve large absorbance in a wide spectrum via microwave experiments. Our work extends the scope of Brewster effect to the horizon of nonmagnetic absorptive materials, which promises an unprecedented wide bandwidth for reflectionless absorption with high efficiency.


Action of oral and parenteral bethanechol on decompensated bladder.
A double blind balanced Latin-square study was conducted on 20 adult patients with decompensated bladders to determine the relative effectiveness of oral and parenteral bethanechol chloride (Urecholine) on the stretch response of bladder muscle. Detrusor reaction was measured by modified cystometry. Five mg. of subcutaneous bethanechol chloride produced a significant increase in intravesical pressure which was more rapid in onset, of larger magnitude, and of shorter duration than oral doses of 100 and 200 mg.


Identification of circulating CD31+CD45+ cell populations with the potential to differentiate into erythroid cells.
Erythro-myeloid progenitors (EMP) are found in a population of cells expressing CD31 and CD45 markers (CD31+CD45+). A recent study indicated that EMPs persist until adulthood and can be a source of endothelial cells. We identified two sub-populations of EMP cells, CD31lowCD45low and CD31highCD45+, from peripheral blood that can differentiate into cells of erythroid lineage. Our novel findings add to the current knowledge of hematopoietic lineage commitment, and our sequential, dual-step, in vitro culture model provides a platform for the study of the molecular and cellular mechanisms underlying human hematopoiesis and erythroid differentiation.


Feedback regulation of human pancreatic secretion. Effects of protease inhibition on duodenal delivery and small intestinal transit of pancreatic enzymes.
To determine the effects of luminal protease inhibition on duodenal delivery and the intraluminal fate of pancreatic enzymes, six healthy subjects were intubated with an oro-ileal multilumen tube assembly. By using nonabsorbable markers, cumulative trypsin, chymotrypsin, lipase, and amylase activities were measured as delivered to duodenum, midjejunum, and distal ileum, with or without simultaneous duodenal perfusion of the protease inhibitor camostat at graded doses. Compared with saline, camostat (a) inhibited trypsin activity in the entire small intestinal lumen by up to 99%, and significantly reduced chymotrypsin activity by up to 89%; (b) significantly increased duodenal deliveries of lipase activity, amylase activity and volume; (c) did not influence plasma cholecystokinin concentrations; and (d) significantly increased jejunal and ileal deliveries of lipase but not amylase activity. Small intestinal transit and motility were not affected by camostat. In additional in vitro studies, camostat significantly reduced the spontaneous decline in lipase activity in fresh human duodenal juice incubated at 37 degrees C. These findings demonstrate that duodenal deliveries of lipase and amylase activities increase when intraluminal protease activity is decreased; they suggest that this increase is not caused by slower proteolytic destruction of enzyme protein but by stimulation of pancreatic secretion. Thus, luminal protease-mediated feedback regulation of pancreatic secretion may be operative in humans. Because plasma cholecystokinin concentrations were not affected, these effects may in part be independent of cholecystokinin. The data further suggest that proteolytic digestion plays a major role in the rapid loss of luminal lipase activity on small intestinal transit.


Patellar shape is associated with femoral trochlear morphology in individuals with mature skeletal development.
As several studies have detected correlations between patellar and femoral trochlear development, this raises the question of whether patellar shape is associated with trochlear developmental outcomes. Patellar shape and femoral trochlear morphology were retrospectively analyzed in 183 subjects, of whom 61 each were classified as having Wiberg type I, II, and III patellae (groups A, B, and C, respectively). The sulcus angle (SA), lateral trochlea inclination angle (LTA), medial trochlear inclination angle (MTA), lateral facet length (LFL), medial facet length (MFL), lateral trochlear height (LTH), medial trochlear height (MTH), trochlea sulcus height (TH), and lateral-medial trochlear facet distance (TD) were analyzed as a means of evaluating trochlear morphology. Trochlear depth, trochlear condyle asymmetry, and trochlear facet asymmetry were additionally calculated, and differences in trochlear morphology and correlations between trochlear morphology and patellar shape were evaluated. The femoral trochlear parameters of patients in group A differed significantly from those of patients in groups B and C. No significant differences between groups B and C were evident. Patellar shape was positively correlated with LTA, MTA, MFL, trochlear condyle asymmetry, and trochlear facet asymmetry, and was negatively correlated with SA. These data indicated that patellar shape and trochlear morphology are related to one another,which suggest normalized patella morphology surgery and trochlear surgery are better choices for patients with patella instability. Retrospectively registered.


Peritoneal dialysis: a clinical update congestive heart failure and PD.
There is a belief that peritoneal dialysis may be an important treatment modality for refractory heart failure, allowing at least an improvement in quality if not quantity of life during the last stage of this debilitating chronic disease. This paper examines the rationale behind this modality, critically appraises the available literature, calls for more research in the area and puts forward a framework for considering peritoneal dialysis in refractory heart failure. When faced with a patient with refractory heart failure admitted to hospital on multiple occasions because of complications of volume overload, the following approach to initiating peritoneal dialysis should be considered: subjects for dialysis must have a minimal blood pressure, and those whose hemodynamic status improves with diuresis, even though they develop a pre-renal picture, may be the best candidates.


Effect of pre-exposure use of hydroxychloroquine on COVID-19 mortality: a population-based cohort study in patients with rheumatoid arthritis or systemic lupus erythematosus using the OpenSAFELY platform.
Hydroxychloroquine has been shown to inhibit entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into epithelial cells in vitro, but clinical studies found no evidence of reduced mortality when treating patients with COVID-19. We aimed to evaluate the effectiveness of hydroxychloroquine for prevention of COVID-19 mortality, as opposed to treatment for the disease. We did a prespecified observational, population-based cohort study using national primary care data and linked death registrations in the OpenSAFELY platform, which covers approximately 40% of the general population in England, UK. We included all adults aged 18 years and older registered with a general practice for 1 year or more on March 1, 2020. We used Cox regression to estimate the association between ongoing routine hydroxychloroquine use before the COVID-19 outbreak in England (considered as March 1, 2020) compared with non-users of hydroxychloroquine and risk of COVID-19 mortality among people with rheumatoid arthritis or systemic lupus erythematosus. Model adjustment was informed by a directed acyclic graph. Between Sept 1, 2019, and March 1, 2020, of 194 637 people with rheumatoid arthritis or systemic lupus erythematosus, 30 569 (15·7%) received two or more prescriptions of hydroxychloroquine. Between March 1 and July 13, 2020, there were 547 COVID-19 deaths, 70 among hydroxychloroquine users. Estimated standardised cumulative COVID-19 mortality was 0·23% (95% CI 0·18 to 0·29) among users and 0·22% (0·20 to 0·25) among non-users; an absolute difference of 0·008% (-0·051 to 0·066). After accounting for age, sex, ethnicity, use of other immunosuppressive drugs, and geographical region, no association with COVID-19 mortality was observed (HR 1·03, 95% CI 0·80 to 1·33). We found no evidence of interactions with age or other immunosuppressive drugs. Quantitative bias analyses indicated that our observed associations were robust to missing information for additional biologic treatments for rheumatological disease. We observed similar associations with the negative control outcome of non-COVID-19 mortality. We found no evidence of a difference in COVID-19 mortality among people who received hydroxychloroquine for treatment of rheumatological disease before the COVID-19 outbreak in England. Therefore, completion of randomised trials investigating pre-exposure prophylactic use of hydroxychloroquine for prevention of severe outcomes from COVID-19 are warranted. Medical Research Council.


Trends in risk factors for cardiovascular disease among Iranian adolescents: the Tehran Lipid and Glucose Study, 1999-2008.
Data on secular trends in adolescent obesity and dyslipidemia are limited. Data on obesity status collected during 3 surveys were used to evaluate these trends in obesity and dyslipidemia among Tehranian adolescents and to assess the likelihood of risk factors for cardiovascular disease. We analyzed data for adolescents (age 10 to 19 years) from 3 cross-sectional surveys of the Tehran Lipid and Glucose Study: 1999-2001 (n = 3010, 47.2% males), 2002-2005 (n = 1107, 48.4% males), and 2006-2008 (n = 1090, 46.6% males). Overweight and abdominal obesity were defined using Iranian body mass index (BMI) percentiles, International Obesity Task Force (IOTF) criteria, and Iranian waist circumference (WC) charts. Hypertension was defined by using the National Heart, Lung, and Blood Institute's recommended cut points, and dyslipidemia was defined according to the recent recommendations of the American Heart Association. The overall adjusted prevalences of "at risk for overweight" and overweight changed from 13% and 8% (using Iranian cutoffs), respectively, and 14.8% and 4.7% (using IOTF criteria) in 1999-2001 to 19% and 15% (Iranian cutoffs) and 23.0% and 9.2% (IOTF criteria) in 2006-2008 (P < 0.01 for all comparisons). The prevalence of abdominal obesity increased in males from 14.5% in 1999-2001 to 33.3% in 2006-2008 (P < 0.001). Almost half the adolescents had low high-density lipoprotein cholesterol (HDL-C) in the 3 surveys. In all surveys, as BMI and WC increased, multivariate age- and sex-adjusted odds ratios of low HDL-C and high triglyceride levels significantly increased. Overweight was associated with a greater likelihood of these risk factors, as compared with increased WC. Overweight and abdominal obesity are increasing in Tehranian adolescents, and these increases are accompanied by abnormalities in levels of serum triglyceride and HDL-C.


Catalyst-Free Trans-Selective Oxyiodination and Oxychlorination of Alkynes Employing N-X (Halogen) Reagents.
β-halogenated enol esters and ethers are versatile building blocks in organic synthesis, which has attracted increasing attention. In this study, we report the facile trans-oxyiodination and oxychlorination of alkynes, leading to the direct construction of versatile halogenated enol esters and ethers. This transformation features an easy operation, optimal atomic economy, a strong functional group tolerance, broad substrate scope, and excellent trans-selectivity. Employing highly electrophilic bifunctional N-X (halogen) reagents was the key to achieving broad reaction generality. To our knowledge, this transformation represents the first oxyhalogenation system employing N-X (halogen) reagents as both oxylation and halogenation sources.


Saliva-based COVID-19 detection: A rapid antigen test of SARS-CoV-2 nucleocapsid protein using an electrical-double-layer gated field-effect transistor-based biosensing system.
Facing the unstopped surges of COVID-19, an insufficient capacity of diagnostic testing jeopardizes the control of disease spread. Due to a centralized setting and a long turnaround, real-time reverse transcription polymerase chain reaction (real-time RT-PCR), the gold standard of viral detection, has fallen short in timely reflecting the epidemic status quo during an urgent outbreak. As such, a rapid screening tool is necessitated to help contain the spread of COVID-19 amid the countries where the vaccine implementations have not been widely deployed. In this work, we propose a saliva-based COVID-19 antigen test using the electrical double layer (EDL)-gated field-effect transistor-based biosensor (BioFET). The detection of SARS-CoV-2 nucleocapsid (N) protein is validated with limits of detection (LoDs) of 0.34 ng/mL (7.44 pM) and 0.14 ng/mL (2.96 pM) in 1× PBS and artificial saliva, respectively. The specificity is inspected with types of antigens, exhibiting low cross-reactivity among MERS-CoV, Influenza A virus, and Influenza B virus. This portable system is embedded with Bluetooth communication and user-friendly interfaces that are fully compatible with digital health, feasibly leading to an on-site turnaround, an effective management, and a proactive response taken by medical providers and frontline health workers.


Upstream flood pattern recognition based on downstream events.
Reverse stream flood routing determines the upstream hydrograph in a stream reach given the downstream hydrograph. The Muskingum model of flood routing involves parameters that govern the routed hydrograph. These parameters are herein estimated using simulation methods coupled with optimization tools to achieve optimized parameters. Different simulation methods are shown to perform unequally in the estimation of nonlinear Muskingum parameters. This paper presents two simulation methods for nonlinear Muskingum reverse flood routing: (1) Euler equations and (2) Runge-Kutta 4th order equations. Moreover, the generalized reduced gradient (GRG) is used as the optimization tool that minimized the sum of the squared deviations (SSQ) between observed and routed inflows in a benchmark flood routing problem. Results show the Runge-Kutta 4th order equations yield better routed hydrographs with smaller SSQ than obtained in previous research and with the first simulation method (Euler equations).


Effectiveness of mindfulness-based interventions on anxiety, depression, and fatigue in people with lung cancer: A systematic review and meta-analysis.
Lung cancer is one of the most common cancers and poses a physical and psychological threat to patients. Mindfulness-based interventions are emerging forms of psychotherapy that are effective in improving physical and psychological symptoms, but no review has summarized their effectiveness on anxiety, depression, and fatigue in people with lung cancer. To evaluate the effectiveness of mindfulness-based interventions in reducing anxiety, depression, and fatigue in people with lung cancer. Systematic review and meta-analysis. We searched the PubMed, Web of Science, Embase, China Biology Medicine disc, Wanfang Data, China National Knowledge Infrastructure, and China Science and Technology Journal databases from inception to 13 April 2022. Eligible studies included randomized controlled trials of people with lung cancer receiving mindfulness-based interventions reporting on the outcomes of anxiety, depression, and fatigue. Two researchers independently reviewed the abstracts and full texts, extracted the data and assessed the risk of bias independently by using the Cochrane 'Risk of bias assessment tool'. The meta-analysis was performed by using Review Manager 5.4, and the effect size was calculated by the standardized mean difference and its 95% confidence interval. The systematic review included 25 studies (2420 participants), whereas the meta-analysis included 18 studies (1731 participants). Mindfulness-based interventions significantly decreased levels of anxiety [standardized mean difference = -1.15, 95% confidence interval (-1.36, -0.94), Z = 10.75, P < 0.001], depression [standardized mean difference = -1.04, 95% confidence interval (-1.60, -0.48), Z = 3.66, P < 0.001], and fatigue [standardized mean difference = -1.29, 95% confidence interval (-1.66, -0.91), Z = 6.79, P < 0.001]. The subgroup analysis indicated that programs lasting less than eight weeks in length with structured intervention components (e.g., mindfulness-based stress reduction and mindfulness-based cognitive therapy) and 45 min of daily home practice implemented in patients with advanced stage lung cancer showed better effects than programs lasting more than eight weeks in length with less structured components and more than 45 min of daily home practice implemented in patients with mixed stage lung cancer. The overall quality of the evidence was low due to the lack of allocation concealment and blinding and the high risk of bias in most studies (80%). Mindfulness-based interventions might be effective in reducing anxiety, depression, and fatigue in people with lung cancer. However, we cannot draw definitive conclusions because the overall quality of the evidence was low. More rigorous studies are needed to confirm the effectiveness and examine which intervention components may be most effective for improved outcomes.


Sox2 cooperates with Lkb1 loss in a mouse model of squamous cell lung cancer.
Squamous cell carcinoma (SCC) of the lung is the second most common subtype of lung cancer. With limited treatment options, the 5-year survival rate of SCC is only 15%. Although genomic alterations in SCC have been characterized, identifying the alterations that drive SCC is critical for improving treatment strategies. Mouse models of SCC are currently limited. Using lentiviral delivery of Sox2 specifically to the mouse lung, we tested the ability of Sox2 to promote tumorigenesis in multiple tumor suppressor backgrounds. Expression of Sox2, frequently amplified in human SCC, specifically cooperates with loss of Lkb1 to promote squamous lung tumors. Mouse tumors exhibit characteristic histopathology and biomarker expression similar to human SCC. They also mimic human SCCs by activation of therapeutically relevant pathways including STAT and mTOR. This model may be utilized to test the contribution of additional driver alterations in SCC, as well as for preclinical drug discovery.


Public engagement in the development of the National Health Insurance: a study involving patients from a central hospital in South Africa.
The National Health Insurance (NHI) is a proposed health policy in South Africa that aims to change the structure of the current health system. Public involvement in policy making is important and it is a constitutional requirement in the legislation development process in South Africa. Patients are key stakeholders and should be engaged in NHI policy process. Before patients can be engaged, they need to be provided with sufficient information about the NHI. Therefore, the aim of this exploratory study was to examine the levels of patient awareness of the NHI, which is a requisite for meaningful engagement. This was a cross sectional study of 244 patients from the follow-up clinics at the Department of Internal Medicine, Charlotte Maxeke Johannesburg Academic Hospital in the Gauteng Province, South Africa. The patients were interviewed using a structured interview process and a questionnaire. Descriptive statistics and logistic regression analyses were conducted. The majority (79.51%) of the participants were not aware of the proposed National Health Insurance (NHI) in South Africa even though the NHI policy process commenced in 2011. Of the participants who were aware of the NHI, 86% responded that they had not been provided with an opportunity to be involved in the policy making process of the NHI. The odds of awareness were higher for male (OR: 2.08, 95% CI: 1.11-3.9, p value: 0.02) than female participants; White (OR: 2.36, 95% CI: 1.06-5.26, p value: 0.04) and Indian (OR: 2.76, 95% CI: 0.10-7.60, p value: 0.05) participants when compared to Black participants; and retired (OR: 3.13, 95% CI: 1.35-7.25, p value: 0.008) than unemployed participants. The levels of awareness of the NHI were low among the participants from Department of Internal Medicine, CMJAH. Without the awareness and information about the NHI, patients are not equipped to be involved in the NHI policy process in a meaningful way. Public patients are the intended beneficiaries of universal health coverage, therefore they should be prioritized in the NHI community engagement process to ensure that the NHI is community and patient centred.


A study of membrane potential across isolated fruit cuticles for NaCl and CaCl2 solutions.
Fixed charge density and ionic diffusion ratio in an isolated tomato fruit cuticular membrane have been estimated from membrane potential measurements for NaCl and CaCl2 electrolyte solutions. The values of the parameters studied show marked differences in the electrical behaviour of the electrolytes, and evidence the asymmetric character of the cuticular membrane. While the membrane potential values for NaCl solutions can be explained in terms of a Donnan potential plus diffusion potentials, for CaCl2 solutions the membrane potential values agree very well with the diffusion potential. These facts could be explained by taking into account some structural features of the cuticular membrane.


Out-of-hospital cardiac arrest outcomes when law enforcement arrives before emergency medical services.
Law enforcement (LE) professionals are often dispatched to out-of-hospital cardiac arrests (OHCA) to provide early cardiopulmonary resuscitation (CPR) and automated external defibrillator (AED) application with mixed evidence of a survival benefit. Our objective was to comprehensively evaluate LE care in OHCA. This is a secondary analysis of adults with non-traumatic OHCA not witnessed by EMS and without bystander AED use from 2018-2021. Our primary outcome was survival with Cerebral Perfusion Category score ≤ 2 (functional survival). Our exposures included: LE On-scene Only (without providing care); LE CPR Only (without applying an AED); LE Ideal Care (ensuring CPR and AED application). Our control group had no LE arrival before EMS. We performed multivariable logistic regression analyses adjusting for confounders and stratified our analyses by patients with and without bystander CPR. There were 2569 adult, non-traumatic OHCAs from 2018-2021 meeting inclusion criteria. There were no differences in the odds of functional survival for LE On-scene Only (adjusted odds ratio [95% CI]: 1.28 [0.47-3.45]), LE CPR Only (1.26 [0.80-1.99]), or LE Ideal Care (1.36 [0.79-2.33]). In patients without bystander CPR, LE Ideal Care had significantly higher odds of functional survival (2.01 [1.06-3.81]) compared to no LE on-scene, with no significant associations for LE On-scene Only or LE CPR Only. There were no significant differences by LE care in patients already receiving bystander CPR. LE arrival before EMS and ensuring both CPR and AED application is associated with significantly improved functional survival in OHCA patients not already receiving bystander CPR.


Clostridium perfringens enterotoxin damages the human intestine in vitro.
In vitro, Clostridium perfringens enterotoxin (CPE) binds to human ileal epithelium and induces morphological damage concurrently with reduced short-circuit current, transepithelial resistance, and net water absorption. CPE also binds to the human colon in vitro but causes only slight morphological and transport changes that are not statistically significant.


Leptomeningeal dissemination in pediatric brain tumors.
Leptomeningeal disease (LMD) in pediatric brain tumors (PBTs) is a poorly understood and categorized phenomenon. LMD incidence rates, as well as diagnosis, treatment, and screening practices, vary greatly depending on the primary tumor pathology. While LMD is encountered most frequently in medulloblastoma, reports of LMD have been described across a wide variety of PBT pathologies. LMD may be diagnosed simultaneously with the primary tumor, at time of recurrence, or as primary LMD without a primary intraparenchymal lesion. Dissemination and seeding of the cerebrospinal fluid (CSF) involves a modified invasion-metastasis cascade and is often the result of direct deposition of tumor cells into the CSF. Cells develop select environmental advantages to survive the harsh, nutrient poor and turbulent environment of the CSF and leptomeninges. Improved understanding of the molecular mechanisms that underlie LMD, along with improved diagnostic and treatment approaches, will help the prognosis of children affected by primary brain tumors.


Toxicity of amphotericin B to analbuminemic rats.
Nagase analbuminemic rats (NAR), a strain derived from Sprague Dawley rats (SDR), are suitable to determine the in vivo effect of hyperlipidemia and analbuminemia on the toxicity of the antifungal agent amphotericin B (AB). Cholesterol content was increased in all plasma lipoprotein fractions when SDR serum was compared with NAR serum. Incubation of AB with plasma from animals of both strains and further isolation of plasma lipoprotein by ultracentrifugation, showed that, while in SDR approximately 40% of the injected AB was in the lipoprotein fraction, in NAR almost all (approximately 80%) AB was associated with lipoproteins, especially in the low density lipoprotein fraction. AB spectrophotometry showed differences in the extent of AB aggregation between SDR and NAR plasma fractions. The lack of albumin results in aggregation of the AB present in the infranatant fraction. In vivo, a strong reduction in lethality was observed for NAR when compared to SDR (LD 50% of 6.4 and 1.9 mg/kg respectively). The preferential distribution of AB in the plasma lipoprotein fraction seems to affect pharmacological parameters, with a consequent reduction of toxicity.


The frontal pole and cognitive insight in schizophrenia.
Absence of insight owing to impaired self-reflection and lack of touch with reality is a hallmark of schizophrenia. Functional imaging studies in healthy individuals have implicated the frontal pole (FP), sub-division of the prefrontal cortex in self-reflective processes. Despite the significance of self-referential processing in the pathogenesis of schizophrenia, the relationship between FP volume and cognitive insight in this disorder is underexplored. We examined the relationship between cognitive insight and volume of FP using precise manual morphometry of high resolution magnetic resonance images in 19 schizophrenia patients (SCZ) and 21 healthy-volunteers (HV). The manual morphometry technique was replicated from a previous study based on a cytoarchitectonically and functionally valid definition of FP and cognitive insight was measured using Beck's cognitive insight scale. Left frontal pole volume was a significant predictor of self-reflection sub-score of Beck's cognitive insight scale (β=0.68; t = 2.86; p = 0.01). A significant inverse relationship between age and bilateral FP volumes was noted in HV (left FP - r=-0.45; p = 0.04; right FP - r=-0.57; p = 0.008) but not in SCZ (p>0.05). Our findings provide anatomical substrates to devise intervention strategies targeting cognitive insight, thereby improving treatment adherence and functional outcomes.


Melkersson-Rosenthal syndrome in the context of sarcoidosis: a case report.
Melkersson-Rosenthal syndrome is a rare disease characterized by the triad of recurrent orofacial swelling with facial paralysis and fissured dorsal tongue. Histologically, noncaseating granulomatous inflammation occurs that confirms the diagnosis. Overlaps between granulomatous diseases such as sarcoidosis and Crohn's disease are described. Systemic corticosteroid therapy is the treatment of choice for acute attacks. We here present a case of a 59-year-old White woman suffering from Melkersson-Rosenthal syndrome with a past history of sarcoidosis on therapy with leflunomide in combination with low-dose tacrolimus successfully treated with the anti-leprosy drug clofazimine after failure of systemic steroid therapy. We propose clofazimine as an alternative treatment in steroid-refractory cases.


Risk assessment of radon in drinking water in Khetri Copper Belt of Rajasthan, India.
Exceptionally high concentrations of radon have been found in drinking water originating from hand pumps in Khetri Copper Belt of Rajasthan. Radon concentration was determined using Durridge RAD7 professional electronic radon detector. The measured radon concentration ranged from 12.5 ± 1.5 to 862 ± 38 Bq l-1. About 35% of the drinking water samples showed radon concentrations above the European Union's parametric value of 100 Bq l-1. The high radon concentration obtained in groundwater is due to local natural geology. The total annual effective doses due to ingestion and inhalation of radon in drinking water varied from 0.10 to 6.7 mSv y-1 for infants, 0.06-3.8 mSv y-1 for children and 0.06-4.4 mSv y-1 for adults.


Sensitive on-chip detection of a protein biomarker in human serum and plasma over an extended dynamic range using silicon photonic microring resonators and sub-micron beads.
We demonstrate a three-step assay on a silicon photonic microring resonator-based detection platform that enables the quantitation of the cardiac biomarker C-reactive protein (CRP) over a dynamic range spanning six orders of magnitude. Using antibody-modified microrings, we sequentially monitor primary CRP binding, secondary recognition of bound CRP by a biotinylated antibody, and tertiary signal amplification using streptavidin-functionalized beads. This detection methodology is applied to CRP quantitation in human serum and plasma samples.


Getting to 100%: Research Priorities and Unanswered Questions to Inform the US Debate on Universal Health Insurance Coverage.
A majority of Americans favor universal health insurance, but there is uncertainty over how best to achieve this goal. Whatever the insurance design that is implemented, additional details that must be considered include breadth of services covered, restrictions and limits on volumes of services, cost-sharing for individuals, and pricing. In the hopes that research can inform this ongoing debate, we review evidence supporting different models for achieving universal coverage in the US and identify areas where additional research and stakeholder input is needed. Key areas in need of further research include how care should be organized, how costs can be reduced, and what healthcare services universal insurance should cover.


Diabetes and Prostate Cancer Outcomes in Obese and Nonobese Men After Radical Prostatectomy.
The link between diabetes and prostate cancer progression is poorly understood and complicated by obesity. We investigated associations between diabetes and prostate cancer-specific mortality (PCSM), castrate-resistant prostate cancer (CRPC), and metastases in obese and nonobese men undergoing radical prostatectomy (RP). We included 4688 men from the Shared Equal Access Regional Cancer Hospital cohort of men undergoing RP from 1988 to 2017. Diabetes prior to RP, anthropometric, and clinical data were abstracted from 6 Veterans Affairs Medical Centers electronic medical records. Primary and secondary outcomes were PCSM and metastases and CRPC, respectively. Multivariable-adjusted hazard ratios (adj-HRs) and 95% confidence intervals (CIs) were estimated for diabetes and PCSM, CRPC, and metastases. Adjusted hazard ratios were also estimated in analyses stratified by obesity (body mass index: nonobese <30 kg/m2; obese ≥30 kg/m2). All statistical tests were 2-sided. Diabetes was not associated with PCSM (adj-HR = 1.38, 95% CI = 0.86 to 2.24), CRPC (adj-HR = 1.05, 95% CI = 0.67 to 1.64), or metastases (adj-HR = 1.01, 95% CI = 0.70 to 1.46), among all men. Interaction terms for diabetes and obesity were statistically significant in multivariable models for PCSM, CRPC, and metastases (P ≤ .04). In stratified analyses, in obese men, diabetes was associated with PCSM (adj-HR = 3.06, 95% CI = 1.40 to 6.69), CRPC (adj-HR = 2.14, 95% CI = 1.11 to 4.15), and metastases (adj-HR = 1.57, 95% CI = 0.88 to 2.78), though not statistically significant for metastases. In nonobese men, inverse associations were suggested for diabetes and prostate cancer outcomes without reaching statistical significance. Diabetes was associated with increased risks of prostate cancer progression and mortality among obese men but not among nonobese men, highlighting the importance of aggressively curtailing the increasing prevalence of obesity in prostate cancer survivors.


What can we learn from monitoring PCBs in the European eel? A Belgian experience.
Between 2000 and 2007 pooled muscle tissue samples of the European eel (Anguilla anguilla) from 48 sites in Flanders (Belgium) were analysed for 30 polychlorinated biphenyl (PCB) congeners. There was a large variation between individual sites (range 11-7752 ng/g wet weight (ww) for the sum of the ICES 7 PCBs), eels from the River Meuse basin (mean 1545 ng/g ww) being considerably more polluted than those from the River Scheldt (615) and IJzer (61) basins. Overall, PCB 153, PCB 138 and PCB 180 were the most prominent congeners, however PCB patterns varied between the monitored locations. Analysis of the weight percentage of congeners demonstrates obvious differences in PCB composition between sites, indicating differential sources of pollution. Due to the variation in patterns, atmospheric fallout does not seem to be the main source of the PCB spread, but instead both local and upstream sources linked to industrial activities seem to be the main cause for PCB presence in Flanders. Considering the levels of the Sum 7 PCBs, eels are not compliant with the Belgian legal limits for consumption (75 ng/g ww) in 71% of the sites. Regular consumption of eels from polluted sites leads to a considerable excess of the WHO Acceptable Daily Intake value. Consumption of wild eels should by all means be prevented, as it presents risks for human health, especially for local anglers consuming their catch.


Annexin A1 protects against cerebral ischemia-reperfusion injury by modulating microglia/macrophage polarization via FPR2/ALX-dependent AMPK-mTOR pathway.
Cerebral ischemia-reperfusion (I/R) injury is a major cause of early complications and unfavorable outcomes after endovascular thrombectomy (EVT) therapy in patients with acute ischemic stroke (AIS). Recent studies indicate that modulating microglia/macrophage polarization and subsequent inflammatory response may be a potential adjunct therapy to recanalization. Annexin A1 (ANXA1) exerts potent anti-inflammatory and pro-resolving properties in models of cerebral I/R injury. However, whether ANXA1 modulates post-I/R-induced microglia/macrophage polarization has not yet been fully elucidated. We retrospectively collected blood samples from AIS patients who underwent successful recanalization by EVT and analyzed ANXA1 levels longitudinally before and after EVT and correlation between ANXA1 levels and 3-month clinical outcomes. We also established a C57BL/6J mouse model of transient middle cerebral artery occlusion/reperfusion (tMCAO/R) and an in vitro model of oxygen-glucose deprivation and reoxygenation (OGD/R) in BV2 microglia and HT22 neurons to explore the role of Ac2-26, a pharmacophore N-terminal peptide of ANXA1, in regulating the I/R-induced microglia/macrophage activation and polarization. The baseline levels of ANXA1 pre-EVT were significantly lower in 23 AIS patients, as compared with those of healthy controls. They were significantly increased to the levels found in controls 2-3 days post-EVT. The increased post-EVT levels of ANXA1 were positively correlated with 3-month clinical outcomes. In the mouse model, we then found that Ac2-26 administered at the start of reperfusion shifted microglia/macrophage polarization toward anti-inflammatory M2-phenotype in ischemic penumbra, thus alleviating blood-brain barrier leakage and neuronal apoptosis and improving outcomes at 3 days post-tMCAO/R. The protection was abrogated when mice received Ac2-26 together with WRW4, which is a specific antagonist of formyl peptide receptor type 2/lipoxin A4 receptor (FPR2/ALX). Furthermore, the interaction between Ac2-26 and FPR2/ALX receptor activated the 5' adenosine monophosphate-activated protein kinase (AMPK) and inhibited the downstream mammalian target of rapamycin (mTOR). These in vivo findings were validated through in vitro experiments. Ac2-26 modulates microglial/macrophage polarization and alleviates subsequent cerebral inflammation by regulating the FPR2/ALX-dependent AMPK-mTOR pathway. It may be investigated as an adjunct strategy for clinical prevention and treatment of cerebral I/R injury after recanalization. Plasma ANXA1 may be a potential biomarker for outcomes of AIS patients receiving EVT.


Combination of Panax notoginseng saponins and aspirin potentiates platelet inhibition with alleviated gastric injury via modulating arachidonic acid metabolism.
High platelet reactivity and gastric mucosal injury after aspirin (ASA) treatment are associated with poor compliance and an increased risk of cardiovascular events. Panax notoginseng saponins (PNS) have been widely used for the treatment of coronary heart disease (CHD) in addition to antiplatelet drugs in China; however, the joint effect and possible mechanism of PNS in addition to ASA on platelet activation and gastric injury remain unclear. This study was designed to investigate the combinational effects of PNS with ASA, and to explore the underlying mechanism via arachidonic acid (AA) metabolism pathway using lipidomic analysis. In a randomized, assessor-blinded trial, 42 patients with stable coronary heart disease (SCHD) and chronic gastritis were randomly assigned to receive ASA (n = 21) or PNS + ASA (n = 21) for 2 months. Compared with ASA alone, PNS + ASA further inhibited CD62p expression, GPIIb-IIIa activation and platelet aggregation and led to increased platelet inhibition rate. PNS + ASA suppressed the activity of platelet cyclooxygenase (COX)-1, and decreased the production of TXB2, PGD2, PGE2, 11-HETE, the downstream oxylipids of AA/COX-1 pathway in platelets, compared with ASA alone. The severity of dyspepsia assessment (SODA) results showed that patients in PNS + ASA group exhibited relieved dyspeptic symptoms as compared with those in ASA group, which might be associated with enhanced secretion of gastrin and motilin. In vivo study of myocardial infarction rats demonstrated that PNS attenuated ASA-induced gastric mucosal injury, which was related to markedly boosted gastric level of 6,15-diketo-13,14-dihydro-prostaglandin (PG)F1α, 13,14-dihydro-15-keto-PGE2 and PGE2 from AA/PG pathway in response to PNS + ASA compared with ASA alone. In summary, our study demonstrated that the combination of PNS and ASA potentiated the antiplatelet effect of ASA via AA/COX-1/TXB2 pathway in platelets, and mitigated ASA-related gastric injury via AA/PG pathway in gastric mucosa.


The 7th cervical vertebra wall distance (C7WD) identifies balance control, functional mobility and the risk of multiple falls in elderly community-dwelling women with thoracic hyperkyphosis.
Thoracic hyperkyphosis is common in the elderly, especially in women, and results in impaired balance control, impaired functional mobility and an increased risk of multiple falls. The 7th cervical vertebra wall distance (C7WD) is a practical method for evaluating thoracic hyperkyphosis. This study calculated C7WD cut-off scores that may identify impaired balance control, impaired functional mobility and an increased risk of multiple falls in elderly community-dwelling women with thoracic hyperkyphosis. This study also explored the correlation between C7WD, balance control and functional mobility. Sixty participants were assessed for thoracic hyperkyphosis using the C7WD, balance control using the functional reach test (FRT), functional mobility using the timed up-and-go test (TUG) and a history of falls using their personal information. The data indicated that a C7WD of at least 7.95 cm, 8.1 cm and 8.8 cm had a good to excellent capability of identifying impaired balance control, impaired functional mobility and an increased risk of multiple falls, respectively. The C7WD results were significant and correlated with balance control (rs=-0.68) and functional mobility (rs= 0.41). The C7WD may be utilised as a screening tool for these three impairments in this population.


In situ immunogold labeling analysis of the rice hoja blanca virus nucleoprotein and major noncapsid protein.
Ribonucleoprotein particles (RNPs) of rice hoja blanca virus (RHBV) were purified and used for electron microscopic analysis and antibody production. Antibodies made to RNPs specifically decorated purified RNPs. The RNPs typically showed characteristic tenuivirus morphologies. They were approximately 8 nm in diameter, mostly circular in nature, and exhibited branching and a high degree of superhelicity. When the RNP antibodies were used for in situ immunogold labeling analysis of RHBV-infected tissues, no specific structures were identified, but gold particles were distributed throughout the cytosol of RHBV-infected but not healthy plants. However, amorphous semi-electron opaque inclusion bodies (ASO-IBs) were abundant in cells of RHBV-infected plants. While the ASO-IBs were not labeled with the anti-RNP antiserum, they were specifically labeled with antibodies to the RHBV major noncapsid protein (NCP) and with antibodies to the NCP of another tenuivirus, maize stripe virus.


In vitro and in vivo characterization of a high-purity, solvent/detergent-treated factor VIII concentrate: evidence for its therapeutic efficacy in von Willebrand's disease.
A factor VIII (FVIII) concentrate, virus-inactivated by the solvent/detergent procedure, was studied in vitro. In contrast with most high-purity, virus-inactivated FVIII concentrates, it contains not only high levels of von Willebrand factor (vWF) antigen and ristocetin cofactor activity but also high molecular weight forms of von Willebrand factor. Furthermore, it is able to promote platelet adhesion on collagen in a perfusion system. In vivo studies performed in patients with different types of von Willebrand's disease provided evidence that this concentrate corrects Duke's bleeding time and prevents or stops haemorrhages. Thus, the particular advantages of this FVIII/vWF preparation are safety, low content of contamination proteins, and efficacy in von Willebrand's disease.


A normative study of auditory perception in Mandarin-speaking children with categories of auditory Performance-II.
The aim of this study is to investigate the development of auditory skills in Mandarin-speaking children with normal hearing using CAP-II, and to establish the baseline data for evaluating the auditory performance of children with hearing loss on which designs of appropriate hearing rehabilitation programs can be based. A total of 223 children participated in this study of which 200 children aged from 1 to 60 months were finally included. Their normal hearing was confirmed by examination of hearing history and high-risk registers for hearing loss, as well as by hearing screening. All children were divided into 10 groups with 20 children in each group based on age. The CAP-II scale was administered to evaluate their development of auditory skills. The categories of auditory performance scores of children with normal hearing improved with their age, the best-fit regression function for prediction of scores from age was Score = 0.94 × ln(age) + 0.08 × (age) + 1.16 and prediction of age from score was Age = 0.65 × (score)2-0.14 × (score)-0.23. The overall CAP-II scale exhibited good reliability and validity. and Significance: An improvement in auditory skill with age in children with normal hearing was observed. Ceiling performance in auditory skills was found at the age of 51 months for normal children. A conversion table between age and scores obtained from the data of this study can be used as a reference for the assessment of clinical hearing ability in children.


Correlation between total homocysteine and cerebral small vessel disease: A Mendelian randomization study.
Cerebral small vessel disease (CSVD) is a clinical imaging syndrome with diverse etiology. Total homocysteine (HCY) level might increase the risk of myocardial and cerebral infarction by damaging the vascular endothelium. We aimed to explore the correlation between total HCY and CSVD imaging burden, based on Mendelian randomization methods. A total of 1,023 participants of the Shunyi study, a population-based cohort study, were included. Vascular risk factors, total HCY levels and methylenetetrahydrofolate reductase (MTHFR) gene mutations (C677T and A1298C) were examined. CSVD imaging markers, including lacunes, cerebral microbleeds, white matter hyperintensity, enlarged perivascular space and brain parenchymal fraction (BPF) were also assessed. Mutations of C677T were significantly correlated with increased total HCY levels (CC→TT: β = 0.28, p < 0.0001), while mutations of A1298C were correlated with decreased total HCY levels (AA→AC: β = -0.13, p < 0.0001; AA→CC: β = -0.25, p = 0.004). In the Mendelian randomization study, the C677T genotype was significantly associated with lacunes (CC→CT: odds ratio [OR] 2.76, p = 0.008; CC→TT: OR 2.50, p = 0.018), and the A1298C genotype was significantly correlated with BPF (AA→CC: β = 1.32, p = 0.015). Similarly, in multivariate regression analysis, total HCY levels were significantly correlated with lacunes (OR 2.14, p < 0.0001) and negatively correlated with BPF (β = -0.55, p = 0.004). Age, sex and vascular risk factors were adjusted for. Total HCY level was correlated with imaging burden of CSVD, especially with lacunes and brain volume loss. For individuals with risk genetic predisposition, enhanced homocysteine-lowering strategies might be necessary to reduce the risk and progress of CSVD.


Hb Tak and Hb Q-Thailand in Thai patients are S-window hemoglobin variants revealed by high performance liquid chromatography.
The S-window hemoglobin (Hb) variants revealed by high performance liquid chromatography (HPLC) were studied in 12 Thai individuals. The variants were identified, using DNA sequencing and multiplex amplification refractory mutation system-polymerase chain reaction (ARMS-PCR), to be six cases of Hb Tak [beta147 (+AC)], and six cases of Hb Q-Thailand [alpha74(EF3)Asp-->His], respectively. By using the Capillarys 2-capillary zone electrophoresis (CE), Hb Tak and Hb Q-Thailand co-migrated with Hb F in zone 7. This might pose a problem as the high Hb F conditions suggest a differential diagnosis. The S-window Hb variants are mostly Hb Tak and Hb Q-Thailand in the Thai population rather than Hb S [beta6(A3)Glu-->Val]. The definite identification of Hb variants detected by HPLC or capillary electrophoresis (CE) requires DNA analysis.


Can the insecticide Imidacloprid affect the health of the Neotropical freshwater fish Astyanax altiparanae (Teleostei: Characidae)?
Female juveniles of the Neotropical fish Astyanax altiparanae were exposed for 96 h to four treatments containing the active ingredient from Imidacloprid® commercial formulation (IMI 1, IMI 2, IMI 3, and IMI 4) and to a control treatment (only dechlorinated tap water). Glutathione content, glutathione S-transferase activity, lipid peroxidation (LPO) and protein carbonylation levels, acetylcholinesterase (AChE) activity, and frequency of micronuclei and erythrocyte nuclear abnormalities (ENA) were measured in the fish. The muscle and gills were the most affected organs; their antioxidant defense was not enough to prevent oxidative damage (LPO) in the IMI 2 and IMI 4 treatment fish. IMI also inhibited AChE activity in the muscle (IMI 3 and IMI 4) and increased ENA frequency (IMI 4). IMI can affect the health of A. altiparanae in environmentally relevant concentrations, causing oxidative damage in different organs, neurotoxic effects in the muscle, and genotoxicity.


Cooperative roles of phosphate and dissolved organic matter in inhibiting ferrihydrite transformation and their distinct fates.
Phosphate and dissolved organic matter (DOM) mediate the crystalline transformation of ferrihydrite catalyzed by Fe(II) in subsurface environments such as soils and groundwater. However, the cooperative mechanisms underlying the mediation of phosphate and DOM in crystalline transformation of ferrihydrite and the feedback effects on their own distribution and speciation remain unresolved. In this study, solid characterization indicates that phosphate and DOM can collectively inhibit the crystalline transformation of ferrihydrite to lepidocrocite and thus goethite, via synergetic effects of inhibiting recrystallization and electron transfer. Phosphate can be retained on the surface or transformed to a nonextractable form within Fe oxyhydroxides; DOM is either released into the solution or preserved in an extractable form, while it is not incorporated or retained in the interior. Element distribution and DOM composition analysis on Fe oxyhydroxides reveals even distribution of phosphate on the newly formed Fe oxyhydroxides, while the distribution of DOM depends on its specific species. Electrochemical and dynamic force spectroscopic results provide molecular-scale thermodynamic evidence explaining the inhibition of electron transfer between Fe(II) and ferrihydrite by phosphate and DOM, thus influecing the crystalline transformation of ferrihydrite and the distribution of phosphate and DOM. This study provides new insights into the coupled biogeological cycle of Fe with phosphate and DOM in aquatic and terrestrial environments.


Synthesis of rigid multivalent scaffolds based on adamantane.
An efficient route to novel 1,3,5,7-tetrasubstituted derivatives of adamantane is described. This route starts from adamantane and gives the tetrafunctionalized derivative 9 in eight steps with an overall yield of 23%. These tetrahedrally shaped molecules possess three identical arms terminated by an activated carboxylic acid derivative and a protected amino function in the 1-position. We propose these tetravalent cage compounds such as 9 as scaffolds for the assembly of ligand/marker conjugates for studies of multivalent ligand receptor interactions. [reaction: see text]


Betel-quid and alcohol use were associated with lipid accumulation product among male factory workers in Taiwan.
In this study, cardiometabolic risk associated with betel-quid, alcohol and cigarette use, based on a simple index-lipid accumulation product (LAP), was investigated in Taiwanese male factory workers. Male factory workers were recruited during their annual routine health examination at a hospital in south Taiwan. The risk of cardiometabolic disorders was estimated by the use of LAP, calculated as (waist circumference [cm]-65)×(triglyceride concentration [mmol/l]). Multiple linear regression analyses were conducted to assess the risk factors of natural logarithm-transformed LAP. Of the 815 participants, 40% (325/815) were current alcohol users, 30% (248/815) were current smokers and 7% (53/815) were current betel-quid users. Current betel-quid use, alcohol use, older age, lack of exercise and higher body mass index were found to be significant and independent factors associated with natural logarithm-transformed LAP. Betel-quid and alcohol, but not cigarette use, were independent risk factors of logarithm-transformed LAP, adjusting for age, exercise and body mass index in male Taiwanese factory workers. LAP can be considered as a simple and useful method for screening of cardiometabolic risk.


Nocardia abscess during treatment of brain toxoplasmosis in a patient with aids, utility of proton MR spectroscopy and diffusion-weighted imaging in diagnosis.
We report the case of a 30-year-old man with known HIV-positive status who developed, 4 months prior to admission, recurrent left partial motor seizures followed by left hemiparesis. At another hospital, contrasted CT scan of the head revealed right frontal hypodense lesion with mass effect and focal contrast enhancement. A small left occipital lesion was also present. HIV-associated brain toxoplasmosis was considered and phenytoin, pyrimethamine, clindamycin and antiretrovirals were administered. Hemiparesis improved but, 3 weeks prior to admission, he developed progressive headache and bilateral visual defects. Upon admission to our center, he was found with left homonymous hemianopsia, right hemiparesis and a large hypodense left occipital lesion on a head CT scan. Proton MR spectroscopy showed lactate at 1.3ppm, amino acids at 0.9ppm, and diffusion-weighted imaging (DWI) revealed hyperintensity at the lesion, suggesting a pyogenic abscess. Aspiration yielded purulent material and Nocardia asteroides grew in culture. The patient was treated with trimethoprim-sulfametoxazole and recovered with a mild visual field residual defect.


[Passive and active reactions of embryonic tissues to the action of dosed mechanical forces].
With the help of a suction manometric device, the relation between the deformation of Xenonus laevis embryo at the gastrula and neurula stages and the value of the applied force has been studied. Stiffness modules of embryonic tissues were in the order of several dozens of Pascal and they were inversely proportional during deformation from 40 to 20%. At the gastrula stage, a uniform or an increasing rate of expansion of the embryo body in the suction capillary with the diameter of approximately half that of the embryo was observed for 30 min after the action of the suction forces. The length of the stretched portion of the embryo correlates with the value of its deformation at the first minute. As a result of the expansion, the total body surface area of the deformed embryo increases more than twice compared to intact embryos. After expelling the embryo from the capillary, its surface reduced and the deformation became smoothened within 5 min, which indicates the existence of tensional force in the expanded embryo. These data confirm that, at the embryo gastrula stage, external mechanical forces do not only passively deform the embryo but also initiate the active expansion of the embryo which takes place at zero external force and overcomes the tensional resistance of tissues. The mechanism of active expansion and its link with the processes of normal morphogenesis are discussed.


Hsa_circ_0072309 inhibits proliferation and invasion of glioblastoma.
Increasing literature reported that circRNAs play vital roles in the occurrence and progression of GBM and regulate GBM cell proliferation, metastases, and chemosensitivity. However, the expression pattern and function of circRNAs in GBM still need further studies. In our work, hsa_circ_0072309 was remarkably downregulated in GBM. Hsa_circ_0072309 inhibits proliferation and invasion of glioblastoma and affects cytoskeletal of GBM cells. Moreover, we found that the function of hsa_circ_0,072,309 in GBM was associated with HSP27, which was reported to be an important regulator of cell proliferation, invasion and cytoskeletal. Our study provides a novel view of hsa_circ_0072309 in GBM cell proliferation and invasion, indicating that hsa_circ_0072309 may act as a potential therapeutic target for GBM comprehensive treatment.


Novel THAP1 variants in Brazilian patients with idiopathic isolated dystonia.
THAP1 mutations are associated with idiopathic isolated dystonia in different ethnicities, but the importance of this gene as a cause of dystonia in the Brazilian population has not been determined. The aim of this study was to investigate the prevalence of THAP1 variants in Brazilian patients with idiopathic dystonia and to describe their clinical characteristics including non-motor symptoms. One hundred and ten unrelated patients with non-TOR1A (DYT1) idiopathic isolated dystonia and family members were evaluated and screened for genetic variants. Variants with a potential pathological role were observed in 9.0% of families studied, of which four were novel. The variants were identified in approximately 12% of patients with the age of onset below 40 years. In most of the patients, the onset of the disease was before early adulthood. The upper limb was the most common site of the onset, and approximately half of the patients had dysphonia. Pain, anxiety, and sleep-onset insomnia were the most prevalent non-motor symptoms, and their prevalence was not different from that observed in THAP1-negative patients. Therefore, THAP1 variants are an important cause of dystonia among individuals with an early-onset disease and a positive family history. The phenotypical heterogeneity among patients carrying similar variants shows that other factors may be modulating the disease.


Crystal structure, Hirshfeld surface analysis and DFT study of (5E,5'E,6Z,6'Z)-6,6'-[ethane-1,2-diyl-bis(aza-nylyl-idene)]bis-{5-[2-(4-fluoro-phen-yl)hydra-zono]-3,3-di-methyl-cyclo-hexa-none} 2.5-hydrate.
The title compound, C30H34F2N6O2·2.5H2O, was obtained by condensation of 2-[2-(4-fluoro-phen-yl)hydrazono]-5,5-di-methyl-cyclo-hexan-1,3-dione with ethyl-enedi-amine in ethanol and crystallized as a 1:2.5 hydrate in space group C2/c. The two independent mol-ecules, with approximate crystallographic C 2 symmetries, have different conformations and packing environments, are stabilized by intra-molecular N-H⋯N hydrogen bonds and linked by O-H⋯O hydrogen bonds involving the water mol-ecules. A Hirshfeld surface analysis showed that H⋯H contacts make by far the largest (48-50%) contribution to the crystal packing. From DFT calculations, the LUMO-HOMO energy gap of the mol-ecule is 0.827 eV.