Histopathological classification of tympanosclerotic plaques.
Tympanosclerotic plaques seen in the middle ear and tympanic membrane as a sequelae of otitis media have different characteristics. Tympanosclerotic plaque consistency shows a wide range from soft to hard during surgical excision and can be classified histologically. The aim of this study is to classify surgically excised tympanosclerotic plaques macroscopically and histologically. Seventeen surgically excised tympanosclerotic tissues were examined otomicroscopically and light microscopically. Otomicroscopically, plaques were classified as type I: soft (four cases), type II: moderately hard (six cases) and type III: very hard (seven cases), according to their consistency and surgical detachment feature. Sections prepared from tympanosclerotic tissues were stained with hematoxylin-eosin, Mallory-Azan and von Kossa stains for light microscopic evaluation. In type I tympanosclerotic tissue, fibroblasts and collagen fibers were equally abundant in typical loose connective tissue. A few small calcium crystals were seen. In type II tympanosclerotic tissue, large bundles of collagen fibers, proliferation of fibroblasts and focal calcification points were seen. In type III tympanosclerotic tissue, round shaped condroblast-like cells located in lacunae and intense calcification points were evident. Tympanosclerotic tissues can be classified in respect of their morphological and histological aspects. Histological classification of tympanosclerotic tissue may inform us about the maturation of the tissue, and therefore the grade of the disease. In type I tympanosclerotic disease, even if complete resection of sclerotic tissue is performed, the underlying process may go on and new sclerotic tissue formation can be expected. Type III sclerotic tissue is associated with limited, inactive disease. Progress of the disease and the patient's benefit from surgery can be interpreted according to this classification. However, these results will need to be verified by long-term patient follow-up and comparison of histological classification and clinical audiological symptoms.


[Natural features of oviposition of Culex (Melanoconion) Group Pilosus (Diptera: Culicidae)].
Eggs of Culex (Melanoconion) Grupo Pilosus were found in three oviposition traps set in the toilet of a Bus Station in Joinville city, State of Santa Catarina, Brazil, during a surveillance study of Aedes aegypti. The intrinsic characteristic of group oviposition not directly on the water was confirmed.


Mechanobiological induction of long-range contractility by diffusing biomolecules and size scaling in cell assemblies.
Mechanobiological studies of cell assemblies have generally focused on cells that are, in principle, identical. Here we predict theoretically the effect on cells in culture of locally introduced biochemical signals that diffuse and locally induce cytoskeletal contractility which is initially small. In steady-state, both the concentration profile of the signaling molecule as well as the contractility profile of the cell assembly are inhomogeneous, with a characteristic length that can be of the order of the system size. The long-range nature of this state originates in the elastic interactions of contractile cells (similar to long-range "macroscopic modes" in non-living elastic inclusions) and the non-linear diffusion of the signaling molecules, here termed mechanogens. We suggest model experiments on cell assemblies on substrates that can test the theory as a prelude to its applicability in embryo development where spatial gradients of morphogens initiate cellular development.


Dietary patterns and cardiovascular risk factors among Brazilians: A population-based study in Viçosa, Minas Gerais.
The aim of this study was to identify dietary patterns (DPs) and analyze their association with cardiovascular risk factors including metabolic biomarkers and markers of inflammation and oxidative stress in a cross-sectional population-based study with 959 Brazilian adults from Viçosa. Food consumption was assessed by food frequency questionnaire, and DPs were identified by principal component analysis. A self-administered questionnaire was applied to assess sociodemographic and behavioral variables. Four distinct DPs were identified: Western, Snacks and Processed Food, Healthy, and Traditional Brazilian. Comparing the highest to the lowest tertile of each DP: Snacks and Processed Food DP was associated with a significantly higher diastolic blood pressure (β = 2.81; 95% confidence interval [CI], 0.48-5.14), waist circumference (β = 4.75; 95% CI, 2.77-6.73), body mass index (β = 1.65; 95% CI, 0.63-2.67), neck circumference (β = 0.74; 95% CI, 0.15-1.34), uric acid (β = 0.32; 95% CI, 0.13-0.51), and C-reactive protein (β = 0.31; 95% CI, 0.07-0.55). The Healthy DP was associated with lower Homeostatic Model Assessment of Insulin Resistance (HOMA-IR; β = -0.17; 95% CI, -0.34 to -0.008), lower tumor necrosis factor-α (odds ratio [OR] = 0.46; 95% CI, 0.26-0.84), lower interleukin (IL)-8 (OR = 0.50; 95% CI, 0.28-0.91), and lower catalase (OR = 0.36; 95% CI, 0.16-0.78). The Traditional Brazilian DP was associated with lower high-density lipoprotein (HDL) cholesterol (β = -5.04; 95% CI, -7.60 to -2.48), non-HDL cholesterol (β: -10.25; 95% CI, -19.07 to -1.43), and superoxide dismutase (OR = 0.52; 95% CI, 0.32-0.87), and higher uric acid (β = 0.24; 95% CI, 0.01-0.48), IL-12p70 (OR = 2.55; 95% CI, 1.23-5.32), IL-1β (OR = 2.22; 95% CI, 1.01-4.89), IL-10 (OR = 2.03; 95% CI, 1.05-3.93), and ferric reducing ability of plasma (OR = 2.23; 95% CI, 1.16-4.27). The Snacks and Processed Food DP was associated with increases in several risk factors for cardiovascular disease, and the Healthy DP with lower HOMA-IR scores, tumor necrosis factor-α, IL-8, and catalase. A diet based on rice and beans (Traditional Brazilian) may have a protective role against non-HDL cholesterol while presenting other risks related to inflammation and oxidative stress, as shown by a direct association with the interleukins IL-12p70, IL-1β, and IL-10 and an inverse association with superoxide dismutase.


Decubitus CT Myelography for Detecting Subtle CSF Leaks in Spontaneous Intracranial Hypotension.
Spontaneous intracranial hypotension is caused by spinal CSF leaks, but the site of the leak is not always detected on spinal imaging. We report on the additional value of decubitus positioning during CT myelography in enhancing the detection of subtle leaks.


The effect of EMPAgliflozin on markers of inflammation in patients with concomitant type 2 diabetes mellitus and Coronary ARtery Disease: the EMPA-CARD randomized controlled trial.
Systemic inflammation and oxidative burden in patients with type 2 diabetes mellitus (T2DM) causes deleterious cardiovascular outcomes. We sought to investigate the clinical antioxidative and anti-inflammatory effects of empagliflozin. Platelet function, oxidant and antioxidant biomarkers and pro-inflammatory agents at baseline and at 26 weeks were measured. A total of 95 patients (41.05% male, mean age 62.85 ± 7.91 years, mean HbA1c 7.89 ± 0.96%) with concomitant T2DM and coronary artery disease (CAD) were randomized (1:1) to receive empagliflozin (10 mg/daily) or placebo. Patients treated with empagliflozin had lower levels of interleukin 6 (IL-6) (adjusted difference (adiff): - 1.06 pg/mL, 95% CI - 1.80; - 0.32, P = 0.006), interleukin 1β (IL-1β) and high-sensitive C-reactive protein (Hs-CRP) (adiff: - 4.58 pg/mL and - 2.86 mg/L; P = 0.32 and 0.003, respectively) compared to placebo. There were elevations in super oxidase dismutase (SOD) activity, glutathione (GSHr), and total antioxidant capacity (TAC) with empagliflozin (adiff: 3.7 U/mL, 0.57 muM, and 124.08 mmol/L, 95% CI 1.36; 6.05, 0.19; 0.95, and 47.98; 200.18, P = 0.002, 0.004, and 0.002, respectively). While reactive oxygen species (ROS) improved significantly (adiff: - 342.51, 95% CI - 474.23; - 210.79, P < 0.001), the changes in catalase activity (CAT), malondialdehyde (MDA), or protein carbonyl groups (PCG) were not significant. Moreover, the P-selectin antigen expression on platelet surface was significantly reduced (adiff: - 8.81, 95% CI - 14.87; - 2.75, P = 0.005). Markers of glycemic status (fasting blood glucose, HbA1c, and HOMA-IR (homeostatic model assessment for insulin resistance) significantly improved (P < 0.001). Among patients with T2DM and CAD, 6-month treatment with empagliflozin can mitigate inflammation, platelet activity and oxidative stress and is associated with clinical cardiovascular benefits.Trial Registration Iranian Registry of Clinical Trials. www.IRCT.ir , Identifier: IRCT20190412043247N2. Registration Date: 6/13/2020. Registration timing: prospective.


Symmetrical Dimethylarginine: Evaluating Chronic Kidney Disease in the Era of Multiple Kidney Biomarkers.
Symmetric dimethylarginine (SDMA) is a valuable surrogate marker for decreased glomerular filtration rate (GFR) and is incorporated into the International Renal Interest Society (IRIS) guidelines for diagnosing, staging, and treating chronic kidney disease (CKD). SDMA increases above the reference interval with smaller reductions in GFR rate than does creatinine and persistent mild increases in SDMA can be used to diagnose early-stage CKD. Evaluation of both SDMA and creatinine is recommended for diagnosis and monitoring of animals with CKD.


Acromegaly with initial negative oral glucose tolerance test: a case report.
Acromegaly can be diagnosed by a growth hormone value ≥ 1 µg/L following an oral glucose tolerance test. However, normal growth hormone suppression following oral glucose tolerance test may not exclude acromegaly. We present a case of a 55-year-old Chinese man with pituitary macroadenoma incidentally noted after a traffic accident. He reported feet enlargement in the past few years. At the beginning, elevated insulin-like growth factor-1 was noted with growth hormone value < 1 µg/L after oral glucose tolerance test. Fracture-related high insulin-like growth factor-1 was suspected. Insulin-like growth factor-1 decreased gradually but was still above the upper limit of normal . However, he suffered from dizziness 1 year later and insulin-like growth factor-1 increased again. Besides, secondary hypocortisolism developed. The size of the pituitary macroadenoma was stationary. Follow-up oral glucose tolerance test showed a growth hormone value > 1 µg/L. Endoscopic endonasal approach to the remove pituitary macroadenoma was performed subsequently. After the resection of the pituitary macroadenoma, pathology showed positive staining of growth hormone and prolactin. Insulin-like growth factor-1 normalized as well. Suppressed growth hormone after oral glucose tolerance test cannot exclude acromegaly, and some patients may have only mild or no clinical presentation of acromegaly. Patients with pituitary microadenoma or macroadenoma and elevated insulin-like growth factor-1 should be closely monitored for signs/symptoms of acromegaly and hypopituitarism.


Reactions of N-methyl-N-nitrosobenzylamine and related substrates with enzyme-containing cell fractions isolated from various organs of rats and mice.
Incubation of the following N-nitroso compounds with microsomes from mouse liver and an NADPH-generating system formed the products stated: benzaldehyde from N-methyl-N-nitrosobenzylamine (MNBA), acetone and formaldehyde from N-methyl-N-nitroso-(alpha-phenyl)-ethylamine (MNPE) and formaldehyde from N-methyl-N-nitroso-(2-phenyl)-isopropylamine (MNPI). Enzymes isolated from mouse liver showed more activity towards MNBA by comparison with rat liver preparations. Microsomes from the organs of female rats showed decreasing activity in the following sequence: esophagus greater than forestomach greater than liver and for female mice: liver greater than forestomach.


Medical countermeasures for the hematopoietic-subsyndrome of acute radiation syndrome in space.
More than 50 years after the Apollo missions ended, the National Aeronautical and Space Administration (NASA) and other international space agencies are preparing a return to the moon as a step towards deep space exploration. At doses ranging from a fraction of a Gray (Gy) to a few Gy, crew will be at risk for developing bone marrow failure associated with the hematopoietic subsyndrome of acute radiation syndrome (H-ARS) requiring pharmacological intervention to reduce risk to life and mission completion. Four medical countermeasures (MCM) in the colony stimulating factor class of drugs are now approved for treatment of myelosuppression associated with ARS. When taken in conjunction with antibiotics, fluids, antidiarrheals, antiemetics, antipyretics, and other treatments for symptomatic illness, the likelihood for recovery and mission completion can be greatly improved. The current review describes the performance and health risks of deep space flight, ionizing radiation exposure during crewed missions to the moon and Mars, and U.S. Food and Drug Administration (FDA)-approved medical interventions to treat ARS. With an expansion of human exploration missions beyond low Earth orbit (LEO), including near-term Lunar and future Mars missions, inclusion of MCMs to counteract ARS in the spaceflight kit will be critical for preserving crew health and performance.


Quinoxaline chemistry. Part XVII. Methyl [4-(substituted 2-quinoxalinyloxy) phenyl] acetates and ethyl N-([4-(substituted 2-quinoxalinyloxy) phenyl] acetyl) glutamates analogs of methotrexate: synthesis and evaluation of in vitro anticancer activity.
Fourteen out of 21 quinoxaline derivatives described in the present paper were selected at NCI for evaluation of their in vitro anticancer activity. Preliminary screening showed that some derivatives exhibited a moderate to strong growth inhibition activity on various tumor panel cell lines between 10(-5) and 10(-4) M concentrations. Interesting selectivities were also recorded between 10(-8) and 10(-6) M for the compounds 9 and 13.


The tertiary structure of a bacterial cellulase determined by small-angle X-ray-scattering analysis.
CenA from Cellulomonas fimi is a beta-1,4-endoglucanase that binds tightly to cellulose. X-ray-scattering analyses show that the enzyme is tadpole-shaped: the previously identified catalytic and cellulose-binding domains comprise the head and tail respectively. It appears that this structural and functional organization is common to several cellulases from bacteria and fungi.


Immobilized artificial membrane chromatography as a tool for the prediction of ecotoxicity of pesticides.
The potential of Immobilized Artificial Membrane (IAM) chromatography to predict ecotoxicological endpoints of pesticides was investigated. For this purpose, retention factors of 39 structurally-diverse pesticides were measured on an IAM stationary phase. A representative test set of 6 pesticides was carefully selected. The training set, involving the remaining pesticides for which experimental data were available, served to establish linear IAM models with LC50/EC50 values in a series of aquatic organisms involving Rainbow Trout, Fathead Minnow, Bluegill Sunfish, Sheepshead Minnow, Eastern Oyster and Water Flea as well as LD50 values in honey bee, compiled from literature sources. For reasons of comparison, corresponding models were derived by replacing IAM retention factors with octanol-water partition coefficients (logP). Considering the similar regression equations obtained for the 4 fish species, general models to predict toxicity in fish were established. Most models were improved upon inclusion of additional physicochemical parameters. The positive contribution of Molecular Weight to ecotoxicity along with the positive sign of hydrogen bond indices in most cases implies that toxic action is manifested mainly by accumulation on the membrane rather than through diffusion across them. IAM models are generally followed by better statistics and superior predictive performance than those based on experimental or computed logP. Predictions based on IAM chromatography were comparable or even superior with those performed by EPI Suite Software. Hence, IAM retention factors are suggested as promising indices in order to screen or rank chemicals with respect to their ecotoxicological risk, especially in the case of new entities.


The paradox of obstetric "near misses": converting maternal mortality into morbidity.
To systematically review evidence of obstetric near-misses and their consequences. PUBMED, OVID, and references of retrieved articles were used. Only 13 original articles describe the occurrence of obstetric/maternal near-miss morbidity to date. All were included in this review, in addition to other articles related to the epidemiology and consequences of severe acute maternal morbidity. Serious forms of maternal morbidity occur in about 1% of women in the United States compared to 3.01 to 9.05% in some developing settings. Worldwide, the leading causes of near-miss morbidity are hemorrhage and pregnancy-related hypertension or eclampsia/pre-eclampsia. These complications can have lasting effects, and their sequelae may result in maternal illness, injury and disability. Based on severity, we have provided three phenotypes of obstetric near-misses: Class I (near-miss with healthy infant); Class II (near-miss with feto-infant morbidity); Class III (near-miss with fetal/infant death). Obstetric near-misses should be considered as potentially chronic illnesses that warrant follow-up care because the theoretical cycle of near-miss (as postulated in this paper) can only be interrupted by the resolution of residual issues or the mother's death. Some may consider near-miss events to be obstetric successes because ultimately the mother's life was spared, but the consequences of these complications can be overwhelming and enduring.


RBM15 promotes hepatocellular carcinoma progression by regulating N6-methyladenosine modification of YES1 mRNA in an IGF2BP1-dependent manner.
The function of the N6-methyladenosine (m6A) methyltransferase RNA-binding motif protein 15 (RBM15) in hepatocellular carcinoma (HCC) has not been thoroughly investigated. Here we determined the clinical value, biological functions, and potential mechanisms of RBM15 in HCC. Expression of RBM15 was identified using tissue microarrays and online databases. A risk-prediction model based on RBM15 was developed and validated. We determined the biological role of RBM15 on HCC cells in vitro and in vivo. RNA sequencing was used to screen candidate targets of RBM15. Subsequently, the m6A dot blot assay, methylated RNA immunoprecipitation qPCR, dual-luciferase reporter assays, RNA decay assay, and RNA immunoprecipitation qPCR were employed to explore the mechanisms of RBM15. Our study showed that RBM15 was highly expressed in HCC, and overexpression of RBM15 indicated a worse outcome. A new nomogram combining RBM15 with age and TNM stage was developed and validated to predict the outcome of HCC patients; our nomogram increased the prediction accuracy of the TNM system. Functionally, RBM15 facilitates the proliferation and invasiveness of HCC. RBM15-mediated m6A modification contributed to a post-transcriptional activation of YES proto-oncogene 1 (YES1) in an insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1)-dependent manner. In addition, YES1 was confirmed as an oncogene in HCC cells by activating the mitogen-activated protein kinase (MAPK) pathway. In conclusion, RBM15-mediated m6A modification might facilitate the progression of HCC via the IGF2BP1-YES1-MAPK axis. RBM15 may be a promising biomarker in the outcome prediction of HCC.


Combined pituitary stimulation test: interactions of hypothalamic releasing hormones in man.
The use of hypothalamic releasing hormones for the clinical assessment of anterior pituitary function is both simple and free of severe side effects. Tests with the recently discovered substances GRF and CRF as well as with combinations of several releasing hormones are therefore used in many clinics. A reliable interpretation of such combined tests, however, is only possible when positive or negative interactions between these releasing hormones are known. After a rest of 2 h to reach basal cortisol levels, 7 groups of 5 male volunteers each received an iv bolus injection consisting of either: A): GRF (100 micrograms) + CRF (50 micrograms) + TRH (200 micrograms) + LHRH (100 micrograms), B): CRF + TRH, C): GRF + TRH, D): LHRH + TRH, E): TRH, F): GRF, G): CRF. During the following 2 h, GH, TSH, cortisol, LH, FSH and prolactin were measured every 15 min. The TSH response after the injection of all 4 releasing hormones was significantly higher (delta TSH = 16.5 +/- 2.0 microU/ml, x +/- SE) compared to the injection of TRH alone (delta TSH = 9.3 +/- 1.4 microU/ml; p less than 0.025). This increment in TSH secretion was confirmed when 2 groups of 5 female volunteers were studied with the TRH-test (delta TSH = 9.9 +/- 1.8 microU/ml) or the combination of all four releasing hormones (delta TSH = 16.8 +/- 2.9 microU/ml; p less than 0.05). This exaggerated TSH-response to TRH was demonstrated to be entirely due to simultaneous administration of GRF, whereas CRF and LHRH in combination with TRH had no additional effect on TSH release.(ABSTRACT TRUNCATED AT 250 WORDS)


Transient evoked otoacoustic emissions after vestibular nerve section in chinchillas.
Transient evoked otoacoustic emissions are believed to be sensitive to the effects of the cochlear efferent system. The most well-known function of this system is inhibitory on cochlear response. It has been demonstrated that crossed medial efferent system section produces inhibitory control of the outer hair cells mechanisms responsible for non-linear transient evoked otoacoustic emissions generation. However, we suppose that the uncrossed medial efferent system plays a role in outer hair cell function too. We recorded the non-linear part of transient evoked otoacoustic emissions in 17 chinchillas before and after section of the vestibular nerve (crossed and uncrossed fibers). Responses at frequencies bands centered on 0.8, 1.6, 2.4, 3.2 and 4.0 kHz, as well as total emission responses, were analyzed. After vestibular nerve section, there were significant increases in the amplitudes of the 2.4- and 4.0 kHz responses and of the total response. These results indicate that the medial efferent system is important to maintain normal cochlear mechanics. Uncrossed medial efferent system and lateral efferent system seem to be not important in maintaining normal cochlear mechanics.


Impact of chemotherapy-associated liver injury on tumour regression grade and survival in patients with colorectal liver metastases.
An inverse relation between chemotherapy-associated liver injury (CALI) and tumour response to chemotherapy has been reported. The aim was to validate these findings, and further investigate the impact of CALI on survival in patients who underwent partial hepatectomy for colorectal liver metastases (CRLM). Patients who received neoadjuvant chemotherapy and underwent partial hepatectomy for CRLM between 2008 and 2014 were included. Liver and tumour specimens were histologically examined for CALI (steatosis, steatohepatitis, sinusoidal dilatation [SD], nodular regeneration) and tumour regression grade (TRG). TRG 1-2 was defined as complete tumour response. 166 consecutive patients were included with a median survival of 30 and 44 months for recurrence-free and overall survival, respectively. Grade 2-3 SD was found in 44 (27%) and TRG 1-2 was observed in 33 (20%) patients. Of studied CALI, only grade 2-3 SD was associated with increased TRG 3-5 (odds ratio 3.99, 95% CI 1.17-13.65, p = 0.027). CALI was not significantly related to survival. TRG 1-2 was associated with prolonged recurrence-free (hazard ratio 0.47, 95% CI 0.25-0.89, p = 0.020) and overall survival (hazard ratio 0.35, 95% CI 0.18-0.68, p = 0.002). CALI was not directly related to survival. CALI was, however, associated with diminished complete tumour response, and diminished complete tumour response, in turn, was associated with decreased survival.


Nanocrystalline SSZ-39 zeolite as an efficient catalyst for the methanol-to-olefin (MTO) process.
The synthesis of nanosized SSZ-39 zeolite has been achieved using a high silica FAU zeolite as the Si and Al source and tetraethylphosphonium (TEP) cations as OSDAs. The obtained SSZ-39 material shows a remarkably high catalyst lifetime compared to conventional SSZ-13 and SSZ-39 materials.


Polar corticosteroids in human neonatal urine; synthesis and gas chromatography-mass spectrometry of ring A reduced 6-hydroxylated corticosteroids.
This report describes the synthesis of 3alpha,6beta,11beta,17alpha,21-pentahydroxy-5beta-pregnane-20-one, 3alpha,6beta,11beta,17alpha,21-pentahydroxy-5beta-pregnane-20-one, 3alpha,6alpha,11beta,17alpha,21-pentahydroxy-5alpha-pregnane-20-one, 3alpha,6beta,17alpha,21-tetrahydroxy-5beta-pregnane-11,20-dione, 3alpha,6beta,17alpha,21-tetrahydroxy-5alpha-pregnane-11,20-dione, 3alpha,6alpha,17alpha,21-tetrahydroxy-5beta-pregnane-11,20-dione and 3alpha,6alpha,17alpha,21-tetrahydroxy-5alpha-pregnane-11,20-dione. The gas chromatographic-mass spectrometric properties of these compounds are given. Proof of structure was accomplished using gas chromatography-mass spectrometry, microchemical reactions, optical rotatory dispersion and nuclear magnetic resonance spectroscopy.


Soluble prefusion-closed HIV-envelope trimers with glycan-covered bases.
Soluble HIV-1-envelope (Env) trimers elicit immune responses that target their solvent-exposed protein bases, the result of removing these trimers from their native membrane-bound context. To assess whether glycosylation could limit these base responses, we introduced sequons encoding potential N-linked glycosylation sites (PNGSs) into base-proximal regions. Expression and antigenic analyses indicated trimers bearing six-introduced PNGSs to have reduced base recognition. Cryo-EM analysis revealed trimers with introduced PNGSs to be prone to disassembly and introduced PNGS to be disordered. Protein-base and glycan-base trimers induced reciprocally symmetric ELISA responses, in which only a small fraction of the antibody response to glycan-base trimers recognized protein-base trimers and vice versa. EM polyclonal epitope mapping revealed glycan-base trimers -even those that were stable biochemically- to elicit antibodies that recognized disassembled trimers. Introduced glycans can thus mask the protein base but their introduction may yield neo-epitopes that dominate the immune response.


Epidemiology and Mortality of Early-Onset Neonatal Sepsis in Suriname: A 2-Year Surveillance Study.
We conducted a nationwide surveillance study to produce reliable national estimates on incidence, etiology, and mortality of early-onset neonatal sepsis (EONS) in Suriname. The estimated national population incidence rate of EONS was 1.37 (95% CI: 0.90-1.99) per 1000 live births and in-hospital mortality was 25.9%.


Association of early pregnancy body mass index and children's birth weight with risk of being overweight in childhood.
To examine the potential effects of mothers' early pregnancy body mass index (BMI) and children's birth weight on childhood overweight/obesity at 1-6 years of age. We performed a cohort study in Tianjin, China, using the health care records from the Tianjin maternal and child health care system with 36 719 mother-child pairs from early pregnancy to children at 6 years of age. Logistic regression analyses were used to assess the single and joint associations of maternal early pregnancy BMI and children's birth weight with the risks of children being overweight at 1-6 years of age in multivariable-adjusted models. Both maternal early pregnancy BMI and children's birth weight were positively associated with the risk of children being overweight at 1-6 years of age. Compared with children who were born to normal weight mothers and had low or normal birth weight (NBW; birth BMI < 85%), higher risks of being overweight at 1-6 years were found among children with low or NBW who were born to overweight mothers, and children with high NBW (BMI ≥ 85%) or macrosomia who were born to normal weight or overweight mothers. Lower risks of being overweight were found among those with low birth weight who were born to normal weight mothers. Maternal early pregnancy BMI may play a more important role than children's birth weight in the risk of being overweight from 4 to 6 years of age. Children with high or NBW need to be given more attention to prevent excessive weight gain.


ST6Gal-I-mediated sialylation of the epidermal growth factor receptor modulates cell mechanics and enhances invasion.
Heterogeneity within the glycocalyx influences cell adhesion mechanics and signaling. However, the role of specific glycosylation subtypes in influencing cell mechanics via alterations of receptor function remains unexplored. It has been shown that the addition of sialic acid to terminal glycans impacts growth, development, and cancer progression. In addition, the sialyltransferase ST6Gal-I promotes epidermal growth factor receptor (EGFR) activity, and we have shown EGFR is an 'allosteric mechano-organizer' of integrin tension. Here, we investigated the impact of ST6Gal-I on cell mechanics. Using DNA-based tension gauge tether probes of variable thresholds, we found that high ST6Gal-I activity promotes increased integrin forces and spreading in Cos-7 and OVCAR3, OVCAR5, and OV4 cancer cells. Further, employing inhibitors and function-blocking antibodies against β1, β3, and β5 integrins and ST6Gal-I targets EGFR, tumor necrosis factor receptor, and Fas cell surface death receptor, we validated that the observed phenotypes are EGFR-specific. We found that while tension, contractility, and adhesion are extracellular-signal-regulated kinase pathway-dependent, spreading, proliferation, and invasion are phosphoinositide 3-kinase-Akt serine/threonine kinase dependent. Using total internal reflection fluorescence microscopy and flow cytometry, we also show that high ST6Gal-I activity leads to sustained EGFR membrane retention, making it a key regulator of cell mechanics. Our findings suggest a novel sialylation-dependent mechanism orchestrating cellular mechanics and enhancing cell motility via EGFR signaling.


Dual Ectopic Thyroid: A Case Report.
Ectopic thyroid gland is an uncommon disorder in which thyroid tissue is located along the line of migration, dual ectopic thyroid is a rare entity where parts of the gland are located in two different locations. A 14-year-old girl presented with dysphagia and odynophagia of six years duration with worsening of two weeks. Physical exam showed tongue base mass. Imaging revealed two enhancing masses at the tongue base and inferior to the hyoid bone. A diagnosis of dual ectopic thyroid was made. Dual ectopic thyroid is a rare occurrence and proper diagnosis is essential for proper management.


Earthworm diet related to soil organic matter dynamics through 13C measurements.
The ability of earthworms to assimilate soil organic pools of different ages was investigated in field conditions through natural 13C labelling. Provided that 13C natural abundance of earthworm tissues is determined by their diet, the assimilation of soil organic matter by earthworms was estimated by measuring 13C/12C ratio of tissues of earthworms sampled in soils containing organic pools with differing 13C/12C ratios. Earthworms were collected in two locations where the vegetation shifted from a C3 to a C4 type (France), or from a C4 to a C3 type (Ivory Coast) 3 to 20 years ago. The results show that irrespective of their ecology (litter or soil-feeding), earthworms mainly feed on recent soil organic pools and assimilate soil organic matter with the same age distribution as the overall decomposers in the soil.


Exploring conformational changes of PPAR-Ɣ complexed with novel kaempferol, quercetin, and resveratrol derivatives to understand binding mode assessment: a small-molecule checkmate to cancer therapy.
Peroxisome proliferator-activated receptors-γ (PPAR-γ), a ligand-activated transcription factor, activated by several ligands like fatty acids (linoleic acid being the most common) or their metabolites, can function as potential therapeutic target for various cancers. Although various synthetic ligands, thiazolidinediones (TZDs), serves as full agonist for PPAR-γ, application of these molecules has been discontinued due to adverse toxicity profile. Hence, with a dire need to identify novel PPAR-γ-agonists, the present in silico study aimed to determine the effectiveness of potent flavonoids, kaempferol (CID: 5280863), quercetin (CID: 5280343), and stilbenoid resveratrol (CID: 445154) and their 806 derivatives towards PPAR-γ that could combat the deleterious effect of TZDs. The molecular docking experiment performed by FlexX elucidated the efficacy of derivatives; Kem204, Qur8, and Res183 of kaempferol, quercetin, and resveratrol respectively to be more effective against PPAR-γ as compared with other derivatives. The physicochemical and pharmacokinetic parameters of Kem204, Qur8, and Res183 follow the drug-likeness and thus comprise a pharmacologically active model to be considered for advancing further potential hits. Further molecular dynamics (MD) simulation study revealed the Qur8 compound to have favorable dynamic interactions within the PPAR-γ which certainly paves away in developing futuristic potential anticancer drugs. Graphical abstract.


Risk factors for cesarean section of primiparous women aged over 35 years.
To determine the perinatal outcome of pregnancy in primiparous women over 35 years of age and to evaluate determinants predicting cesarean delivery in these women. Two hundred and seven mothers aged at least 35 years (1.8% of the total deliveries) delivered in the Department of Obstetrics and Gynecology between 1995 and 2000. These women were matched with women aged 20-29 years according to gravidity. Multiple logistic regression analysis was used to evaluate the risk of cesarean delivery, with controls for possible confounding factors. Cesarean section was 2.09-fold more prevalent among the older than among the younger women; the difference being significant (odds ratio, OR=3.36, 95%CI 2.22-5.09; p<0.001). The advanced maternal age was associated with a significantly higher rate of assisted reproductive techniques involvement (OR 6.54; 95%CI 3.54-12.38; p<0.001). The difference between the rates of preeclampsia in the two groups did not reach the level of significance (OR 1.85; 95%CI 1.02-3.34; p=0.056). There were no significant differences in perinatal outcome between the two groups. The logistic regression model demonstrated an increased risk of cesarean section among the primiparous women aged over 35 years. The risk of cesarean section at this advanced age is 6.54-fold. The determinants are included in the pregnancy, delivery and neonatal outcome.


Quantification of polyols in sugar-free foodstuffs by qNMR.
We present a qNMR method for the determination of low calories sweeteners (erythritol, mannitol, maltitol, sorbitol, isomalt and xylitol) in sugar-free foodstuff. The structural similarities of these compounds determine often a severe spectral overlap that hampers their quantification via conventional 1D and 2D NMR spectra. This problem is here overcome by exploiting the resolving capabilities of the CSSF-TOCSY experiment, allowing the quantification of all six polyols, with satisfactory results in terms of LoQ (2.8-7.4 mg/L for xylitol, mannitol, sorbitol, 15 mg/L for erythritol, 38 mg/L for maltitol and 91 mg/L for isomalt), precision (RSD% 0.40-4.03), trueness (bias% 0.15-4.81), and recovery (98-104%). Polyol's quantification in different sugar-free confectionary products was performed after a simple water extraction without any additional sample treatment. While these results demonstrate the robustness of the proposed method for polyols quantification in low calories foods, its applicability can be further extended to other food matrices or biofluids.


Uncovering multiple pathways to substance use: a comparison of methods for identifying population subgroups.
This paper describes and compares a selection of available modeling techniques for identifying homogeneous population subgroups in the interest of informing targeted substance use intervention. We present a nontechnical review of the common and unique features of three methods: (a) trajectory analysis, (b) functional hierarchical linear modeling (FHLM), and (c) decision tree methods. Differences among the techniques are described, including required data features, strengths and limitations in terms of the flexibility with which outcomes and predictors can be modeled, and the potential of each technique for helping to inform the selection of targets and timing of substance intervention programs.


Trends in mortality in patients with systemic autoimmune rheumatic diseases (SARD) during the COVID-19 pandemic in Mexico.
The study aimed to analyze the influence of the COVID-19 pandemic on mortality rates in patients with systemic autoimmune rheumatic diseases (SARD) in Mexico. We selected SARD-related deaths using National Open Data and Information from the Ministry of Health, Mexico, and ICD-10 codes. We assessed the observed compared to the predicted mortality values for 2020 and 2021, employing trends from 2010 to 2019 with joinpoint and prediction modelling analyses. Among 12,742 deaths due to SARD between 2010 and 2021, the age-standardized mortality rate (ASMR) increased significantly between 2010 and 2019 (pre-pandemic) (annual percentage change [APC] 1.1%; 95% CI 0.2-2.1), followed by a non-significant decrease during the pandemic period (APC 13.9%; 95% CI 13.9-5.3). In addition, the observed ASMR of 1.19 for 2020 for SARD and of 1.14 for 2021 were lower than the predicted values of 1.25 (95% CI 1.22-1.28) for 2020 and 1.25 (95% CI 1.20-1.30) for 2021. Similar findings were identified for specific SARD, mainly systemic lupus erythematosus (SLE), or by sex or age group. Interestingly, the observed mortality rates for SLE in the Southern region of 1.00 in 2020 and 1.01 in 2021 were both significantly greater than the predicted values of 0.71 (95% CI 0.65-0.77) in 2020 and 0.71 (95% CI 0.63-0.79). In Mexico, the observed SARD mortality rates were not higher than the expected values during the pandemic, except for SLE in the Southern region. No differences by sex or age group were identified.


Comparing an in vivo egg reduction test and in vitro egg hatching assay for different anthelmintics against Fasciola species, in cattle.
This study aimed to compare between the efficiency of in vivo fecal egg reduction test (FERT) and in vitro egg hatching assay (EHA) in evaluating of the anti-Fasciola activity of albendazole, triclabendazole, oxyclozanide and praziquantel. A field trial was carried out on fifty naturally Fasciola infected cattle that were divided equally into 5 groups (A-E). On day zero; groups A-D were drenched with albendazole, triclabendazole, oxyclozanide or praziquantel, respectively, while the remaining one, group E, was kept as untreated control. Fecal egg counts of the different groups were conducted weekly over a period of one month post-treatment. In vitro, commercial albendazole and oxyclozanide were diluted to 0.0002, 0.002, 0.02, 0.2 and 2.0 μg/ml, while commercial triclabendazole and praziquantel were diluted to concentrations of 25, 50, 75 and 100 μg/ml with dimethyl sulfoxide (DMSO). In vivo, at the 2nd week post-treatment, triclabendazole and oxyclozanide showed 100% fecal egg reduction (FER), and albendazole had a maximum of 73.7% reduction (P < 0.0001), however, praziquantel did not record any reduction of Fasciola egg counts. In vitro, triclabendazole treated Fasciola gigantica eggs showed early embryonic lysis with zero% hatching at the different concentrations (P < 0.01). In albendazole, the hatching varied according to the drug concentration. At the highest two concentrations; 0.2 and 2.0 μg/ml, the hatching percentages were 7.4 ± 1.6 and 5.6 ± 1.5 (P < 0.01) respectively. On the contrary, there were no significant differences in egg development and hatching percentage of oxyclozanide or praziquantel treated groups. In conclusion, the efficacy of triclabendazole and albendazole as fasciolicdes could be predicted by Egg Hatching Assay (EHA). Meanwhile fasciolicide activity of oxyclozanide could not be assessed with EHA. Based on in vivo and in vitro findings, paraziquantel did not show any fasciolicide effect.


Constraints to obtaining consistent annual yields in perennials. II: Environment and fruit load affect induction of flowering.
In many commercial fruit crop species, high fruit load inhibits vegetative growth and floral induction. As a result, trees that had a high fruit load will bear few flowers and fruit the following year, along with abundant vegetative growth. We previously discussed how high fruit load interferes with concurrent shoot growth. Here we focus on how high fruit load impacts the process of flowering. Ascertaining the precise time at which specific buds begin the floral transition in each species is challenging. The use of indirect approaches to determine time of floral induction or evocation may lead to questionable conclusions. Annual and perennial plants appear to use conserved proteins for flowering induction and initiation. The accumulation or reduction of transcripts encoding proteins similar to Arabidopsis (annual) FLOWERING LOCUS T (FT) and TERMINAL FLOWER1 (TFL1), respectively, correlates well with flower induction in several diverse species. The recent use of such markers provides a means to formulate an accurate timeframe for floral induction in different species and holds promise in providing new insight into this important developmental event. A role for hormones in modulating the inhibitory effect of fruit load on floral induction is also discussed.


Development of communicative behavior in autistic children: a parent program using manual signs.
Mothers of four 6- and 7-year-old autistic classmates were taught to use manual signs for verbalizations to aid development of appropriate communicative behavior and to deter undesirable behavior in their children. The experimental treatment was initiated in a daily mother-child laboratory session using a multiple-baseline design across subjects. The preschool classroom program remained unchanged. Data were recorded for each child daily over a 5-week period, in the classroom and in a mother-child session, on four types of communicative behavior and four types of inappropriate behavior. Communicative behaviors increased and inappropriate behaviors decreased in relation to baseline conditions for each child. The manual sign program facilitated generalization of communicative behavior to the child's total environment. Desirable behaviors were maintained and had improved in the classroom 3 months after initiation of the program.


YTHDC2 Retards Cell Proliferation and Triggers Apoptosis in Papillary Thyroid Cancer by Regulating CYLD-Mediated Inactivation of Akt Signaling.
N6-Methyladenosine (m6A) mRNA methylation modification is regarded as an important mechanism involved in diverse physiological processes. YT521-B homology (YTH) domain family members are associated with the tumorigenesis of several cancers. However, the role of YTHDC2 in papillary thyroid cancer (PTC) progression remains unknown. Results showed that YTHDC1, YTHDF1, YTHDF2, and YTHDF3 showed no observable difference in thyroid cancer samples. YTHDC2 was significantly downregulated in thyroid cancer samples and cells. YTHDC2 inhibited cell proliferation in PTC cells. YTHDC2 elicited apoptosis in PTC cells, as demonstrated by the elevated expression of pro-apoptotic factors cl-caspase-3/caspase-3 and Bcl-2-associated (Bax), and the reduced anti-apoptotic B cell lymphoma-2 (Bcl-2) expression. There was a positive correlation between YTHDC2 and cylindromatosis (CYLD) expression based on GEPIA database. YTHDC2 increased CYLD expression in PTC cells. CYLD knockdown abolished the effects of YTHDC2 on PTC cell proliferation and apoptosis. Additionally, YTHDC2 inactivated the protein kinase B (Akt) pathway by increasing CYLD in PTC cells. Overall, YTHDC2 inhibited cell proliferation and induced apoptosis in PTC cells by regulating CYLD-mediated inactivation of Akt pathway.


Psychosexual outcome of assigned females and males with 46,XX virilizing congenital adrenal hyperplasia.
Seven genotypic female (46,XX) patients with congenital adrenal hyperplasia, four reared as girls and three reared as boys were evaluated at 16-26 years of age with psychological interviews and testing. A small penis in the three young men produced a practical and psychological barrier that severely injured their personality. In spite of some degree of pre-adolescent tomboyism and a somewhat injured body image, the girls adjusted to their feminine gender identity. It is concluded that in cases of both early and late diagnosis, the genotypic female sex should be preferred.


Membrane Ultrafiltration-Based Sample Preparation Method and Sheath-Flow CZE-MS/MS for Top-Down Proteomics.
Mass spectrometry (MS)-based denaturing top-down proteomics (dTDP) identify proteoforms without pretreatment of enzyme proteolysis. A universal sample preparation method that can efficiently extract protein, reduce sample loss, maintain protein solubility, and be compatible with following up liquid-phase separation, MS, and tandem MS (MS/MS) is vital for large-scale proteoform characterization. Membrane ultrafiltration (MU) was employed here for buffer exchange to efficiently remove the sodium dodecyl sulfate (SDS) detergent in protein samples used for protein extraction and solubilization, followed by capillary zone electrophoresis (CZE)-MS/MS analysis. The MU method showed good protein recovery, minimum protein bias, and nice compatibility with CZE-MS/MS. Single-shot CZE-MS/MS analysis of an Escherichia coli sample prepared by the MU method identified over 800 proteoforms.


Characterization of Actinomyces isolates from samples from the human urogenital tract: description of Actinomyces urogenitalis sp. nov.
Three strains of a previously undescribed Actinomyces-like bacterium were isolated from human clinical sources (urine, urethra and vaginal secretion). Biochemical testing and PAGE analysis of whole-cell proteins indicated that the strains were phenotypically homogeneous and distinct from previously described Actinomyces and Arcanobacterium species. Comparative 16S rRNA gene sequencing studies showed the bacterium to be a hitherto unknown subline within a group of Actinomyces species which includes Actinomyces bovis, the type species of the genus. Based on phylogenetic and phenotypic evidence it is proposed that the unknown bacterium from humans be classified as Actinomyces urogenitalis sp. nov. The type strain of Actinomyces urogenitalis is CCUG 38702T (= CIP 106421T).


On the analysis of competition at the level of the individual plant.
The extent to which some measure of local crowding can account for the performance of individual plants is examined with reference to populations of two species of annual plant. Only a relatively small proportion of the variation in individual plant yield could be accounted for by measures of local crowding. These included the number of close neighbours, an estimate of the area available to each plant and competitive pressure. A multiple regression that took account of both emergence time and local crowding increased the proportion of variance that could be accounted for up to 50%. Computer simulations of the growth of indivudual plants in monoculture were then caried out in order to determine whether the unexplained variation resulted from fundamental flaws in the models or from unaccounted for sources of variation in the field. The results from the simulations again indicated that only a relatively low proportion of the variation in individual plant yield could be accounted for by emergence time and local density, even though these were known to be the only variables present. These findings are discussed in relation to the relative importance of one-sided and two-sided competition, and the complex cross-correlations that occur between individuals in plant populations. These two factors will make it very difficult for field workers to determine accurately what factors determine individual plant yield and in particular to predict the effects of local crowding on the performance of individual plants.


Molecular cloning and characterization of NPC1L1 in the Chinese tree shrew (Tupaia belangeri chinensis).
The Niemann-Pick C1-Like 1 protein, a multi-transmembrane domain molecule, is critical for intestinal cholesterol absorption, and is the entry factor for hepatitis C virus (HCV). The Chinese tree shrew (Tupaia belangeri chinensis) is closer to primates in terms of genetic evolution than rodents. Previous studies indicated that the tree shrew was suitable for HCV research; however, little is known about tree shrew NPC1L1. TsNPC1L1 cDNA was amplified by rapid amplification of cDNA ends (RACE) technology. The cDNA sequence, its encoded protein structure, and expression profile were analyzed. Results indicated that the tsNPC1L1 mRNA is 4948 bp in length and encodes a 1326 amino acid protein. TsNPC1L1 possesses 84.97% identity in homology to human NPC1L1 which is higher than both mouse (80.37%) and rat (81.80%). The protein structure was also similar to human with 13 conserved transmembrane helices, and a sterol-sensing domain (SSD). Like human NPC1L1, the tsNPC1L1 mRNA transcript is highly expressed in small intestine, but it was also well-expressed in the lung and pancreas of the tree shrew. The homology of tree shrew NPC1L1 was closer to human than that of rodent NPC1L1. The expression of tsNPC1L1 was the highest in small intestine, and was detectable in lung and pancreas. These results may be useful in the study of tsNPC1L1 function in cholesterol absorption and HCV infection.


Andegerebenha vowel phonology.
The most common vowel system in Australian languages and the system ancestral to other Australian vowel systems is the triangular system /i-u-a/, with or without phonemic length. This paper shows that this is not appropriate for Andegerebenha, considers the suitability of a two-vowel system /e-a/, and rejects this in favour of one vowel plus length /a-a-/. The short vowel is greatly influenced in quality by the adjacent consonants; the longer one much less so. The consonant inventory is augmented by the addition of a number of labialised consonants, which embody the rounding of earlier *u. Conversely, the phenome/V/, a velar glide, was introduced when an earlier *w acquired the feature [-round] of adjacent vowels.


Muscle force-stiffness characteristics influence joint stability: a spine example.
The muscle force-stiffness relationship has often been modeled as linear, while in situ muscle research has clearly demonstrated non-linearity. Estimation of rotational joint stability relies on both a muscle's instantaneous pre-perturbation force and stiffness. Under conditions of static equilibrium, a muscle's stiffness will function in a stabilizing manner, while its force can function in either a stabilizing or destabilizing manner depending on the muscle's orientation about the joint. A single muscle (rectus abdominis) was modeled and its individual direct stabilizing potential about the L4-L5 spine joint was analyzed. Three force-stiffness relationships were examined: (1) linear; (2) non-linear with moderate stiffness magnitudes; (3) non-linear with higher stiffness magnitudes. With a linear force-stiffness relationship, stability increased proportional to muscle force; with a non-linear relationship, stability peaked and subsequently decreased at submaximal muscle forces. When considering the lower, as opposed to the higher non-linear stiffness magnitudes, the stabilizing potential of the muscle peaked at a lower muscle force level and actually became negative (destabilizing) at a critical stiffness magnitude. It was concluded that a non-linear muscle force-stiffness relationship greatly alters the individual stabilizing potential of the muscle throughout its progression of force development. A muscle's stabilizing contribution may actually peak at and subsequently decrease above a critical submaximal force level. Incorporating this knowledge into stability models may assist in recognizing unstable events that lead to injury at higher levels of muscle activation.


The mechanisms related to fibroblasts in burn surface.
Mesenchymal stem cells (MSCs) can promote burn wound healing, skin appearance, and function recovery by promoting the differentiation and migration of fibroblasts of a wound. The burn environment can activate the autophagy of MSCs. However, it is not clear whether this autophagy can affect the proliferation and migration of fibroblasts. In this study, pretreated MSCs with rapamycin and 3-methyladenine modulated autophagy and co-cultured with fibroblasts of burn. Cell migration was detected by immunofluorescence chemical staining. Western blot analysis and enzyme-linked immunosorbent assay were performed to detect 2,3-Dioxygenase (IDO), cytokine synthesis inhibitory factor 10 (IL-10), cytokine synthesis inhibitory factor 6 (IL-6), prostaglandin E2 (PGE2), transforming growth factor beta 1 (TGF-β1) proteins levels, and the autophagy proteins p62 and microtubule-associated protein LC3-II/I. We demonstrated that autophagy regulates MSCs survival and proliferation in burn wound transplants and found that autophagy inhibition with 3-methyladenine reduced MSCs-mediated, fibroblast proliferation and migration in burn environment. However, rapamycin-induced autophagy had the opposite effect and increased the TGF-β1 expression. Therefore, we speculate that MSCs may promote fibroblast proliferation and migration by secreting TGF-β1 via the AKT/mTOR (RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin) pathway. Autophagy of MSCs regulates burn wound fibroblast proliferation and migration by affecting TGF-β1 and prostaglandin E2 production adjacent to MSCs transplanted on the burn wound. The results of this study provide a potential strategy for promoting MSCs treatment of burns.


Effectiveness of molsidomine in the long-term treatment of exertional angina pectoris and chronic congestive heart failure.
Molsidomine, similar to nitrates, improves myocardial blood flow in hypoperfused, poststenotic myocardial regions, reduces left ventricular pressure and volumes, and leads to improvement in impaired regional wall motion. In patients with chronic, stable anginal pectoris who underwent long-term treatment with 2 mg of molsidomine three times daily there were reductions in ST segment depression of 45% and 9% at 1 and 3 hours after administration, respectively, and slight but statistically significant reductions in the rates of anginal attacks and nitrate consumption of 16% and 18%. Administration of 3 mg three times daily did not render more significant effects. Doubling the frequency of administration--that is, 2 mg six times daily--led to reductions in the rates of anginal attacks and nitrate consumption of 38% and 36%, respectively, and 4 mg led to a more marked reduction in ST segment depression of 57%. With administration of 8 mg of sustained-release molsidomine, a prolonged antiischemic effect was documented with reductions in ST segment depression of 74% at 1 hour and 31% at 8 hours after medication. In patients with congestive heart failure, 1 hour after administration of 4 mg of molsidomine there were significant reductions in systolic and diastolic pulmonary artery pressures of 25% and 30%, respectively. After 7 days of continuous treatment with 4 mg of molsidomine four times daily, comparable reductions in pulmonary artery pressure were observed. Thus molsidomine, in adequate dosages, elicits an unequivocal anti-ischemic and antianginal effect as well as a salutary reduction in left ventricular filling pressure.


Risk scores' performance and their impact on operative decision-making in left-sided endocarditis: a cohort study.
The accuracy of contemporary risk scores in predicting perioperative mortality in infective endocarditis (IE) remains controversial. The aim is to evaluate the performance of existent mortality risk scores for cardiovascular surgery in IE and the impact on operability at high-risk thresholds. A single-center retrospective review of adult patients diagnosed with acute left-sided IE undergoing surgery from May 2014 to August 2019 (n = 142) was done. Individualized risk calculation was obtained according to the available mortality risk scores: EuroScore I and II, PALSUSE, Risk-E, Costa, De Feo-Cotrufo, AEPEI, STS-risk, STS-IE, APORTEI, and ICE-PCS scores. A cross-validation analysis was performed on the score with the best area under the curve (AUC). The 30-day survival was 96.5% (95%CI 91-98%). The score with worse area under the curve (AUC = 0.6) was the STS-IE score, while the higher was for the RISK-E score (AUC = 0.89). The AUC of the majority of risk scores suggested acceptable performance; however, statistically significant differences in expected versus observed mortalities were common. The cross-validation analysis showed that a large number of survivors (> 75%) would not have been operated if arbitrary high-risk threshold estimates had been used to deny surgery. The observed mortality in our cohort is significantly lower than is predicted by contemporary risk scores. Despite the reasonable numeric performance of the analyzed scores, their utility in judging the operability of a given patient remains questionable, as demonstrated in the cross-validation analysis. Future guidelines may advise that denial of surgery should only follow a highly experienced Endocarditis Team evaluation.


Superdiversity, migration and use of internet-based health information - results of a cross-sectional survey conducted in 4 European countries.
Studies of factors associated with the use of Internet-based health information generally focus on general, rather than migrant populations. This study looked into the reasons why Internet-based health information is used and the effects of migration-related factors, other socio-demographic characteristics and health-related factors on the tendency to consult the Internet. In a cross-sectional survey conducted in eight superdiverse neighbourhoods - two each in Birmingham, United Kingdom; Bremen, Germany; Lisbon, Portugal and Uppsala, Sweden - participants were presented with six scenarios and asked to indicate the resources they most relied on when addressing a health concern from a given list. The scenarios included establishing the underlying causes of a health concern and seeking information about prescription drugs, treatments and services available as part of the public healthcare system. The list of resources included the public healthcare system, alternative medicine, family and friends, and the Internet. Frequencies for which the Internet was consulted for each different scenario were calculated and compared across the participating cities. The association between consulting Internet-based health information and migration-related factors, and further socio-demographic characteristics as well as health-related factors such as self-reported health and health literacy was assessed using multivariable logistic regressions. Of the 2570 participants from all four cities who were included in the analyses, 47% had a migrant background and 35% originated from non-EU countries. About a third reported relying on Internet-based health information for at least one of the given scenarios. The two most frequently chosen scenarios were to find out about other possible treatments and prescription drugs. Generally, using Internet-based health information was negatively associated with being a first generation migrant (OR 0.65; 95% CI 0.46-0.93), having poor local language competency (OR 0.25; 95% CI 0.14-0.45), older age (≥60 years, OR 0.21; 95% CI 0.15-0.31), low education (OR 0.35; 95% CI 0.24-0.50) and positively associated with low trust in physicians (OR 2.13; 95% CI 1.47-3.10). Our findings indicate the need to consider migration background and language competency when promoting the provision of healthcare services via the Internet so that information and services are widely accessible.


Dysregulation of the basal RNA polymerase transcription apparatus in cancer.
Mutations that directly affect transcription by RNA polymerases rank among the most central mediators of malignant transformation, but the frequency of new anticancer drugs that selectively target defective transcription apparatus entering the clinic has been limited. This is because targeting the large protein-protein and protein-DNA interfaces that control both generic and selective aspects of RNA polymerase transcription has proved extremely difficult. However, recent technological advances have led to a 'quantum leap' in our comprehension of the structure and function of the core RNA polymerase components, how they are dysregulated in a broad range of cancers and how they may be targeted for 'transcription therapy'.


Status of stigma on the health care workers related to COVID-19 at the first wave of the pandemic in Iran: A qualitative study.
Stigma can be seen as a mark of disgrace that can lead to the separation of one person from another. In this qualitative study, we assess the status of stigma among in front-line health care workers (HCWs) during the first wave of the COVID-19 pandemic in Iran. The participants were selected from frontline HCWs related to COVID-19 in Imam Ali and Imam Hossein referral hospitals in Alborz province, Iran. Study was conducted between May and June 2020. The 32-item checklist Consolidated Criteria for Reporting Qualitative Research (COREQ) was used to report this qualitative study. Interview questions were prepared based on the grounded theory method. The thematic approach was used to analyze the data content. Data analysis was based on open and axial coding and after implementing the codes in MAXQDA software. The results of this study included 4 themes, 8 categories and 33 sub-categories. Themes included extrinsic and intrinsic elements of stigma, perplexity and stigma removal requirements. Extrinsic elements included "creating blame and shame" and "discrimination" categories. Intrinsic elements included "the desire to be avoidance," "feeling depressed and frustrated" and "feeling anxious and scared" categories. Perplexity included "feeling loss" category. Stigma removal requirements included "factors causing stigma" and "protective agents against stigma" categories. Low public awareness on COVID-19 and inadequate public care, limited personal protective equipment and inadequate facilities for HCWs along with lack of appreciation for their efforts, lack of proper psychiatric/psychological counseling to identify and treat symptoms associated with mental health and the limitations of training to maintain mental health skills are considered to be factors in the formation of stigma among HCWs related to COVID-19. Health policymakers should implement coherent strategies related to increasing public awareness and providing personal protection needs and counseling care for HCWs in relation to COVID-19.


Adapted cabling of an EEG cap improves simultaneous measurement of EEG and fMRI at 7T.
The combination of EEG and ultra-high-field (7 T and above) fMRI holds the promise to relate electrophysiology and hemodynamics with greater signal to noise level and at higher spatial resolutions than conventional field strengths. Technical and safety restrictions have so far resulted in compromises in terms of MRI coil selection, resulting in reduced, signal quality, spatial coverage and resolution in EEG-fMRI studies at 7 T. We adapted a 64-channel MRI-compatible EEG cap so that it could be used with a closed 32-channel MRI head coil thus avoiding several of these compromises. We compare functional and anatomical as well as the EEG quality recorded with this adapted setup with those recorded with a setup that uses an open-ended 8-channel head-coil. Our set-up with the adapted EEG cap inside the closed 32 channel coil resulted in the recording of good quality EEG and (f)MRI data. Both functional and anatomical MRI images show no major effects of the adapted EEG cap on MR signal quality. We demonstrate the ability to compute ERPs and changes in alpha and gamma oscillations from the recorded EEG data. Compared to MRI recordings with an 8-channel open-ended head-coil, the loss in signal quality of the MRI images related to the adapted EEG cap is considerably reduced. The adaptation of the EEG cap permits the simultaneous recording of good quality whole brain (f)MRI data using a 32 channel receiver coil, while maintaining the quality of the EEG data.


Effect of anti-sense oligodeoxynucleotides homeobox B2 on the proliferation and expression of primary human umbilical vein endothelial cells.
To explore the effect of homeobox B2 (HOXB2) anti sense oligodeoxynucleotides (asodn) on the proliferation and expression of primary human umbilical vein endothelial cells (HUVECs). Various concentrations of HOXB2 asodn modified by thiophosphate transfected the induction of liposome into HUVECs. MTT a nd RT-PCR methods were employed to determine the effect of different conc ent rations of asodn on the endothelial proliferation and the expression level of HOXB2 mRNA. After the transfection of HOXB2 asodn, the endothelial proliferation was inhibited in a dose-dependent fashion. Simultaneously, the expression of HOXB2 mRNA decreased significantly. HOXB2 plays an important role in the proliferation of endothelia.


Evaluation of masticatory muscle response to clear aligner therapy using ambulatory electromyographic recording.
Patients undergoing clear aligner therapy (CAT) report muscle tenderness and produce wear facets on their aligner trays. However, little is known about the masticatory muscle response to clear aligners. Here, we measured the activity of the masseter during CAT using ambulatory electromyography. We also explored whether psychological traits modulate the masticatory muscle response to CAT. Using portable data loggers, we recorded the electromyographic (EMG) activity in the right masseter muscle of 17 healthy adults without temporomandibular disorder (16 females, 1 male; mean age ± standard deviation, 35.3 ± 17.6 years) commencing treatment with CAT over 4 weeks, under the following conditions: week 1 without aligners (baseline), week 2 with a passive aligner (dummy), week 3 with their first active aligner (active1), and week 4 with their second active aligner (active2). We used a mixed-effect model to test differences in EMG activity over the 4-weeks and a general linear model to test the effect of psychological traits on EMG activity. The EMG activity of the masseter increased significantly with aligners compared with baseline. The largest relative increase in EMG activity was seen during the dummy (152%; P <0.001) and active1 (155%; P <0.001) stages. During active2, the activity of the masseter decreased significantly toward baseline levels. Participants' trait anxiety was positively associated with increases in EMG activity (P = 0.027). CAT is associated with a transient increase in masticatory muscle activity, possibly because of an increase in wake-time parafunctional tooth clenching. Temporomandibular disorder-free patients adapt well to CAT as the masticatory muscle activity decreases toward baseline levels after 2 weeks.


Continuous Microfluidic Self-Assembly of Hybrid Janus-Like Vesicular Motors: Autonomous Propulsion and Controlled Release.
A microfluidic strategy is developed for the continuous fabrication of hybrid Janus vesicular motors that uniquely combine the capability of autonomous propulsion and externally controlled delivery of encapsulated payload.


The role of awareness in human conditioning.
The cognitive view of human classical conditioning is that Ss are active in thinking about the pattern of stimulus events which occurs, the demands of the situation, and the kind of responses which they give. A question crucially central to conditioning theory is whether these thoughts and expectations determine conditional responding. This paper reports on two conditioning and personality experiments, employing the standard procedure of a single cue CS-UCS schedule and masking task, which assess awareness of stimulus contingencies and demand characteristics by means of a postexperimental questionnaire. Results were quite clear in showing no significant relationship between measures of awareness and eyelid conditioning.


Proteasomal components required for cell growth and stress responses in the haloarchaeon Haloferax volcanii.
Little is known regarding the biological roles of archaeal proteases. The haloarchaeon Haloferax volcanii is an ideal model for understanding these enzymes, as it is one of few archaea with an established genetic system. In this report, a series of H. volcanii mutant strains with markerless and/or conditional knockouts in each known proteasome gene was systematically generated and characterized. This included single and double knockouts of genes encoding the 20S core alpha1 (psmA), beta (psmB), and alpha2 (psmC) subunits as well as genes (panA and panB) encoding proteasome-activating nucleotidase (PAN) proteins closely related to the regulatory particle triple-A ATPases (Rpt) of eukaryotic 26S proteasomes. Our results demonstrate that 20S proteasomes are required for growth. Although synthesis of 20S proteasomes containing either alpha1 or alpha2 could be separately abolished via gene knockout with little to no impact on growth, conditional depletion of either beta alone or alpha1 and alpha2 together rendered the cells inviable. In contrast, the PAN proteins were not essential based on the robust growth of the panA panB double knockout strain. Deletion of genes encoding either alpha1 or PanA did, however, render cells more sensitive to growth on organic versus inorganic nitrogen sources and hypo-osmotic stress and limited growth in the presence of l-canavanine. Abolishment of alpha1 synthesis also had a severe impact on the ability of cells to withstand thermal stress. This contrasted with what was seen for panA knockouts, which displayed enhanced thermotolerance. Together, these results provide new and important insight into the biological role of proteasomes in archaea.


NUDT15 genetic testing-guided 6-mercaptopurine dosing in children with ALL likely to be cost-saving in China.
The cost-effectiveness of NUDT15 genetic testing-guided initial 6-mercaptopurine (6-MP) dosing in children with acute lymphoblastic leukemia (ALL) was evaluated. A decision tree model was used to evaluate the cost to China's medical system per quality-adjusted life-year (QALY) gained and cost per case of severe leukopenia avoided of NUDT15 genetic testing using public clinical data. Genetic testing-guided initial 6-MP dosing reduced overall costs by $518.61, and prevented 0.221 cases of Grade III-IV leukopenia and increased QALY by 0.00136 per patient. Results were robust in one-way analyses and probabilistic sensitivity analyses. NUDT15 genetic testing prior to the initial administration of 6-MP in pediatric ALL patients in China is less expensive than standard dosing without genetic testing.


Trichostatin A reduced phospholipase C gamma-1 transcript and protein contents in MCF-7 breast cancer cells.
It has recently been demonstrated that phospholipase C gamma-1 (PLCγ1) activation may contribute to breast carcinoma cell motility and their metastasis. Employing MCF-7 breast cancer cells, we showed the effect of trichostatin A (TSA) on the cellular contents of the PLCγ1 molecule. Using reverse transcription, real-time quantitative PCR and western blot analysis, we demonstrated that TSA reduced the PLCγ1 transcript and protein levels in MCF-7 cells. We also found that TSA decreased the half-life of the PLCγ1 transcript from approximately 7hours to 5hours. Moreover, we observed that protein synthesis appears to be essential in the TSA reduction of PLCγ1 mRNA stability. Since PLCγ1 activation is considered a key factor in the initiation of events that increase malignant cell motility, our observations may support the validity of TSA in anticancer studies.


The impact of sonority on onset-rime and peak-coda lexical decision and naming of lexical items by children with different spelling ability.
The present study used the lexical decision (making YES/NO decision) and the vocalization (naming) paradigms in two reaction time experiments to examine the cohesiveness of onset-rime and peak-coda in the syllable structure of English lexical items. The aim was to study the effect of sonority hierarchy of liquids, nasals and obstruents on the accurate and rapid identification and naming of CCVCC words and pseudowords in relation to the spelling performance of 222 grades 4, 5 and 6 students. In the onset-rime lexical decision and naming tasks nasals were processed faster than the liquids and the obstruents. In the peak-coda lexical decision and naming the obstruents were processed faster than the liquids and nasals. The reaction time results suggest relationship with the spelling of English words even though the significant main effects of grade, spelling performance, mode of response and lexicality of the stimulus items need to be interpreted in the context of statistical interactions.


Newer concepts of analgesia and anesthesia.
Intracerebroventricular (ICV) administration of the peptidase inhibitors amastatin, trasylol, bacitracin, or phe-D-ala and systemic administration of phenylmethylsulfonyl fluoride resulted in one or more of the following responses: analgesia, reduced withdrawal severity in opiate tolerant rats, alterations in motor activity and behavior, hypo- and hyperthermia and others; some of these effects were antagonized by naloxone, suggesting participation of opioid and other endogenous peptides. In addition, peptidase inhibitors enhanced analgesic and other responses to opioid peptides given ICV. Peptidase inhibition affords another method of inducing selective pharmacological responses such as pain relief in individuals resistant to other forms of therapy. ICV administration of beta-endorphin in the rat induces general anesthesia that is instantly reversed by systemic naloxone. Extensions of this work include identification of specific neural pathways that mediate anesthesia and characterization of opiate receptor subtype(s) at these sensitive loci. This approach offers the potential for the design of systemically effective opioid peptide anesthetics with little or no secondary effects and rapid reversibility.


Discrimination of metamorphic diamond populations by Raman spectroscopy (Kokchetav, Kazakhstan).
Metamorphic diamond is a powerful but frequently debated indicator for ultrahigh-pressure metamorphic (UHPM) conditions. Because of their small size, their optical identification needs confirmation. Characteristics of chemically extracted microdiamonds from Kokchetav, identified by different analytical methods, are used here for unambiguous in situ identification by Raman microspectroscopy. Differences appear in the diamond spectra and the Raman analytical method is explored as a helpful tool in the discrimination between diamond populations from four different UHPM lithologies of Kokchetav. Not considering the graphite-coated diamond, out of the reach of the laser wavelength used here, the comparison of these Kokchetav Raman spectra may provide additional information in other UHPM studies.


Undetectable transcription of cap in a clinical AAV vector: implications for preformed capsid in immune responses.
In a gene therapy clinical trial for hemophilia B, adeno-associated virus 2 (AAV2) capsid-specific CD8(+) T cells were previously implicated in the elimination of vector-transduced hepatocytes, resulting in loss of human factor IX (hFIX) transgene expression. To test the hypothesis that expression of AAV2 cap DNA impurities in the AAV2-hFIX vector was the source of epitopes presented on transduced cells, transcription of cap was assessed by quantitative reverse transcription-PCR (Q-RT-PCR) following transduction of target cells with the vector used in the clinical trial. Transcriptional profiling was also performed for residual Amp(R), and adenovirus E2A and E4. Although trace amounts of DNA impurities were present in the clinical vector, transcription of these sequences was not detected after transduction of human hepatocytes, nor in mice administered a dose 26-fold above the highest dose administered in the clinical study. Two methods used to minimize encapsidated DNA impurities in the clinical vector were: (i) a vector (cis) production plasmid with a backbone exceeding the packaging limit of AAV; and (ii) a vector purification step that achieved separation of the vector from vector-related impurities (e.g., empty capsids). In conclusion, residual cap expression was undetectable following transduction with AAV2-hFIX clinical vectors. Preformed capsid protein is implicated as the source of epitopes recognized by CD8(+) T cells that eliminated vector-transduced cells in the clinical study.


Nocardia rubra cell-wall skeleton promotes CD4+ T cell activation and drives Th1 immune response.
Several lines of evidences have shown that Nocardia rubra cell wall skeleton (Nr-CWS) has immunoregulatory and anti-tumor activities. However, there is no information about the effect of Nr-CWS on CD4+ T cells. The aim of this study was to explore the effect of Nr-CWS on the phenotype and function of CD4+ T cells. Our results of in vitro experiments showed that Nr-CWS could significantly up-regulate the expression of CD69 and CD25 on CD4+ T cells, promote the proliferation of CD4+ T cells, increase the production of IFN-γ, TNF-α and IL-2 in the supernatants, but has no significant effect on the apoptosis and death of CD4+ T cells. Results of in vivo experiments showed that Nr-CWS could promote the proliferation of CD4+ T cells, and increase the production of IL-2, IFN-γ and TNF-α (Th1 type cytokines). These data suggest that Nr-CWS can enhance the activation of CD4+ T cells, promote the proliferation of CD4+ T cells and the differentiation of CD4+ T cells to Th1 cells.


Sources of declarative memory impairment in bipolar disorder: mnemonic processes and clinical features.
There is mounting evidence that declarative memory processes are impaired in patients with bipolar disorder. However, predictors of the observed impairment are not well understood. This study seeks to: (i) better characterize the nature of declarative memory impairment in bipolar disorder, and (ii) determine the relationship between clinical variables and memory function in bipolar disorder. 49 adult patients with bipolar disorder in varying mood states and 38 demographically matched healthy participants completed a comprehensive neurocognitive battery assessing general cognitive functioning, processing speed, and declarative memory. The California verbal learning test was used to characterize learning and memory functions. Although patients with bipolar disorder utilized a similar semantic clustering strategy to healthy controls, they recalled and recognized significantly fewer words than controls, suggesting impaired encoding of verbal information. In contrast, lack of rapid forgetting suggests relative absence of a storage deficit in bipolar patients. While severity of mood symptomatology and illness duration were not associated with task performance, gender and family history significantly affected memory function. Results suggest that declarative memory impairments in bipolar patients: (1) are consistent with deficits in learning, but do not appear to be related to different organizational strategies during learning, and (2) do not appear to be secondary to clinical state, but rather may be associated with the underlying pathophysiology of the illness.


Applying the COM-B behaviour model to understand factors which impact school immunisation nurses' attitudes towards designing and delivering a HPV educational intervention in post-primary schools for 15-17 year old students in Northern Ireland, UK.
Human Papilloma Virus (HPV) is responsible for the development of cervical, vaginal, vulvar, penile, oropharyngeal and anal cancers. Throughout the UK, Immunisation nurses (IMNs) deliver school-based HPV vaccinations to students 12-13 years old. Providing HPV education to 15-17 year old students may promote decision-making regarding their sexual health and award opportunity for unvaccinated students to self-consent to the vaccination. This study aims to explore the perceptions of IMNs regarding the value of providing HPV education to 15-17 year old students and to explore whether IMNs feel that the design/delivery of this education should form part of their professional role. Six focus groups were conducted online with IMNs from all five Health and Social Care Trusts in Northern Ireland, UK, between January-June 2021. Data were analysed using the COM-B model to identify factors that might influence IMNs' behaviour towards designing/delivering this education for 15-17 year old students. IMNs were highly motivated to design and deliver this HPV education. Facilitators promoting this behaviour included their specialist training, their previous sexual health teaching experience and their desire to educate young people. Barriers negatively influencing this behaviour included lack of time/resources, parental influences, lack of school support and lack of teaching/presentation skills training. IMNs feel that they are the most appropriate professionals to design/deliver HPV education for 15-17 year old students. National policy change, based on collaboration between the Public Health Agency and Education Authority, is a key factor in facilitating IMNs to implement this school-based HPV education intervention.


Midterm results of titanium conical Wagner stem with challenging femoral anatomy: Survivorship and unique bone remodeling.
Complex anatomy of the proximal femur makes total hip arthroplasty (THA) more challenging. Short, straight, fluted and conical titanium stem like the Wagner Cone can be helpful to address small femoral canal, increased femoral neck version, important leg length discrepancy or proximal femoral deformity. The outcome in these patients is less assured and associated with high rate of complications. Therefore, we did a retrospective study aiming to answer: 1) can the Wagner Cone stem provide acceptable mid- to long-term implant survivorship; 2) help minimizing perioperative adverse events; 3) produce favorable clinical outcome measured by WOMAC score; and 4) be associated with a favorable radiographic femoral bone remodeling at the last follow-up? Wagner Cone stem is an advantageous solution for the distorted proximal femur in complex THA. Our cohort was derived from the patient registries where medical records of 88 patients (103 hips) who underwent primary THA using the Wagner prosthesis were retrospectively reviewed. Then, data was analyzed for patients' demographics and surgical data, and comparing preoperative, immediate postoperative and last follow-up data. Eleven patients (12 hips) were excluded (7 hips followed up less than 2 years or lost to follow-up, 3 hips that had the Wagner stem for revision and 2 Wagner stems inserted for periprosthetic fracture). This left 77 patients (91 hips) with Wagner cone stems implanted for more than 2 years between March 2003 and February 2017 by 7 surgeons in 3 academic hospitals. Implant revision, reoperations, WOMAC score and radiographic analyses were recorded at last follow-up. After a mean follow-up of 7.8 (range, 2.0-16.2) years, Wagner stem survivorship was 98.9% (95% CI: 94 to 100%) with one (1.1%) stem revision for failure of osteointegration. Five (5.5%) acetabular revisions, one for aseptic loosening, 2 for adverse reaction to metal debris and 2 for infection. One (1.1%) sciatic neuropathy and 4 (4.4%) intraoperative fractures were encountered. The mean WOMAC score was 90.5±11.4 (59-100). Radiographic analysis showed clear signs of stem osseointegration and hypertrophic bone remodeling in 82 cases (92.1%). Used in complex cases with proximal distorted femurs, the Wagner Cone stem demonstrated a low complication rate, a high-rate consistent adaptive bone remodeling, excellent clinical results, and midterm survival. It is a safe, reliable and advantageous option in complex primary THA. However, the contribution of the underlying cause of the secondary osteoarthritis on the long-term survival of the stem remains to be demonstrated. IV; retrospective study.


Systematic development of a bioanalytical UPLC-MS/MS method for estimation of risperidone and its active metabolite in long-acting microsphere formulation in rat plasma.
A systematic approach to develop a UPLC-MS/MS method was applied for quantifying of risperidone (RISP), its active metabolite, 9-hydroxy risperidone (9-OH-RISP) and internal standard (propranolol) in rat plasma. Liquid-liquid extraction was performed using methyl tert-butyl ether for quantification of drug and its active metabolite by MS detection in the positive ion mode. Acquity UPLC system with BEH C18 (2.1 mm × 100 mm, particle size 1.7 μm) column was used along with acetonitrile (0.1% formic acid)-2 mM (milli mole) ammonium acetate in isocratic condition was used as the mobile phase. Detection was performed by multiple reactions monitoring with precursor-to-product ion transitions with m/z 411.2 → 191.0 for RISP, m/z 427.2 → 207.0 for 9-OH-RISP and m/z 260.1 → 116.0 for IS. The method was validated as per the FDA guidance on bioanalytical method validation. Linearity (r2 = 0.999) was observed in the drug concentration ranging between 0.1 and 50 ng mL-1, while all other parameters were found to be within the acceptable ranges. Method robustness was optimized by Box-Behnken design to monitor the influential variables to achieve maximal recovery of the analytes in the rat plasma. Pharmacokinetic evaluation of the analytes from long-acting microparticles in rat plasma showed two peaks indicating an initial burst effect within 24 h of administration followed by controlled drug release pattern upto 45 days, while marketed formulation (Risperdal Consta®) showed no plasma concentration during the lag-time of 21 days followed by maximal drug absorption between 28 and 40 days.


Decreased serum essential and aromatic amino acids in patients with chronic pancreatitis.
To investigate the influence of chronic pancreatitis (CP) on serum concentrations of amino acids. Thirty-five male patients with alcoholic CP and 21 healthy male subjects were examined. Serum concentrations of amino acids were assayed by ion-pair high-performance liquid chromatography with mass detection. Serum glutamate concentration was increased in CP patients as compared to controls. In contrast, serum concentrations of glutamine, histidine, tyrosine, proline, tryptophan and threonine were significantly decreased in CP patients. A trend towards decreasing concentrations of serum lysine, alanine, methionine and valine as well as for total serum amino acids was observed. The sum of aromatic and the sum of essential amino acid concentrations were significantly lower in CP patients than in controls. CP leads to decreased serum concentrations of several amino acids, such as essential and aromatic serum amino acids, most likely due to decreased exocrine function.


Distribution of cesium-137 in Japanese forest soils: correlation with the contents of organic carbon.
The spatial and vertical distributions of 137Cs in surface soils were surveyed and analyzed then correlated with the contents of organic carbon in the hinoki (Chamaecyparis obtusa Sieb. et Zucc.) plantation forest and secondary forest dominated by red pine (Pinus densiflora Sieb. et Zucc.) in Japan. The spatial variation of 137Cs activity was observed in the surface soil around the red pine. The average activity of 16 samples around the tree is 42.4 Bq/kg and the standard deviation is 25.9 Bq/kg. This finding indicates the importance in the selection of a sampling site and the number of samples from the surface soils especially around a tree. For the vertical distribution of 137Cs activity, it was found that the concentration in the surface soil is highest, 149 Bq/kg in the hinoki stand and 101 Bq/kg in the red pine stand, and decreases with depth. The relationship between 137Cs activity and carbon content in the forest soil was investigated in two undisturbed forest stands. The relations were more precisely expressed using an exponential equation than by a linear equation. From the same forest, similar regression equations were obtained. This indicates that the distribution of 137Cs could be characterized by the organic carbon content in an undisturbed forest. It is also suggested that the coefficient values in the regression equation help to define the movement of 137Cs accompanying the decomposition of organic matter.


Assessing exposure to allied ground troops in the Vietnam War: a comparison of AgDRIFT and Exposure Opportunity Index models.
The AgDRIFT aerial dispersion model is well validated and closely related to the AGDISP model developed by the USDA Forest Service to determine on- and off-target deposition and penetration of aerially applied pesticide through foliage of trees. The Exposure Opportunity Index (EOI) model was developed to estimate relative exposure of ground troops in Vietnam to aerially applied herbicides. We compared the output of the two models to determine whether their predictions were in substantial agreement, but found a total lack of concordance. While the AgDRIFT model estimated that ground-level deposition through foliage was reduced more than 20 orders of magnitude at less than 1 km from the flight line, the EOI model predicted deposition declines less than one order of magnitude 4 km from the flight line. Interestingly the EOI model predicts a four-fold variability in EOI on the flight line, where exposure should be essentially invariant because the spray apparatus is designed to apply herbicide at a constant rate. We believe that the EOI model cannot be used to provide individual exposure estimates for the purpose of conducting epidemiologic studies. Moreover, evaluation of the position data for both herbicide spray swaths and troop locations, together with the actual patterns of spray deposition predicted by the AgDRIFT model, suggests that precise individual-level exposure assessments for ground troops in Vietnam are impossible. However, we suggest that well-validated tools like AgDRIFT can be used to estimate exposure to groups of individuals.


Complete investigations (autopsy, toxicology, and histology) in a death due to apixaban overdose.
The dead body of a 54-year-old man was found at home by his partner. He was off work due to depression. A letter with suicidal intention was present on the scene. He was known to be a heavy drinker, and near the body, an empty bottle of whisky was found. In addition, 2 empty blisters of Eliquis (apixaban) 5 mg, corresponding to 40 tablets, were identified. Apixaban is an oral anticoagulant, acting as a factor Xa inhibitor. Autopsy findings were mostly unremarkable, except numerous bruises and some superficial self-inflected wounds. Histology showed hematomas of calyces and renal pelvis and in the liver, several areas of perivenular haemorrhagic necrosis. Others organs were congestive. Femoral venous blood alcohol was 0.11 g/L. In femoral venous blood, a toxic concentration of apixaban was measured at 1184 ng/mL using LC-MS/MS. Other drugs found at therapeutic concentrations included diazepam (99 ng/mL), nordiazepam (171 ng/mL), flecainide (447 ng/mL), and mianserine (65 ng/mL). Using liquid chromatography coupled to high-resolution mass spectrometry, 2 metabolites were identified, O-desmethyl-apixaban (61.8% of the apixaban response) and hydroxyl-apixaban (4.5% of the apixaban response). Long-term therapy was confirmed by a concentration of 10390 pg/mg in pubic hair.


Mechanical stability and post-traumatic osteitis: an experimental evaluation of the relation between infection of bone and internal fixation.
Stable and unstable internal fixation of fractures was performed in rabbits. After inoculation with Staphylococcus aureus, clinically manifest osteitis occurred only in the very unstable fractures. Abscesses, sinuses and sequestra developed in 45 per cent of the unstable fractures, whereas clinically manifest osteitis did not occur after rigid fixation. With rigid fixation there was no significant difference in the time to bony union between the infected and uninfected fractures. It seems that the development of osteitis and the healing of a fracture are both related to the degree of rigidity, but remain independent of each other. The significance of these findings in the management of posttraumatic osteitis is discussed.


Production of alkaline protease from an alkaliphilic actinomycete.
The repression of alkaline protease synthesis from alkaliphilic actinomycete was studied by using glucose, peptone, yeast extract, KH2PO4 and amino acids; tyrosine, tryptophan, lysine, and arginine. There was a critical limit of stimulation of enzyme production by these components. Crude components such as molasses, wheat flour, and wheat bran were found to be effective for growth and enzyme production. The high level of enzyme production using agro-industrial by-products is commercially significant due to cheap nature of these sources. The findings are quite attractive, as only few actinomycetes, particularly alkaliphilic ones, have so far been explored for their enzymatic potential and regulation of enzyme synthesis.


Super enhancers - new analyses and perspectives on the low hanging fruit.
Significant attention has recently been given to a class of enhancers termed "super enhancers", while implying that "typical enhancers" are less important. In this report, we examine criteria for identification of super enhancers and address the need to evaluate the differences between BRD4-occupied "typical" and "super" enhancers.


Radioanatomical Study of the Skull Base and Septum in Chinese: Implications for Using the HBF for Endoscopic Skull Base Reconstruction.
Radioanatomy provides surgeons with different choices to prevent the failure of reconstruction caused by improper flap selection and the occurrence of CSF leakage or other severe complications. To establish a radioanatomical model, this study radioanatomically investigated the use of the Hadad-Bassagasteguy nasoseptal flap (HBF) in skull base reconstruction performed via the transethmoidal, transsphenoidal, and transclival approaches to provide preoperative guidance for the selection of approaches for skull base reconstruction and preparation of the HBF. The computed tomography images of 40 Chinese adults were selected for the radioanatomical measurement of data related to the HBF and skull base reconstruction via the transethmoidal, transsphenoidal, and transclival approaches. The results were analyzed using radioanatomy combined with SPSS-based analysis. In the 40 patients, the area of the HBF exceeded that of skull base defects reconstructed via the transethmoidal approach by 10.21 ± 1.97 cm2, and the anterior margin width, posterior margin width, upper margin length, and lower margin lengths of the HBF all exceeded the corresponding values of skull base defects requiring reconstruction by at least 8.4 mm. The area of the HBF exceeded that of reconstructed skull base defects by an average of 10.72 ± 2.04 cm2. The area of the HBF exceeded that of skull base defects reconstructed via the transclival approach by 9.01 ± 2.87 cm2. The difference between the anterior margin width of the HBF and the middle width of skull base defects reconstructed via the transclival approach did not exceed 6 mm in only one case (5.4 mm). In Chinese adults, the HBF can cover skull base defects reconstructed via the transethmoidal, transsphenoidal, and transclival approaches, permitting its use in skull base reconstruction performed via all three approaches. Radioanatomy can be used for preoperative guidance to plan surgery via the transethmoidal, transsphenoidal, and transclival approaches.