Infectious Agents as Potential Drivers of α-Synucleinopathies.
α-synucleinopathies, encompassing Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, are devastating neurodegenerative diseases for which available therapeutic options are scarce, mostly because of our limited understanding of their pathophysiology. Although these pathologies are attributed to an intracellular accumulation of the α-synuclein protein in the nervous system with subsequent neuronal loss, the trigger(s) of this accumulation is/are not clearly identified. Among the existing hypotheses, interest in the hypothesis advocating the involvement of infectious agents in the onset of these diseases is renewed. In this article, we aimed to review the ongoing relevant factors favoring and opposing this hypothesis, focusing on (1) the potential antimicrobial role of α-synuclein, (2) potential entry points of pathogens in regard to early symptoms of diverse α-synucleinopathies, (3) pre-existing literature reviews assessing potential associations between infectious agents and Parkinson's disease, (4) original studies assessing these associations for dementia with Lewy bodies and multiple system atrophy (identified through a systematic literature review), and finally (5) potential susceptibility factors modulating the effects of infectious agents on the nervous system. © 2022 International Parkinson and Movement Disorder Society.


New Isoquinoline Alkaloids from Paraphaeosphaeria sporulosa F03, a Fungal Endophyte Isolated from Paepalanthus planifolius.
As part of our continuing efforts to discover new bioactive compounds from endophytic fungal sources, we have investigated the extract of the Paraphaeosphaeria sporulosa F03 strain. The study led to the isolation of four new 3-methyl-isoquinoline alkaloids (1: - 4: ) and four known polyketides (5: - 8: ). The structures of compounds 1: - 4: were elucidated by 1D and 2D NMR experiments and HRMS analysis. The absolute configuration of 4: was determined by comparison of its experimental electronic circular dichroism spectrum with calculated data. Compounds 1: - 4: exhibited antifungal activity with minimal inhibitory concentration values ranging from 6.25 - 50 µg/mL against six Candida species but they did not present any cytotoxic activity against the human tumor cell lines A549 (lung), MCF-7 (breast), and HepG2 (hepatocellular). In addition, compound 4: exhibited antiplasmodial activity in the low micromolar range (IC50 = 4 µM).


Predicting Ca2+ and Mg2+ ligand binding sites by deep neural network algorithm.
Alkaline earth metal ions are important protein binding ligands in human body, and it is of great significance to predict their binding residues. In this paper, Mg2+ and Ca2+ ligands are taken as the research objects. Based on the characteristic parameters of protein sequences, amino acids, physicochemical characteristics of amino acids and predicted structural information, deep neural network algorithm is used to predict the binding sites of proteins. By optimizing the hyper-parameters of the deep learning algorithm, the prediction results by the fivefold cross-validation are better than those of the Ionseq method. In addition, to further verify the performance of the proposed model, the undersampling data processing method is adopted, and the prediction results on independent test are better than those obtained by the support vector machine algorithm. An efficient method for predicting Mg2+ and Ca2+ ligand binding sites was presented.


Pregnant women with more seizures have lower allopregnanolone concentrations.
Neuroactive steroids have rapid, nongenomic effects on neuronal excitability. The effects in humans are less clear. We compared seizure control and concentrations of neuroactive steroids, known to influence neuroexcitability in animal studies, in pregnant women. Participants were prospectively followed throughout pregnancy with seizure-medication diaries and blood samples, assayed for steroid concentrations with gas chromatography-mass spectrometry. Baseline seizure frequency was calculated for the preconception year, and it was determined if seizure frequency was increased in each trimester. The Wilcoxon rank-sum test was used to compare neuroactive steroid concentrations in between the group with increased frequency to the group without, as calculated for the respective trimester, with the Holm-Bonferroni method to correct for multiple comparisons. Among eighty-three pregnancies included, twenty-eight had increased seizure frequency during at least one trimester (15, 18 and 10, respectively) compared to preconception seizure frequency. Allopregnanolone concentrations were lower in the 3rd trimester (p < 0.001), with a similar trend in the 1st (p = 0.08), for pregnancies with increased compared to those with stable seizure frequency. Other neuroactive steroid concentrations were similar. Our findings suggest that lower allopregnanolone concentrations are associated with increased seizure frequency during pregnancy. Validation of these finding in a larger cohort has potential important clinical applications.


Endothelial function in obstructive sleep apnea.
Untreated obstructive sleep apnea (OSA) is an independent risk factor for hypertension, myocardial infarction, and stroke. The repetitive hypoxia/reoxygenation and sleep fragmentation associated with OSA impair endothelial function. Endothelial dysfunction, in turn, may mediate increased risk for cardiovascular diseases. Specifically, in OSA, endothelial nitric oxide availability and repair capacity are reduced, whereas oxidative stress and inflammation are enhanced. Treatment of OSA improves endothelial vasomotor tone and reduces inflammation. We review the evidence and possible mechanisms of endothelial dysfunction as well as the effect of treatment on endothelial function in OSA.


Investigation of relative risk estimates from studies of the same population with contrasting response rates and designs.
There is little empirical evidence regarding the generalisability of relative risk estimates from studies which have relatively low response rates or are of limited representativeness. The aim of this study was to investigate variation in exposure-outcome relationships in studies of the same population with different response rates and designs by comparing estimates from the 45 and Up Study, a population-based cohort study (self-administered postal questionnaire, response rate 18%), and the New South Wales Population Health Survey (PHS) (computer-assisted telephone interview, response rate ~60%). Logistic regression analysis of questionnaire data from 45 and Up Study participants (n = 101,812) and 2006/2007 PHS participants (n = 14,796) was used to calculate prevalence estimates and odds ratios (ORs) for comparable variables, adjusting for age, sex and remoteness. ORs were compared using Wald tests modelling each study separately, with and without sampling weights. Prevalence of some outcomes (smoking, private health insurance, diabetes, hypertension, asthma) varied between the two studies. For highly comparable questionnaire items, exposure-outcome relationship patterns were almost identical between the studies and ORs for eight of the ten relationships examined did not differ significantly. For questionnaire items that were only moderately comparable, the nature of the observed relationships did not differ materially between the two studies, although many ORs differed significantly. These findings show that for a broad range of risk factors, two studies of the same population with varying response rate, sampling frame and mode of questionnaire administration yielded consistent estimates of exposure-outcome relationships. However, ORs varied between the studies where they did not use identical questionnaire items.


[Acquired effluvium of head hair: common conditions in women].
Acquired disorders of hair growth in women may present clinically either as effluvium or alopecia. The relevant pathologies include androgenetic alopecia, postpartum effluvium, tinea capitis, trichotillomania and alopecia areata.


Irrigated radiofrequency ablation with transmurality feedback reliably produces Cox maze lesions in vivo.
Irrigated bipolar radiofrequency ablation has been used to replicate Cox maze surgical scars in pig hearts ex vivo. Impedance monitoring accurately predicted complete transmurality for all lesions. This study aimed to assess the feasibility and reliability of irrigated radiofrequency ablation and impedance monitoring to produce electrically isolating Cox maze lesions in vivo. A modified Cox maze procedure was performed in 8 adult sheep during cardiopulmonary bypass using irrigated bipolar and unipolar radiofrequency ablation. For bipolar radiofrequency ablation, atrial tissues were clamped between opposing electrodes; ablation was terminated at the plateau in impedance decline. Unipolar radiofrequency ablation lesions were painted on the endocardium, and transmurality was assessed visually. Animals survived 30 days. Bipolar lesions (n = 48) were thinner (7.4 +/- 2.4 mm versus 12.7 +/- 3.2 mm) and required less time (14.1 +/- 3.4 seconds versus 41.4 +/- 21.8 seconds) and energy (377.5 +/- 99.2 W.s versus 995.1 +/- 547.1 W.s) to create despite being longer (31.7 +/- 8.6 mm versus 19.2 +/- 5.6 mm) than unipolar lesions (n = 26). The left atrial pacing threshold across selected bipolar lesions increased at least fivefold above baseline (1.6 +/- 0.2 mA) at 1 hour (18.4 +/- 4.6 mA; n = 8; p < 0.001) and 30 days (17.2 +/- 5.2 mA; n = 6; p < 0.001), indicating functional conduction block. Bipolar lesions had no adherent thrombus or endocardial defects. Cross-section examination confirmed transmurality in 100% of bipolar lesions and 98.7% of unipolar lesions. Irrigated bipolar radiofrequency ablation with impedance monitoring safely and reliably produces electrically isolating, transmural Cox maze lesions in vivo.


Clinical characteristics and prognostic factors of hepatoblastoma in 316 children aged under 3 years - a 14-year retrospective single-center study.
The aim of the present study was to summarize the clinical characteristics of in children aged under 3 years and analyze the related factors affecting the prognosis. The clinical data of 316 children aged under 3 years (192 males and 124 females) who were admitted to Beijing Tongren Hospital with a pathological diagnosis of HB between May 2005 and May 2019 were analyzed retrospectively. The factors influencing the therapeutic effects on and survival of HB in children with HB were analyzed. (1) The median age of the enrolled patients was 1.45 years. The most common initial symptom was an abdominal mass (69.0%). The average serum alpha-fetoprotein (AFP) level and platelet count at the initial visit were (97,406.5 ± 5022.8) ng/mL and (418 ± 206) × 109/L, respectively. The epithelial type was the main pathological type (51.9%). According to the PRETEXT preoperative typing system, the most common stage was stage III (57.0%), whereas according to the postoperative Evans staging system, the most common stage was stage IV (41.8%). At the initial visit, 62 cases (19.6%) had vascular invasion, 52 cases (16.5%) had extrahepatic tumor extension, and 20 cases (6.3%) had tumor rupture. Distant metastasis occurred in 132 cases, and the most common metastatic site was the lung (80.3%). The incidence in East China was relatively high (35.4%). (2) The children were followed up until May 2020 (the median follow-up duration was 62 months). It was found that 194 patients had complete remission and 62 had partial remission. The Kaplan-Meier survival analysis showed that the overall survival was 95.3, 88.2, and 79.8% at 1 year, 3 years, and 5 years, respectively, and the event-free survival was 91.1, 83.2, and 75.1%, respectively. The Cox regression analysis showed that AFP level, platelet count, PRETEXT IV, vascular invasion, and distant metastasis at the initial visit were independent risk factors for the prognosis of children with HB (p < 0.05 in all). The prognosis of HB was correlated with the AFP level, platelet count, PRETEXT staging, vascular invasion, and distant metastasis at initial diagnosis.


Protective effect of blackcurrant on liver cell membrane of rats intoxicated with ethanol.
Chronic ethanol intoxication oxidative stress participates in the development of many diseases. Nutrition and the interaction of food nutrients with ethanol metabolism may modulate alcohol toxicity. One such compound is blackcurrant, which also has antioxidant abilities. We investigated the effect of blackcurrant as an antioxidant on the composition and electrical charge of liver cell membranes in ethanol-intoxicated rats. Qualitative and quantitative phospholipid composition and the presence of integral membrane proteins were determined by high-performance liquid chromatography. Electrophoresis was used to determine the surface charge density of the rat liver cell membranes. Ethanol intoxication is characterized by changes in cell metabolism that alter the structure and function of cell membrane components. Ethanol increased phospholipid levels and altered the level of integral proteins as determined by decreased phenylalanine, cysteine, and lysine. Ethanol significantly enhanced changes in the surface charge density of the liver cell membranes. Administration of blackcurrant to rats intoxicated with ethanol significantly protected lipids and proteins against oxidative modifications. It is possible that the beneficial effect of blackcurrant is connected with its abilities to scavenge free radicals and to chelate metal ions.


Ureteral obstruction owing to endometriosis: reversal with synthetic progestin.
A case of unilateral ureteral obstruction owing to extensive pelvic endometriosis is presented. There was complete resolution of ureteral obstruction following treatment with synthetic progestin. Sequential assessment of renal function was provided by renal imaging and renograms. It would appear that selected patients with obstructive uropathy may respond favorably to medical management, which would allow for preservation of reproductive capabilities and restoration of renal excretory function.


Psychomotor agitation in major depressive disorder is a predictive factor of mood-switching.
The relationship between psychomotor agitation in unipolar depression and mood-switching from depression to manic, hypomanic and mixed states has been controversial. We investigated the future risk of initial mood-switching as a function of psychomotor agitation in unipolar depression. We identified 189 participants diagnosed with major depressive disorder (MDD). We divided all patients with MDD into two categories (1) agitated patients (n=74), and (2) non-agitated patients (n=115). These groups were prospectively followed and compared by time to mood-switching. Kaplan-Meier survival curves, log-rank test for trend for survivor functions, and Cox proportional hazard ratio estimates for a multivariate model were conducted to examine the risk of mood-switching by psychomotor agitation. During follow-up, mood-switching occurred in 20.3% of the agitated patients and 7.0% of the non-agitated patients. In the Kaplan-Meier survival estimates for time to incidence of mood-switching with agitated or non-agitated patients, the cumulative probability of developing mood-switching for agitated patients was higher than those for non-agitated patients (log-rank test: χ(2)=7.148, df=1, p=0.008). Survival analysis was also performed using Cox proportional hazards regression within a multivariate model. The agitation remained significantly associated with incidence of mood-switching (HR=2.98, 95% CI: 1.18-7.51). We did not make a clear distinction between antidepressant-induced mood-switching and spontaneous switching. The main finding demonstrated that MDD patients with agitation were nearly threefold as likely to experience mood-switching, suggesting that psychomotor agitation in MDD may be related to an indicator of bipolarity.


Collecting and processing records from the ultracentrifuge in "real-time" using an on-line computer.
An analytical system consisting of an analytical cantrifuge coupled 'on-line' to a computer was assembled and tested. Collection of records from up to 9 solutions was achieved through programmes which sum readings to reduce noise as well as controlling the positioning of the scanner. With this system it was found that the limit on accuracy for molecular weights at concentrations less than 0.01 g cm-3 was +/- 3% estimated from sedimentation equilibrium experiments. The same system was used to collect records for similar concentrations from velocity experiments by employing a scanning schlieren. In this case the accuracy in estimating sedimentation coefficients was similar to those found when measuring photographs. Since the collection yields detailed information about the shape of the sedimenting boundary, the centroids of the boundary were routinely computed by second moment analysis rather than relying on the position of the maximum of the schlieren peak. In the same analysis estimates of diffusion coefficients were made routinely by calculating corrected height/area ratios for each scan. These calculations were made during the real-time of the experiment, so making available molecular parameters rather than records which must be evaluated some time after stopping the experiment.


A handheld device for measuring the diameter at breast height of individual trees using laser ranging and deep-learning based image recognition.
Accurate and efficient measurement of the diameter at breast height (DBH) of individual trees is essential for forest inventories, ecological management, and carbon budget estimation. However, traditional diameter tapes are still the most widely used dendrometers in forest surveys, which makes DBH measurement time-consuming and labor-intensive. Automatic and easy-to-use devices for measuring DBH are highly anticipated in forest surveys. In this study, we present a handheld device for measuring the DBH of individual trees that uses digital cameras and laser ranging, allowing for an instant, automated, and contactless measurement of DBH. The base hardware of this device is a digital camera and a laser rangefinder, which are used to take a picture of the targeted tree trunk and record the horizontal distance between the digital camera and the targeted tree, respectively. The core software is composed of lightweight convolutional neural networks (CNNs), which includes an attention-focused mechanism for detecting the tree trunk to log the number of pixels between the edges. We also calibrated the digital camera to correct the distortion introduced by the lens system, and obtained the normalized focal length. Parameters including the horizontal distance between the digital camera and the targeted tree, number of pixels between the edges of the tree trunk, and normalized focal length were used to calculate the DBH based on the principles of geometrical optics. The measured diameter values, and the longitudes and latitudes of the measurement sites, were recorded in a text file, which is convenient to export to external flash disks. The field measurement accuracy test showed that the BIAS of the newly developed device was - 1.78 mm, and no significant differences were found between the measured diameter values and the true values (measured by the conventional tape). Furthermore, compared with most other image-based instruments, our device showed higher measurement accuracy. The newly developed handheld device realized efficient, accurate, instant, and non-contact measurements of DBH, and the CNNs were proven to be successful in the detection of the tree trunk in our research. We believe that the newly developed device can fulfill the precision requirement in forest surveys, and that the application of this device can improve the efficiency of DBH measurements in forest surveys.


[Bessel Hagen's deformity, Madelung's deformity: cosmopolitan diseases (author's transl)].
These two deformities are rare and the 8 reported cases give evidence of the cosmopolitan feature of these malformations (Madagascar, Ivory Coast, Central African Empire, Djibouti).


Infant holding policies and practices in neonatal units.
To describe neonatal unit policies and practices regarding the holding of infants by parents. U.S. national cross-sectional descriptive survey. Nurses representing 215 neonatal units providing regional-level (22 percent), community-level (45 percent), and intermediate-level (33 percent) care. Proportion of respondents who reported neonatal intensive care unit criteria permitting parents and family members to hold their infant by conventional and skin-to-skin methods. All but one of the neonatal units offered parents the chance to hold their extubated infants conventionally; 73 percent offered parents to hold their extubated infants skin-to-skin. Sixty-four percent of neonatal units offered parents the option to hold their intubated infants conventionally. In contrast, only 45 percent of the units offered parents to hold their intubated infants skin-to-skin. Factors that influenced parental holding practices included potential benefits to infants and parents, concerns about infant safety, and level of support from neonatal staff members.


Histological Assessment of the Bile Duct before Liver Transplantation: Does the Bile Duct Injury Score Predict Biliary Strictures?
Histological injury to the biliary tree during organ preservation leads to biliary strictures after liver transplantation. The Bile Duct Injury (BDI) score was developed to assess histological injury and identify the grafts most likely to develop biliary strictures. The BDI score evaluates the bile duct mural stroma, peribiliary vascular plexus (PVP) and deep peribiliary glands (DPGs), which were correlated with post-transplant biliary strictures. However, the BDI score has not been externally validated. The aim of this study was to verify whether the BDI score could predict biliary strictures at our transplant centre. Brain-dead donor liver grafts transplanted at a single institution from March 2015 to June 2016 were included in this analysis. Bile duct biopsies were collected immediately before transplantation and assessed for bile duct injury by two blinded pathologists. The primary outcome was the development of clinically significant biliary strictures within 24 months post-transplant. Fifty-seven grafts were included in the study which included 16 biliary strictures (28%). Using the BDI score, mural stromal, PVP and DPG injury did not correlate with biliary strictures including Non-Anastomotic Strictures. Severe inflammation (>50 leucocytes per HPF) was the only histological feature inversely correlated with the primary outcome (absent in the biliary stricture group vs. 41% in the no-stricture group, p = 0.001). The current study highlights limitations of the histological assessment of bile duct injury. Although all grafts had bile duct injury, only inflammation was associated with biliary strictures. The BDI score was unable to predict post-transplant biliary strictures in our patient population.


Correlation coefficients for predicting canine diameters from premolar and molar sizes.
The permanent canine is the most widely used tooth for sex estimation because it is the tooth with the highest degree of sexual dimorphism; however, there are several factors that can limit the analysis (e.g., pathologies, postmortem loss). The aim of this work was to analyse the correlation between the dimensions of the canines and those of the premolars and molars, and evaluate the correspondence of real and predicted canine dimensions by applying the equations developed. The sample was composed of digital models of 80 adult individuals from Temuco, Chile. The buccolingual and mesiodistal diameters of the canine, premolar and molar dental crowns were measured and Pearson's linear regression analysis was performed in order to determine the correlation between the diameters. The equations obtained from the reference subsample were applied to a validation subsample to predict canine dimensions from the dimensions of the postcanine teeth. Four regression equations were obtained, all for prediction of the size of the lower canines, whose correlation coefficient ranged from 0.701 to 0.738. The regression equations developed with the reference sample were tested on the validation sample using a Student's t-test for paired samples and the intraclass correlation coefficient. The differences between actual dental size and that predicted by the equations were not significantly different, and concordance analysis showed a moderate degree (0.485-0.585). There is a limited correlation of canine dimensions with respect to premolars and molars. The correspondence between the actual and predicted canines dimensions is moderate.


Antiplasmodial activities of indole alkaloids from Tabernaemontana penduliflora K. Schum (Apocynaceae).
Five undescribed carboxy-indole alkaloids with corynanthe skeleton, penduflorines A-E (1-3) as well as a voacangine-N-oxide alkaloid, tabernaemontine (4), were isolated along with eight other known compounds (5-12) from the trunk bark of Tabernaemontana penduliflora K. Schum (Apocynaceae). Their structures were determined by means of spectroscopic and spectrometric methods such as UV, IR, NMR and HR-ESI-MS. Antiplasmodial activities of new isolates were evaluated against two strains of Plasmodium falciparum 3D7 and Dd2 by the Sybr green I-based fluorescence assay setup. Those compounds showed good in vitro activities. Among them, penduflorines A and B (1a and 1b) as well as tabernaemontine (4) showed significant inhibitory activities against the two strains with IC50 values ranged between 1.85 and 7.88 μg/mL. This is the first report of quaternary-N-indole alkaloids (1a, 1b, 2, 3a, 3b and 4) occurring in the form of zwitterion from Tabernaemontana genus.


Fetal and neonatal origins of altered brain development.
Abnormal development of the brain during fetal life is now thought to contribute to the aetiology of many neurological disorders that manifest throughout life. Many factors are likely to underlie such abnormal development including genetic makeup and an adverse intrauterine environment. This review will focus on prenatal hypoxic/ischaemic injury, inflammatory/infective insults and preterm birth. A range of experimental models have been used to characterize lesions formed in response to these insults and to determine mechanisms of damage resulting from such events. Relatively brief periods of fetal hypoxia result in neuronal death (cerebellum, hippocampus, and cerebral cortex), white matter damage and reduced growth of neural processes. These effects are more profound at mid than late gestation. Chronic mild placental insufficiency can result in fetal growth restriction and deficits in neural connectivity and myelination. Exposure of the preterm fetus to inflammatory agents causes brain damage particularly in the white matter and this is exacerbated by hypoxia. Premature birth without potentiating factors can result in subtle neuropathologies including cerebral white matter gliosis, hippocampal sclerosis and subarachnoid haemorrhage; the extent of the damage appears to be related to the regimen of ventilatory support. These studies show that the timing, severity and nature of specific insults are critical in determining the pattern of injury and thus the extent to which neurological function will be affected postnatally. Defining the causes, patterns and mechanisms of brain injury is crucial if we are to develop rational neuroprotective strategies to reduce the burden of altered brain growth and poor functional and behavioural outcomes.


Review Global seroprevalence of legionellosis - a systematic review and meta-analysis.
Legionella is a ubiquitous pathogen yet the global occurrence of legionellosis is poorly understood. To address this deficit, this paper summarises the available evidence on the seroprevalence of Legionella antibodies and explores factors that may influence seroprevalence estimates. Through a systematic review, a total of 3979 studies were identified with seroprevalence results published after 1 January 1990. We tabulated findings by World Health Organization (WHO) region, location, study period and design, composition of study population(s) for all ages in terms of exposure, sex, detection methods, IFA titre, Legionella species measured, and present seroprevalence point estimates and 95% confidence intervals. Sampled populations were classified according to income, WHO region, gender, age, occupation and publication date. We conducted a meta-analysis on these subgroups using Comprehensive Meta-Analysis 3.0 software. Heterogeneity across studies was evaluated by the Q test in conjunction with I2 statistics. Publication bias was evaluated via funnel plot and Egger's test. Fifty-seven studies met our inclusion criteria, giving an overall estimate of seroprevalence for Legionella of 13.7% (95% CI 11.3-16.5), but with substantial heterogeneity across studies.


Chinese Ecliptae herba (Eclipta prostrata (L.) L.) extract and its component wedelolactone enhances osteoblastogenesis of bone marrow mesenchymal stem cells via targeting METTL3-mediated m6A RNA methylation.
Chinese Ecliptae herba (Eclipta prostrata (L.) L.) is an ethnomedicinal herb, which is used mainly to nourish kidney and thus strengthen bones according to traditional Chinese medicine theory. Pharmacological studies have supported the ethnomedicine use, showing that Ecliptae herba extract has an anti-osteoporotic effect in vivo and promoted osteoblast proliferation and activity in vitro. However, the molecular mechanism of Ecliptae herba on osteoblast differentiation from bone marrow mesenchymal stem cells (BMSC), the progenitors of osteoblasts, is still unclear. N6-methyladenosine (m6A) mRNA epigenetic modification may play a key role in promoting osteoblastic differentiation, and thus treating osteoporosis. This study sought to assess the mechanism through which Eclipate herba and its component wedelolactone influence m6A modification during the process of osteoblastogenesis from BMSC. The alkaline phosphatase (ALP) and Alizarin red S (ARS) staining were applied to determine osteoblastogenesis from BMSC. Western blot and quantitative real-time PCR were performed. RNA sequencing analysis was used to determine the characteristics of m6A methylation. Stable knocking down of METTL3 using lentiviral-based shRNA was performed. Upon 9 d treatment of BMSC with ethyl acetate extract of Ecliptae herba (MHL), ALP activity and ossification level increased in comparison with osteogenic medium (OS)-treated control. The expression of methyltransferase METTL3 and METTL14 was significantly increased, but WTAP expression had no change in response to MHL treatment. Knocking down of METTL3 resulted in a decrease in MHL-induced ALP activity, ossification level as well as mRNA expression of Osterix and Osteocalcin, two bone formation-related markers. The level of m6A increased when BMSC was treated with MHL for 9 d. RNA sequencing analysis indicated that MHL treatment altered mRNA m6A modification of genes associated with osteoblastogenesis. By kyoto encyclopedia of genes and genomes (KEGG) pathway analysis, HIF-1α, PI3K/Akt, and Hippo signaling pathways were enriched and associated with m6A modification. The expression of m6A-modified genes including HIF-1α, VEGF-A, and RASSF1, was upregulated by MHL, but the upregulation was reversed after METTL3 knockdown. Additionally, the enhanced expression of METTL3 was also observed after treatment with wedelolactone, a component from MHL. These results suggested a previously uncharacterized mechanism of MHL and wedelolactone on osteoblastogenesis, by which METTL3-mediated m6A methylation is involved and thus contributes to the enhancement of osteoblastogenesis.


Diabetes is associated with greater leg pain and worse patient-reported outcomes at 1 year after lumbar spine surgery.
Although patients with diabetes reportedly have more back pain and worse patient-reported outcomes than those without diabetes after lumbar spine surgery, the impact of diabetes on postoperative recovery in pain or numbness in other regions is not well characterized. In this study, the authors aimed to elucidate the impact of diabetes on postoperative recovery in pain/numbness in four areas (back, buttock, leg, and sole) after lumbar spine surgery. The authors retrospectively reviewed 993 patients (152 with diabetes and 841 without) who underwent decompression and/or fixation within three levels of the lumbar spine at eight hospitals during April 2017-June 2018. Preoperative Numerical Rating Scale (NRS) scores in all four areas, Oswestry Disability Index (ODI), and Euro quality of life 5-dimension (EQ-5D) were comparable between the groups. The diabetic group showed worse ODI/EQ-5D and greater NRS scores for leg pain 1 year after surgery than the non-diabetic group. Although other postoperative NRS scores tended to be higher in the diabetic group, the between-group differences were not significant. Diabetic neuropathy caused by microvascular changes may induce irreversible nerve damage especially in leg area. Providers can use this information when counseling patients with diabetes about the expected outcomes of spine surgery.


Diabetic Macular Edema Treated With Intravitreal Aflibercept Injection After Treatment With Other Anti-VEGF Agents (SWAP-TWO Study)-12-Month Analysis.
This article reports 12-month outcomes of patients with diabetic macular edema previously treated with other antivascular endothelial growth factor agents and transitioned to fixed dosing of intravitreal aflibercept (IAI). This prospective, single-arm study enrolled patients to receive IAI 2 mg (0.05 mL) every 4 weeks until optical coherence tomography demonstrated no fluid. Patients then received fixed dosing of IAI 2 mg once every 8 weeks through 12 months. Primary outcome was mean absolute change from baseline central subfield thickness (CST) at 12 months measured by optical coherence tomography. Twenty eyes were enrolled. At baseline, best-corrected visual acuity was 70.0 letters, mean CST was 419.7 µm ± 92.0, superficial capillary perfusion density (CPD) was 46.0 ± 4.2%, and deep CPD was 50.8 ± 4.3%. At 12 months, the mean CST improved to 287.2 µm ± 80.2 (P < .001), superficial CPD decreased to 43.6 ± 4.8% (P = .04), and deep CPD decreased to 47.6 ± 4.8% (P = .05). Patients who switched to fixed dosing of IAI demonstrated significant anatomic improvements in CST at 12 months. CPD values decreased significantly both in superficial and deep layers without significant changes in vision.


The effects of a complex yoga-based intervention on healthy psychological functioning.
Yoga based interventions were found to have a positive impact on various indicators of psychological functioning, such as perceived stress, satisfaction with life, positive and negative affectivity. Additionally, such interventions improved bodily or interoceptive awareness and spirituality. The present study assessed the effects of a 3-month long complex yoga-based intervention compared to a passive control group in a Hungarian community sample. The final sample consisted of 44 intervention (Mage = 47.5, SD = = 8.76) and 29 control participants (Mage = 47.4, SD = 9.47). The aforementioned constructs were measured 1 week before and after the intervention. The intervention reduced participants' perceived stress (p = <0.001, ηp 2 = 0.153) and negative affectivity (p = 0.019, ηp 2 = 0.113), improved spirituality (p = 0.048, ηp 2 = 0.054) and various aspects of interoceptive awareness such as noticing (p = <0.001, ηp 2 = 0.169) attention regulation (p = <0.001, ηp 2 = 0.211), self-regulation (p = 0.002, ηp 2 = 0.190) body listening (p = 0.010, ηp 2 = 0.097), trusting (p = 0.026, ηp 2 = 0.070), but did not impact positive affectivity and satisfaction with life. A 3-months long complex yoga-based intervention has a positive impact on many aspects of healthy psychological functioning.


Age estimation in children by measurement of open apices in teeth.
This paper concerns a method for estimating the age of children based on their teeth. The sample consisted of 455 Italian white children (213 boys, 242 girls) aged between 5 and 15 years. The purpose of the present investigation was to present a method for assessing chronological age based on the relationship between age and measurement of the open apices in teeth. Pearson's correlation coefficients between age and these variables showed that the correlations between age and the open apices in teeth were significant and negative. Furthermore, gender and the number of teeth with the apical end of the root canals completely closed (N(0)) showed a significant correlation with chronological age. With the aid of a stepwise multiple regression model, a linear relationship between open apices, N(0), and age was shown. Statistical analysis indicated that these morphological variables explain 83.6% of the variations in estimated chronological age. The median of residual errors between the actual and estimated ages was -0.035 years [interquartile range (IQR)=1.18 years].


Modeling repetitive firing and bursting in a small unmyelinated nerve fiber.
The Hodgkin-Huxley equations, originally developed to describe the electrical events in the squid giant axon, have been modified to simulate the ionic and electrical events in a small unmyelinated nerve fiber. The modified equations incorporate an electrogenic sodium-potassium pump, finite intra-axonal volume, a periaxonal space, a calcium current, and calcium-dependent potassium conductance (GKCa). The model shows that adaptation can occur in two ways: increased Na-K pump activity because of periaxonal K accumulation or intra-axonal Na accumulation; or from an increase in (GKCa) caused by calcium accumulating within the axon. Bursting is an extension of adaptation and occurs when the sensitivity of the Na-K pump or (GKCa) to changes in ionic concentration is increased.


Incidence and Mortality of Proximal and Distal Colorectal Cancer in Germany—Trends in the Era of Screening Colonoscopy.
The use of colonoscopy has increased and colorectal cancer (CRC) incidence has decreased after the introduction of screening colonoscopy in Germany. However, it remains unknown to what extent progress has been achieved in the prevention of cancer in the proximal colon, distal colon, and rectum. We analyzed trends in CRC incidence (2000-2016) and mortality (2000-2018) in Germany by sex, age, and tumor location. The age-standardized incidence of CRC declined by 22.4% (from 65.3 to 50.7 per 100 000) in men and by 25.5% (from 42.7 to 31.8 per 100 000) in women. CRC mortality declined by 35.8% (from 29.6 to 19.0 per 100 000) in men and by 40.5% (19.0 to 11.3 per 100 000) in women. Despite demographic changes, the annual numbers of CRC cases and deaths still decreased from about 60 400 to 58 300 and from around 28 700 to 24 200, respectively. The decline in incidence was greatest in groups aged ≥ 55 years. While the incidence of cancer in the distal colon and rectum decreased by 34.5% and 26.2%, respectively, in men and by 41.0% and 27.9% in women, the incidence of proximal colon cancer remained stable in men and decreased by only 7.0% in women. However, a major shift towards earlier stages was observed for the proximal cancers. The results support the assumption that the increased use of colo - noscopy has contributed to substantial reductions in the incidence of distal CRC incidence and the mortality from cancers in the entire colon and rectum.


Trajectories of functional health: the 'long arm' of childhood health and socioeconomic factors.
Few studies have specifically examined trajectories of functional health status or estimated the extent to which they are influenced by childhood health and socioeconomic conditions. This study examines how circumstances associated with early life may shape the level and progression of functional limitations among adults at or near retirement. Employing data from the US Health and Retirement Study (HRS), it estimates latent growth curve models (LGM) of functional limitation. The results demonstrate that functional health trajectories in old age continue to be shaped by childhood health and socioeconomic circumstances. Poor childhood health and disadvantaged social origins are associated with both more functional limitations at baseline and higher rates of increase over time. This association is net of baseline adult chronic disease and socioeconomic status. While both childhood and adult factors influence the baseline level of functional limitation, only childhood health and socioeconomic status are associated with the rate of change in limitations over time.


[Somatogenic and somatogenically provoked psychoses in hematologic malignancies. Typology and therapy of somatogenic psychoses in hematologic malignancies].
To specify clinical typology and develop therapeutic approaches to somatogenic psychoses (SP) in hematologic malignancy (HM). Clinical assessment was made in 118 patients with SP corresponding to diagnostic rubric F05 or F06 in International Disease Classification 10. Three types of SP in HM were identified: delirium (n = 73, 61.9%), aberration and somatogenically provoked attacks of schizophrenia (n = 7, 5.9%). Clinical picture and conditions of the above diseases onset in HM patients are described. Delirium developing in HM is characterized by subclinical psychoses, endogenomorphic psychoses. Endogenomorphic psychoses in the sample were represented by hallucinative-paranoid and depressive- delirious psychoses. SP classification proposed directly influences the choice of treatment methods. Psychotropic drugs with known clinical activity with wide-spectrum therapeutic action are effective in the above patients.


The Effect of Cadmium Tolerant Plant Growth Promoting Rhizobacteria on Plant Growth Promotion and Phytoremediation: A Review.
Cadmium (Cd) is a heavy metal of considerable toxicity with destructive impacts on plants, microbes and environments. Its toxicity is due to mishandling and manual hazards in plants and is primarily observed within the soil to cause decline of plants and microbial activity inside the rhizosphere. Cadmium accumulation in crops and the probability of Cd entering the food chain are grave for public health in the worldwide. Cadmium toxicity leads to depletion in seed germination, initial seedling growth, plant biomass, chlorosis, necrosis, hindrance of photosynthetic machinery and other physiological and biological activities in plants. Cadmium triggers the reactive oxygen species (ROS) that influences gene mutation and DNA damage that affects the cell cycle and cell division. Cd toxicity altered the levels of phenolic compounds, carbohydrates, glycine betaine, proline and organic acids in crops. Under stress conditions, the plant growth promoting rhizobacteria (PGPR) have various properties such as enzymatic activities, plant growth hormones production, phosphate solubilization, siderophores production and chelating agents that help the plants tolerate against Cd stress and also increase phenolic compound levels and osmolytes. Hence, this review highlights the crucial role of cadmium tolerant PGPR for crop production, declining metal phytoavailability and enhancing morphological and physiological boundaries of plants under stress conditions. It could be an environment friendly and cost effective technology under sustainable crop production.


Surveillance and epidemiology of syphilis, gonorrhoea and chlamydia in the non-European Union countries of the World Health Organization European Region, 2015 to 2020.
BackgroundEpidemics of sexually transmitted infections (STI) are a major public health challenge in the World Health Organization (WHO) European Region.AimWe aimed to provide an overview of case reporting and other surveillance data for syphilis, gonorrhoea and chlamydia for the non-European Union (EU)/European Economic Area (EEA) countries of the Centre and East part of the WHO European Region as per classification used by the WHO Regional Office for Europe (WHO/Europe) and the European Centre for Disease Prevention and Control.MethodsData were provided by the surveillance agencies of the Member States for the period 2015 to 2019 through the WHO/Europe Communicable Diseases Annual Reporting Form. We analysed reported cases, explored data reported to the WHO Gonococcal Antimicrobial Surveillance Programme (GASP) and performed a review of publications on antimicrobial resistance (AMR) in gonorrhoea in the period 2015 to 2020 using systematic methodology.ResultsFrom 2015 to 2019, in most of the countries with three or more data points, there was a pattern of decrease in reported syphilis, gonorrhoea and chlamydia cases, which is in contrast to the EU/EEA. The number of reported cases per 100,000 population was 0.4-26.5 for syphilis, 0-18.5 for gonorrhoea and 0-43.3 for chlamydia. Four countries reported recent data on AMR in gonorrhoea to GASP, and we identified further publications from Georgia, Russia and Ukraine.ConclusionWe found wide heterogeneity in reported rates of STI. There is a strong need to improve availability and quality of STI surveillance data in the non-EU/EEA countries.


Identification and physiological function of CsPrip, a new aquaporin in Chilo suppressalis.
Aquaporin (AQP) transport solutes across cell membranes in both unicellular and multicellular organisms. In this study, the aquaporin CsPrip was identified in Chilo suppressalis, an important pest of rice. CsPrip was comprised of two variants, CsPrip_v1 and CsPrip_v2; the former variant was <103 bp was shorter than the latter, although both exhibited the same open reading frame (ORF). Transmembrane topology and protein structure analyses showed that CsPrip retained the conserved features of water-selective insect AQPs, including six transmembrane domains, two conserved hydrophobic asparagine-proline-alanine motifs and the aromatic/arginine constriction region. Expression in Xenopus oocytes revealed that CsPrip preferentially transported water and urea instead of trehalose and glycerol. The CsPrip transcript was expressed in multiple organs and tissues of C. suppressalis larvae and was most abundant in the hindgut and Malpighian tubules. CsPrip transcription was highest in male adults and was relatively stable throughout development. CsPrip expression in larvae was significantly altered by thermal stress, and relative humidity levels impacted CsPrip transcription in 3rd and 5th instar larvae. This study confirms that the aquaporin CsPrip performs multiple critical functions in maintaining water equilibrium in C. suppressalis.


The impact of histological grade on outcomes in follicular lymphoma: An analysis of patients in the SEER database in the context of evolving disease classification and treatment.
Currently, there is no convincing evidence that the grade of follicular lymphoma (FL) impacts patient outcome. We correlated grades in 33 925 patients with nodal FL during 1992-2018 in the SEER database with disease-specific survival (DSS) and overall survival (OS). Patients with FL grade 3 had lower DSS and OS as compared to FL grades 1-2. During 1992-2005, the 10-year DSS for patients with FL grades 3 and grades 1-2 were 68.6%, and 71.4%, respectively, and in 2006-2018, they were 77.7% and 82.6%, respectively. The 10-year OS estimates in 1992-2005 were 49.9% and 54.2% for grade 3 and grades 1-2 respectively, and in 2006-2018, they were 59.1% and 63.5% for grade 3 and grades 1-2, respectively. After adjustment for stage and age, the hazard ratios for death due to FL and death from any cause for patients with FL grade 3 during 1992-2005 were 1.09 (1.02-1.16) and 1.07 (1.02-1.12), respectively, compared to FL grades 1-2; and during 2006-2018, the hazard ratios for death due to FL and death from any cause for patients with FL grade 3 were 1.34 (1.22-1.45) and 1.16 (1.10-1.23), respectively compared to FL grades 1-2. The grade of FL is an important determinant of disease biology.


Similarity in context.
Similarity comparisons are highly sensitive to judgment context. Three experiments explore context effects that occur within a single comparison rather than across several trials. Experiment 1 shows reliable intransitivities in which a target is judged to be more similar to stimulus A than to stimulus B, more similar to B than to stimulus C, and more similar to C than to A. Experiment 2 explores the locus of Tversky's (1977) diagnosticity effect in which the relative similarity of two alternatives to a target is influenced by a third alternative. Experiment 3 demonstrates a new violation of choice independence which is explained by object dimensions' becoming foregrounded or backgrounded, depending upon the set of displayed objects. The observed violations of common assumptions to many models of similarity and choice can be accommodated in terms of a dynamic property-weighting process based on the variability and diagnosticity of dimensions.


Genome-wide identification and functional analysis of cupin_1 domain-containing members involved in the responses to Sclerotinia sclerotiorum and abiotic stress in Brassica napus.
Cupin_1 domain-containing proteins (CDPs) are ubiquitously present in higher plants, which are known to play essential roles in various biological processes. In this study, we carried out genome-wide characterization and systematic investigation of the CDP genes in Brassica napus. A total of 96 BnCDPs, including 71 germin-like proteins (GLPs; proteins with a single cupin_1 domain) and 25 CDP bicupins (proteins with two cupin_1 domains), were identified and clustered into six distinct subfamilies (I-VI) based on the phylogenic analysis, gene structure and motif distribution. Further analysis indicated that whole-genome duplication (WGD) and segmental duplication are main contributors to the species-specific expansion of the BnCDP gene family, and all the duplicated genes subsequently underwent strong purification selection. The promoter region of BnCDPs showed enrichment of cis-regulatory elements associated with development, hormone and stress, as well as transcription factor binding sites, which validates the prediction that BnCDPs are widely involved in plant growth and biotic and abiotic stress responses. The BnCDPs in different subfamilies exhibited obvious differences in expression among 30 developmental tissues/stages of B. napus, implying that BnCDPs may be involved in tissue- and stage-specific developmental processes. Similar trends in expression of most BnCDPs were observed under Sclerotinia sclerotiorum inoculation and four abiotic stresses (dehydration, cold, ABA and salinity), particularly the BnGLPs in subfamily I and III with single cupin_1 domain, revealing that BnCDPs are of great importance in the environmental adaption of B. napus. We then performed a genome-wide association study (GWAS) of 274 B. napus core germplasms on S. sclerotiorum resistance and identified four significantly associated loci harboring five BnGLPs. The expression levels of two candidate genes, BnGLP1.A08 and BnGLP1.C08, were significantly correlated with S. sclerotiorum resistance. Their functional responses to multiple stages of S. sclerotiorum inoculation and four abiotic stresses were further examined through qPCR. Overall, this study provides rich resources for research on the function and evolutionary playground of CDP genes.


[Physical activity and exercise for rehabilitation of type 2 diabetes].
Along with diet and medication, exercise is the third cornerstone of type 2 diabetes treatment. However, current guidelines do not provide detailed information for designing effective exercise interventions. Based on a review of the health-enhancing effects of endurance and resistance training, recommendations for exercise interventions for persons with type 2 diabetes and different comorbidities are derived to optimize the benefits of exercise. A hierarchic, systematic literature analysis was conducted. The evidence is summarized, and evidence-based recommendations are given. Aerobic training, resistance training, and combined training programmes hold equal potential to reduce the HbA1c by about 0.5-0.8. Endurance training improves cardiorespiratory fitness and cardiovascular risk factors. Compared to resistance training it will lead to superior effects on hypertension and blood lipids. Combined training is generally a little superior to aerobic and resistance training showing greater improvements for body weight, HDL-cholesterol and blood pressure. Health-enhancing effects are found for a broad range of exercise types, intensities and scope. Persons with type 2 diabetes should perform at least 90 min per week of vigorous (> 65% of VO (2)max) aerobic exercise or 150 min per week of moderate-intensity (40-65% of VO (2)max) aerobic physical activity. Performing at least 240 min of physical activity per week is associated with greater cardiovascular disease risk reductions as well as with less cardioÂ-vascular events compared with lower volumes of activity. Optimizing therapeutic benefits with different types and doses of exercise in combination with dietary and drug treatments needs further research.


Factors associated with appropriate and low-value PSA testing.
Prostate-specific antigen (PSA) testing for early detection of prostate cancer is low-value when it is not indicated by guidelines and the harms outweigh the benefits. In this retrospective cohort study, we identify provider and patient factors associated with PSA testing, particularly in situations where testing would be low-value. We used electronic health record data from 2011 to 2018 representing 1,738,021 health system encounters in the United States. Using logistic generalized estimating equation models, we examined patient factors (age, comorbid illness, family history, race and prior PSA results), provider factors (gender, specialty, graduation year and medical school rank), and overall time trends associated with PSA testing in low-value and appropriate settings. Comorbid illness (odds ratio (OR) 0.0 for 3+ conditions vs none) and no prior PSA testing (OR 0.2) were associated with a lower likelihood of PSA testing in low-value situations, while family history of prostate cancer (OR 1.6) and high prior PSA test results (OR 2.2 for PSA > 6 vs 0-1) were associated with a greater likelihood. Men aged 55-65 years were at greatest risk for PSA testing in low-value situations. The provider factor associated with PSA testing in low-value situations was specialty, with urologists being most likely (OR 2.3 versus advanced practice providers). Internal medicine physicians were more likely to perform PSA testing during low-value situations (OR 1.3 versus advanced practice providers) but much more likely to order a PSA test where appropriate (OR 2.2). All PSA testing decreased since 2011. We identified several patient and provider factors associated with PSA testing in low-value settings. Some aspects suggest attention to relevant factors for PSA testing in low-value settings (e.g. comorbid illness), while others may encourage PSA testing in low-value settings (e.g. family history). The greatest likelihood of PSA testing in low-value settings is among men within the age range most commonly recommended by guidelines.


Gender and other risk factors associated with risky behaviours among Nigerian adolescents.
Risky behaviours in adolescents, apart from substance use, and their associate factors, have not been thoroughly investigated in Nigeria. Hence, there is a need to study the prevalence of risky behaviours and their relationship with gender and other potential risk factors. Data comprising socio-demographic, risky behaviours, personality traits, religious orientation and substance use were obtained from 300 randomly selected secondary school students. Two risk groups (low and high) based on the number of risky behaviours were determined. Male was a risk factor for theft (OR = 2.1; 95%CI = 1.17-3.95), bullying (OR = 2.76; 95%CI = 1.37-5.56) and fighting (OR = 2.14; 95%CI = 1.35-3.40). Fifty-two (17.3%) of the students were of high-risk behaviour group. Furthermore, private school (β = 1.05; P = 0.010), poor perceived relationship with teachers (β = 1.21; P = 0.002), polygamy (β = 1.20; P = 0.002) and lifetime cigarette use (β = 1.07; P = 0.027) were predictors of high-risk behaviour group. Substantial proportion of adolescents in Nigeria exhibit risky behaviours of which gender and other factors play a significant role.


Drop-in, drop-out allele-specific PCR: a highly sensitive, single-tube method.
Allelotyping large numbers of samples by allele-specific polymerase chain reaction (PCR) can be problematic if the DNA samples to be tested are of highly variable concentration. On the one hand, analysis of dilute DNA samples often requires nested PCR to produce a product of sufficient yield to be detectable on ethidium bromide-stained agarose gels. Such two-step assays require additional reagents, are labor-intensive, and have a higher risk of contamination. On the other hand, the specificity of allele-specific PCR assays can be lost at high input DNA concentrations. Large population-based genetic studies using DNA from varied sources would benefit from one-tube assays that could detect mutations in samples over a wide range of concentration. We describe a one-tube nested allele-specific PCR-based assay, in which the input DNA concentration has little effect on the assay's yield or specificity. An assay using this method is highly sensitive and specific, and was used to type several thousand DNA samples, obtained from various sources, for a G to A transition at human transthyretin codon 122. Similar assays could be readily adapted to any high-throughput allelotype assay where input DNA is of highly variable concentration.


State-of-the-Art of Endomyocardial Biopsy on Acute Myocarditis and Chronic Inflammatory Cardiomyopathy.
Histologic evidence of myocardial inflammatory infiltrate not secondary to an ischemic injury is required by current diagnostic criteria to reach a definite diagnosis of myocarditis. Endomyocardial biopsy (EMB) is therefore often indicated for the diagnosis of myocarditis, although it may lack sufficient sensitivity considering the limited possibility of myocardial sampling. Improving the diagnostic yield and utility of EMB is of high priority in the fields of heart failure cardiology and myocarditis in particular. The aim of the present review is to highlight indications, strengths, and shortcomings of current EMB techniques, and discuss innovations currently being tested in ongoing clinical studies, especially in the setting of acute myocarditis and chronic inflammatory cardiomyopathy. EMB provides unique diagnostic elements and prognostic information which can effectively guide the treatment of myocarditis. Issues affecting the diagnostic performance in the setting of acute myocarditis and chronic inflammatory cardiomyopathies will be discussed in this review in the light of recent expert consensus documents on the management of these conditions and on indication to EMB. Recent innovations using electroanatomic mapping (EAM)-guided EMB and fluoroscopic-guided EMB during temporary mechanical circulatory support have improved the utility of the procedure. EMB remains an important diagnostic test whose results need to be interpreted in the context of (1) clinical pre-test probability, (2) timing of sampling, (3) quality of sampling (4) site of sampling, (5) histologic type of myocarditis, and (6) analytic methods that are applied. Herein we will review these caveats as well as perspectives and innovations related to the use of this diagnostic tool.


Underlying neural mechanisms of degraded speech intelligibility following noise-induced hearing loss: The importance of distorted tonotopy.
Listeners with sensorineural hearing loss (SNHL) have substantial perceptual deficits, especially in noisy environments. Unfortunately, speech-intelligibility models have limited success in predicting the performance of listeners with hearing loss. A better understanding of the various suprathreshold factors that contribute to neural-coding degradations of speech in noisy conditions will facilitate better modeling and clinical outcomes. Here, we highlight the importance of one physiological factor that has received minimal attention to date, termed distorted tonotopy, which refers to a disruption in the mapping between acoustic frequency and cochlear place that is a hallmark of normal hearing. More so than commonly assumed factors (e.g., threshold elevation, reduced frequency selectivity, diminished temporal coding), distorted tonotopy severely degrades the neural representations of speech (particularly in noise) in single- and across-fiber responses in the auditory nerve following noise-induced hearing loss. Key results include: 1) effects of distorted tonotopy depend on stimulus spectral bandwidth and timbre, 2) distorted tonotopy increases across-fiber correlation and thus reduces information capacity to the brain, and 3) its effects vary across etiologies, which may contribute to individual differences. These results motivate the development and testing of noninvasive measures that can assess the severity of distorted tonotopy in human listeners. The development of such noninvasive measures of distorted tonotopy would advance precision-audiological approaches to improving diagnostics and rehabilitation for listeners with SNHL.


Validation of a dried blood spot LC-MS/MS approach for cyclosporin A in cat blood: comparison with a classical sample preparation.
A rapid, selective and sensitive bioanalytical method was developed and validated for cyclosporin A (CsA) in cat blood samples using dried blood spot (DBS) coupled with high pressure liquid chromatography hyphenated to positive electrospray tandem mass spectrometry (HPLC-ESI-MS/MS). CsA was quantified using a structural analog cyclosporin D (CsD) as internal standard in multiple reaction monitoring mode (MRM) using the transitions 1220→1203 for CsA and 1234→1217 for CsD. A 5-μL blood aliquot was spotted onto a DBS card, then after a drying step, blood spots were punched out from the cards and extracted with MeOH before injection into a LC-MS/MS system. The linear range of the method was 5-2000 ng/mL, with accuracy and precision within the FDA acceptance criteria (i.e., ±15% and ±20% for the lowest level). In the study presented herein a comparison was made between this new methodology, based on the use of DBS, and a previously developed solid phase extraction (SPE) procedure, applied to blood samples from a cat pharmacokinetic study. Good correlation (r(2)=0.97) was demonstrated between the data obtained with the two methods. The DBS methodology revealed to be cheaper, faster, less solvent-consuming and requiring less blood volume from animals than the previous SPE method. Thus, the proposed HPLC-ESI-MS/MS method, based on DBS, has demonstrated to be a suitable and advantageous approach for the analysis of CsA in cat blood.


The structure of Brazilian Amazonian gut microbiomes in the process of urbanisation.
Shifts in subsistence strategy among Native American people of the Amazon may be the cause of typically western diseases previously linked to modifications of gut microbial communities. Here, we used 16S ribosomal RNA sequencing to characterise the gut microbiome of 114 rural individuals, namely Xikrin, Suruí and Tupaiú, and urban individuals from Belém city, in the Brazilian Amazon. Our findings show the degree of potential urbanisation occurring in the gut microbiome of rural Amazonian communities characterised by the gradual loss and substitution of taxa associated with rural lifestyles, such as Treponema. Comparisons to worldwide populations indicated that Native American groups are similar to South American agricultural societies and urban groups are comparable to African urban and semi-urban populations. The transitioning profile observed among traditional populations is concerning in light of increasingly urban lifestyles. Lastly, we propose the term "tropical urban" to classify the microbiome of urban populations living in tropical zones.


Minocycline black bone disease in arthroplasty: a systematic review.
Minocycline black bone disease is a rare finding that can cause concern when unexpectedly encountered during routine arthroplasty. Prolonged minocycline use can cause selective staining of subchondral bone, whilst peri-articular soft tissue and cartilage appear uninvolved. A systematic review according to PRISMA guidelines was performed to identify all reported cases in the literature. Including the patient we present, eleven cases of minocycline black bone disease encountered during arthroplasty have been reported in the literature. All cases have had an excellent outcome, with no complications reported to date. Minocycline black bone disease can be a concerning intra-operative finding when unexpectedly encountered during routine arthroplasty, but should not affect the operative plan. Surgeons should exclude alternative causes of bone discolouration when the history is unclear.


Extensions of the mTPI and TEQR designs to include non-monotone efficacy in addition to toxicity for optimal dose determination for early phase immunotherapy oncology trials.
With the emergence of immunotherapy and other novel therapies, the traditional assumption that the efficacy of the study drug increases monotonically with dose levels is not always true. Therefore, dose-finding methods evaluating only toxicity data may not be adequate. In this paper, we have first compared the Modified Toxicity Probability Interval (mTPI) and Toxicity Equivalence Range (TEQR) dose-finding oncology designs for safety with identical stopping rules; we have then extended both designs to include efficacy in addition to safety - we determine the optimal dose for safety and efficacy using these designs by applying isotonic regression to the observed toxicity and efficacy rates, once the early phase trial is completed. We consider multiple types of underlying dose response curves, i.e., monotonically increasing, plateau, or umbrella-shaped. We conduct simulation studies to investigate the operating characteristics of the two proposed designs and compare them to existing designs. We found that the extended mTPI design selects the optimal dose for safety and efficacy more accurately than the other designs for most of the scenarios considered.


Conformational analysis by NMR and molecular dynamics of adamantane-doxorubicin prodrugs and their assemblies with β-cyclodextrin: A focus on the design of platforms for controlled drug delivery.
Nanoscale design and construction of affinity-based drug delivery systems (ADDS) is an active research area with enormous potential for the improvement of cancer treatment. For the therapeutic load of these ADDS, a promising strategy is the design of pH-sensitive prodrugs based on the construction of conjugates between adamantane and doxorubicin (Ad-Dox), which stands out as an excellent model system to obtain novel supramolecular materials. Construction of these prodrugs involves a modification of three zones of doxorubicin which in principle does not affect the action mechanism: the carbonyl group C13 (hydrazone linker), the primary alcohol neighboring the carbonyl (ester linker) and the 3' amino group of daunosamine sugar (amide linker). These modifications are aimed to improve the efficacy and reduce the systemic toxicity of the drug chemotherapy by controlling its release in cancer cells. In this work, we performed 2D NMR experiments and molecular dynamics simulations to characterize the conformational changes of three constructed prodrugs. Our results demonstrated that ring A and the daunsamine sugar of the hydrazone and amide linkers conserve the half-chair state 9H8, while the ester linker disrupts this conformation. Our study also showed that the hydrazone-linked compound (Ad-h-Dox) does not modify the conformation of the original drug and maintains cytotoxic activity. Moreover, the inclusion complex (IC) of Ad-h-Dox with β-cyclodextrin (βCD) generated a highly soluble platform in water, whereas the ester-linked compound (Ad-e-Dox) causes the loss of biological activity. This study proves that Ad-h-Dox prodrug can be an optimum prodrug and act as a building block for a more complex drug transport system.


The comparison of oxidative stress effect in classic and tubeless percutaneous nephrolithotomy.
Surgical stone treatment induces oxidative stress in kidney tissue. We hypothesized that tubeless percutaneous nephrolithotomy (tPCNL) may induce less oxidative stress than classic percutaneous nephrolithotomy (cPCNL) with nephrostomy tube. Seventy-two consecutive patients with kidney stones qualified for PCNL were enrolled in the study. Patients were assigned to one of two groups (first group 33 patients-cPCNL and second group 39 patients-tPCNL). Four urine samples were collected in four consecutive days, starting the day before operation. Four oxidative stress markers were analyzed in each sample: catalase (CAT), protein sulfhydryl group (SH), total antioxidant capacity (TAC) and superoxide dismutase (SOD). Baseline mean levels of CAT (IU/l), SH (μmol/l), TAC (mmol/l) and SOD (NU/ml) were 19.4 versus 11.7; 18 versus 58.7; 2.02 versus 1.99; 20.5 versus 22.6 in cPCNL and tPCNL group, respectively. On day two, the levels were 89 versus 104.9; 334.7 versus 518.9; 1.87 versus 1.79; 33.7 versus 41.4, respectively. On the third day, the levels were: 67.4 versus 28.3; 206.8 versus 306.9; 2.01 versus 2.06; 38.2 versus 36.6, respectively. On the fourth day, the concentrations were 47.4 versus 18.5; 129.3 versus 208.7; 2 versus 2.06; 35 versus 45.2, respectively. Significant differences were observed only for CAT and TAC concentrations in days 3 (p = 0.04 and 0.04) and 4 (p = 0.02 and < 0.001) in favor of tPCNL. CAT, SH and SOD significantly rise after operation. TAC represents the inversion of other parameters. CAT is significantly lower, and TAC is significantly higher in tPCNL postoperatively favoring this method.


Targeting the super elongation complex for oncogenic transcription driven tumor malignancies: Progress in structure, mechanisms and small molecular inhibitor discovery.
Oncogenic transcription activation is associated with tumor development and resistance derived from chemotherapy or target therapy. The super elongation complex (SEC) is an important complex regulating gene transcription and expression in metazoans closely related to physiological activities. In normal transcriptional regulation, SEC can trigger promoter escape, limit proteolytic degradation of transcription elongation factors and increase the synthesis of RNA polymerase II (POL II), and regulate many normal human genes to stimulate RNA elongation. Dysregulation of SEC accompanied by multiple transcription factors in cancer promotes rapid transcription of oncogenes and induce cancer development. In this review, we summarized recent progress in understanding the mechanisms of SEC in regulating normal transcription, and importantly its roles in cancer development. We also highlighted the discovery of SEC complex target related inhibitors and their potential applications in cancer treatment.


The dual orexin receptor antagonist almorexant blocks the sleep-disrupting and daytime stimulant effects of methamphetamine in rhesus monkeys.
The present study investigated the effects of the dual orexin receptor antagonist (DORA) almorexant, a sleep-modulating drug, on the sleep-disrupting effects of methamphetamine in adult rhesus monkeys. Monkeys were fitted with primate collars to which actigraphy monitors were attached. To determine the effects of methamphetamine on daytime activity and sleep-like parameters, monkeys were given acute injections of vehicle or methamphetamine (0.03, 0.1 or 0.3 mg/kg, i.m.) in the morning (9:00 h) (n = 4 males). We then determined the ability of almorexant to alter the daytime and/or sleep-like effects of the largest (effective) dose of methamphetamine. Vehicle or almorexant (1, 3 or 10 mg/kg, i.m.) were administered in the evening (16:30 h, 1.5 h before "lights off") following morning (9:00 h) administration of methamphetamine (0.3 mg/kg, i.m.), or as a pretreatment (8:30 h) before methamphetamine injections (9:00 h) (n = 4 males). The ability of almorexant (10 mg/kg) to improve sleep-like behaviors also was assessed in a group of monkeys quantitatively identified with short-duration sleep (n = 2 males, 2 females). Morning methamphetamine administration dose-dependently impaired sleep in rhesus monkeys (0.3 mg/kg significantly increased sleep latency and decreased sleep efficiency). Administration of almorexant, both as a pretreatment or as an evening treatment, improved methamphetamine-induced sleep impairment in a dose dependent manner. Morning pretreatment with almorexant also blocked the daytime stimulant effects of methamphetamine. Evening, but not morning, treatment with almorexant in a group of monkeys with baseline short-duration sleep improved sleep measures. Our findings indicate that orexin receptor systems are involved in methamphetamine-induced hyperarousal and sleep disruption.


Severity assessment in asthma: An evolving concept.
Guidelines for the clinical management of asthma base specific treatment recommendations on the assessment of disease severity. Thus, the accuracy of such assessments is essential for proper clinical management. The consistency of asthma severity assessment in patients with difficult-to-treat disease is unknown. The objectives of this analysis were to compare the asthma severity assessment according to 3 methodologies in patients from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens study. Asthma severity on the basis of the National Asthma Education and Prevention Program and the Global Initiative for Asthma guidelines was compared with physician assessment and benchmarked against asthma-related health care use. Guideline-based asthma severity symptom components were derived from patient-reported questionnaires. Lung function levels were determined by prebronchodilator FEV(1) measurements; asthma-related medication and recent health care use were reported by patients. There was a clear lack of agreement among the asthma severity assessment modalities. Asthma severity was associated with asthma-related health care use, and patients considered to have severe asthma according to both sets of guidelines and physicians' assessment had the highest health care and medication use. Classification of asthma severity on the basis of current asthma symptoms and lung function may be useful but not completely reflective of a patient's true asthma condition. Clinical assessment of asthma severity should consider a patient's medication use and consumption of health care resources for asthma exacerbations. Additional studies that apply criteria for asthma severity longitudinally are needed to support recommendations for optimal assessment of asthma severity.


Multiple inputs of GABA-immunoreactive neurons in the cuneate nucleus of the rat.
Using anterograde transport of WGA-HRP and the experimental degeneration method for identification of corticocuneate (CCT) and primary afferent (PAT) terminals in conjunction with gamma-amino butyric acid (GABA) and glutamate immunocytochemistry, this study has demonstrated that the GABA-immunoreactive (GABA-IR) neurons in the rat cuneate nucleus were post-synaptic to PATs (some of them being glutamate-IR), GABA-IR and GABA-negative terminals. The HRP-labelled CCTs did not make any synaptic contacts with GABA-IR neurons but with some GABA-negative dendrites. PATs labelled by HRP or showing degenerating features made direct synaptic contacts with the dendrites of GABA-IR neurons. Beside the above GABA-IR boutons also showed axosomatic and axodendritic synapses with the GABA-IR neurons. In 'triple labeling' method for GABA, PAT and glutamate, it was found that the PATs which were usually glutamate-positive were presynaptic to the dendrites of GABA-IR neurons. Furthermore, some glutamate-IR terminals which were of non-PAT's origin also synapsed with the dendrites and somata of GABA-IR neurons. It is concluded from this study that the major inputs of GABA-IR neurons were from glutamate immunopositive PATs and glutamate terminals of non-PATs origin; other GABA-IR terminals either intrinsic or extrinsic also contributed to the afferent sources of GABA-IR neurons. The CCTs contributed very little, if any, to this input. It is suggested that the PATs and glutamate-IR terminals on GABA-IR neurons may be involved in lateral inhibition for increase of spatial precision. The synaptic contacts between GABA-IR boutons and dendrites or somata of GABA-IR neurons may provide a possible means for disinhibition.


Purine nucleoside phosphorylase activity in rat cerebrospinal fluid.
The sequential hydrolysis of purines is present in rat CSF and generates nucleosides as inosine and guanosine that are usual substrates for purine nucleoside phosphorylase (PNP). PNP catalyzes phosphorolysis of the purine nucleosides and deoxynucleosides releasing purine bases. Here we investigated the presence of PNP in CSF of rats using: i) a specific chromophoric analogue of nucleosides, 2-amino-6-mercapto-7-methylpurine ribonucleoside (MESG), and ii) an inhibitor of PNP activity, immucillin-H. Additionally, we performed a preliminary kinetic characterization (K(M): Henry-Michaelis-Menten constant; V: maximal velocity) for MESG and inorganic phosphate (Pi). The values of K(M) and V for MESG (n = 3, mean+/-SD) were 142.5+/-29.5 microM and 0.0102+/-0.0006 U mg(-1), respectively. For Pi (n=3, mean+/-SD), the K(M) values and V were 186.8+/-43.7 microM and 0.0104+/-0.0016 U mg(-1), respectively. The results indicated that PNP is present in rat CSF and provided a preliminary kinetic characterization.


Cost-Effectiveness of Multifactorial Interventions in Preventing Falls among Elderly Population: A Systematic Review.
To review the cost-effectiveness of multifactorial interventions to prevent falls in elderly people. In this systematic review, the databases including PubMed via MEDLINE, Web of Science, Embase, Scopus, Cochrane Library and Google Scholar (from 1st January 2000 to 30th February) were used. All pre-reviewed articles related to cost-effectiveness analysis of multifactorial interventions to prevent falls in elderly were included in this paper and congresses abstracts were excluded. Descriptive statistics were used for quantitative data and content-analysis method to analyze qualitative data. Out of the 456 articles, 19 were finally included in the study. Eighteen articles were conducted in High-Income Countries (HICs) and 16 were at the community level. Medical visits consultation and education were the most common interventions. Most studies were cost-effectiveness and using the Randomized Control Trial (RCT) methods. A fall of prevention costs ranged from $ 272 to $ 987. Incremental Cost-Effectiveness Ratio (ICER) interventions also ranged from the US $ 120,667 to the US $ 4280.9. The results show that despite the high effectiveness of multifactorial interventions to prevent elderly falls, the cost of the interventions are high and they are not very cost-effective. It would be better to design and implement multifactorial interventions with low cost and high effectiveness that are appropriate for each country.


Efficacy of eculizumab in refractory life-threatening warm autoimmune hemolytic anemia associated with chronic myelomonocytic leukemia.
Eculizumab may be considered as an emergency therapeutic option in refractory life-threatening warm autoimmune hemolytic anemia especially if direct antiglobulin test is positive for both IgG and C3d and after failure of all conventional treatments.


Asymptomatic bacteriuria in schoolgirls. VI. The correlation between urinary and faecal Escherichia coli. Relation to the duration of the bacteriuria and the sampling technique.
The occurrence of the urinary strain in the anus, rectum and faeces was investigated in 27 girls with asymptomatic bacteriuria (ABU). In patients with bacteriuria of relatively short duration 46% of the faecal isolates were of the urinary strain as compared to only 18% in patients with bacteriuria of relatively long duration. In general the correlation between the urinary and faecal flora is striking at the time of establishment of ABU but diminishes with time. The diminished correlation may be due to two factors: firstly, the composition of the faecal flora changes with time. Secondly, the correlation may be obscured by complex changes in the properties of bacterial strains established in the urinary tract. Contamination by the infected urine did not seem to be a serious problem when the rectal mucosa was swabbed proximal to the anal canal.


Toward robust N-glycomics of various tissue samples that may contain glycans with unknown or unexpected structures.
Glycans in tissues are structurally diverse and usually include a large number of isomers that cannot be easily distinguished by mass spectrometry (MS). To address this issue, we developed a combined method that can efficiently separate and identify glycan isomers. First, we separated 2-aminopyridine (PA)-derivatized N-glycans from chicken colon by reversed-phase liquid chromatography (LC) and directly analyzed them by electrospray ionization (ESI)-MS and MS/MS to obtain an overview of the structural features of tissue glycans. Next, we deduced the structures of isomers based on their elution positions, full MS, and MS/MS data, before or after digestions with several exoglycosidases. In this method, the elution position differed greatly depending on the core structure and branching pattern, allowing multiantennary N-glycan structures to be easily distinguished. To further determine linkages of branch sequences, we modified PA-N-glycans with sialic acid linkage-specific alkylamidation and/or permethylation, and analyzed the products by LC-MS and multistage MS. We determined the relative abundances of core structures, branching patterns, and branch sequences of N-glycans from chicken colon, and confirmed presence of characteristic branch sequences such as Lex, sialyl Lex, sulfated LacNAc, LacNAc repeat, and LacdiNAc. The results demonstrated that our method is useful for comparing N-glycomes among various tissue samples.


Functional characterization of mouse T lymphocytes with IgM-Fc receptors. I. Studies on ADCC and helper cell function.
The function of mouse T lymphocytes with receptors for IgM-Fc was analyzed by using immunofluorescence and a column separation method. The cellular uptake of FITC-IgM was inhibited with unlabeled Fc5 mu. IgM-FcR+ cells were active in ADCC against IgM-sensitized target cells, but not against IgG-coated target cells. The cells mediating ADCC with IgM antibody were shown to be distinct and physically separable from those mediating ADCC with IgG antibody. Helper T lymphocytes for humoral antibody formation in a hapten-carrier system were shown to be IgM-FcR+ and Fc-IgG-.


[The enhancement of the diagnostic reliability of immunoblot for HIV-1 antibodies by enriching the preparation for immunoblot with the HIV-1 gp120 protein].
The diagnostic value of original immunoblot system depends on the availability of enveloped protein GP120 because it is the antibodies to this polypeptide that frequently indicate the running virus infection. This polypeptide is lost during purification of viral material but remains free in culture medium. The extraction of GP120 from culture fluid with immunosorbent based on sepharose 4B with ligated immunoglobulins from HIV-1-infected persons enriched the preparation for immunoblot with proteins increasing its diagnostic value.


A case of spatial neglect dysgraphia in Wilson's Disease.
We report here on a single neuropsychological case study of a young girl, KH, who presented with Wilson's Disease (WD) associated with a peripheral spatial neglect dysgraphia without major problems in the standard clinical tests of spatial neglect. Few studies have demonstrated a visuospatial deficit in WD and to date there has been no report of neglect syndrome arising from WD. However, recent studies have demonstrated that neglect is frequently associated with brain damage including the primary site of WD, the basal ganglia. KHs writing abilities were evaluated just after her admission to the rehabilitation department and 6 months later. The baseline evaluation demonstrated that KH had neglect dysgraphia with verbal stimuli (e.g., words or sentences) although her deficit was less evident in drawing multiple geometric shapes. Six months after the initial evaluation, KH showed evidence of neglect dysgraphia only when writing was associated with a secondary memory task. KHs writing performance is discussed with reference to previous cases of spatial neglect dysgraphia and in the context of spatial neglect. We suggest that the asymmetry between verbal writing and nonverbal drawing disturbances was caused by different attentional loads.


Aerosol SARS-CoV-2 in hospitals and long-term care homes during the COVID-19 pandemic.
Few studies have quantified aerosol concentrations of SARS-CoV-2 in hospitals and long-term care homes, and fewer still have examined samples for viability. This information is needed to clarify transmission risks beyond close contact. We deployed particulate air samplers in rooms with COVID-19 positive patients in hospital ward and ICU rooms, rooms in long-term care homes experiencing outbreaks, and a correctional facility experiencing an outbreak. Samplers were placed between 2 and 3 meters from the patient. Aerosol (small liquid particles suspended in air) samples were collected onto gelatin filters by Ultrasonic Personal Air Samplers (UPAS) fitted with <2.5μm (micrometer) and <10 μm size-selective inlets operated for 16 hours (total 1.92m3), and with a Coriolis Biosampler over 10 minutes (total 1.5m3). Samples were assayed for viable SARS-CoV-2 virus and for the viral genome by multiplex PCR using the E and N protein target sequences. We validated the sampling methods by inoculating gelatin filters with viable vesicular stomatitis virus (VSV), and with three concentrations of viable SARS-CoV-2, operating personal samplers for 16hrs, and quantifying viable virus recovery by TCID50 assay. In total, 138 samples were collected from 99 rooms. RNA samples were positive in 9.1% (6/66) of samples obtained with the UPAS 2.5μm samplers, 13.5% (7/52) with the UPAS 10μm samplers, and 10.0% (2/20) samples obtained with the Coriolis samplers. Culturable virus was not recovered in any samples. Viral RNA was detected in 15.1% of the rooms sampled. There was no significant difference in viral RNA recovery between the different room locations or samplers. Method development experiments indicated minimal loss of SARS-CoV-2 viability via the personal air sampler operation.


Approaches and advances in the development of potential therapeutic targets and antiviral agents for the management of SARS-CoV-2 infection.
Virus onslaughts continue to spread fear and cause rampage across the world every now and then. The twenty first century is yet again witnessing a gross global pandemic, Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Globally no vaccines or drug specific to COVID-19 is available. Corona viruses have been in mutual relationship with humans and other hosts over many decades though aggressive zoonotic strains have caused havoc. Zoonotic emergent corona viruses prior to SARS-COV-2 included severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), with the former leading to aggressive infectious spread and the later with high mortality rate. Although they emerged in the early period of the twenty first century, resilient biomedical and expertise in pharmaceutical domain could not appropriate any proprietary therapeutics. Studies envisaged towards curtailing their spread employed different stages of the virus life cycle with all zoonotic coronaviruses (CoVs) sharing genomic and structural similarities. Hence the strategies against SARS-CoV and MERS-CoV could prove effective against the recent outbreak of SAR-CoV-2. The review unravels key events involved in the lifecycle of SARS-CoV-2 while highlighting the possible avenues of therapy. The review also holds the scope in better understanding a broad-spectrum antivirals, monoclonal antibodies and small molecule inhibitors against viral glycoproteins, host cell receptor, viral mRNA synthesis, RNA-dependent RNA polymerase (RdRp) and viral proteases in order to design and develop antiviral drugs for SARS-CoV-2.


A Higher Dose of Dasatinib May Increase the Possibility of Crossing the Blood-brain Barrier in the Treatment of Patients With Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia.
Dasatinib is a second-generation tyrosine kinase inhibitor with higher central nervous system (CNS) penetration compared with imatinib and nilotinib in in vitro studies. However, limited clinical data are available regarding the dosage and CNS penetration of dasatinib. The purpose of this study was to investigate the actual ability of dasatinib to cross the blood-brain barrier in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Plasma and cerebrospinal fluid (CSF) samples collected from Ph+ ALL patients treated with dasatinib were analyzed by using an LC-MS/MS assay. Orally administered dasatinib 100 mg once daily was well absorbed by the patient but penetrated poorly into the CSF. The use of a higher drug dosage (140 mg/d) may increase systemic drug exposure and enhance the penetration of dasatinib into the CSF. Based on this study, the use of a higher dosage of dasatinib (140 mg/d) is recommended in patients at high risk of CNS relapse or patients who need treatment for CNS leukemia. ClinicalTrials.gov identifier: NCT02523976.


Mosaicism for sulfoiduronate sulfatase deficiency in carriers of Hunter's syndrome.
Using an assay for sulfoiduronate sulfatase based on the degradation of 35S mucopolysaccharides in a cell-free system, two clonal populations have been demonstrated in fibroblasts of heterozygotes for Hunter's syndrome. The locus responsible for sulfoiduronate sulfatase deficiency in this X-linked mucopolysaccharidosis is therefore subjected to dosage compensation in females.


Studies on extracellular ribonucleases of Ustilago sphaerogena. Purification and properties.
1. Four ribonucleases were isolated from culture media of Ustilago sphaerogena. They were designated ribonucleases U(1), U(2), U(3) and U(4). 2. They were purified about 1600-, 3700-, 1100- and 16-fold respectively. 3. It was shown by gel filtration that ribonucleases U(1), U(2) and U(3) have molecular weights about 10000 like ribonuclease T(1), and that ribonuclease U(4) is much larger. 4. Ribonucleases U(1), U(2) and U(3) are thermostable, but ribonuclease U(4) is not. 5. The pH optimum of ribonucleases U(1) and U(4) is pH8.0-8.5, and that of ribonucleases U(2) and U(3) is pH4.5.


Adolescent Self-Consent for COVID-19 Vaccination: Views of Healthcare Workers and Their Adolescent Children on Vaccination Autonomy.
This study explored the perceptions of healthcare worker parents (physicians, nurses, and staff) and their adolescents (aged 12-17 years) on adolescent self-consent to COVID-19 vaccination by applying the concept of positive deviance of those already vaccinated against COVID-19. We used a qualitative descriptive design to conduct individual, semi-structured interviews with COVID-19-vaccinated healthcare workers in Southern California and their vaccinated adolescent children. Separate interviews were conducted with parents and adolescents from November to December 2021 using digital phone conferencing software. All interviews were recorded and transcribed. Thematic and constant comparative analysis techniques were used to identify relevant themes and subthemes. Twenty one healthcare workers (9 nurses, one nurse practitioner, one technologist, and 10 physicians) and their adolescents (N = 17) participated. Three overarching themes were identified to describe participants' perspectives about adolescent self-consent for COVID-19 vaccination: (1) Family values and practices around adolescent vaccination; (2) Differences in parent and adolescent support for vaccine self-consent laws; and (3) Parent and adolescent uncertainty on readiness for vaccine self-consent laws. Adolescents largely supported self-consent while parents supported the policy if they would be able to have a discussion with their adolescent prior to the decision. Parents and adolescents supported adolescent self-consent for COVID-19 vaccination, with the reservation that adolescents should discuss the decision alongside their parents to exercise their medical autonomy with supportive guidance. Greater adolescent involvement in making decisions and providing self-consent for healthcare, including vaccines, could prepare adolescents to have a greater sense of autonomy over their health and contribute to population health measures.


Real-time PCR detection of Brucella spp. DNA in lesions and viscera of bovine carcasses.
This study reports a real-time PCR assay for the detection of Brucella spp. associated with the FTA® Elute method in lesions observed during sanitary inspections in beef slaughter. Of the total 276 samples, 78 (28.3%) tested positive and 198 (71.7%) negative for Brucella spp. The real-time PCR technique associated with the FTA® Elute method proved to be an important tool for the diagnosis, judgment about and disposal of carcasses and viscera of slaughtered animals.


Novel chelating resin with cyanoguanidine group: useful recyclable materials for Hg(II) removal in aqueous environment.
A novel chelating resin containing cyanoguanidine moiety has been successfully prepared by the functionalizing reaction of a macroporous bead based on chloromethylated copolymer of styrene-divinylbenzene (CMPS) with dicyandiamide (DCDA) in the presence of phase transfer catalyst. The Fourier transform-infrared spectra (FT-IR) and scanning electron microscopy (SEM) were employed in the characterization of the resulting chelating resin, meanwhile, the adsorption properties of the resin for Hg(II) were investigated by batch and column methods. The results indicated that the resin displayed a marked advantage in Hg(II) binding capacity, and the saturated adsorption capacity estimated from the Langmuir model was dramatically up to 1077 mg g(-1) at 45 °C. Furthermore, it was found that the resin was able to selectively separate Hg(II) from multicomponent solutions with Zn(II), Cu(II), Pb(II) and Mg(II). The desorption process of Hg(II) was tested with different eluents and the ratio of the highest recovery reached to 96% under eluting condition of 1M HCl+10% thiourea. Consequently, the resulting chelating resin would provide a potential application for treatment process of Hg(II) containing wastewater.


Spasticity and pain in adults with cerebral palsy.
To evaluate whether spasticity measures are related to pain in adults with cerebral palsy (CP). This cross-sectional study recruited individuals aged 16 to 89 years with a diagnosis of CP. Participants completed the Penn Spasm Frequency Scale (PSFS), Brief Pain Inventory (BPI), and PROMIS Pain Interference measures. The Modified Ashworth Scale (MAS) and Tardieu spasticity angles of six joints were rated and summed to composite MAS and Tardieu scores for each participant. Associations between spasticity and pain measures were evaluated. Forty-seven participants (27 females, 20 males) with a mean age of 35 years 7 months (range 18-77y) spanning all Gross Motor Function Classification System (GMFCS) levels were included. Twenty-six participants reported their average pain level on BPI as greater than 0 over the past week (median pain level 4.0). Median PSFS was 1.0 (range 0.0-1.0) and this correlated with average BPI and Pain Interference T scores (median 40.7; ρ=0.33 and ρ=0.31 respectively [both p=0.01]). When adjusted for pain medication use and age, MAS correlated with BPI (ρ=0.30; p=0.04). Other pain and spasticity measures, or GMFCS level, were not significantly related with pain interference or BPI rating. Age was weakly associated with BPI (slope=0.10; p<0.01). PROMIS Pain Interference was lower than population-based norms. Patient-rated spasm frequency demonstrated better association with pain levels and interference than physician-rated MAS and Tardieu. Pain was not associated with Gross Motor Function Classification System level. Pain increased with age, as anticipated. Self-reported spasm scores were associated with increased pain in contrast to clinical examination scales. Adjusted, summed spasticity on the Modified Ashworth Scale was associated with pain scores on the Brief Pain Inventory. Although pain is experienced by adults with cerebral palsy, pain did not interfere with activities.