Enantioselective high-performance liquid chromatographic determination of nicardipine in human plasma.
A sensitive method for the enantioselective high-performance liquid chromatography (HPLC) determination of nicardipine in human plasma is described. (+)-Nicardipine, (-)-nicardipine and (+)-barnidipine as an internal standard are detected by an ultraviolet detector at 254 nm. Racemic nicardipine in human plasma was extracted by a rapid and simple procedure based on C18 bonded-phase extraction. The extraction samples were purified and concentrated on a pre-column using a C1 stationary phase and the enantiomers of nicardipine are quantitatively separated by HPLC on a Sumichiral OA-4500 column, containing a chemically modified Pirkle-type stationary phase. Determination of (+)- and (-)-nicardipine was possible in a concentration range of 5-100 ng ml(-1) and the limit of detection in plasma was 2.5 ng ml(-1). The recoveries of (+)- and (-)-nicardipine added to plasma were 91.4-98.4% and 93.3-96.7%, respectively, with coefficients of variation of less than 9.0 and 9.4% respectively. The method was applied to low level monitoring of (+)- and (-)-nicardipine in plasma from healthy volunteers.


Sex Differences in Recovery and Device Replacement After Left Ventricular Assist Device Implantation as Destination Therapy.
Background The relevance of sex and preimplant factors for clinical outcomes among patients with left ventricular assist devices intended for destination therapy is unclear. Methods and Results INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) data (2006-2017) from 6771 men and 1690 women with left ventricular assist devices as destination therapy were analyzed to evaluate the contribution of preimplant clinical, demographic, and clinically judged psychosocial characteristics to time until death, heart transplant, device explant due to recovery, or complication-related device replacement. Associations of sex with time until each competing outcome were evaluated using cumulative incidence functions and event-specific Cox proportional hazards models. Women were younger, more likely to have nonischemic diagnoses, and reported less substance abuse but were more likely to be unmarried, not working for an income, overweight, and depressed than men. After 2 years, women had higher probabilities for recovery (3.7% versus 1.6%, P<0.001) and device replacement (12.1% versus 10%, P=0.019) than men but not for death and transplant (P>0.12). The sex differences remained after controlling for covariates (adjusted hazard ratio [HRadj] recovery, 1.85; 95% CI, 1.30-2.70; P<0.001; HRadj device replacement, 1.22; 95% CI, 1.04-1.33; P=0.015). Female-specific diagnoses (eg, postpartum heart failure) contributed to women's enhanced rate of recovery. Demographic and psychosocial factors were unrelated to women's increased event rates. Conclusions In destination therapy, women have higher rates of device replacement and recovery than men. The latter was partly explained by female-specific diagnoses. Standardized assessments of psychosocial characteristics are needed to elucidate their association with sex differences in outcomes.


Pyeloplasty in Adults With Ureteropelvic Junction Obstruction in Poorly Functioning Kidneys: A Systematic Review.
To systematically summarize the available evidence concerning the impact of pyeloplasty on symptoms and differential renal function (DRF) in adults with unilateral UPJO in poorly functioning kidneys (PFK), and to identify potential predictors of kidney function recovery that could help clinicians select candidates for pyeloplasty. A literature search (MEDLINE, Embase, Google Scholar, Scopus, ClinicalTrials.gov, and the WHO Clinical Trials Registry) and systematic review were performed up to September 2020 according to the PRISMA guidelines. PFK were defined as a baseline DRF ≤30% on renal scintigraphy. The primary endpoints were symptom relief and postoperative scintigraphic DRF. Predictors of kidney function recovery were evaluated and compared among studies. Nine studies comprising 731 patients met the inclusion criteria and were included for evidence synthesis. A DRF increase >5% occurred in 13.3%-53.8% of 160 patients with a pre- and postoperative renal scan. Symptoms improved in 73.3%-93.3% of 141 adults after pyeloplasty. Neither patient's age, baseline DFR, comorbidities, degree of hydronephrosis, kidney parenchymal thickness, nor kidney biopsy findings consistently predicted a significant DRF increase among 375 patients undergoing pyeloplasty. Based on a low level of evidence, pyeloplasty may relieve symptoms and stabilize kidney function in adults with UPJO in PFK. A significant number of patients showed a DRF increase >5%, yet no consistent predictor of kidney function recovery was identified. Until more evidence becomes available, pyeloplasty could be considered for selected cases after accounting for the risks of a failure requiring a future nephrectomy.


Computer-Assisted Diagnosis System for Breast Cancer in Computed Tomography Laser Mammography (CTLM).
Computed tomography laser mammography (Eid et al. Egyp J Radiol Nucl Med, 37(1): p. 633-643, 1) is a non-invasive imaging modality for breast cancer diagnosis, which is time-consuming and challenging for the radiologist to interpret the images. Some issues have increased the missed diagnosis of radiologists in visual manner assessment in CTLM images, such as technical reasons which are related to imaging quality and human error due to the structural complexity in appearance. The purpose of this study is to develop a computer-aided diagnosis framework to enhance the performance of radiologist in the interpretation of CTLM images. The proposed CAD system contains three main stages including segmentation of volume of interest (VOI), feature extraction and classification. A 3D Fuzzy segmentation technique has been implemented to extract the VOI. The shape and texture of angiogenesis in CTLM images are significant characteristics to differentiate malignancy or benign lesions. The 3D compactness features and 3D Grey Level Co-occurrence matrix (GLCM) have been extracted from VOIs. Multilayer perceptron neural network (MLPNN) pattern recognition has developed for classification of the normal and abnormal lesion in CTLM images. The performance of the proposed CAD system has been measured with different metrics including accuracy, sensitivity, and specificity and area under receiver operative characteristics (AROC), which are 95.2, 92.4, 98.1, and 0.98%, respectively.


Snail transmitters of schistosomiasis and other mollusks of medical and economic importance at the Simplício Queda Única Hydroelectric Plant, Southeast Brazil.
This paper presents the results of an extensive survey of freshwater mollusks in the Simplício Queda Única Hydroelectric Development area, Southeast Brazil. Mollusks were collected between 2008 and 2013. All specimens were examined for the presence of larval trematodes. In total, 12,507 specimens classified into 16 genera were obtained. Known snail vectors of schistosomiasis and fascioliasis and exotic species were identified, and new records are reported. No specimens parasitized by larval trematodes of medical interest were detected. However, the results reinforce the importance of surveillance in study areas vulnerable to the occurrence of schistosomiasis transmission.


Anterior and posterior corneal curvature: normal values in healthy Iranian population obtained with the Orbscan II.
The objective of study was to determine the normative values of anterior and posterior best fit sphere (A-BFS and P-BFS) measured with Orbscan II Topography System. In this cross-sectional study, patients (age range: 18-40 years) referred to the Khatam Eye Hospital (Mashhad, Iran) were put in an observational cross-sectional study. The A-BFS and P-BFS were measured with the Orbscan II. The differences between genders, between right and left eyes, and age-related changes were evaluated. A total of 977 healthy participants consisted of 614 female and 363 male subjects aged 18-35 years participated. The average A-BFS in our study population was recorded as 43.060 ± 1.541 D (median: 43.00 D, mode: 43.10 D, range: 38.80-55.80 D). The average P-BFS in our study population was recorded as 52.702 ± 2.190 D (median: 52.60 D, mode: 53.10 D range: 46.9-62.20 D). The A-BFS and P-BFS were respectively 42.753 ± 1.629 and 52.327 ± 2.376 D in males and 43.242 ± 1.457 and 52.924 ± 2.041 D in females, which were statistically different between the genders (P < 0.001). However, A-BFS and P-BFS were not statistically different between right and left eyes (P = 0.649 and P = 0.688 respectively). In addition, A-BFS and P-BFS were not correlated with the age (r = 0.038, P = 0.096 and r = -0.142, P = 0.178 respectively). Considering 95 % confidence interval, A-BFS less than 43.13 D and greater than 42.99 D and P-BFS less than 52.80 D and greater than 52.60 D would be considered abnormal. Detailed description and analysis of A-BFS and P-BFS with Orbscan demonstrated that the obtained average value of BFS were higher in male than female and did not change with increasing age.


Role of thromboxane and serotonin as mediators in the development of spontaneous alterations in coronary blood flow and neointimal proliferation in canine models with chronic coronary artery stenoses and endothelial injury.
Platelet-mediated obstruction of stenotic and endothelium-injured coronary arteries may be important in the abrupt progression from chronic stable to unstable coronary heart disease syndromes in patients. Transcardiac accumulation of thromboxane A2 and serotonin has been demonstrated in patients as chronic stable angina is converted to unstable angina. In this study in anesthetized open chest dogs with coronary artery stenosis and endothelial injury, thromboxane A2 and serotonin were shown to be important mediators of intermittent coronary obstruction caused by platelet aggregation and dynamic vasoconstriction. Furthermore, thromboxane A2 synthesis inhibitors and receptor antagonists and serotonin receptor antagonists, singly and together, provided substantial protection against repetitive platelet aggregation and dislodgment in canine models with coronary artery stenosis and endothelial injury even when systemic catecholamine concentrations were markedly elevated. These same observations apply in chronically instrumented, awake, unsedated dogs with coronary artery stenosis and endothelial injury in which recurrent platelet attachment and dislodgment cause cyclic flow alterations that may be prevented by thromboxane A2 synthesis inhibitors and receptor antagonists and serotonin receptor antagonists. Chronically instrumented dogs with coronary stenosis and endothelial injury in which recurrent platelet attachment and dislodgment occurred also developed neointimal proliferation of varying severity within 10 days to 3 weeks; the morphologic appearance of the neointimal proliferation was identical to that found in patients who develop restenosis after coronary angioplasty.


Retrospective analysis of the incidence and predictive factors of parametrial involvement in FIGO IB1 cervical cancer.
Radical surgery is the standard primary treatment for patients with stage IB1 (FIGO 2009 staging) cervical cancer due to latent parametrial involvement. Recent studies suggested that less radical surgery was applicable for patients with no or low risk of parametrial involvement. In this study, we aimed to determine the incidence and possible predictive factors of parametrial involvement in patients with stage IB1 cervical cancer so as to evaluate whether less radical surgery was suitable for selected patients. Clinical data of patients who underwent type C radical hysterectomy with pelvic lymphadenectomy and diagnosed as stage IB1 cervical cancer at Union Hospital, Wuhan, China from October 2014 to December 2017 were collected and analysed retrospectively. The incidence of parametrial involvement was calculated and the risk factors for parametrial involvement were evaluated by univariate and multivariate logistic regression. Among 282 eligible patients, 33 (11.7%) had parametrial involvement. Postmenopause, lymphovascular space invasion (LVSI), lymph node metastasis (LNM), deep stromal invasion (outer 1/3) and tumor size larger than 2 cm were statistically associated with parametrial involvement. Multivariate analysis showed that LNM (OR = 11.431; 95%CI: 3.455 - 37.821), deep stromal invasion (OR = 6.080; 95%CI: 1.814 - 20.382) and LVSI (OR = 7.147; 95%CI: 1.863-27.411) remained as independent risk factors for parametrial involvement in patients with stage IB1 cervical cancer. The incidence of parametrial involvement in stage IB1 cervical cancer is non-negligible. Only LNM, LVSI and deep stromal invasion were independent predictors, which were not easy to evaluate accurately before surgery. Less radical surgery requires modified pre-treatment evaluation methods and prospective data support.


Predicting drive for muscularity behavioural engagement from body image attitudes and emotions.
We examined the potential moderating effects of appearance investment, body image disturbance, and situational body image dysphoria on the drive for muscularity attitude-behaviour relationship. Participants (339 British college men, M(AGE)=20.00 years, SD=2.59) completed drive for muscularity attitude and behaviour, appearance investment, body image disturbance, and situational body image dysphoria measures. Results indicated higher levels of appearance investment, body image disturbance, and situational body image dysphoria were associated with increases in the drive for muscularity attitude's relationship with physique-enhancing behavioural engagement. Results help extend recent research that has moved beyond identifying correlates to examining ways that groups of variables interact to predict drive for muscularity behavioural engagement and may contribute to theory development.


Growth spurt in a lens with a posterior subcapsular cataract.
Over a period of 5 years, the lenses of a patient with a unilateral posterior subcapsular cataract were documented using Scheimpflug slit-image photography. For the first time ever, a growth spurt was observed of the cataractous lens. It is postulated that this could be a reflection of either a mitotic spurt of the lens epithelium or a failure of compaction of the deeper lens fibres.


Application of chemometrics for detection and modeling of adulteration of fresh cow milk with reconstituted skim milk powder using voltammetric fingerpriting on a graphite/ SiO2 hybrid electrode.
In the present work, an analytical approach for the voltammetric detection and prediction of adulteration of fresh cow milk with reconstituted skim milk powder is developed. After precipitation of milk proteins upon addition of ethanol and centrifugation, the supernatant liquid of the samples was analyzed by cyclic voltammetry on a novel graphite/SiO2 hybrid working electrode (GSiHE) using LiClO4 as electrolyte. Under these conditions, fresh milk samples gave broadened peaks/plateaus in both forward and backward potential scanning, attributed mainly to oxidases. Such peaks were not evident in the case of reconstituted skim milk powder samples due to inactivation of enzymes and breakdown of certain antioxidants caused by heat and pressure-treatments. The differences between fresh and reconstituted skim milk powder samples in their voltammetric profile were exploited for the detection of fresh milk adulteration by submitting voltammetric data to chemometrics. As datapoints, the differences between forward and backward current values, recorded at the same potentials, were determined and submitted to multivariate analysis. Principal Component Analysis (PCA) provided a clear differentiation between fresh milk and reconstituted skim milk powder samples. Soft independent modeling of class analogy (SIMCA) was employed to model the class of fresh milks, using samples from 12 commercially available fresh milk brands. Prediction of fresh milk adulteration with reconstituted skim milk powders was achieved by means of Partial Least Squares (PLS) regression analysis. Detection limit of the technique was found to be below 6% (v/v) and the linearity of model in terms of observed/predicted values was confirmed up to 100% (v/v). Validation and applicability of both SIMCA and PLS models were confirmed using a suitable test set, consisting of commercial fresh milk and skim milk powder samples as well as synthetic adulterated fresh milk samples.


The stability of Cl-, Br-, and I-passivated Si(100)-(2 × 1) in ambient environments for atomically-precise pattern preservation.
Atomic precision advanced manufacturing (APAM) leverages the highly reactive nature of Si dangling bonds relative to H- or Cl-passivated Si to selectively adsorb precursor molecules into lithographically defined areas with sub-nanometer resolution. Due to the high reactivity of dangling bonds, this process is confined to ultra-high vacuum (UHV) environments, which currently limits its commercialization and broad-based appeal. In this work, we explore the use of halogen adatoms to preserve APAM-derived lithographic patterns outside of UHV to enable facile transfer into real-world commercial processes. Specifically, we examine the stability of H-, Cl-, Br-, and I-passivated Si(100) in inert N2and ambient environments. Characterization with scanning tunneling microscopy and x-ray photoelectron spectroscopy (XPS) confirmed that each of the fully passivated surfaces were resistant to oxidation in 1 atm of N2for up to 44 h. Varying levels of surface degradation and contamination were observed upon exposure to the laboratory ambient environment. Characterization byex situXPS after ambient exposures ranging from 15 min to 8 h indicated the Br- and I-passivated Si surfaces were highly resistant to degradation, while Cl-passivated Si showed signs of oxidation within minutes of ambient exposure. As a proof-of-principle demonstration of pattern preservation, a H-passivated Si sample patterned and passivated with independent Cl, Br, I, and bare Si regions was shown to maintain its integrity in all but the bare Si region post-exposure to an N2environment. The successful demonstration of the preservation of APAM patterns outside of UHV environments opens new possibilities for transporting atomically-precise devices outside of UHV for integrating with non-UHV processes, such as other chemistries and commercial semiconductor device processes.


Expression of 36-kDa microfibril-associated glycoprotein (MAGP-36) in human keratinocytes and its localization in skin.
Microfibril-associated glycoprotein-36 (MAGP-36) is a recently isolated elastin-binding protein and considered to be a member of microfibril-associated glycoproteins (MAGPs). We studied the expression of MAGP-36 in cultured normal human keratinocytes and its localization in the skin. MAGP-36 was found to be expressed in cultured human keratinocytes by Western blot and RT-PCR assays. The levels of MAGP-36 (polypeptide and mRNA) and the number of MAGP-36-producing keratinocytes were greatly increased during Ca(2+)-induced differentiation of keratinocytes. Immunohistochemical studies demonstrated that MAGP-36 colocalized with elastic fibers and formed candelabra like-fibers in the superficial dermis of normal skin. In the elderly skin of sun-exposed region, immunoreactivity of MAGP-36 in the superficial dermis disappeared. In the lesional skin of pseudoxanthoma elasticum which is an elastin-related disorder, immunoreactivity of MAGP-36 was found in the accumulation of disintegrated elastic fibers. The results show that MAGP-36 is a component of elastic fibers in the dermis and co-operates with elastin in normal and diseased conditions.


Antibiotic resistance is an emerging threat to public health: an urgent call to action at the Antimicrobial Resistance Summit 2011.
A national interdisciplinary body is urgently needed to manage the looming antimicrobial resistance crisis.


Hypermethylation of the WT1 and calcitonin gene promoter regions at chromosome 11p in human colorectal cancer.
The short arm of the chromosome 11, known to harbour a number of putative and established tumour-suppressor genes, is frequently hypermethylated in various human neoplasms. We subjected the promoter regions of two genes residing at 11p, namely the tumour-suppressor gene WT1 (Wilms' tumour gene) (11p13) and the calcitonin gene (11p15.5), to methylation analysis in human sporadic colorectal cancer using genomic sequencing. Both genes showed significant hypermethylation of CpG sites within their promoter regions in adenomas and carcinomas compared with normal colonic mucosa. Although the WT1 promoter region was significantly hypermethylated, two CpG sites located in Sp1 motifs were unmethylated in the majority of cases (68-74% of carcinomas). The expression of WT1 gene, as revealed by in situ hybridization, showed no differences between normal colonic mucosa and malignant carcinoma. Together with earlier observations, our present results support the view that the short arm of human chromosome 11 is subjected to widespread regional hypermethylation in various human malignancies.


Low-dose intrathecal rituximab is a safe and potentially effective treatment for pediatric neuroimmunologic disorders.
Historically, treatment options for refractory neuroimmunologic disorders have been limited. Use of intrathecal rituximab has been described in a few case reports but experience in pediatric patients is limited. Here, we report our experience with intrathecal rituximab in 5 pediatric patients with refractory neuroimmunologic conditions. Patients were identified based on treatment-refractory symptoms despite first and second-line therapies and treated according to a standardized protocol. Although individual outcomes varied, intrathecal rituximab showed a favorable safety profile and was well-tolerated. Three out of five patients showed evidence of a positive clinical response assessed by modified Rankin score or Mitchell-Pike Opsoclonus-Myoclonus score. Findings from this retrospective observational study suggest that intrathecal rituximab is a safe and potentially effective therapy in carefully selected patients with refractory neuroimmunologic disorders despite appropriate first and second-line therapies.


Neonates and infants requiring life-long cardiac pacing: How reliable are epicardial leads through childhood?
In the literature, data is lacking on mid-term results of epicardial pacemaker implantation in neonates and infants. Our aim was to evaluate the mid-term results of epicardial pacemakers implanted in infants under 1 year of age. We conducted a retrospective review of patients who underwent pacemaker implantation between 2000 and 2017. Pacemaker and lead parameters were reviewed at discharge, 2, 4 and more than 5 years after implantation. A total of 71 patients aged 4 ± 3 months and weighing 4 ± 2 kg were included in the study. Indications for pacemaker implantation were: acquired AV-block (n = 44), congenital AV block (n = 22), sick sinus syndrome (n = 4) and AV block type Mobitz II (n = 1). Median follow-up time was 5 years (range: 1 month-17 years). At 5 years of follow-up, atrial lead energy threshold for pacing decreased significantly (0.72 ± 0.71 μJ to 0.45 ± 0.35 μJ; P < 0.001) but was stable for ventricular leads (0.57 μJ [0.05; 39.47] to 0.64 μJ [0.13; 9.45], P = 0.97). Atrial lead impedance increased significantly (569 ± 137 Ω to 603 ± 134 Ω, P < 0.001), whereas ventricular lead impedance decreased (603 ± 202 Ω to 490 ± 150 Ω, P < 0.001) after 5 years. Repeat operations were required for generator change (n = 55), lead exchange (n = 17) and infection (n = 1). At 2, 5 and 10 years, atrial lead survival was 96%, 91% and 76% and ventricular lead survival was 94%, 82% and 75%, respectively (P = 0.45). Stable pacing thresholds after 5 years indicated that epicardial pacemakers are safe for infants under 1 year of age until at least school enrolment age. However, due to stimulation at higher heart rates in infancy, battery depletion is a frequent occurrence.


Progress and prospects of polysaccharide-based nanocarriers for oral delivery of proteins/peptides.
The oral route has long been recognized as the most preferred route for drug delivery as it offers high patient compliance and requires minimal expertise. Unlike small molecule drugs, the harsh environment of the gastrointestinal tract and low permeability across the intestinal epithelium make oral delivery extremely ineffective for macromolecules. Accordingly, delivery systems that are rationally constructed with suitable materials to overcome barriers to oral delivery are exceptionally promising. Among the most ideal materials are polysaccharides. Depending on the interaction between polysaccharides and proteins, the thermodynamic loading and release of proteins in the aqueous phase can be realized. Specific polysaccharides (dextran, chitosan, alginate, cellulose, etc.) endow systems with functional properties, including muco-adhesiveness, pH-responsiveness, and prevention of enzymatic degradation. Furthermore, multiple groups in polysaccharides can be modified, which gives them a variety of properties and enables them to suit specific needs. This review provides an overview of different types of polysaccharide-based nanocarriers based on different kinds of interaction forces and the influencing factors in the construction of polysaccharide-based nanocarriers. Strategies of polysaccharide-based nanocarriers to improve the bioavailability of orally administered proteins/peptides were described. Additionally, current restrictions and future trends of polysaccharide-based nanocarriers for oral delivery of proteins/peptides were also covered.


Controlling the transmission of stereochemical information through space in terphenyl-edged Fe4L6 cages.
A series of terphenyl-edged Fe(4)L(6) cages were synthesized from substituted 4,4''-diamino-p-terphenyls, 2-formylpyridine, and iron(II). For the parent diaminoterphenyl, all three possible diastereomers, with T, S(4), and C(3) point symmetries, were formed in nearly equal amounts, as determined by (1)H and (13)C NMR. When 2,2″-dimethylterphenylenediamine was used, the T-symmetry diastereomer was observed to predominate. The use of 2',3',5',6'-tetramethylterphenylenediamine generated predominantly the S(4) cage diastereomer, whereas 2',5'-dimethylterphenylenediamine produced the C(3)-symmetric cage to a greater degree than the other two diastereomers. The factors contributing to the transfer of chiral information between metal vertices were analyzed, and the general principles underlying the delicately balanced thermodynamics were determined.


[Multiple benign fibrous histiocytoma of the lung (authors' translation)].
Multiple benign fibrous histiocytomas in both lungs of a 45-year-old woman are described. The tumors were found incidentally on routine roentgenograms. The lesions were resected, with no recurrence after two years. The tumors were predominantly fibroblastic and included histiocytes, xanthomatous cells, lymphocytes, plasma cells, and giant cells. Cells and fibers had a characteristic storiform pattern. Because of their absolutely benign biological behavior, resection of benign fibrous histiocytomas should be minimal. This appears to be the first case of multiple benign fibrous histiocytomas in both lungs.


Symptoms of post-traumatic stress disorder (PTSD) in next of kin during suspension of ICU visits during the COVID-19 pandemic: a prospective observational study.
During the COVID-19 pandemic, suspension of visits by next of kin to patients in intensive care units (ICU), to prevent spread of the SARS-CoV-2 virus, has been a common practice. This could impede established family-centered care and may affect the mental health of the next of kin. The aim of this study was to explore symptoms of post-traumatic stress syndrome (PTSD) in the next of kin of ICU patients. In this prospective observational single-center study, next of kin of ICU patients were interviewed by telephone, using the Impact of Event Scale-Revised (IES-R), to assess symptoms of acute stress disorder during the ICU stay and PTSD symptoms at 3 months after the ICU stay. The primary outcome was the prevalence of severe PTSD symptoms (IES-R score ≥ 33) at 3 months. The secondary outcomes comprised the IES-R scores during the ICU stay, at 3 months, and the prevalence of severe symptoms of acute stress disorder during ICU stay. An inductive content analysis was performed of the next of kin's comments regarding satisfaction with patient care and the information they were given. Of the 411 ICU patients admitted during the study period, 62 patients were included together with their next of kin. An IES-R score > 33 was observed in 90.3% (56/62) of next of kin during the ICU stay and in 69.4% (43/62) 3 months later. The median IES-R score was 49 (IQR 40-61) during the ICU stay and 41 (IQR 30-55) at 3 months. The inductive content analysis showed that communication/information (55%), support (40%), distressing emotions (32%), and suspension of ICU visits (24%) were mentioned as relevant aspects by the next of kin. During the suspension of ICU visits in the COVID-19 pandemic, high prevalence and severity of both symptoms of acute stress disorder during the ICU stay and PTSD symptoms 3 months later were observed in the next of kin of ICU patients.


Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Atacicept in a Randomized Trial in Healthy Caucasian and Japanese Subjects.
Atacicept is an inhibitor of the B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), and is being studied in relation to immunological disease. Currently, limited data on atacicept are available in non-Caucasian subjects. Pharmacokinetic data from earlier studies of atacicept were derived using an enzyme-linked immunosorbent assay (ELISA), which was subsequently found to have inadequacies. Hence, a new bioanalytical ELISA for total atacicept was developed and validated. We conducted this randomized, double-blind, placebo-controlled phase I study to compare the safety, tolerability, pharmacokinetics, and pharmacodynamics of atacicept in healthy Japanese and Caucasian subjects while generating pharmacokinetic data using the new ELISA. Japanese subjects aged ≥ 18 to ≤ 55 years (n = 24) were randomized (1:1:1:1) to a single subcutaneous dose of atacicept 25, 75, or 150 mg or placebo. Caucasian subjects were then enrolled to match the Japanese subjects' gender, body weight (± 20%), and height (± 15%). Atacicept was well tolerated and there were no clinically significant differences in treatment-emergent adverse events (TEAEs), vital signs, or laboratory parameters between the Japanese and Caucasian subjects. Most (90%) TEAEs were mild; no severe or serious TEAEs or deaths occurred. Weight-adjusted atacicept exposure was comparable between ethnicities and across doses: the Japanese/Caucasian ratio of the area under the serum concentration-time curve from time zero to the last sampling point (AUC0-t) was 107.21% (90% CI 93.42-123.02%) and the Japanese/Caucasian ratio of maximum serum concentration (Cmax) was 95.74% (90% CI 74.26-123.43%; ANCOVA). Median time to reach Cmax (tmax) was 20-60 h across all subjects. Dose-exposure relationships were comparable for the two ethnicities, with dose-normalized AUC0-t decreasing with increasing dose, indicating nonlinear pharmacokinetics for the doses examined. There were no statistically significant differences between ethnicities in the pharmacokinetics-dose relationship. Some transient dose-related decreases in mean serum immunoglobulin (Ig)A and IgM, but not IgG, were observed after atacicept administration. There were small transient increases in peripheral B cell numbers in the first 4 days after dosing that were larger with atacicept than with placebo, with no apparent dose relationship. No anti-atacicept antibodies were detected. The safety, pharmacokinetic, and pharmacodynamic profiles of atacicept in healthy Japanese subjects were comparable to those in healthy Caucasian subjects. EudraCT-ID: 2013-002703-34.


Effects of enalapril on human sperm motility.
The angiotensin converting enzyme inhibitor, enalapril, reduced the motility of washed human spermatozoa. The concentrations producing 50% inhibition were: (percentage motility) 11.6 +/- 2.6 mM, (average forward velocity) 8.0 +/- 1.5 mM and (motility index) 8.5 +/- 2.1 mM (mean + s.e.m.). Enalapril 20 mM prevented all forward movement and reduced percentage motility to an extremely low level. Motility was reduced within 20 sec of addition and little further change occurred during a 60-min incubation period. Inhibition of percentage motility by enalapril was reversible with a 5-min washing procedure following a 5-min incubation period, but not following a 60-min incubation period. Enalapril 20 mM did not impair plasma membrane integrity (hypoosmotic swelling test) or viability (nigrosin-eosin stain). It is concluded that the antimotility effects of enalapril are not caused by inhibition of angiotensin converting enzyme, but may be of interest in the search for new spermicidal agents.


Set-valued mode recognition-based Bayesian estimation for nonlinear stochastic systems with unknown sensor mode.
This paper proposes the problem of joint state estimation and mode recognition for nonlinear stochastic systems with unknown sensor mode. The considered sensor mode is represented by a random finite set, whose elements can be one specific mode or a set of certain modes. A set-valued mode recognition-based Bayesian estimation framework is proposed to propagate the posterior density of the state conditioned on sensor modes and measurements, where the mode is recognized based on the maximum correntropy criterion. Furthermore, a mode-separability metric is proposed to discern the reliability of mode recognition, and utilized to derive two distinct implementation schemes, including state estimation based on separable and inseparable modes. Simulation results of fault detection and target tracking are provided to demonstrate the superiority of the proposed method in terms of state estimation accuracy and mode recognition effectiveness.


Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects.
Pyruvate carboxylase (PC) deficiency is a rare metabolic disease. Recently, therapeutic possibilities have been introduced. We aimed to report the largest series of the B type of PC deficiency, focusing on some neurological aspects that have not yet been documented. We retrospectively studied nine patients with the severe neonatal form of PC deficiency diagnosed in our hospital. Detailed clinical features, brain imaging, biochemical characteristics, and global outcome are reported. All patients had axial hypotonia and tachypnea during the first hours of life. The initial level of consciousness was preserved in most patients. Abnormal movements (high-amplitude tremor and hypokinesia) and bizarre ocular behavior were the most common findings, whereas epilepsy was infrequent. Brain magnetic resonance imaging mostly disclosed cystic periventricular leukomalacia. Hypoglycemia, lactic acidosis, and hypercitrullinemia were invariably found. Hyperammoniemia, hypernatremia, and high proline and lysine were frequently detected. A rapid fatal outcome was observed in most patients. Clinical and biochemical characteristics of this deficiency are highly suggestive. Abnormal movements such as rigidity and hypokinesia (hypokinetic-rigid syndrome) are an important hallmark and may orientate to PC deficiency when associated with severe lactic acidosis.


Pathogenomics of Xanthomonas: understanding bacterium-plant interactions.
Xanthomonas is a large genus of Gram-negative bacteria that cause disease in hundreds of plant hosts, including many economically important crops. Pathogenic species and pathovars within species show a high degree of host plant specificity and many exhibit tissue specificity, invading either the vascular system or the mesophyll tissue of the host. In this Review, we discuss the insights that functional and comparative genomic studies are providing into the adaptation of this group of bacteria to exploit the extraordinary diversity of plant hosts and different host tissues.


Expression of subunit II of chloroplast H(+)-ATPase in an Escherichia coli mutant lacking subunit b of its H(+)-ATPase.
The DNA of subunit II of the H(+)-ATPase from spinach chloroplast was expressed in Escherichia coli. It was found that a high gene dose is lethal to E. coli. With a lower gene dose subunit II was not able to substitute for the homologous subunit b in the E. coli ATP synthase.


Correlations between urinary excretion of catecholamines and electrocardiographic parameters of vagal hyperreactivity in infants with fainting spells. Implication of sympathetic hypotonia?
Vagal hyperreactivity (VHR) is a frequent etiology of infant fainting spells; but it is sometimes difficult to diagnose. A biochemical test would therefore be useful, especially as the oculocardiac reflex (OCR) test innocuity is not absolute. To evaluate urinary excretions of norepinephrine, epinephrine and dopamine as markers for vagal hyperreactivity. During check-up of 55 infants from 0.5 to 11 months of age, for discomfort episodes, including OCR and Holter recording, 24h urinary assays of total norepinephrine, epinephrine and dopamine were carried out to evaluate sympathetic activity. Epinephrine and norepinephrine urinary excretions were negatively correlated with VHR intensity, as measured by the OCR ECG parameters: RRmax, % cardiac deceleration and minimal frequency; dopamine excretion was not. When RRmax(OCR) was greater or equal to 800 ms, epinephrine urinary excretion tended to be less or equal to 9 nmol/mmol creatinine and norepinephrine excretion less or equal to 190 nmol/mmol creatinine. A delay in maturation of the sympathetic system and/or adrenomedullary glands with low secretion of norepinephrine and epinephrine inducing a desequilibrium of the sympathetic/parasympathetic balance may contribute to the fainting spells observed with VHR. Epinephrine and norepinephrine urinary excretions may provide informative complementary noninvasive markers for VHR.


Prevalence of food allergy in Taiwan: a questionnaire-based survey.
Food allergy is common in children and adults, and could be potentially fatal in minor groups. It is important for physicians to identify the prevalence of food allergies and to recognise common food allergens to make precise diagnosis and choose correct therapeutic approaches. We used a nationwide, cross-sectional, random questionnaire-based survey to estimate the self-reported and expert-screened prevalence of food allergies and to identify the common food allergens in Taiwan. In this study, the perceptional diagnosis of food allergies was screened by physicians according to descriptions of convincing symptoms and medical recordings; in the meantime, non-allergic adverse reactions to foods, including food intolerance or food avoidance, were clarified. A total of 30 018 individuals who met the inclusion criteria was evaluated, and 6.95% of them were diagnosed as victims of food allergies. The prevalence was 3.44% in children under 3 years of age, 7.65% in children aged 4-18 years and 6.40% in adults respectively. About 77.33% of the food allergy population had experienced recurrent allergic attacks. Systemic reactions happened about 4.89% in food allergies group. The most commonly reported food allergen in Taiwan is seafood, including shrimp, crab, fish and mollusc. In addition, mango, milk, peanuts and eggs were also important food allergens in the general population; while milk, shellfish, peanuts and eggs were common in children. Less than 10% of the Taiwan population suffers from food allergy with different allergic symptoms to variable food allergens in different age groups.


TldD/TldE peptidases and N-deacetylases: A structurally unique yet ubiquitous protein family in the microbial metabolism.
Here we provide a review on TldD/TldE family proteins, summarizing current knowledge and outlining further research perspectives. Despite being widely distributed in bacteria and archaea, TldD/TldE proteins have been escaping attention for a long time until several recent reports pointed to their unique features. Specifically, TldD/TldE generally act as peptidases, though some of them turned out to be N-deacetylases. Biological function of TldD/TldE has been extensively described in bacterial specialized metabolism, in which they participate in the biosynthesis of lincosamide antibiotics (as N-deacetylases), and in the biosynthesis of ribosomally synthesized and post-translationally modified bioactive peptides (as peptidases). These enzymes possess special position in the relevant biosynthesis since they convert non-bioactive intermediates into bioactive metabolites. Further, based on a recent study of Escherichia coli TldD/TldE, these heterodimeric metallopeptidases possess a new protein fold exhibiting several structural features with no precedent in the Protein Data Bank. The most interesting ones are structural elements forming metal-containing active site on the inner surface of the catalytically active subunit TldD, in which substrates bind through β sheet interactions in the sequence-independent manner. It results in relaxed substrate specificity of TldD/TldE, which is counterbalanced by enclosing the active centre within the hollow core of the heterodimer and only appropriate substrates can entry through a narrow channel. Based on the published data, we hypothesize a yet unrecognized central metabolic function of TldD/TldE in the degradation of (partially) unfolded proteins, i.e., in protein quality control.


Bioaccumulation and depuration of anthracene in Penaeus monodon (Fibricius) through food ingestion.
Understanding on the bioaccumulation and depuration of PAHs (polycyclic aromatic hydrocarbons) in Penaeus monodon is important in seafood safety because it is one of the most popular seafood consumed worldwide. In this study, we used anthracene as the precursor compound for PAHs accumulation and depuration in the shrimp. Commercial feed pellets spiked with anthracene were fed to P. monodon. At 20 mg kg(-1) anthracene, P. monodon accumulated 0.1% of the anthracene from the feed. P. monodon deputed the PAH two times faster than its accumulation. The shrimp reduced its feed consumption when anthracene content in the feed exceeded 20 mg kg(-1). At 100 mg kg(-1) anthracene, P. monodon started to have necrosis tissues on the posterior end of their thorax. The bioaccumulation factor (BAF), uptake rate constant (k(1)) and depuration rate constant (k(2)) of anthracene in P. monodon were 1.15×10(-3), 6.80×10(-4) d(-1) and 6.28×10(-1) d(-1), respectively. The depuration rate constant is about thousand times higher than the uptake rate constant and this indicated that this crustacean is efficient in depurating hydrocarbons from their tissue.


Pragmatic responses to under-informative some-statements are not scalar implicatures.
A highly emblematic paradigm in experimental pragmatics consists in presenting participants with an existentially quantified sentence of the form Some X are Y in a context in which all X are obviously Y. Participants who reject such sentences as false or infelicitous are said to adopt a 'pragmatic' instead of a 'logical' reading of some, and to derive the scalar implicature Some, but not all X are Y. Although there are several competing accounts of scalar implicatures, virtually all of them assume that a participant who responds pragmatically to an under-informative some-sentence mentally entertains a linguistic representation of the negation of a stronger alternative (All X are Y). Yet, there is no evidence that judging an under-informative some-sentence false or infelicitous actually involves the derivation of the some, but not all scalar implicature. We report three experiments consisting of a sentence-picture verification task followed by a forced choice between two paraphrases of the sentence initially assessed. These experiments robustly show that hearers who reject an under-informative some-sentence do so without explicitly entertaining a some, but not all implicature. Our results represent a strong challenge for grammatical accounts of scalar implicature, which all presuppose a mechanism of negation of stronger alternatives, and force a drastic reinterpretation of processing data on scalar implicatures. More generally, our findings show that one should not conflate psychological models of pragmatic processing with a reconstructed link between sentences and their potential meanings.


Persistent BCG bacilli perpetuate CD4 T effector memory and optimal protection against tuberculosis.
Tuberculosis (TB) remains one of the most important infectious diseases of man and animals, and the only available vaccine (BCG) requires urgent replacement or improvement. To facilitate this, the protective mechanisms induced by BCG require further understanding. As a live attenuated vaccine, persistence of BCG bacilli in the host may be a crucial mechanism. We have investigated the long term persistence of BCG following vaccination and the influence on the induced immune response and protection, using an established murine model. We sought to establish whether previously identified BCG-specific CD4 TEM cells represent genuine long-lived memory cells of a relatively high frequency, or are a consequence of continual priming by chronically persistent BCG vaccine bacilli. By clearing persistent bacilli, we have compared immune responses (spleen and lung CD4: cytokine producing T effector/TEM; TCR-specific) and BCG-induced protection, in the presence and absence of these persisting vaccine bacilli. Viable BCG bacilli persisted for at least 16 months post-vaccination, associated with specific CD4 T effector/TEM and tetramer-specific responses. Clearing these bacilli abrogated all BCG-specific CD4 T cells whilst only reducing protection by 1log10. BCG may induce two additive mechanisms of immunity: (i) dependant on the presence of viable bacilli and TEM; and (ii) independent of these factors. These data have crucial implications on the rational generation of replacement TB vaccines, and the interpretation of BCG induced immunity in animal models.


The association between experiences of being defrauded and depressive symptoms of middle-aged and elderly people: a cross-sectional study in China.
This study assessed the correlation between middle-aged and elderly fraud victimhood's experiences of being defrauded (EOBD) and depressive symptoms. This was a prospective study. Data from China Health and Retirement Longitudinal Study 2018 (N = 15,322, mean age = 60.80 years) were used. Logistic regression models were used to identify the association between EOBD and depressive symptoms. Independent analyses were used to examine the association between different types of the fraud and depressive symptoms. Among the middle-aged and elderly people, 9.37% of them have EOBD, and it was significantly associated with depressive symptoms. Among those with EOBD, fundraising fraud (3.72%) and fraudulent pyramid scheme and sales fraud (22.4%) were significantly associated with depressive symptoms, whereas telecommunication fraud (73.88%) had a limited role in inducing depressive symptoms in victimhood. This study suggested that the government should make further efforts to prevent fraud, pay more attention to the mental health of the middle-aged and elderly victimhood, and provide timely psychological assistance to reduce the secondary harm caused by fraud.


Studies on substrate specificity of the hog liver flavin-containing monooxygenase. Anionic organic sulfur compounds.
The influence of anionic groups on interaction of nucleophilic sulfur compounds with the purified hog liver flavin-containing monooxygenase was evaluated from kinetic constants obtained with various dithiobenzoates, thiolbenzoates, and thiolalkylcarboxylic acids. All compounds tested bearing a single negative charge localized on sulfur were excellent substrates but derivatives with a carboxylic acid group one or two carbons removed from the heteroatom exhibited low or no substrate activity. The effect of a carboxylic acid group more distal from sulfur appeared to depend on steric factors that are not well defined. For instance, none of the carboxylic acids (C2-C8) bearing a single thiol on the terminal carbon were oxygenated at detectable rates, whereas dihydrolipoic acid appeared to be a substrate although the concentration required for half-maximal activity was quite high (approximately 2 mM). Lipoic acid was a much better substrate (Km = 0.12 mM), and kinetic constants obtained with lipoic acid analogues suggest that position of the negative charge relative to the dithiolane ring is critical, since increasing the length of the side chain increased the Km. None of the alicyclic disulfides or sulfides containing one or more carboxylic acid groups showed detectable substrate activity. However, the more lipophilic sulfur-containing fatty acids inhibited the enzyme which may mask their potential substrate activity.


Psychological problems of families and health workers dealing with people infected with human immunodeficiency virus 1.
The psychological problems of the families of human immunodeficiency virus 1 (HIV-1)-infected people, and of the health workers taking care of them, have been addressed in a few empirical studies and in several anecdotal reports and theoretical contributions. Apparently, HIV-1 infection and acquired immunodeficiency syndrome (AIDS) are able to elicit a wide range of emotional reactions, from rejection and refusal to provide care to immersion in the infected person's needs and burnout. Since irrational fears and attitudes play an important role in conditioning these reactions, education may not be sufficient to change behaviour. Counselling sessions and mutual support groups are often the most appropriate contexts where fears and concerns can receive an individually tailored response, and where formal and informal caregivers can be helped to manage stress.


Urokinase plasminogen activator, a strong independent prognostic factor in breast cancer, analysed in steroid receptor cytosols with a luminometric immunoassay.
Urokinase plasminogen activator (uPA) is involved in the activation of different proteases which participate in the degradation of extracellular matrix, thereby enhancing the invasive capacity of tumour cells. uPA has been shown to be of prognostic importance in breast cancer. We have analysed uPA with a new luminometric immunoassay (LIA), applicable in cytosol samples routinely used for oestrogen-receptor (ER) and progesterone-receptor (PgR) analyses. At a cut-off value of 0.62 ng uPA/mg protein, 33% (230/688) samples were classified as representing high uPA tumours. High uPA content was found to be associated with shorter recurrence-free survival (median observation time: 42 months), ER and PgR negativity, increased p53 expression, DNA non-diploidy and a high S-phase fraction (SPF), but not with lymph node involvement or tumour size (< or = 20 mm versus > 20 mm). In the subgroup of patients not treated with systemic adjuvant therapy, multivariate analysis showed uPA to be an independent prognostic factor together with lymph node status and SPF. If these results can be reproduced, uPA may be a factor suitable for inclusion in a prognostic index.


The effects of paradoxical sleep deprivation on estrous cycles of the female rats.
The present purpose was to examine how sleep deprivation affects the estrous cycle of the female rat. Paradoxical sleep-deprived (PSD) adult female Wistar rats were compared to home-cage control (CTRL) on their estrous cyclicity. Forty-four PSD and forty-four CTRL female rats were distributed into 4 subgroups of 11 animals each according to the phase of estrous cycle and were subjected to sleep deprivation for 96 h by the multiple platform technique. After PSD period, vaginal estrous cycles were taken for an additional 9 days. Animals that were submitted to PSD in diestrus phase (PSD-diestrus) had their estrous cycles disrupted during the recovery period by showing a constant diestrus during the first week. As for hormone alterations, progesterone concentrations were statistically higher in PSD-diestrus compared to respective phase control and to PSD-proestrus and PSD-estrus rats while CTRL-metestrus had higher levels than CTRL-proestrus and estrus groups. Testosterone was significantly decreased in PSD-estrus in relation to PSD-proestrus and PSD-diestrus groups and was lower in CTRL-diestrus rats than in home-cage rats in proestrus. In addition, PSD-diestrus phase exhibited higher concentrations of corticosterone and lower estrogen than the respective control rats. These data indicate that PSD may modulate the ovarian hormone release through alterations in hormonal-neurochemical mechanisms.


ARALAR/AGC1 deficiency, a neurodevelopmental disorder with severe impairment of neuronal mitochondrial respiration, does not produce a primary increase in brain lactate.
ARALAR/AGC1 (aspartate-glutamate mitochondrial carrier 1) is an important component of the NADH malate-aspartate shuttle (MAS). AGC1-deficiency is a rare disease causing global cerebral hypomyelination, developmental arrest, hypotonia, and epilepsy (OMIM ID #612949); the aralar-KO mouse recapitulates the major findings in humans. This study was aimed at understanding the impact of ARALAR-deficiency in brain lactate levels as a biomarker. We report that lactate was equally abundant in wild-type and aralar-KO mouse brain in vivo at postnatal day 17. We find that lactate production upon mitochondrial blockade depends on up-regulation of lactate formation in astrocytes rather than in neurons. However, ARALAR-deficiency decreased cell respiration in neurons, not astrocytes, which maintained unchanged respiration and lactate production. As the primary site of ARALAR-deficiency is neuronal, this explains the lack of accumulation of brain lactate in ARALAR-deficiency in humans and mice. On the other hand, we find that the cytosolic and mitochondrial components of the glycerol phosphate shuttle are present in astrocytes with similar activities. This suggests that glycerol phosphate shuttle is the main NADH shuttle in astrocytes and explains the absence of effects of ARALAR-deficiency in these cells.


Design of a microprocessor-controlled thermoregulated chamber for perfusing in vitro mammalian brain preparations.
A system is described that allows to perfuse in vitro isolated mammalian brain preparations obtained from adult guinea-pigs. It consists of a microprocessor controlled thermoregulation unit, a perfusion line and a perfusion/recording chamber. The main features of the thermoregulation unit include the ability to maintain stable temperatures between 10 and 37 degrees C and to precisely control the time course of the temperature changes. Using this system, perfused tissue blocks can be kept viable for 8-10 h.


Multilayer zirconia: Influence of positioning within blank and sintering conditions on the in vitro performance of 3-unit fixed partial dentures.
Multilayer zirconia blanks comprise material layers with different optical and mechanical properties. Whether positioning within the blank, as well as variation in the sintering procedure, will lead to restorations with different properties is unclear. The purpose of this in vitro study was to test the influence of sintering procedures and positioning in a multilayer blank on the in vitro performance of 3-unit zirconia fixed partial dentures. Human molars were embedded in acrylic resin and prepared for 3-unit fixed partial dentures. Anatomic contour prostheses were milled from zirconia blanks (ZirCAD Prime 16 mm) in 3 different positions: above (cusp-top at the top of the blank), central (center of the prosthesis in the center of the blank), and bottom (margins at the lower edge of the blank). Sintering time (2:26, 4:25, 9:50 hours:minutes) was varied for the central and bottom prostheses. All prostheses were glazed and adhesively bonded. Thermocycling and mechanical loading was performed at 2×3000×5 °C/55 °C in distilled water for 1.2×106 cycles at a 50-N load. Then, fracture force was determined with a universal testing device by using central loading, a Ø12-mm steel ball, a 1-mm tin foil, and a rate of 1 mm/min. Failure was defined as 10% force drop or acoustic signal (crack). Statistical analysis was performed with 1-way ANOVA and Bonferroni correction (α=.05). All fixed partial dentures survived thermocycling and mechanical loading. Fracture forces varied between 1002 ±446 N (above; 9:50 hours) and 1760 ±607 N (central; 9:50 hours). The 1-way ANOVA revealed no statistically significant differences (P=.059) among the groups. Individual significant differences (P=.048) were found between prostheses from positions above, 9:50 hours, and central, 9:50 hours. For normal and long sintering times, fracture forces were highest in the central position. The sintering process and positioning of restorations within a multilayer zirconia blank have little effect on the mechanical properties of the prostheses.


Health-related quality of life in patients with metastatic hormone-sensitive prostate cancer treated with androgen receptor signaling inhibitors: the role of combination treatment therapy.
While the addition of androgen receptor signaling inhibitors (ARSIs) to androgen deprivation therapy (ADT) results in better of overall survival in patients with metastatic hormone-sensitive prostate cancer (mHSPC), information regarding health related quality of life (HR-QoL) is sparse. We aimed at summarizing current evidence on the impact of ARSIs on HR-QoL. We performed a systematic review of the published literature on PubMed/EMBASE, Web of Science, SCOPUS, and the Cochrane libraries between January 2011 and April 2022. We included only phase III randomized controlled trials (RCT), which were selected according to the PRISMA guidelines. We aimed at evaluating differences in HR-QoL, assessed by validated patient reported outcomes instruments. We analyzed global scores and sub-domains such as sexual functioning, urinary symptoms, bowel symptoms, pain/fatigue, emotional and social/family wellbeing. We reported data descriptively. Six RCTs were included: two used enzalutamide with ADT as intervention arms (ARCHES, ENZAMET); one used apalutamide with ADT (TITAN); two abiraterone acetate and prednisone (AAP) with ADT (STAMPEDE, LATITUDE); and one darolutamide with ADT (ARASENS). Enzalutamide or AAP with ADT increase overall HR-QoL in comparison with ADT alone, ADT with first generation nonsteroideal anti-androgens or ADT with docetaxel, whereas apalutamide and darolutamide with ADT maintain HR-QoL similarly to ADT alone or ADT with docetaxel, respectively. Time to first deterioration of pain was longer with combination therapy with enzalutamide, AAP or darolutamide, but not with apalutamide. No worsening of emotional wellbeing was reported from the addition of ARSIs to ADT than ADT alone. The addition of ARSIs to ADT in mHSPC tends to increase overall HR-QoL and prolong time to first deterioration of pain/fatigue compared with ADT alone, ADT with first generation nonsteroideal anti-androgens, and ADT with docetaxel. ARSIs show a complex interaction with remaining HR-QoL domains. We advocate a standardization of HR-QoL measurement and reporting to allow further comparisons.


The expression of phosphorylated and non-phosphorylated forms of MAP5 in the amphibian CNS.
MAP5 is a microtubule-associated protein that in rat and quail is more abundant in the developing than in the adult brain. Previous studies in our laboratory have shown that MAP5 can be resolved into two forms by SDS-PAGE, MAP5a and MAP5b (Mr 300,000-320,000 Da) with MAP5a representing a highly phosphorylated form of this protein. In the present study, the relationship between MAP5 expression and neuronal growth and plasticity was investigated by assessing the amount and distribution of MAP5a and MAP5b in both the developing Xenopus brain and in different regions of the adult brain where neurons of varying growth potential and plasticity are present. In the larval and metamorphic Xenopus brain, like the neonatal rat brain, MAP5 is present in the highly phosphorylated form, MAP5a, and in concentrated in neuronal processes. In the adult Xenopus brain, MAP5a remains high in the optic tectum but, like the situation in the adult rat brain, is undetectable in the telencephalon. Immunohistochemistry showed that MAP5 was concentrated in the outer layer of the tectum, where ingrowing and plastic retinal ganglion cell axons are found. The correlation between MAP5 expression and phosphorylation and growth potential suggests that this molecule plays an important role in the regulation and organization of the neuronal cytoskeleton during neurite outgrowth and plasticity.


T-cell immune function in tumor, skin, and peripheral blood of advanced stage melanoma patients: implications for immunotherapy.
To predict the potential antitumor effect of antigen-specific T cells in melanoma patients, we investigated T-cell effector function in relation to tumor-escape mechanisms. CD8(+) T cells isolated from tumor, adjacent normal skin, and peripheral blood of 17 HLA-A2(+) patients with advanced-stage melanoma were analyzed for their antigen specificity and effector function against melanocyte differentiation antigens MART-1, gp100, and tyrosinase by using HLA-A2/peptide tetramers and functional assays. In addition, the presence of tumor-escape mechanisms PD-L1/PD-1 pathway, FoxP3 and loss of HLA or melanocyte differentiation antigens, both required for tumor cell recognition and killing, were studied. Higher percentages of melanocyte antigen-specific CD8(+) T cells were found in the melanoma tissues as compared with adjacent normal skin and peripheral blood. Functional analysis revealed 2 important findings: (i) in 5 of 17 patients, we found cytokine production after specific peptide stimulation by tumor-infiltrating lymphocytes (TIL), not by autologous peripheral blood lymphocytes (PBL); (ii) CD8(+) T cells from 7 of 17 patients did not produce cytokines after specific stimulation, which corresponded with significant loss of tumor HLA-A2 expression. The presence of other tumor-escape mechanisms did not correlate to T-cell function. Our data show that functional T-cell responses could be missed when only PBL and not TIL are evaluated, emphasizing the importance of TIL analysis for immunomonitoring. Furthermore, loss of tumor HLA-A2 may explain the lack of T-cell functionality. These findings have important implications for selecting melanoma patients who may benefit from immunotherapy.


Seasonality in hip fracture among haemodialysis patients and kidney transplant recipients in South Korea.
The seasonality of hip fracture in haemodialysis (HD) patients and kidney transplant recipients (KTRs) have not been reported. We assessed seasonal variations in hip fractures among patients with end-stage kidney disease who undergo maintenance HD and KTRs. Using the Korean National Health Insurance System database from January 2012 to December 2017, monthly counts of hip fracture were calculated among HD patients (n = 77 420) and KTRs (n = 8921). The 6-year normalized monthly fraction and seasonal fractions of hip fractures were calculated. A cosinor analysis was performed to determine the seasonality of the monthly incidence of hip fractures. The 6-year average monthly fraction of hip fractures was lowest in June and highest in October in HD patients, and lowest in February and highest in November in KTRs. The 6-year average seasonal fraction among HD patients was lowest in summer and highest in winter, and lowest in summer and highest in autumn among KTRs, but there was no significant difference. The incidence ratio of hip fractures was lowest in June and highest in January in HD patients, and lowest in August and highest in November in KTRs. On cosinor analysis, HD patients showed significant seasonality in hip fracture incidence, with a trough in summer and a peak in winter (p = .031), whereas KTRs did not exhibit a significant trend (p = .44). Hip fractures occurred more frequently in winter and less frequently in summer in patients undergoing HD, whereas KTRs did not show a seasonal trend.


[Assessment of the curative effective of cochlear implantation in childer with GJB2-associated NSSNHL].
To analyze the curative effect of CI in children with GJB2-associated NSSNHL. The evaluations of curative effect with CI include auditory threshold, IT-MAIS/MAIS, CAP, SIR. MESP. The outcomes of 40 cases with GJB2-associated NSSNHI, were compared 80 patients with negative results of screening of gene mutation (control group). In comparison with control group the auditory threshold in children with GJB2-associated NSSNIL is better, however had no significant difference in other tests (P > 0.05). CI could he performed on children with GJB2-associated NSSNHL. Postoperative outcomes of hearing and speech were satisfied.


Eater profile and associated factors in pediatric patients of the PEDIANUT cohort.
Appetite traits have multifactorial origins. In association with environmental and genetic factors, they could become problematic and lead to Feeding or Eating Disorders (FED). As the DSM-5 classification is not suitable for pediatric FED, another way to describe eating behavior is to distinguish the clinical profiles of "small eater" and "big eater". The aim of this study was to identify socio-demographic and medical factors associated with these profiles, and to compare problematic and non-problematic profiles. From the Pedianut study, we analyzed socio-demographic, medical and family history data among 401 children according to 4 age groups (<1 year n = 101, 1-6 years n = 99, 6-12 years n = 100, 12-18 years n = 101). The information collected on eating behavior made it possible to define small eater profile (SEP) and big eater profile (BEP) using predefined grids. BEP was more frequent in adolescents (35.6%), and SEP was more frequent in children aged 1-6 years (34.3%). BEP was associated with having separated parents, being male and the oldest sibling (p < 0.05). Problematic BEP was associated with eating while watching television, being a girl, and having sensory disorders (p < 0.05). SEP was associated, whatever age, with non-breastfeeding, chronic illness, psychological history, sensory disorders, language delays (in the 1-6 year age group), and family history of FED (in the adolescent group) (p < 0.05). This analysis of factors associated with eater profile opens new perspectives for research on risk factors associated with eating traits, which warrants further study in larger populations to delineate transition from healthy to problematic eating.


Variation in tobacco use profiles obtained from periodontal maintenance patients.
To compare methods of tobacco use profiling in patients undergoing maintenance treatment for periodontitis. The smoking status of 108 subjects attending a university-based specialist periodontics clinic was assessed by examination of referring records, patient-completed questionnaires, clinician-administered interviews and by salivary cotinine and expired-air carbon monoxide (ECO) measurement. Ten percent of the detected smokers (salivary cotinine>14.2ngml(-1)) reported to be non-smokers in the clinician-administered interview. 4.2% of the smokers detected by ECO analysis (ECO>8ppm) reported to be non-smokers in the clinician-administered interview. Systematic under reporting of tobacco use was also apparent in patient-completed questionnaires from the periodontics clinic and, to a larger degree, in the referring clinic records when compared to the clinician-administered interview. By biochemically analyzing recent cigarette smoke exposure, our data show that clinician assessment is the most accurate means by which to obtain anamnestic data concerning tobacco use. ECO analysis using portable CO monitors is inexpensive and simple with no requirement for laboratory support. The combination of ECO measurement and clinician-administered tobacco use interview represents a clinically applicable method to improve the detection of an important, periodontally susceptible population-regular smokers who deny smoking.


Accelerated long-term forgetting in neurodegenerative disorders: A systematic review of the literature.
Accelerated Long-term Forgetting (ALF) is a memory deficit characterised by normal retention up to relatively short intervals (e.g., minutes, hours) with increased forgetting over longer periods (e.g., days, weeks). ALF is often underestimated due to a lack of common memory assessments beyond 30-60 min. The purpose of this review was to provide an overview of ALF occurrence in neurodegenerative disorders, evaluating whether it can be considered a cognitive deficit useful for diagnosing and monitoring patients. We included 19 experimental studies that investigated ALF in neurodegenerative disorders. Most papers were focused on Alzheimer's disease (AD) dementia and related forms of cognitive decline (Mild Cognitive Impairment, Subjective Cognitive decline, Pre-symptomatic subjects at risk of AD dementia). The major finding of the present work concerns the presence of ALF in very early forms of cognitive decline related to AD. These findings, supporting the hypothesis that ALF is a subtle and undetected hallmark of pre-clinical AD, highlights the importance of investigating forgetting over a longer period and devising standardised measures to be included in clinical practice.


Transforming Growth Factor-β Activated Kinase 1 (Tak1) Is Activated in Hepatocellular Carcinoma, Mediates Tumor Progression, and Predicts Unfavorable Outcome.
Although knowledge on inflammatory signaling pathways driving cancer initiation and progression has been increasing, molecular mechanisms in hepatocarcinogenesis are still far from being completely understood. Hepatocyte-specific deletion of the MAPKKK Tak1 in mice recapitulates important steps of hepatocellular carcinoma (HCC) development, including the occurrence of cell death, steatohepatitis, dysplastic nodules, and HCCs. However, overactivation of Tak1 in mice upon deletion of its deubiquitinase Cyld also results in steatohepatitis and HCC development. To investigate Tak1 and Cyld in human HCCs, we created a tissue microarray to analyze their expression by immunohistochemistry in a large and well-characterized cohort of 871 HCCs of 561 patients. In the human liver and HCC, Tak1 is predominantly present as its isoform Tak1A and predominantly localizes to cell nuclei. Tak1 is upregulated in diethylnitrosamine-induced mouse HCCs as well as in human HCCs independent of etiology and is further induced in distant metastases. A high nuclear Tak1 expression is associated with short survival and vascular invasion. When we overexpressed Tak1A in Huh7 cells, we observed increased tumor cell migration, whereas overexpression of full-length Tak1 had no significant effect. A combined score of low Cyld and high Tak1 expression was an independent prognostic marker in a multivariate Cox regression model.


The exponentiation formula of reliability and survival: does it always hold?
In reliability and biometry, it is common practice to choose a failure model by first assessing the failure rate function subjectively, and then invoking the well known "exponentiation formula". The derivation of this formula is based on the assumption that the underlying failure distribution be absolutely continuous. Thus, implicit in the above approach is the understanding that the selected failure distribution will be absolutely continuous. The purpose of this note is to point out that the absolute continuity may fail when the failure rate is assessed conditionally, and in particular when it is conditioned on certain types of covariates, called "internal covariates". When such is the case, the exponentiation formula should not be used.


[On the vocational prognoses of patients with peroneal muscular atrophy (author's transl)].
Examined were 43 patients and 27 relatives all suffering from a hypertrophic type of peroneal muscular atrophy. Owing to foot deformities and a slowing of the nerve conduction velocity a diagnosis was already possible in their childhoods in the majority of cases. Although, after the 20th year of age, the pareses of the legs progress only slowly, considerable pareses of the small hand muscles can still develop in adults. With adequate counselling, rehabilitation measures should become necessary only in rare cases, or, if a kypho-scoliosis has already developed in childhood (10% of our cases).


Activation of dendritic cells via TLR7 reduces Foxp3 expression and suppressive function in induced Tregs.
Exogenous and endogenous RNA ligands of Toll-like receptor (TLR) 7 which are present during viral infection or autoimmune diseases such as systemic lupus erythematosus (SLE) directly activate DCs and B cells and thus support the generation of effector T and B lymphocytes. However, the generation of effective antiviral or autoreactive adaptive immune responses requires blocking of immunosuppression by Tregs. In this study, we show that TLR7 ligands reduce the number of Tregs generated de novo from naïve murine T cells in vitro and in vivo. In the presence of TLR7-activated splenic DCs, Foxp3 was transiently induced in naïve T cells by TGF-β but was downregulated at later time points. Neutralization experiments revealed that loss of Foxp3 after initial induction was mostly dependent on IL-6 produced in the DC-T-cell cocultures containing TLR7 ligands. Thus, under the influence of TLR7 ligands fewer Tregs were generated and these expressed lower levels of Foxp3 correlating with a reduced capacity to suppress responder T-cell proliferation. Thus, we provide evidence that TLR7 ligands affect Treg-dependent immune regulation and may thereby contribute to the development of autoimmune diseases such as systemic lupus erythematosus.


Dysfunctional auditory gamma oscillations in developmental dyslexia: A potential target for a tACS-based intervention.
Interventions in developmental dyslexia typically consist of orthography-based reading and writing trainings. However, their efficacy is limited and, consequently, the symptoms persist into adulthood. Critical for this lack of efficacy is the still ongoing debate about the core deficit in dyslexia and its underlying neurobiological causes. There is ample evidence on phonological as well as auditory temporal processing deficits in dyslexia and, on the other hand, cortical gamma oscillations in the auditory cortex as functionally relevant for the extraction of linguistically meaningful information units from the acoustic signal. The present work aims to shed more light on the link between auditory gamma oscillations, phonological awareness, and literacy skills in dyslexia. By mean of EEG, individual gamma frequencies were assessed in a group of children and adolescents diagnosed with dyslexia as well as in an age-matched control group with typical literacy skills. Furthermore, phonological awareness was assessed in both groups, while in dyslexic participants also reading and writing performance was measured. We found significantly lower gamma peak frequencies as well as lower phonological awareness scores in dyslexic participants compared to age-matched controls. Additionally, results showed a positive correlation between the individual gamma frequency and phonological awareness. Our data suggest a hierarchical structure of neural gamma oscillations, phonological awareness, and literacy skills. Thereby, the results emphasize altered gamma oscillation not only as a core deficit in dyslexia but also as a potential target for future causal interventions. We discuss these findings considering non-invasive brain stimulation techniques and suggest transcranial alternating current stimulation as a promising approach to normalize dysfunctional oscillations in dyslexia.


Safety and immunological proof-of-concept following treatment with tolerance-inducing cell products in patients with autoimmune diseases or receiving organ transplantation: A systematic review and meta-analysis of clinical trials.
In the past years, translational approaches have led to early-stage clinical trials assessing safety and efficacy of tolerance-inducing cell-based treatments in patients. This review aims to determine if tolerance-inducing cell-based therapies, including dendritic cells, regulatory T cells and mesenchymal stem cells, are safe in adult patients who underwent organ transplantation or in those with autoimmune diseases, including multiple sclerosis, diabetes mellitus type 1, Crohn's disease and rheumatoid arthritis. Immunological and clinical outcomes were reviewed, to provide evidence for proof-of-concept and efficacy. To summarize the current knowledge, a systematic review and meta-analysis were conducted. A total of 8906 records were reviewed by 2 independent assessors and 48 records were included in the final quantitative analysis. The overall frequency of serious adverse events was low: 0.018 (95% CI: 0.006-0.051). Immunological outcomes could not be assessed quantitatively because of heterogeneity in outcome assessments and description as well as lack of individual data. Most randomized controlled studies were at a medium risk of bias due to open-label treatment without masking of assessors and/or patients to the intervention. In conclusion, tolerance-inducing cell-based therapies are safe. We advocate for harmonization of study protocols of trials investigating cell-based therapies, adverse event reporting and systematic inclusion of immunological outcome measures in clinical trials evaluating tolerance-inducingcell-basedtreatment. Registration: PROSPERO, registration number CRD42020170557.


Ferulic acid-induced anti-depression and prokinetics similar to Chaihu-Shugan-San via polypharmacology.
Selective serotonin reuptake inhibitors (SSRIs), one of popular antidepressants as "one-compound-one-target" paradigm, cannot but discontinue because of inhibiting gut movement. Traditional Chinese medicine (TCM) Chaihu-Sugan-San (CSS) can simultaneously exert anti-depression and prokinetics. From this thread, we aimed to find a new antidepressant with polypharmacological mechanisms. In vivo antidepressive and prokinetic comparisons between CSS and its absorbed compound ferulic acid (FA) were made. And FA's action mechanisms involved in monoaminergic systems, HPA axis and gastrointestinal peptide ghrelin was then studied in forced swimming test (FST) of rat. Lastly, the jejunal contraction activity evoked by FA was measured in vitro. Compared with vehicle, FA reduced immobility time, increased locomotor activity, accelerated gastric emptying and intestinal transit similar to CSS whose absorbable component FA was identified in hippocampus and jejunum. FA's prokinetics in vivo was further supported by its jejunal contraction in vitro. FA-induced anti-immobility was prevented by pretreated with PCPA, WAY-100635, ketanserin, sulpiride, SCH233390, haloperidol and yohimbine, respectively. CRH, ACTH and 5-HT were significantly decreased, but ghrelin was apparently increased compared with vehicle. In summary, FA induced anti-depression and prokinetics similar to CSS via inhibiting serotonin, norepinephrine and dopamine reuptakes, regulating HPA axis, increasing ghrelin and stimulating jejunal contraction simultaneously.


Comparison of Operative and Fertility Outcome Between Groups of Women with Intrauterine Adhesions after Adhesiolysis
We evaluated intraoperative difficulty and fertility outcome in women with intrauterine synechiae of different severity after hysteroscopic adhesiolysis. The 86 women were recruited before fertility treatment, during hysterosalpingogram (HSG) or diagnostic hysteroscopy, over 3 years. Fifty-eight women had a history of pregnancy terminations or miscarriages, and 28 had undergone myomectomy or correction of congenital uterine anomalies by conventional surgical procedures. Group A (11 women) had over 50% of the fundal cavity obliterated by fibrous tissue, and no tubal ostia could be seen; group B (26 women) had less than 50% of the fundal cavity obliterated by fibrous tissue, and one tubal ostium could be seen; group C (49 women) had a single adhesion thicker than 1 cm. Postoperative hemorrhage requiring treatment occurred in three women from group A and two from group B. All had subsequent HSGs, and three from group A (with previous myomectomies) required a second operation and still failed to achieve an adequate fundal cavity. All patients subsequently received in vitro fertilization. Three women from group A became pregnant. Ten in group B became pregnant, eight of whom delivered or have a continuing pregnancy. In group C, 17 became pregnant, of whom 13 delivered or have a continuing pregnancy. Adhesions after suturing the uterine cavity after open myomectomy or corrective surgery seem to cause maximum damage and yield poor results in both hysteroscopic correction and reproductive performance.


Correlation between human development index and its components with COVID-19 indices: a global level ecologic study.
Given that COVID-19 continues to spread worldwide, attempts to restrain the virus and to prevent the effects that critically ill patients with COVID-19 have on healthcare systems, has become a public health priority. This ecological study aimed to investigate the correlation between the Human Development Index (HDI) and the epidemiological indicators of COVID-19, including the cumulative incidence rate of cases, the cumulative incidence rate of death, performed COVID-19 tests per million, recovery rate, and case fatality rate. In this ecological study, a data set was provided, which included the epidemiologic indices of COVID-19, HDI, and its components for each country. Correlation coefficients were used to determine linear correlation. Also, the scatter plots of the HDI for the studied countries based on the epidemiologic indices of COVID-19 were drawn. This study showed that HDI and its components had positive correlation with a cumulative incidence rate of cases, the cumulative incidence rate of death, and performed COVID-19 tests (p < 0.001). HDI and two of its components, including literacy and Gross National Income (GNI) components had negative correlation with case fatality rate (CFR). Also, HDI and two of its components, including literacy and life expectancy components had negative correlation with recovery rate. Our study showed that the HDI and its components can affect the epidemiological status of COVID-19. As HDI increased, the cumulative incidence rate of cases, cumulative incidence rate of death, and COVID-19 tests increased as well. As HDI increased, CFR and recovery rate decreased as well. Although the HDI is higher in high-income countries, these countries may have also better reporting and surveillance systems.


Polymer Membranes for Gas Separation.
Over the past decade, polymeric membranes have been widely investigated for a variety of industrial gas separation applications [...].


Renal failure: emergency evaluation and management.
Patients with altered renal function are frequently encountered in the emergency department (ED) and emergency physicians often play an important role in the evaluation and management of renal disease. Early recognition, diagnosis, prevention of further iatrogenic injury, and management of renal disease have important implications for long-term morbidity and mortality. This article reviews basic renal physiology, discusses the differential diagnosis and approach to therapy, as well as strategies to prevent further renal injury, for adult patients who present to the ED with renal injury or failure.


Oscillation of ADP-ribosyl cyclase activity during the cell cycle and function of cyclic ADP-ribose in a unicellular organism, Euglena gracilis.
In Euglena gracilis, the activity of ADP-ribosyl cyclase, which produces cyclic ADP-ribose, oscillated during the cell cycle in a synchronous culture induced by a light-dark cycle, and a marked increase in the activity was observed in the G2 phase. Similarly, the ADP-ribosyl cyclase activity rose extremely immediately before cell division started, when synchronous cell division was induced by adding cobalamin (which is an essential growth factor and participates in DNA synthesis in this organism) to its deficient culture. Further, cADPR in these cells showed a maximum level immediately before cell division started. A dose-dependent Ca2+ release was observed when microsomes were incubated with cADPR.


Kinetic study of proton-transfer reactions of phenylnitromethanes. Implication for the origin of nitroalkane anomaly.
Measurements of rate constants and substituent effects for three important elementary steps of proton-transfer reactions of phenylnitromethane were reported. The Hammett ρ values for the deprotonation of ArCH(2)NO(2) with OH(-), protonation of ArCH═NO(2)(-) with H(2)O, and protonation of ArCH═NO(2)(-) with HCl were determined in aqueous MeOH at 25 °C. Comparison of these experimentally observed ρ values with those calculated at B3LYP/6-31G* revealed that aci-nitro species (ArCH═NO(2)H), which is formed on the O-protonation of ArCH═NO(2)(-), does not lie on the main route of the proton-transfer reaction. Analysis of the Brønsted plot implies that the proton-transfer reaction of most XC(6)H(4)CH(2)NO(2) exhibits nitroalkane anomaly, but not for p-NO(2)C(6)H(4)CH(2)NO(2), and that the transition state charge imbalance is an origin of anomaly.


Estimating antibiotics use in major cities in China through wastewater-based epidemiology.
Antibiotics have been widely used for disease treatment and may pose adverse effects on human health due to increasing presence of antibiotic-resistant genes in environment. Therefore, it is important to understand antibiotic use in a specific region or country. China is a major producer of antibiotic and has a large number of consumers. In this work, wastewater samples were collected from 76 wastewater treatment plants in 31 major cities covering all of the geographic regions of China. Concentrations of eight metabolites of sulfonamide, quinolone and macrolide antibiotics were determined. The consumption levels of corresponding antibiotics were estimated based on wastewater-based epidemiology (WBE) approach. Desmethyl ofloxacin, desethylene norfloxacin, desmethyl azithromycin and N4-acetyl sulfamethoxazole were detected in all or the overwhelming majority of wastewater samples. The estimated ∑8Antibiotics consumption levels ranged from 275.1 ± 139.4 mg/1000 inh/d (Nanchang) to 3860.9 ± 1332.3 mg/1000 inh/d (Harbin) with a mean level of 1170.0 ± 452.1 mg/1000 inh/d. Quinolones accounted for the highest proportion (74.3%, national average contribution) in the total consumption level, with norfloxacin being the dominant one (38.4%), followed by ofloxacin (29.1%) and ciprofloxacin (6.8%). The ∑8Antibiotics consumption level in northern China (1517.0 ± 1022.8 mg/1000 inh/d) was statistically higher than the level in southern China (1060.7 ± 989.1 mg/1000 inh/d) (t-test, p < 0.05). In contrast, no significant difference was found between eastern (1256.2 ± 1105.1 mg/1000 inh/d) and western China (988.3 ± 474.5 mg/1000 inh/d) (t-test, p > 0.05). The overview of antibiotics consumption derived from this work can serve as a baseline to assess the implementation of related plans/policies in China.


Influence of menopause on blood cholesterol levels in women: the role of body composition, fat distribution and hormonal milieu. Virgilio Menopause Health Group.
In this study we investigated the relationships between blood lipids and menopausal status. All data were obtained from the first cross-sectional examination of the Virgilio Menopause Health Project in a large cohort of middle-aged women in pre, peri-, and postmenopausal age. The data refer to 426 women without metabolic or endocrine diseases, relevant hepatic, renal and cardiovascular abnormalities, none were dieting or taking medications. A precoded questionnaire including full clinical history, socio-economic and personal information, habitual diet, physical activity, drug use and smoking habits, careful recording of gynaecological events and family history for disease was completed. Several anthropometric parameters and the bioelectrical impedance analysis was used to measure free fatty mass. Blood samples for hormones and biochemistry were also obtained. There were no significant differences on body mass index, fatty mass, free fatty mass and parameters of body fat distribution between the three groups. Again, there were no differences in smoking habits, dietary intake or indices of physical activity amongst the groups. There was a significant increase from pre to postmenopause of LH and FSH and a decrease of oestradiol and testosterone, whereas no difference was found in sex hormone-binding globulin. Age-adjusted values of glucose, triglycerides and high density lipoprotein (HDL-) cholesterol were similar in all groups, whereas postmenopausal women had significantly higher values of total and low density lipoprotein (LDL-) cholesterol. On the contrary, there was a significant fall in insulin levels passing from pre to postmenopause. In multiple regression models, total and LDL-cholesterol correlated positively with body mass index, waist-to-hip ratio and age, and negatively with free fatty mass and oestradiol blood levels. These results are consistent with the hypothesis that menopausal status may have a significant and independent effect in determining increased total and LDL-cholesterol concentrations in postmenopausal women.


Occupational eye dose to medical staff in various interventional cardiologic procedures: is the need for lead goggles the same in all groups of radiation workers?
Considering the increased use of interventional cardiologic procedures and concern about irradiation to the eyes, it is necessary to measure eye dose in radiation workers. The assessment of eye dose using collar dose is a routine but inaccurate method. Therefore this study was designed to measure eye dose in the radiation workers of various interventional cardiologic procedures. In this study eye dose was measured for left and right eyes in three groups of radiation workers in angiography ward of Afshar hospital in various procedures using TLD. Measurements were done separately for cardiologists, nurses and radio-technologists in 100 procedures. The nurses functioned as surgical assistants and were usually close to the table. The correlation of staff dose to exposure parameters was also investigated. Eye dose in physicians were higher than other staff in all procedures. Also the left eye dose was considerably higher than right one, especially for physicians. The median equivalent dose per procedure of left eye for physicians, nurses and radio-technologists were 7.4, 3.6, 1.4 µSv (PCI) and 3.2, 3.1, 1.3 µSv (Adhoc) and 3.2, 1.7, 1.1 µSv (CA), respectively. The annual left eye equivalent dose with (without) using lead goggles were 2.4 (15.3), 1.4 (2.2), 1.0 (1.1) mSv for physicians, nurses and radio-technologists, respectively. There were also a positive correlation between eye dose and KAP for procedures without lead goggles. The lead goggles showed lower protection effects for radio-technologists than other staff. Only 30% of physicians received a dose higher than 1/3 of the ICRP annual dose limit, therefor only physician eye dose should be monitored in catheterization labs.


The World's First Clam Shrimp Symposium: Drawing Paleontology and Biology Together.
After a symposium and special issue devoted to the study of clam shrimp, it is tempting to ask what is next... where is the study of clam shrimp going? Rather than try to read the tea leaves to predict the future, we will instead offer some closing thoughts on where the study of clam shrimp should go and what areas are ripe for investigation. Many of these ideas integrate both fossil and modern clam shrimp to get at a more complete view of their evolution and ecology.


PET imaging reveals early and progressive dopaminergic deficits after intra-striatal injection of preformed alpha-synuclein fibrils in rats.
Alpha-synuclein (a-syn) can aggregate and form toxic oligomers and insoluble fibrils which are the main component of Lewy bodies. Intra-neuronal Lewy bodies are a major pathological characteristic of Parkinson's disease (PD). These fibrillar structures can act as seeds and accelerate the aggregation of monomeric a-syn. Indeed, recent studies show that injection of preformed a-syn fibrils (PFF) into the rodent brain can induce aggregation of the endogenous monomeric a-syn resulting in neuronal dysfunction and eventual cell death. We injected 8 μg of murine a-syn PFF, or soluble monomeric a-syn into the right striatum of rats. The animals were monitored behaviourally using the cylinder test, which measures paw asymmetry, and the corridor task that measures lateralized sensorimotor response to sugar treats. In vivo PET imaging was performed after 6, 13 and 22 weeks using [11C]DTBZ, a marker of the vesicular monoamine 2 transporter (VMAT2), and after 15 and 22 weeks using [11C]UCB-J, a marker of synaptic SV2A protein in nerve terminals. Histology was performed at the three time points using antibodies against dopaminergic markers, aggregated a-syn, and MHCII to evaluate the immune response. While the a-syn PFF injection caused only mild behavioural changes, [11C]DTBZ PET showed a significant and progressive decrease of VMAT2 binding in the ipsilateral striatum. This was accompanied by a small progressive decrease in [11C]UCB-J binding in the same area. In addition, our histological analysis revealed a gradual spread of misfolded a-syn pathology in areas anatomically connected to striatum that became bilateral with time. The striatal a-syn PFF injection resulted in a progressive unilateral degeneration of dopamine terminals, and an early and sustained presence of MHCII positive ramified microglia in the ipsilateral striatum and substantia nigra. Our study shows that striatal injections of a-syn fibrils induce progressive pathological synaptic dysfunction prior to cell death that can be detected in vivo with PET. We confirm that intrastriatal injection of a-syn PFFs provides a model of progressive a-syn pathology with loss of dopaminergic and synaptic function accompanied by neuroinflammation, as found in human PD.


The pituitary-gonadal axis in spinal cord injury.
Our study documented that serum levels of luteinizing hormone, follicle-stimulating hormone, testosterone, and estradiol in 14 of 15 males with spinal cord injury (SCI) were within the normal range of those of age-matched controls. One patient had gynecomastia with compensated gonadal insufficiency of undetermined etiology. Five males with SCI showed a normal rise in serum testosterone levels following stimulation with human chorionic gonadotropin. Testicular biopsy in one of two males with SCI showed spermatogenic arrest. One of the biopsies showed immunoglobulin G immunofluorescence around the seminiferous tubule; the other demonstrated immunoglobulin A immunofluorescence in the spermatogonia. These findings suggest that, if a high incidence of impaired spermatogenesis does occur in spinal cord-injured patients, it is unlikely to be secondary to hormonal imbalance.


Surface localized magnetism in transition metal doped alumina.
Alumina is a structural ceramic that finds many uses in a broad range of applications. It is widely employed in the aerospace and biomedical sectors due to its stability at high temperatures and in harsh chemical environments. Here, we show that magnetism can be induced at alumina surfaces by doping with 3d transition metals. We analyze the electronic structure, spin magnetic moments, and spin density of [Formula: see text]-Al[Formula: see text]O[Formula: see text] as a function of both dopant species (Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu) and depth using first principles calculations. Our results show that all dopants, with the exception of Sc, produce magnetic moments that are concentrated to the surface of alumina with varying degrees of delocalization. It is seen that all of the dopants are at least meta-stable on the surface and must overcome an energy barrier of 0.19-1.14 eV in order to diffuse from the surface into the bulk. As a result of judiciously doping with select 3d transition metals the surface of alumina can be made magnetic. This could lead to novel applications in data storage, catalysis, and biomedical engineering through an added surface functionality.


Multiple facets of Arabidopsis seedling development require indole-3-butyric acid-derived auxin.
Levels of auxin, which regulates both cell division and cell elongation in plant development, are controlled by synthesis, inactivation, transport, and the use of storage forms. However, the specific contributions of various inputs to the active auxin pool are not well understood. One auxin precursor is indole-3-butyric acid (IBA), which undergoes peroxisomal β-oxidation to release free indole-3-acetic acid (IAA). We identified ENOYL-COA HYDRATASE2 (ECH2) as an enzyme required for IBA response. Combining the ech2 mutant with previously identified iba response mutants resulted in enhanced IBA resistance, diverse auxin-related developmental defects, decreased auxin-responsive reporter activity in both untreated and auxin-treated seedlings, and decreased free IAA levels. The decreased auxin levels and responsiveness, along with the associated developmental defects, uncover previously unappreciated roles for IBA-derived IAA during seedling development, establish IBA as an important auxin precursor, and suggest that IBA-to-IAA conversion contributes to the positive feedback that maintains root auxin levels.