Galcanezumab in patients with episodic migraine: results from the open-label period of the phase 3 PERSIST study.
The phase 3 randomized PERSIST study demonstrated the efficacy and tolerability of galcanezumab, a humanized anti-calcitonin gene-related peptide (CGRP) monoclonal antibody for prevention of episodic migraines. We present findings from the open-label extension (OLE) of PERSIST, which evaluated the long-term efficacy and safety of galcanezumab in patients from China, India, and Russia. Patients completing the 3-month double-blind period of PERSIST were eligible for the 3-month OLE. Patients previously randomized to galcanezumab (GMB/GMB group) continued to receive galcanezumab 120 mg at all three visits during the OLE whereas patients randomized to placebo received a 240 mg loading dose of galcanezumab and then two 120 mg doses (PBO/GMB group). The primary outcome was the mean change (from double-blind baseline) in the number of monthly migraine headache days (MHDs) to month 6. Other endpoints included percent reduction in monthly MHDs from double-blind baseline to month 6, functional outcomes, safety and tolerability. Overall, 99% of patients completing the double-blind period entered the OLE, and 96% completed through month 6. Patients in the GMB/GMB group achieved continued improvements in efficacy, with the reduction from baseline in the mean number of monthly MHDs, and slightly increasing from 4.01 days at the end of the double-blind period to 4.62 at the end of the OLE. Of patients who were ≥ 50% responders to galcanezumab at month 3, 66% maintained this response through to month 6. Patients in the PBO/GMB group experienced a rapid reduction in the number of monthly MHDs after initiation of galcanezumab, with a mean reduction from baseline of 4.56 days by month 6. The long-term benefits of galcanezumab were also supported by improvements in other efficacy and functional endpoints. All safety findings were consistent with the known long-term safety profile of galcanezumab; no patients experienced a treatment-related serious adverse event. Galcanezumab was efficacious and well-tolerated in patients with episodic migraine from China, India and Russia, for up to 6 months. ClinicalTrisABSTRACT_pals.gov NCT03963232, registered May 24, 2019.


Tumor markers carbohydrate antigens CA 19-9 and CA-50 and carcinoembryonic antigen in pancreatic cancer and benign diseases of the pancreatobiliary tract.
Sera from patients with diseases in the pancreas, gallbladder, and bile duct were analyzed for the tumor markers CA 19-9, CA-50, and carcinoembryonic antigen. In particular CA 19-9 and CA-50 appear to be valuable in differentiating malignant from benign disease in these organs. Our sample of 72 patients with pancreatic cancer also indicates that CA 19-9 and CA-50 complement each other in 21% of the cases. They are also shown to be reliable for monitoring disease: following radical surgery for pancreatic cancer low levels of CA 19-9 and CA-50 were noted, while progressive rises of these tumor markers were related to disease progression.


Deciphering the molecular genetic basis of NPC through molecular, cytogenetic, and epigenetic approaches.
Nasopharyngeal carcinoma (NPC) is consistently associated with EBV infection and prevalence in southern China and Southeast Asia. In addition to EBV, the development of NPC involves cumulative genetic and epigenetic changes influenced by predisposing genetic factors and environmental carcinogens. Over the past two decades, knowledge of genetic and epigenetic alterations of NPC has rapidly accumulated. Multiple chromosomal abnormalities (e.g. copy number changes on chromosomes 3p, 9p, 11q, 12p, and 14q), gene alterations (e.g. p16 deletion and LTBR amplification), and epigenetic changes (e.g. RASSF1A and TSLC1 methylation) have been identified by various genome-wide approaches, such as allelotyping, CGH, and microarray analysis. In this review, we will discuss the critical genetic events that contribute to the initiation and progression of NPC. Studies on the precancerous lesions and in vitro immortalized nasopharyngeal epithelial cell models provide important evidence for the involvement of genetic alterations and EBV infection in early development of this cancer. A hypothetical model describing the role of EBV latent infection and multiple genetic changes in NPC tumorigenesis is proposed.


Incisional adenocarcinoma after intracranial metastasis resection.
Skin and subcutaneous secondary tumors are unusual, especially in cases of colonic adenocarcinoma. They usually signify disseminated metastases. A rare case of an isolated incisional tumor after resection of a metastasis to the cerebellum is presented. The pathophysiology and management of such an event is discussed. The clinical setting suggests that this occurrence represented the result of microscopic deposits of neoplastic cells in the wound rather than hematogenous spread.


Validation of the Portuguese Version of the Voice Handicap Index-10.
The aim of this study is to validate the Voice Handicap Index 10, to be implemented on the Portuguese population. Fourty-five subjects were included on the study with vocal complaints and 45 subjects with no vocal complaints, followed on Otorhinolaryngology external appointment at Centro Hospitalar Universitário of Porto. The Voice Handicap Index 30 (VHI-30) and The Voice Handicap Index 10 (VHI-10) questionnaires were applied to the subjects by phone call. Posteriorly, VHI-10 was again applied in the next two to seven days after the first call. These procedures helped validating VHI-10 according to its reproducibility, internal consistency and correlation between questionnaires. In the group with vocal complaints, we verified a significant statistical correlation and a strong linear correlation between VHI-30 and VHI-10 (r = 0.915; P< 0.001). The group without vocal complaints has shown a significant statistical correlation and a moderate linear correlation between VHI-30 and VHI-10 (r = 0.647; P< 0.001). Regarding VHI-10, It was detected a significant statistical difference between patients with and without vocal complaints. VHI-10 in Portuguese of Portugal was applied to a sample that included, not only subjects with different ages, but also subjects with and without vocal complaints. Among patients with vocal complaints, it was included subjects with different diagnosis (organic and functional pathology). Thus, the sample was representative, and VHI-10 was reliable and reproducible. VHI-10 is a valid representation of VHI-30 that helps evaluate the impact of vocal complaints on life quality, with proven psychometric properties to be implemented on the Portuguese population.


Revolutionary Potential of ChatGPT in Constructing Intelligent Clinical Decision Support Systems.
Recently, Chatbot Generative Pre-trained Transformer (ChatGPT) is recognized as a promising clinical decision support system (CDSS) in the medical field owing to its advanced text analysis capabilities and interactive design. However, ChatGPT primarily focuses on learning text semantics rather than learning complex data structures and conducting real-time data analysis, which typically necessitate the development of intelligent CDSS employing specialized machine learning algorithms. Although ChatGPT cannot directly execute specific algorithms, it aids in algorithm design for intelligent CDSS at the textual level. In this study, besides discussing the types of CDSS and their relationship with ChatGPT, we mainly investigate the benefits and drawbacks of employing ChatGPT as an auxiliary design tool for intelligent CDSS. Our findings indicate that by collaborating with human expertise, ChatGPT has the potential to revolutionize the development of robust and effective intelligent CDSS.


Association of body weight and physical activity with blood pressure in a rural population in the Dikgale village of Limpopo Province in South Africa.
Africa is faced with an increasing burden of hypertension attributed mainly to physical inactivity and obesity. Paucity of population based evidence in the African continent hinders the implementation effective preventive and control strategies. The aim of this study was to determine the association of body weight and physical activity with blood pressure in a rural black population in the Limpopo Province of South Africa. A convenient sample of 532 subjects (396 women and 136 men) between the ages 20-95 years participated in the study. Standard anthropometric measurements, blood pressure, and physical activity were recorded by trained field workers. Anthropometric measurements showed that a high percentage of women were significantly (p < 0.001) overweight and obese than men. Hypertension was significantly high among women (38.1%) compared to men (27.9%). In the univariate analysis mean body mass index (BMI), waist circumference (WC), hip circumference (HC) and waist hip ratio (WHR) showed a significant positive association (p ≤ 0.05) with systolic and diastolic BP in women, and only WHR was statistically significant in men. The odds of being hypertensive also increased with BMI, WC and WHR in both women and men, including HC in women. No relationship was found between physical activity and high blood pressure. In the multivariate analysis only increase in HC and WHR was consistently associated with increase in SBP in women and WHR with hypertension in men. The study findings indicate that women in this black South African rural population are overweight and obese than men and are at higher risk of hypertension as determined by selected anthropometric parameters.


Molecular sensitization patterns of common food-and respiratory allergens in the Hungarian population.
Recently developed Immunoglobulin-E (IgE) based molecular allergy diagnostics provide the ability of identifying allergenic components or ingredients at the molecular level (component-resolved-diagnosis, CRD). Compared to the classical IgE-based allergy diagnostics, molecular technology is providing more sensitive and specific IgE-sensitization patterns. Certain sensitization patterns are characteristic of large geographic regions. There are only few data available on the molecular IgE sensitization patterns in East-Central Europe. This study aims to present further data from this region. Data of 3993 stored, anonymized molecular ImmunoCap IgE measurements (CRD), performed in Hungary between January-December 2019 from sera of 1288 subjects (mean age: 27 years ±18 years, male/female ratio 0.56) were analyzed retrospectively, in order to get a local distributional pattern of the sensitizing (IgE >0.35 KU/l) molecular allergens. The proportion of CRD positive cases was 24.3%. Amongst them, the most prevalent inhalative allergens were Amb a 1 (18%) Art v 1 (8%) in adults and Der p 2 (3%) and Der p 1 (3%) and Amb a 1 (4%) in subjects below 18 years of age. The same for food allergens were Gal d 2 (21%), Bos d 4 (17%), Bos d 5 (11%) in adults and Gal d 2 (38%), Gal d 1 (28%), Bos d 4 (21%), Bos d 5 (13%) and Bos d 8 (7%) in children. The ratio of mono-sensitivities among CRD-positive cases was 37.5%. Our results provide region-specific patterns of sensitization and molecular allergen spreading for Hungary. The relatively higher abundance of polysensitization's among allergic cases underlines the need for early diagnostic -and preventive measures in the future.


Advances of neuroimaging in chemotherapy related cognitive impairment (CRCI) of patients with breast cancer.
Chemotherapy related cognitive impairment (CRCI) has seriously affected the quality of life (QOL) of patients with breast cancer (BCs), thus the neurobiological mechanism of CRCI attracted widespread attention. Previous studies have found that chemotherapy causes CRCI through affecting brain structure, function, metabolism, and blood perfusion. A variety of neuroimaging techniques such as functional magnetic resonance imaging (fMRI), event-related potential (ERP), near-infrared spectroscopy (NIRS) have been widely applied to explore the neurobiological mechanism of CRCI. This review summarized the progress of neuroimaging research in BCs with CRCI, which provides a theoretical basis for further exploration of CRCI mechanism, disease diagnosis and symptom intervention in the future. Multiple neuroimaging techniques for CRCI research.


Detrimental actions of obesity-associated advanced glycation end-products on endometrial epithelial cell proliferation are alleviated by antioxidants.
Advanced glycation end-products (AGE) are elevated in the uterine environment of obese infertile women. Can the detrimental effects of AGE on endometrial epithelial cells be mitigated with therapeutics, and recapitulated in a more physiologically relevant primary model (organoids)? Human endometrial epithelial cells (ECC-1) were exposed to AGE at concentrations physiologically representative of uterine fluid in lean or obese individuals, and three potential therapeutics: 25 nmol/l receptor for AGE (RAGE) antagonist FPS-ZM1, 100 μmol/l metformin, or a combination of antioxidants (10 μmol/l N-acetyl-l-cysteine, 10 μmol/l N-acetyl-l-carnitine and 5 μmol/l α-lipoic acid). Real-time cell analysis (xCELLigence, ACEA Biosciences) determined the rate of adhesion and proliferation. The proliferation of organoid-derived cells and secretion of cytokines from organoids was characterized in the presence of AGE (n = 5). The uterine fluid of women undergoing assisted reproduction was profiled for AGE-associated inflammatory markers (n = 77). ECC-1 proliferation was reduced by AGE from obese versus lean conditions and vehicle control (P = 0.04 and P < 0.001, respectively), and restored to a proliferation corresponding to lean conditions by antioxidants. AGE influenced organoid derived primary endometrial epithelial cell proliferation in a donor-dependent manner. AGE increased the organoid secretion of the proinflammatory cytokine CXCL16 (P = 0.006). Clinically, CXCL16 correlated positively to maternal body mass index (R = 0.264, P = 0.021) and intrauterine glucose concentration (R = 0.736, P < 0.0001). Physiologically relevant concentrations of AGE alter endometrial epithelial cell function. Antioxidants restore the rate of proliferation of AGE-treated endometrial epithelial (ECC-1) cells. Primary endometrial epithelial cells, cultured as organoids, demonstrate altered proliferation and CXCL16 secretion in the presence of AGE equimolar with the uterine fluid from obese individuals.


Identification of key biomarkers associated with development and prognosis in patients with ovarian carcinoma: evidence from bioinformatic analysis.
Ovarian cancer (OC) is the deadliest cause in the gynecological malignancies. Most OC patients are diagnosed in advanced stages with less than 40% of women cured. However, the possible mechanism underlying tumorigenesis and candidate biomarkers remain to be further elucidated. Gene expression profiles of GSE18520, GSE54388, and GSE27651 were available from Gene Expression Omnibus (GEO) database with a total of 91 OC samples and 22 normal ovarian (OV) tissues. Three hundred forty-nine differentially expressed genes (DEGs) were screened between OC tissues and OV tissues via GEO2R and online Venn software, followed by KEGG pathway and gene ontology (GO) enrichment analysis. The enriched functions and pathways of these DEGs contain male gonad development, cellular response to transforming growth factor beta stimulus, positive regulation of transcription from RNA polymerase II promoter, calcium independent cell-cell adhesion via plasma membrane cell adhesion molecules, extracellular matrix organization, pathways in cancer, cell cycle, cell adhesion molecules, PI3K-AKT signaling pathway, and progesterone mediated oocyte maturation. The protein-protein network (PPI) was established and module analysis was carried out using STRING and Cytoscape. Next, with PPI network analyzed by four topological methods in Cytohubba plugin of Cytoscape, 6 overlapping genes (DTL, DLGAP5, KIF15, NUSAP1, RRM2, and TOP2A) were eventually selected. GEPIA and Oncomine were implemented for validating the gene expression and all the six hub genes were highly expressed in OC specimens compared to normal OV tissues. Furthermore, 5 of 6 genes except for DTL were associated with worse prognosis using Kaplan Meier-plotter online tool and 3 of 6 genes were significantly related to clinical stages, including RRM2, DTL, and KIF15. Additionally, cBioPortal showed that TOP2A and RRM2 were the targets of cancer drugs in patients with OC, indicating the other four genes may also be potential drug targets. Six hub genes (DTL, DLGAP5, KIF15, NUSAP1, RRM2, and TOP2A) present promising predictive value for the development and prognosis of OC and may be used as candidate targets for diagnosis and treatment of OC.


Pharmacokinetics of Pamidronate Disodium in Cancer Patients after a Single Intravenous Infusion of 30-, 60- or 90-mg Dose over 4 or 24 Hours.
The objective of this study was to determine the pharmacokinetics of pamidronate disodium in plasma and urine after a single intravenous infusion of the drug to cancer patients at risk for developing bone metastases. Thirty-six patients were randomized into six treatment groups to receive 30-, 60- or 90-mg doses of the drug by 4- or 24-h intravenous infusions. Plasma and urine samples were collected at intervals for up to 144 h after drug administration and were assayed for pamidronate disodium using validated reversed-phase HPLC methods. The percentage of the administered dose excreted in urine following a 4- or 24-h infusion of 30-, 60- or 90-mg pamidronate disodium ranged from 30% to 60% except for one individual who excreted 96% by this route of elimination. There was a linear relationship between amount of drug excreted in urine and dose. Curve fitting of ARE (amount of drug to be excreted in urine) data indicated that the disposition kinetics of the drug was consistent with a biexponential process with overall mean plus minus S.D. half-life values of 2.1 plus minus 1.8 and 26.9 plus minus 8.7 h for the alpha and beta phases, respectively. The results of this study showed that the drug exhibited dose proportionality in its pharmacokinetic behavior over the 30--90-mg range regardless of whether it was infused over a 4- or 24-h interval.


Dephosphorylation is the mechanism of fibroblast growth factor inhibition of guanylyl cyclase-B.
Activating mutations in fibroblast growth factor receptor 3 (FGFR3) and inactivating mutations of guanylyl cyclase-B (GC-B, also called NPRB or NPR2) cause dwarfism. FGF exposure inhibits GC-B activity in a chondrocyte cell line, but the mechanism of the inactivation is not known. Here, we report that FGF exposure causes dephosphorylation of GC-B in rat chondrosarcoma cells, which correlates with a rapid, potent and reversible inhibition of C-type natriuretic peptide-dependent activation of GC-B. Cells expressing a phosphomimetic mutant of GC-B that cannot be inactivated by dephosphorylation because it contains glutamate substitutions for all known phosphorylation sites showed no decrease in GC-B activity in response to FGF. We conclude that FGF rapidly inactivates GC-B by a reversible dephosphorylation mechanism, which may contribute to the signaling network by which activated FGFR3 causes dwarfism.


Acceptability of Using Geosocial Networking Applications for HIV/Sexually Transmitted Disease Partner Notification and Sexual Health Services.
Geosocial networking (GSN) app use among men who have sex with men (MSM) has presented new opportunities for increasing the reach and efficiency of sexual health interventions but also poses challenges to HIV/sexually transmitted disease partner notification. Understanding MSM's attitudes toward app-based preventive sexual health services can help inform their development and delivery. We recruited US MSM who had met a sex partner on GSN apps in the last year to participate in an online survey assessing acceptability and preferences regarding app-based partner notification, health department presence, and sexual health services. Three app-based notification strategies were presented: sending notification messages through participant's/partner's app profile, health department app profile, or in-app anonymous messaging. Of 791 respondents, a majority (70%) preferred to be notified by their partner directly; however, most would get tested if notified by health department profile (95%) or anonymous in-app message (85%). Given the options provided, 50% preferred notifying a partner using their own profile, 26% with health department assistance, and 24% via in-app anonymous message. A majority (71%) were comfortable notifying a partner through a health department profile, and 74% were comfortable using in-app anonymous messaging. Most participants (82%) were comfortable with health departments having app profiles to provide sexual health services. Our results suggest that GSN app-based partner notification and sexual health services would be used by and are acceptable to US MSM. Partnering with app companies to integrate these services and increase access to public health programs has potential to improve MSM sexual health.


Associations between red reflex abnormality, consanguinity and intensive care hospitalization of newborns in Turkey.
Red reflex screening is the primary but unheeded test for the detection of vision- and life-threatening eye conditions. To evaluate the red reflex of newborns, percentage of ocular diseases resulting in red reflex abnormality, and their relation with consanguinity in Southeast Turkey. Newborns (n = 1358) were examined with pencil light and direct ophthalmoscopy. Eight hundred of these newborns were hospitalized in a rooming-in unit. (RIU) and 558 were in the neonatal intensive care service (NICS). In the RIU there were 7 (0.88%) newborns with abnormal red reflex and in the NICS there were 14 (2.51%). Sensitivity of pencil light examination was 71.4%. Studies from the Middle East have shown potential recessive genetic causes of common paediatric ocular conditions. In our study, consanguineous marriage was found to have a significant association with red reflex abnormality (P = 0.017). Red reflex screening test is important in the early diagnosis of vision- and life-threatening eye disorders in Southeast Turkey where consanguinity is common.


Regulation of the translation activity of antigen-specific mRNA is responsible for antigen loss and tumor immune escape in a HER2-expressing tumor model.
Tumor cells tend to behave differently in response to immune selective conditions. Contrary to those in therapeutic antitumor conditions, tumor cells in prophylactic antitumor conditions lose antigen expression for antitumor immune escape. Here, using a CT26/HER2 tumor model, we investigate the underlying mechanism(s). We selected tumor cell variants (CT26/HER2-A1 and -A2) displaying resistance to antitumor protective immunity and loss of HER2 antigen expression. These immune-resistant cells failed to induce Ag-specific IgG and IFN-γ responses while forming tumors at the same rate as CT26/HER2 cells. RT-PCR, qRT-PCR, PCR, Western blot and DNA sequencing analyses demonstrated that HER2 expression was inhibited at the post-transcriptional level in these immune-resistant cells, suggesting that tumor cells may escape antitumor immunity through the post-transcriptional regulation of antigen gene expression. The proteasome and lysosomal protein degradation pathways were not responsible for antigen loss, as determined by an inhibitor assay. Finally, HER2 mRNA was found to be not present in the monosomes and polysomes of CT26/HER2-A2 cells, as opposed to CT26/HER2 cells, suggesting that the translation activity of HER2 mRNAs may be suppressed in these immune-resistant cells. Taken together, our results report a new mechanism by which tumor cells respond to antitumor protective immunity for antitumor immune evasion.


Birth weight related essential, non-essential and conditionally essential amino acid blood concentrations in 12,000 breastfed full-term infants perinatally.
Essential, non-essential and conditionally essential amino acid blood concentrations play a critical role in newborns. We aimed to quantitate most of these amino acids in the blood of full-term breastfed infants, perinatally and correlate the obtained values with their birth weight. Breastfed full-term infants (n = 12,000; 6000 males, 6000 females) with birth weight 2000-4000 g were divided into 4 equal groups: Group A, 2000-2500 g; B, 2500-3000 g; C, 3000-3500 g and D, 3500-4000 g. Blood samples as Dried Blood Spots (DBS) were collected on the 3rd day of life and analyzed via liquid chromatography-tandem mass spectrometry (LC-MS/MS) protocol. Blood concentrations of the amino acids, Phenylalanine, Leucine, Glutamine, Ornithine, Alanine, Tyrosine and Glycine in full-term breastfed newborns, were found to be related to their birth weight, perinatally. On the contrary, no relationship between birth weight and blood concentrations of the amino acids Valine, Methionine, Citrulline and Arginine was found. Due to the number of the samples, data from this study could be applied as neonatal screening reference values for full-term breastfed newborns in relation to their birth weight.


Improved numerical stability for the bounded integer model.
This article highlights some numerical challenges when implementing the bounded integer model for composite score modeling and suggests an improved implementation. The improvement is based on an approximation of the logarithm of the error function. After presenting the derivation of the improved implementation, the article compares the performance of the algorithm to a naive implementation of the log-likelihood using both simulations and a real data example. In the simulation setting, the improved algorithm yielded more precise and less biased parameter estimates when the within-subject variability was small and estimation was performed using the Laplace algorithm. The estimation results did not differ between implementations when the SAEM algorithm was used. For the real data example, bootstrap results differed between implementations with the improved implementation producing identical or better objective function values. Based on the findings in this article, the improved implementation is suggested as the new default log-likelihood implementation for the bounded integer model.


The effects of a global postural reeducation program on an adolescent handball player with isthmic spondylolisthesis.
This report describes and evaluates a physical therapy intervention in a 15-year-old male handball player with low grade isthmic spondylolisthesis and associated spinopelvic misalignment (shear-stress type). Upon examination, increased lumbar lordosis, horizontal sacrum and anterior pelvic tilting were mainly associated with altered resting length and extensibility of the iliopsoas, hip adductors and erector spinae muscles. The intervention was directed at improving the muscles resting length and extensibility balance within a global postural alignment perspective (global postural reeducation). After the treatment period, lumbar lordosis, sacral slope and anterior pelvic tilting decreased 17.2°, 16.5° and 15.1° respectively. Global postural reeducation was effective in changing spinopelvic alignment related to low grade isthmic spondylolisthesis. This treatment option should be considered as a potential nonsurgical alternative for this condition.


Hypothyroidism following partial thyroidectomy for thyrotoxicosis and its relationship to thyroid remnant size.
One hundred and twenty-two patients were reviewed 1-7 years after partial thyroidectomy for thyrotoxicosis by two surgeons who had left thyroid remnants of different size. There was no significant difference in the prevalence of hypothyroidism or in the serum levels of thyroxine, tri-iodothyronine or thyroid-stimulating hormone between the two groups of patients. The overall prevalence of hypothyroidism was 16 per cent.


Implementation of the Strategy for Breastfeeding and Complementary Feeding in the Federal District in Brazil.
The Brazilian Breastfeeding and Complementary Feeding Strategy-Estratégia Amamenta e Alimenta Brasil (EAAB) aims to promote optimal breastfeeding (BF) and complementary feeding (CF) practices through the training of primary health professionals. Competition among health priorities and programs is one of the organizational contextual barriers to consolidating the implementation of the EAAB. This case study included six Primary Health Units (PHU) certified in the EAAB. Documentary analysis, interviews, and surveys were conducted, which informed a conceptual logical model. Organizational context indicators (positive and negative) were identified across the logical model based on the Matus Triangle, and they were used to analyze the degree of implementation of the EAAB in the PHUs. The logic model elucidated six stages of EAAB implementation, but none on post-certification monitoring. Ten indicators positively influenced the implementation, including having legislation that prioritizes BF and CF. Seven indicators exerted negative influence, especially the lack of specific funding resources for the EAAB. Only one PHU had a consolidated degree of implementation. Lack of specific funding, monitoring of BF and CF practices, and compliance with certification criteria are the main challenges for the EAAB's sustainability.


Exercise-induced changes in brain activity during memory encoding and retrieval after long-term bed rest.
Episodic memory depends decisively on the hippocampus and the parahippocampal gyrus, brain structures that are also prone to exercise-induced neuroplasticity and cognitive improvement. We conducted a randomized controlled trial to investigate the effects of a high-intensity exercise program in twenty-two men resting in bed for 60 days on episodic memory and its neuronal basis. All participants were exposed to 60 days of uninterrupted bed rest. Eleven participants were additionally assigned to a high-intensity interval training that was performed five to six times weekly for 60 days. Episodic memory and its neural basis were determined four days prior to and on the 58th day of bed rest using functional magnetic resonance imaging (fMRI). We found increased BOLD signal in the left hippocampus and parahippocampal gyrus in the non-exercising group compared to the exercising bed rest group whereas the mnemonic performance did not differ significantly. These findings indicate a higher neuronal efficiency in the training group during memory encoding and retrieval and may suggest a dysfunctional mechanism in the non-exercising bed rest group induced by two months of physical inactivity. Our results provide further support for the modulating effects of physical exercise and adverse implications of a sedentary lifestyle and bedridden patients.


Is immunoglobulin E to Staphylococcus aureus enterotoxins associated with asthma at 20 years?
In adults, subjects sensitized to Staphylococcus aureus enterotoxins (SE) seem to have an increased risk of asthma, whereas this association is less clear in childhood and adolescence. The primary aim of the present analysis was to examine the association between sensitization to SE and asthma at the age of 20 years. The German Multicentre Allergy Study recruited 1314 healthy newborns in 1990. We analyzed data from 61 asthmatics (based on at least two criteria: physician diagnosed asthma ever, wheezing in the last 12 months, asthma medication in the last 12 months) and 122 healthy study participants at age 20. In serum, specific Immunoglobulin E (IgE) to SE and common aeroallergens were measured. The association between asthma at age 20 and sensitization to SE was estimated by logistic regression models considering allergic, socio-demographic, and lifestyle factors as potential confounders. Fifty-five percent of the included participants were female. At age 20, subjects sensitized to SE were more likely to have asthma than not-sensitized subjects: raw odds ratio (OR) 2.5, 95%-confidence interval (95%CI) [1.3-4.7]; adjusted OR 1.6, 95%CI [0.8-3.4]. Asthmatics at age 20 were more often sensitized to SE compared to controls. Our study may indicate a moderate relationship between SE-sensitization and asthma; however, this association attenuated after adjusting for potential confounders and was no longer statistically significant. Longitudinal investigations with SE-IgE measurements at different time points in larger samples are needed to explore the temporal manner of this relationship.


Goniothalamin induces cell cycle-specific apoptosis by modulating the redox status in MDA-MB-231 cells.
Goniothalamin, a natural occurring styryl-lactone, is a novel compound with putative anticancer activities. In the present study, the mechanism of action of goniothalamin was further investigated in human breast cancer MDA-MB-231 cells. Goniothalamin treatment of cells significantly induced cell cycle arrest at G(2)/M phase and apoptosis. By means of cell cycle synchronization, the G(2)/M phase cells proved to be the most sensitive fraction to goniothalamin-induced apoptosis. Cells treated with goniothalamin revealed an increase in intracellular reactive oxygen species and a decrease in intracellular free thiol contents. The disruption of intracellular redox balance caused by goniothalamin was associated an enhancement of cdc25C degradation. Furthermore, the antioxidant N-acetylcysteine and the glutathione synthesis inhibitor dl-buthionine-(S, R)-sulfoximine, inhibited and enhanced, respectively, the effects of goniothalamin on cell cycle arrest and apoptosis. Taken together, our result demonstrates for the first time that goniothalamin disrupts intracellular redox balance and induces cdc25C degradation, which in turn causes cell cycle arrest and cell death maximally at G(2)/M phase in MDA-MB-231 cells.


Pharmacokinetics and antidiuretic effect of intravenous administration of desmopressin in orally overhydrated male volunteers.
In order to study the antidiuretic activity of desmopressin in healthy human subjects, a study design has previously been used with subjects orally hydrated. The objective of the present study was to investigate the pharmacokinetics and the antidiuretic activity of desmopressin administered as an intravenous infusion to eight orally hydrated male volunteers. After initial ingestion of water corresponding to 15 ml.kg-1 body weight, the overhydration was maintained by replacing the urinary fluid loss by drinking-water. Desmopressin (4 micrograms) was administered intravenously over 10 min. 1.5 hr after the start of the hydration procedure. Blood was sampled and urine was collected at intervals throughout the study day (9.5 hr). The terminal half-life of elimination (t1/2,) of desmopressin was calculated to be 2.97 +/- 0.24 (S.E.M.) hr while the clearance was 1.77 +/- 0.10 ml.min.-1.kg-1 and the volume of distribution at steady state was 373 +/- 30 ml.kg-1. The infusion caused a marked and long-lasting reduction of the urine flow rate. Four hr after the start of the infusion the mean urine osmolality was 909 +/- 46 mOsm.kg-1.


The hemodynamic effects of rapacuronium in patients with coronary artery disease: succinylcholine and vecuronium compared.
Rapacuronium is a nondepolarizing muscle relaxant similar in structure to pancuronium, rocuronium, and vecuronium. Rapacuronium has a mild to moderate effect on heart rate and arterial blood pressure in ASA physical status I and II patients. However, rapacuronium was often administered after, e.g., thiopental, an inhaled anesthetic, and fentanyl, thus modifying or masking the hemodynamic effects of rapacuronium. In this study, we investigated the hemodynamic effects of rapacuronium and compared its effects with those of vecuronium and succinylcholine. Sixty patients scheduled to undergo routine coronary artery bypass grafting were selected to receive rapacuronium 1.5 mg/kg, vecuronium 0.1 mg/kg, or succinylcholine 1 mg/kg. Heart rate, blood pressure, pulmonary artery pressures, and cardiac index were measured at 30- and 60-s intervals during the 2 min after the induction of anesthesia with diazepam and for a 3-min period after study drug administration. The Rapacuronium group exhibited significantly larger decreases in blood pressure and systemic vascular resistance than the Vecuronium or Succinylcholine groups. One patient in the Rapacuronium group experienced cutaneous flushing associated with a 33% decrease in blood pressure. Rapacuronium is associated with a significantly larger decrease in blood pressure than succinylcholine or vecuronium, and this decrease should be considered when using rapacuronium in patients who cannot tolerate this decrease.


Altered thalamic functional connectivity and cerebral blood flow in insomnia disorder: a resting-state functional magnetic resonance imaging study.
The thalamus plays a crucial role in sleep regulation, but few studies have examined functional connectivity of the thalamus in insomnia disorder. This study aimed to investigate the connectivity patterns and perfusion of the thalamus in patients with insomnia disorder using resting-state functional connectivity and three-dimensional arterial spin labeling (3D ASL). In total, 56 patients with insomnia disorder and 59 healthy control participants with a similar age-, gender-, and education lever distribution underwent resting-state functional magnetic resonance imaging (rs-fMRI) and 3D-ASL. The thalamus was selected as the seed region. Whole-brain connectivity was assessed using rs-fMRI. Cerebral blood flow (CBF) of the bilateral thalamus was measured with 3D-ASL using region-of-interest (ROI) analysis. All participants completed a series of neuropsychological assessments. Sleep parameters were assessed via polysomnography (PSG). The relationships between imaging parameters and clinical variables were assessed with Pearson correlation analysis. Compared with healthy controls, patients with insomnia disorder exhibited increased connectivity between the left thalamus and right precentral gyrus, and right thalamus and left middle frontal gyrus (MFG), right superior parietal lobule (SPL) and right superior frontal gyrus (SFG). Whereas decreased connectivity was noted between the right thalamus and left posterior cerebellar lobe including Crus I, Crus II, and VII b/VII. Connectivity between the right thalamus and left Crus I was positively correlated with MoCA scores (r = 0.286, P = 0.036) in insomnia disorder. Our findings illustrate functional abnormalities in brain connectivity and their relationship with cognitive impairments in insomnia disorder, providing novel insight into the neural mechanisms of insomnia disorder.


Elicitation of HIV-1 neutralizing antibodies by presentation of 4E10 and 10E8 epitopes on Norovirus P particles.
Eliciting efficient broadly neutralizing antibodies (BnAbs) is a major goal in vaccine development against human immunodeficiency virus type 1 (HIV-1). Conserved epitopes in the membrane-proximal external region (MPER) of HIV-1 are a significant target. In this study, Norovirus P particles (NoV PPs) were used as carriers to display conformational 4E10 and 10E8 epitopes in different patterns with an appropriate linker. Immune responses to the recombinant NoV PPs were characterized in guinea pigs and Balb/c mice and could induce high levels of MPER-binding antibodies. Modest neutralizing activities could be detected in sera of guinea pigs but not of Balb/c mice. The 4E10 or 10E8 epitopes dispersed on three loops on the outermost surface of NoV PPs (4E10-loop123 PP or 10E8-loop123 PP) elicited higher neutralizing activities than the equivalent number of epitopes presented on loop 2 only (4E10-3loop2 PP or 10E8-3loop2 PP). The epitopes on different loops of the PP were well-exposed and likely formed an appropriate conformation to induce neutralizing antibodies. Although sera of immunized guinea pigs could neutralize several HIV envelope-pseudoviruses, a vaccine candidate for efficiently inducing HIV-1 BnAbs remains to be developed.


Laundry detergents as a source of heavy metals in Irish domestic wastewater.
Concentrations of Cd, Cu and Zn in 175 detergent samples representing twenty-one brands of washing powders were analysed. Mean concentrations of 3.03 (+/- 0.50) microg Cd/g, 2.61 (+/- 1.22) microg Cu/g and 15.23 (+/- 7.26) microg Zn/g were recorded. The concentration of cadmium was much lower than previously reported. The daily contribution of metals from laundry washing are in the order of 54.5 microg Cd/ca/d, 47.0 microg Cu/ca/d and 274.1 microg Zn/ca/d. In Irish municipal wastewater the contribution from detergents of these metals are 31.9% for Cd, 0.24% Cu and 0.30% for Zn. This has important implications for sewage sludge disposal.


Trace Metals in Two Geoduck Clams (Panopea generosa and P. Globosa) Exploited for the Regional Market from Two Areas of Northwest Mexico.
Biological and fishery features of Panopea sp. clams have been studied in northwest Mexico because of their importance for human consumption. However, the content of pollutants in their tissues, along with their implications have not been addressed yet. The concentrations of cadmium (Cd), copper (Cu), mercury (Hg), and zinc (Zn) in soft tissues of Panopea generosa and P. globosa clams were examined in this region by atomic absorption spectroscopy. The metal concentrations (µg/g wet weight) ranged from 6.5 to 14.2, 0.97-8.09, 0.60-1.18, and 0.01-0.07, for Zn, Cu, Cd, and Hg, respectively. This study proposes that metal presence is related to weathering, upwelling, and drainage from adjacent agricultural lands to the coast. According to the Official Mexican Standard (NOM-242-SSA1-2009) and the World Health Organization (WHO, 2022), the metal content in siphon tissue indicates safe levels for human consumption.


Relations between a dermatoglyphic measure, hemispheric specialization, and intellectual abilities in 47,XXY males.
Verbal IQ is usually lower than performance IQ in neonatally identified 47,XXY males. A dermatoglyphic measure reflecting prenatal growth rates and indices of sex-related hormonal functioning are also frequently abnormal in 47,XXY males. This paper presents evidence indicating that a measure of prenatal growth rate predicts right hemispheric specialization for nonverbal processing in extra X males, whereas levels of testosterone, estradiol, luteinizing hormone, and follicle-stimulating hormones do not. Findings are also reported which indicate that the low verbal IQs of 47,XXY males are the result of abnormalities in right hemispheric functioning.


N-nitrosamines in the rubber and tire industry.
Airborne N-nitrosomorpholine (0 to 27 micrograms per cubic meter) was found in two of four rubber industry factories. N-Nitrosodimethylamine was also found in two factories, but at lower levels. These findings may be relevant to the reported increased risk of certain types of cancer in rubber workers in some of the same areas where the N-nitrosomorpholine levels were highest.


Fibrinolytic therapy of St. Jude valve thrombosis under guidance of digital cinefluoroscopy.
Fibrinolytic therapy is an alternative to urgent reoperation for patients with St. Jude prosthetic valve thrombosis, but requires an accurate method for repeated assessment of prosthetic function. Since the St. Jude valve is not well visualized by conventional cinefluoroscopy, digital subtraction techniques were developed that improved visualization of the value and allowed assessment of leaflet separation and velocity. A 74 year old woman with prosthetic valve thrombosis 5 years after St. Jude aortic valve placement had an opening angle of 58 degrees (normal range 10 to 13; n = 8) with a maximal opening velocity of 1.37 degrees/ms (normal range 2.46 to 2.93). The closing angle was 125 degrees (normal range 120 to 127) with a maximal closing velocity of 1.38 degrees/ms (normal range 2.24 to 3.60). The patient received 250,000 U of streptokinase intravenously, then 100,000 U/h for 72 hours. Improvement in auscultatory findings occurred at 12 hours; repeat digital cinefluoroscopy showed an opening angle of 20 degrees with a maximal velocity of 2.77 degrees/ms, and a closing angle of 126 degrees with a maximal velocity of 1.91 degrees/ms. Digital cinefluoroscopy 4 weeks after discharge on warfarin and dipyridamole therapy was unchanged. There have been no thromboembolic complications after 6 months of follow-up. Thus, digital cinefluoroscopy is a new noninvasive technique that permits accurate measurement of normal and abnormal St. Jude leaflet function. Intravenous streptokinase dissolution of prosthetic valve thrombosis under digital cinefluoroscopic guidance may be an acceptable alternative to emergency reoperation. The frequency and significance of residual subclinical leaflet dysfunction after fibrinolytic therapy and the indications for elective reoperation require further evaluation.


Improvement of androgenetic alopecia with topical Sophora flavescens Aiton extract, and identification of the two active compounds in the extract that stimulate proliferation of human hair keratinocytes.
Androgenetic alopecia (AGA) is a hair loss disorder that commonly affects middle-aged men. To date, the properties of a number of natural or synthetic substances have been investigated for their ability to improve the condition. To evaluate the hair growth-promoting activities of an extract from the root of Sophora flavescens Aiton. We used a human hair keratinocyte proliferation assay and ex vivo organ cultures of human hair follicle to examine the potential of the extract to stimulate hair growth via anagen elongation. We isolated the compounds promoting the growth of epithelial cells, and determined their chemical structures. A randomized, double-blinded, placebo-controlled clinical study for S. flavescens extract was carried out for 6 months with patients with AGA. The extract stimulated the proliferation of hair keratinocytes at a concentration of 0.1 ng/mL, while 100 ng/mL of the extract had a marked effect on hair shaft elongation in an organ culture of human hair follicle. Cell proliferation assay-directed fractionation led to the identification of two pterocarpan derivatives, L-maackiain and medicarpin, as active compounds that promote the proliferation of human hair keratinocytes. Studies in human subjects showed that improvement in the inspected alopecia scores in the lotion plus extract group were significant over a period of 6 months (P < 0.01). S. flavescens root extract is effective for the treatment of AGA. The isolated two pterocarpans might have important role in this effect.


The fate of miniplates in facial trauma and orthognathic surgery: a retrospective study.
The fate of 279 Champy miniplates used routinely as permanent implants over a 5-year-period in the management of maxillofacial trauma and orthognathic surgery has been analysed retrospectively. Trauma patients (62) and orthognathic patients (47) were analysed separately; in each group those patients who had plates removed were compared to the patients with retained plates. This study indicates that the morbidity of retaining plates is within acceptable limits and that the routine removal of plates at 3 months may be unnecessary.


Fuzzy material surrounding measles virus nucleocapsids identified as matrix protein. Brief report.
Measles virus grown in Vero cell cultures was examined at the ultrastructural level after immunoperoxidase staining with antiserum against the matrix protein. The antiserum clearly preferentially labeled the fuzzy material surrounding cytoplasmic nucleocapsids, but not the nucleocapsids themselves.


Optic disc cupping as clinically estimated from photographs.
Cup-to-disc ratios of 204 right eyes were evaluated by two clinicians and by a trained grader using a standardized grading scheme. Mean measurements by the grader were greater than estimates made by either clinician. The measurement scheme used by the trained grader has a high degree of reliability and validity. The standard protocol provides an objective assessment of optic disc cupping and could be easily adapted for office use.


Pharmaceutical cost management and access to psychotropic drugs: the U.S. context.
In recent years, prescription drug expenditures in the United States have increased rapidly. In 2003, spending on prescription medications totaled $179.2 billion dollars, or approximately 11% of national health expenditures [Smith, C., Cowan, C., Sensenig, A., Catlin, A., the Health Accounts Team. (2005). Health spending growth slows in 2003. Health Affairs, 24 (1) 185-194]. In response to rapid increases in prescription drug expenditures, both public and private payers of health care services have adopted strategies to try to contain drug costs, including drug formularies, prior authorization programs, cost sharing and utilization management. In this paper, I provide a background on prescription drug spending trends, financing, and access to medications; describe some of the tools used most commonly to manage prescription drug utilization; present results from the literature on the impact of these tools; and discuss some implications of this information for the new Medicare prescription drug benefit to be implemented in 2006 as well as for future prescription drug innovation.


From Macro- to Microscale: A combined modelling approach for near-surface wind flow on Mars at sub-dune length-scales.
The processes that initiate and sustain sediment transport which contribute to the modification of aeolian deposits in Mars' low-density atmosphere are still not fully understood despite recent atmospheric modelling. However, detailed microscale wind flow modelling, using Computational Fluid Dynamics at a resolution of <2 m, provides insights into the near-surface processes that cannot be modeled using larger-scale atmospheric modeling. Such Computational Fluid Dynamics simulations cannot by themselves account for regional-scale atmospheric circulations or flow modifications induced by regional km-scale topography, although realistic fine-scale mesoscale atmospheric modeling can. Using the output parameters from mesoscale simulations to inform the input conditions for the Computational Fluid Dynamics microscale simulations provides a practical approach to simulate near-surface wind flow and its relationship to very small-scale topographic features on Mars, particularly in areas which lack in situ rover data. This paper sets out a series of integrated techniques to enable a multi-scale modelling approach for surface airflow to derive surface airflow dynamics at a (dune) landform scale using High Resolution Imaging Science Experiment derived topographic data. The work therefore provides a more informed and realistic Computational Fluid Dynamics microscale modelling method, which will provide more detailed insight into the surface wind forcing of aeolian transport patterns on martian surfaces such as dunes.


Medicaid Expansion and Medicare-Financed Hospitalizations Among Adult Patients With Incident Kidney Failure.
Although Medicare provides health insurance coverage for most patients with kidney failure in the US, Medicare beneficiaries who initiate dialysis without supplemental coverage are exposed to substantial out-of-pocket costs. The availability of expanded Medicaid coverage under the Patient Protection and Affordable Care Act (ACA) for adults with kidney failure may improve access to care and reduce Medicare-financed hospitalizations after dialysis initiation. To examine the implications of the ACA's Medicaid expansion for Medicare-financed hospitalizations, health insurance coverage, and predialysis nephrology care among Medicare-covered adults aged 19 to 64 years with incident kidney failure in the first year after initiating dialysis. This cross-sectional study used a difference-in-differences approach to assess Medicare-financed hospitalizations among adults aged 19 to 64 years who initiated dialysis between January 1, 2010, and December 31, 2018, while covered by Medicare Part A (up to 5 years postexpansion). Data on patients were obtained from the Renal Management Information System's End Stage Renal Disease Medical Evidence Report, which includes data for all patients initiating outpatient maintenance dialysis regardless of health insurance coverage, treatment modality, or citizenship status, and these data were linked with claims data from the Medicare Provider Analysis and Review. Data were analyzed from January to August 2022. Living in a Medicaid expansion state. Primary outcomes were number of Medicare-financed hospitalizations and hospital days in the first 3 months, 6 months, and 12 months after dialysis initiation. Secondary outcomes included dual Medicare and Medicaid coverage at 91 days after dialysis initiation and the presence of an arteriovenous fistula or graft at dialysis initiation for patients undergoing hemodialysis. The study population included 188 671 adults, with 97 071 living in Medicaid expansion states (mean [SD] age, 53.4 [9.4] years; 58 329 men [60.1%]) and 91 600 living in nonexpansion states (mean [SD] age, 53.0 [9.6] years; 52 677 men [57.5%]). In the first 3 months after dialysis initiation, Medicaid expansion was associated with a significant decrease in Medicare-financed hospitalizations (-4.24 [95% CI, -6.70 to -1.78] admissions per 100 patient-years; P = .001) and hospital days (-0.73 [95% CI, -1.08 to -0.39] days per patient-year; P < .001), relative reductions of 8% for both outcomes. Medicaid expansion was associated with a 2.58-percentage point (95% CI, 0.88-4.28 percentage points; P = .004) increase in dual Medicare and Medicaid coverage at 91 days after dialysis initiation and a 1.65-percentage point (95% CI, 0.31-3.00 percentage points; P = .02) increase in arteriovenous fistula or graft at initiation. In this cross-sectional study with a difference-in-differences analysis, the ACA's Medicaid expansion was associated with decreases in Medicare-financed hospitalizations and hospital days and increases in dual Medicare and Medicaid coverage. These findings suggest favorable spillover outcomes of Medicaid expansion to Medicare-financed care, which is the primary payer for patients with kidney failure.


Direct gene transfer in potato: a comparison of particle bombardment of leaf explants and PEG-mediated transformation of protoplasts.
Direct gene transfer methods in potato would facilitate the transfer of multiple genes and the manipulation of metabolic pathways in this species. In this study, up to 1.8 transformation events per shot (=0.5 per bombarded leaf) and 67.2 events per million protoplasts treated were obtained with particle bombardment and PEG-mediated direct DNA uptake, respectively. Limited disassociation of both HPT and GUS genes appeared to occur during the process of integration in only 19% of transformants. A large number of transformed potato plants with transgene expression at levels comparable to Agrobacterium-mediated transformation was obtained. High levels of GUS expression were only obtained in lines derived from PEG treatment. No correlation between the number of gene insertions and gene expression levels was found, suggesting that multiple insertions may have little or no effect on transgene expression.


7TM domain structures of adhesion GPCRs: what's new and what's missing?
Adhesion-type G protein-coupled receptors (aGPCRs) have long resisted approaches to resolve the structural details of their heptahelical transmembrane (7TM) domains. Single-particle cryogenic electron microscopy (cryo-EM) has recently produced aGPCR 7TM domain structures for ADGRD1, ADGRG1, ADGRG2, ADGRG3, ADGRG4, ADGRG5, ADGRF1, and ADGRL3. We review the unique properties, including the position and conformation of their activating tethered agonist (TA) and signaling motifs within the 7TM bundle, that the novel structures have helped to identify. We also discuss questions that the kaleidoscope of novel aGPCR 7TM domain structures have left unanswered. These concern the relative positions, orientations, and interactions of the 7TM and GPCR autoproteolysis-inducing (GAIN) domains with one another. Clarifying their interplay remains an important goal of future structural studies on aGPCRs.


Perinatal outcomes of singleton live births with and without vanishing twin following transfer of multiple embryos: analysis of 113 784 singleton live births.
Does transfer of multiple embryos affect perinatal outcomes of resulting singleton live births following ART? There is a higher risk of preterm birth (PTB) and low birthweight (LBW) in singleton live births associated with spontaneous reduction of an initial multiple to singleton gestation following transfer of multiple embryos. Singleton pregnancies following ART are at a higher risk of adverse perinatal outcomes compared to spontaneous conceptions. Earlier studies have found an increased risk of PTB and LBW in singletons following transfer of multiple embryos versus single embryo transfer (SET). However, these studies did not address the specific role of vanishing twin, i.e. spontaneous reduction of an initial multiple to singleton gestation. Anonymised data on all ART cycles performed in the UK were obtained from the Human Fertilization and Embryology Authority. Data from 1991 to 2011 involving 508 410 fresh and 131 157 frozen autologous ART cycles resulting in 95 779 and 18 005 singleton live births, respectively, were analyzed. Fresh and frozen ART cycles were analyzed separately to compare perinatal outcomes of PTB and LBW of singleton live births resulting from transfer of multiple (≥2) embryos versus SET. Logistic regression analysis was performed adjusting for confounders. Subgroup analyses were carried out for perinatal outcomes of singleton live births with initial multiple or initial single gestational sacs following transfer of multiple embryos versus singleton live births following SET. In fresh cycles, there was a significantly higher risk of PTB (adjusted odds ratio (aOR) 2.70, CI 2.37-3.05) and LBW (aOR 2.76, CI 2.44-3.13) in singleton live births with initial multiple gestational sacs but there was no significant difference in the risk of PTB (aOR 1.08, CI 1.00-1.16) or LBW (aOR 1.08, CI 1.00-1.16) in singleton live births with an initial single gestational sac following transfer of ≥2 embryos compared to those following SET. In frozen cycles, there was a significantly higher risk of PTB (aOR 2.13, CI: 1.55-2.93) and LBW (aOR 2.61, CI: 1.87-3.64) in singleton live births with initial multiple gestational sacs but there was no significant difference in the risk of PTB (aOR 1.02, CI: 0.88-1.18) or LBW (aOR 0.91, CI: 0.77-1.07) in the singleton live births with an initial single gestational sac following transfer of ≥2 embryos compared to those following SET. While the analysis was adjusted for a number of known confounders, the dataset had no information for confounders such as smoking, BMI, previous obstetric history and comorbid medical conditions during pregnancy. The lack of information about the timing of occurrence of the vanishing phenomenon is another limitation because poorer perinatal outcomes of a surviving twin have been reported following second trimester fetal demise compared to the first trimester. The study results suggest that the vanishing twin phenomenon is associated with increased risk of PTB and LBW in the resulting singleton live births and there was no increased risk when there was a single gestational sac from the outset following transfer of multiple embryos. Nil.


Resuscitation of viable but nonculturable bacteria promoted by ATP-mediated NAD+ synthesis.
Entry into the viable but nonculturable (VBNC) state is a survival strategy adopted by bacteria to survive harsh environment. Although VBNC cells still have metabolic activity, they lose the ability to form colonies on nonselective culture media. Thus, conventional bacterial detection methods, such as plate counting, are unable to detect the presence of VBNC cells. When the environmental conditions are appropriate, VBNC cells can initiate resuscitation, posing a great risk to the safety of public health. The study of the VBNC resuscitation mechanism could provide new insights into the prevention and control of VBNC resuscitation. Uncovering the molecular mechanism of VBNC cell resuscitation by investigating the role of O-antigen ligase (RfaL) in inhibiting the resuscitation of Escherichia coli O157:H7 in the VBNC state. RfaL was screened and verified as a resuscitation inhibitor of VBNC Escherichia coli O157:H7 by detecting resuscitation curve and time-lapse microscopy. The mechanism of RfaL impacts VBNC E. coli resuscitation was investigated by detecting the single cell ATP content, metabolomic changes, NAD(H) content and new protein biosynthesis of WT and ΔrfaL at different stage of resuscitation. Mutation of rfaL, which encoded an O-antigen ligase, markedly shortened the resuscitating lag phase. Further studies indicated that ΔrfaL VBNC cells contained higher ATP levels, and ATP consumption during the resuscitating lag phase was highly correlated with resuscitation efficiency. Metabolomic analysis revealed that ATP was utilized to activate the Handler and salvage pathways to synthesize NAD+, balancing redox reactions to recover cell activity and promote cell resuscitation. Our findings revealed a strategy employed by VBNC cells for revival, that is, using residual ATP to primarily recover metabolic activity, driving cells to exit dormancy. The synthesis pathway of lipopolysaccharide (LPS) in rfaL null mutant was inhibited and could supply more ATP to synthesis NAD+ and promote resuscitation.


Efficacy and Safety of Ixazomib Plus Lenalidomide and Dexamethasone Following Injectable PI-Based Therapy in Relapsed/Refractory Multiple Myeloma.
This nationwide, multicenter, open-label, single-arm study evaluated the efficacy and safety of the oral proteasome inhibitor (PI), ixazomib plus lenalidomide (LEN) and dexamethasone (DEX) (IRd) following injectable PI-based therapy for relapsed/refractory multiple myeloma (RRMM). Of 45 patients enrolled, 36 patients received IRd after achieving at least a minor response to 3 cycles of bortezomib or carfilzomib plus LEN + DEX (VRd, n=6; KRd, n=30). At median follow-up of 20.8 months, the 12-month event-free survival rate (primary endpoint) was 49% (90% CI: 35.9-62.0), counting 11 events of progressive disease/death, 8 dropouts and 4 missing response data. The 12-month progression-free survival (PFS) rate by Kaplan-Meier analysis (dropouts as censoring) was 74% (95% CI: 56-86). Median PFS and time to next treatment (95% CI) were 29.0 (21.3-NE) and 32.3 (14.9-35.4) months, respectively; median OS was not evaluable. The overall response rate was 73%, and 42% of patients had a very good partial response or better. Frequent (≥10% incidence) grade ≥3 treatment emergent adverse events were decreased neutrophil and platelet counts (n=7 [16%] each). Two deaths occurred (one during KRd treatment and one during IRd treatment), both due to pneumonia. IRd following injectable PI-based therapy was tolerable and efficacious in RRMM patients. TRIAL REGISTRATION NUMBER: NCT03416374; Date of registration: January 31, 2018.


Permeability of ammonia and amines in Rhodobacter sphaeroides and Bacillus firmus.
Permeabilities of uncharged ammonia (NH3), methylamine (CH3NH2), and ethylamine (CH3CH2NH2) in the gram-negative phototrophic bacterium Rhodobacter sphaeroides were measured directly in cells grown heterotrophically under aerobic conditions. The permeability of NH3 was 2.55 +/- 0.73 microns s-1 (n = 20), but the permeabilities of CH3NH2 (MA) and CH3CH2NH2 (EA) were higher, PMA = 17.8 +/- 2.8 microns s-1 (n = 50), PEA = 24.7 +/- 3.9 microns s-1 (n = 44). The relative permeabilities of amines were also determined from their effect on the pH gradient across the cell membrane at alkaline external pH. In aerobically grown R. sphaeroides, both techniques indicated that the permeability of CH3CH2NH2 was about 30% greater than that of CH3NH2 but that the permeability of NH3 was only about 1/5 that of CH3NH2. The relative permeabilities of NH3 (A) and CH3NH2 were different in R. sphaeroides cells grown under three different physiological conditions: (a) cells grown aerobically with ammonium sulfate (PA/PMA about 0.20), (b) cells grown anaerobically with ammonium sulfate as their nitrogen source (PA/PMA about 0.29), and (c) diazotrophic cells (PA/PMA about 0.38). NH3 was also found to be only about 1/3 as permeable as CH3NH2 in the alkalophilic gram-positive bacterium Bacillus firmus. The findings that permeability properties of NH3 and CH3NH2 are very different in different bacteria and vary according to the conditions under which the organism is grown need to be taken into account in the interpretation of experiments where [14C]methylamine is used as an ammonia analog.


The comparison of sonochemistry, electrochemistry and sonoelectrochemistry techniques on decolorization of C.I Reactive Blue 49.
In this paper, the ability of three decolorization techniques including sonochemistry, electrochemistry and sonoelectrochemistry for decolorization of C.I Reactive Blue 49 in aqueous solutions have been compared. Various parameters affecting decolorization efficiency, such as pH, initial concentration of the dye, the decolorization time, H2O2 concentration and effect of applied potential on electrochemistry and sonoelectrochemistry, were evaluated. For further comparison, the methods were evaluated based on their ability in COD removal percentage. The maximum COD removal at the optimum condition of each method were 36.0%, 68.0%, 87.8% and 76.2% for sonochemistry, electrochemistry, sonoelectrochemistry with H2O2 and sonoelectrochemistry without H2O2, respectively. The result was an environment friendly method for removal of C.I Reactive Blue 49 from aqueous solutions.


The efficacy of fenbendazole and albendazole against the lungworm Muellerius capillaris in goats.
In five trials it was found that the daily administration of fenbendazole in the food for 1 or 2 weeks at dosages of 1.25, 2.5 or 5 mg kg-1 live weight was highly effective against Muellerius capillaris infection in goats. Treated animals had significantly lower numbers of larvae in the faeces for up to 223 days after treatment. There was no obvious difference between the different dose levels. Daily treatment for 2 weeks seemed to be slightly more effective than treatment for 1 week. Treatment for 1 week twice with an intervening period of 1 week seemed to be more effective than treatment for 2 weeks continuously. Goats given a single treatment with fenbendazole at 25 mg kg-1 had a significantly lower number of M. capillaris larvae in their faeces on Days 34 and 69 after treatment than the controls, but on Days 126 and 156 after treatment there was no significant difference between these two groups. Albendazole given daily for 2 weeks at a dose of 1.0 mg kg-1 showed a significant effect for up to 153 days after treatment, which was similar to the result of daily treatment with 1.25 mg kg-1 fenbendazole. Goats treated with albendazole twice at 10 mg kg-1 with a 1 week interval showed a significant reduction in the number of Muellerius larvae in the faeces on Day 41 after treatment, but not on Days 97 and 153 after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)


Urban meteorological modelling for nuclear emergency preparedness.
The main objectives of the current EU project "Integrated Systems for Forecasting Urban Meteorology, Air Pollution and Population Exposure" (FUMAPEX) are the improvement of meteorological forecasts for urban areas, the connection of numerical weather prediction (NWP) models to urban air pollution and population dose models, the building of improved urban air quality information and forecasting systems, and their application in cities in various European climates. In addition to the forecast of the worst air-pollution episodes in large cities, the potential use of improved weather forecasts for nuclear emergency management in urban areas, in case of hazardous releases from nuclear accidents or terror acts, is considered. Such use of NWP data is tested for the Copenhagen metropolitan area and the Øresund region. The Danish Meteorological Institute (DMI) is running an experimental version of the HIRLAM NWP model over Zealand including the Copenhagen metropolitan area with a horizontal resolution of 1.4km, thus approaching the city-scale. This involves 1-km resolution physiographic data with implications for the urban surface parameters, e.g. surface fluxes, roughness length and albedo. For the city of Copenhagen, the enhanced high-resolution NWP forecasting will be provided to demonstrate the improved dispersion forecasting capabilities of the Danish nuclear emergency preparedness decision-support system, the Accident Reporting and Guidance Operational System (ARGOS), used by the Danish Emergency Management Agency (DEMA). Recently, ARGOS has been extended with a capability of real-time calculation of regional-scale atmospheric dispersion of radioactive material from accidental releases. This is effectuated through on-line interfacing with the Danish Emergency Response Model of the Atmosphere (DERMA), which is run at DMI. For local-scale modelling of atmospheric dispersion, ARGOS utilises the Local-Scale Model Chain (LSMC), which makes use of high-resolution DMI-HIRLAM NWP model data provided to DEMA by DMI four times a day under operational surveillance and covering Denmark and surroundings. The integration of DERMA in ARGOS is effectuated through automated on-line digital communication and exchange of data. The calculations are carried out in parallel for each NWP model to which DMI has access, thereby providing a mini-ensemble of dispersion forecasts for the emergency management.


Nitric oxide generation affects pro- and anti-angiogenic growth factor expression in primary human trophoblast.
Preeclampsia is associated with reduced trophoblast placenta growth factor (PGF) expression, elevated soluble fms-like tyrosine kinase-1 (sFlt-1) and decreased bioactivity of nitric oxide (NO). Elevated sFlt-1 reduces bio-availability of PGF and vascular endothelial growth factor (VEGF) leading to maternal endothelial dysfunction. Although NO can regulate gene expression, its ability to regulate trophoblast expression of angiogenic growth factors is not known. Human primary term trophoblast and JEG-3 choriocarcinoma cells were cultured under 21%O(2) or 1%O(2) conditions in the presence or absence of NO donor (SNP) or inhibitor (L-NAME). Effects on PGF, VEGF and Flt-1 isoform mRNA expression were determined by quantitative real-time PCR. Changes in expression of soluble protein isoforms of FLT-1 was monitored by ELISA. Hypoxia decreased PGF mRNA but increased VEGF, sFlt-1 and Flt-1 mRNA expression in trophoblast. Generation of NO in trophoblast under 1%O(2) culture conditions significantly reversed sFlt-1 mRNA and protein expression, independent of mFlt-1. Conversely NO generation in hypoxic trophoblast increased VEGF and PGF mRNA expression. NO production in primary human trophoblast cultures had divergent effects on pro-angiogenic (PGF, VEGF) versus anti-angiogenic (sFlt-1) mRNA expression, resulting in an enhanced pro-angiogenic gene expression environment in vitro.


Default mode network functional connectivity altered in failed back surgery syndrome.
The purpose of this study was to identify alterations in the default mode network of failed back surgery syndrome patients as compared to healthy subjects. Resting state functional magnetic resonance imaging was conducted at 3 Tesla and data were analyzed with an independent component analysis. Results indicate an overall reduced functional connectivity of the default mode network and recruitment of additional pain modulation brain regions, including dorsolateral prefrontal cortex, insula, and additional sensory motor integration brain regions, including precentral and postcentral gyri, for failed back surgery syndrome patients. This article presents alterations in the default mode network of chronic low back pain patients with failed back surgery syndrome as compared to healthy participants.


Monitoring coccidia in commercial broiler chicken flocks in Ontario: comparing oocyst cycling patterns in flocks using anticoccidial medications or live vaccination.
Coccidiosis, the parasitic disease caused by Eimeria spp., is controlled during broiler chicken production through the inclusion of in-feed anticoccidial medications. Live-coccidiosis vaccination has become an increasingly common alternative to these medications. Monitoring infections with Eimeria spp. in flocks can be accomplished through determining the concentration of oocysts excreted in the fecal material (i.e., oocysts per gram; OPG). The purpose of our study was to sample commercial Ontario broiler chicken flocks at various times of the year to determine weekly OPG counts for flocks that use either an in-feed anticoccidial medication or a live-coccidiosis vaccine. Weekly sampling of 95 flocks from placement to market permitted documentation of oocyst cycling patterns typical of conventional and antibiotic-free flocks, and variation of these patterns in summer and winter. Medicated flocks had higher and later peak oocyst shedding compared with vaccinated flocks. Flocks reared in the summer peaked in oocyst shedding earlier than flocks reared in the winter. Despite what appears to be poorer coccidiosis control in the medicated flocks, the performance data were similar for these flocks compared with vaccinated flocks. This is the first study describing typical patterns of parasite shedding in Ontarian commercial broiler chicken flocks; these data will provide a baseline of expected Eimeria spp. infections in Canadian broiler chicken flocks to ensure optimal coccidiosis prevention.


Effect of ultraviolet radiation on chlorophyll, carotenoid, protein and proline contents of some annual desert plants.
Investigation was carried out to find whether enhanced ultraviolet radiation influences the Malva parviflora L., Plantago major L., Rumex vesicarius L. and Sismbrium erysimoids Desf. of some annual desert plants. The seeds were grown in plastic pots equally filled with a pre-sieved normal sandy soil for 1 month. The planted pots from each species were randomly divided into equal groups (three groups). Plants of the first group exposed to white-light tubes (400-700 nm) 60 w and UV (365 nm) 8 w tubes. The second group was exposed to white-light tubes (400-700 nm) 60 w and UV (302 nm) 8 w tubes. The third group was exposed to white-light tubes (400-700 nm) 60 w and UV (254 nm) 8 w tubes, respectively, for six days. The results indicated that the chlorophyll contents were affected by enhanced UV radiation. The chlorophyll a, b, and total contents were decreased compared with the control values and reduced with the enhanced UV radiation, but the carotenoid was increased compared with the control and also reduced with the enhanced UV radiation. So, the contents of chlorophylls varied considerably. M. parviflora showed the highest constitutive levels of accumulated chlorophyll a, b, and total chlorophyll (0.463, 0.307 and 0.774 mg g(-1) f w) among the investigated plant species. P. major showed the lowest constitutive levels of the chloroplast pigments, 0.0036, 0.0038 and 0.0075 mg g(-1) f w for chlorophyll a, b, and total chlorophyll at UV-365 nm, respectively. The protein content was decreased significantly in both root and shoot systems compared with the control values but, it was increased with increasing wave lengths of UV-radiation of all tested plants. R. vesicarius showed the highest protein contents among the investigated plants; its content was 3.8 mg g(-1) f w at UV-365 nm in shoot system. On the other hand, decreasing ultraviolet wave length induced a highly significant increase in the level of proline in both root and shoot of all tested plants. From the results obtained, it is suggested that proline can protect cells against damage induced by ultraviolet radiation. Statistically, the variations of the studied metabolic activities were significant due to UV radiation treatment in shoot and root system of all investigated plant species.


Periodontal disease and adverse birth outcomes: a study from Pakistan.
Periodontal disease may increase the risk of adverse birth outcomes; however, results have been mixed. Few studies have examined periodontal disease in developing countries. We describe the relationship between periodontal disease and birth outcomes in a community setting in Pakistan. This was a prospective cohort study. Enrollment occurred at 20-26 weeks of gestation. A study dentist performed the periodontal examination to assess probing depth, clinical attachment level, gingival index, and plaque index. Outcomes included stillbirth, neonatal death, perinatal death, < 32 weeks preterm birth, 32-36 weeks preterm birth, and low birthweight and are presented for increasing periodontal disease severity by quartiles. Dental examinations and outcome data were completed for 1152 women: 81% of the women were multiparous, with a mean age of 27 years; 33% of the women had no education. Forty-seven percent of the women had dental caries; 27% of the women had missing teeth, and 91% of the women had had no dental care in the last year. Periodontal disease was common: 76% of the women had > or = 3 teeth with a probing depth of > or = 3 mm; 87% of the women had > or = 4 teeth with a clinical attachment level of > or = 3 mm; 56% of the women had > or = 4 teeth with a plaque index of 3; and 60% of the women had > or = 4 teeth with a gingival index of 3. As the measures of periodontal disease increased from the 1st to 4th quartile, stillbirth and neonatal and perinatal death also increased, with relative risks of approximately 1.3. Early preterm birth increased, but the results were not significant. Late preterm birth and low birthweight were not related to measures of periodontal disease. Pregnant Pakistani women have high levels of moderate-to-severe dental disease. Stillbirth and neonatal and perinatal deaths increased with the severity of periodontal disease.


Resolution of Cerebral Inflammation Following Subarachnoid Hemorrhage.
Aneurismal subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke that, despite improvement through therapeutic interventions, remains a devastating cerebrovascular disorder that has a high mortality rate and causes long-term disability. Cerebral inflammation after SAH is promoted through microglial accumulation and phagocytosis. Furthermore, proinflammatory cytokine release and neuronal cell death play key roles in the development of brain injury. The termination of these inflammation processes and restoration of tissue homeostasis are of utmost importance regarding the possible chronicity of cerebral inflammation and the improvement of the clinical outcome for affected patients post SAH. Thus, we evaluated the inflammatory resolution phase post SAH and considered indications for potential tertiary brain damage in cases of incomplete resolution. Subarachnoid hemorrhage was induced through endovascular filament perforation in mice. Animals were killed 1, 7 and 14 days and 1, 2 and 3 months after SAH. Brain cryosections were immunolabeled for ionized calcium-binding adaptor molecule-1 to detect microglia/macrophages. Neuronal nuclei and terminal deoxyuridine triphosphate-nick end labeling staining was used to visualize secondary cell death of neurons. The gene expression of various proinflammatory mediators in brain samples was analyzed by quantitative polymerase chain reaction. We observed restored tissue homeostasis due to decreased microglial/macrophage accumulation and neuronal cell death 1 month after insult. However, the messenger RNA expression levels of interleukin 6 and tumor necrosis factor α were still elevated at 1 and 2 months post SAH, respectively. The gene expression of interleukin 1β reached its maximum on day 1, whereas at later time points, no significant differences between the groups were detected. By the herein presented molecular and histological data we provide an important indication for an incomplete resolution of inflammation within the brain parenchyma after SAH. Inflammatory resolution and the return to tissue homeostasis represent an important contribution to the disease's pathology influencing the impact on brain damage and outcome after SAH. Therefore, we consider a novel complementary or even superior therapeutic approach that should be carefully rethought in the management of cerebral inflammation after SAH. An acceleration of the resolution phase at the cellular and molecular levels could be a potential aim in this context.


Tbx12, a novel T-box gene, is expressed during early stages of heart and retinal development.
T-box genes encode transcription factors that regulate many developmental processes. We have cloned a novel mouse T-box gene, Tbx12. Tbx12 is the vertebrate homologue of the Drosophila H15 gene and the Caenorhabditis elegans tbx-12 gene. Tbx12 is expressed in extraembryonic tissues such as the amnion and allantois. In the embryo, Tbx12 is strongly expressed in the neural retina and the heart.


Prehospital pulse pressure and mortality of septic shock patients cared for by a mobile intensive care unit.
Septic shock medical treatment relies on a bundle of care including antibiotic therapy and hemodynamic optimisation. Hemodynamic optimisation consists of fluid expansion and norepinephrine administration aiming to optimise cardiac output to reach a mean arterial pressure of 65mmHg. In the prehospital setting, direct cardiac output assessment is difficult because of the lack of invasive and non-invasive devices. This study aims to assess the relationship between 30-day mortality and (i) initial pulse pressure (iPP) as (ii) pulse pressure variation (dPP) during the prehospital stage among patients cared for SS by a prehospital mobile intensive care unit (MICU). From May 09th, 2016 to December 02nd, 2021, septic shock patients requiring MICU intervention were retrospectively analysed. iPP was calculated as the difference between systolic blood pressure (SBP) and diastolic blood pressure (DBP) at the first contact between the patient and the MICU team prior to any treatment and, dPP as the difference between the final PP (the difference between SBP and DBP at the end of the prehospital stage) and iPP divided by prehospital duration. To consider cofounders, the propensity score method was used to assess the relationship between (i) iPP < 40mmHg, (ii) positive dPP and 30-day mortality. Among the 530 patients analysed, pulmonary, digestive, and urinary infections were suspected among 43%, 25% and 17% patients, respectively. The 30-day overall mortality rate reached 31%. Cox regression analysis showed an association between 30-day mortality and (i) iPP < 40mmHg; aHR of 1.61 [1.03-2.51], and (ii) a positive dPP; aHR of 0.56 [0.36-0.88]. The current study reports an association between 30-day mortality rate and iPP < 40mmHg and a positive dPP among septic shock patients cared for by a prehospital MICU. A negative dPP could be helpful to identify septic shock with higher risk of poor outcome despite prehospital hemodynamic optimization.


Visualization of the craniocervical subarachnoid spaces.
A very simple procedure is described which leads to adequate visualization of the structures in the craniocervical area that are otherwise often very insufficiently investigated during myelography routinely performed with metrizamide.


Induction of the fragile X on BrdU-substituted chromosomes with direct visualization of sister chromatid exchanges on banded chromosomes.
After incorporation of BrdU for one or more replication cycles, the fragile site at Xq27 [fra(X)] was induced by a late pulse with excess thymidine (dT), resulting in the simultaneous visualization of G bands and differentially stained sister chromatids. The degree of BrdU substitution (uni- vs bifilarly substituted DNA) did not affect the expression of hte fra(X). Without addition of dT, expression was the same in M1, M2, and M3 cells. With the addition of dT, expression was reduced in M1 cells and increased in M2 and M3 cells. One way to explain this fact would be an increased repair of the fragile site in M1 cells by illegitimate G:BrdU pairing under dCTP-deficient conditions. A preferential depletion of M3 cells, and to a lesser extent also M2 cells, could suggest a synergistic toxic effect of BrdU substitution and dCTP depletion. With this technique, sister chromatid exchanges (SCEs) could be directly localized at band level, facilitating a more detailed study of SCEs at the Xq27 fragile site.


The evolution of dispersal rates in a heterogeneous time-periodic environment.
A reaction-diffusion model for the evolution of dispersal rates is considered in which there is both spatial heterogeneity and temporal periodicity. The model is restricted to two phenotypes because of technical difficulties, but a wide range of mathematical techniques and computational effort are needed to obtain useful answers. We find that the question of selection is a great deal richer than in the autonomous case, where the phenotype with the lowest diffusion is selected for. In the current model either the lower or higher diffuser rate may be selected, or there may be coexistence of phenotypes. The paper raises several open questions and suggests in particular that a mutation-selection multi-phenotypic model would repay study.


Binding characteristics of [(3)H]-irbesartan to human recombinant angiotensin type 1 receptors.
The aim of the present work was to investigate the binding properties of the selective AT(1)-receptor antagonist irbesartan to human AT(1)-receptors by direct radioligand binding. For this purpose the specific binding of [(3)H]-irbesartan to intact Chinese Hamster Ovary (CHO) cells expressing human recombinant AT(1)-receptors was determined. Specific binding of [(3)H]-irbesartan rapidly reached equilibrium and was saturable with a KD of 1.94 +/- 0.12 to a homogeneous class of binding sites. Its binding was inhibited by other AT(1) antagonists (AIIAs) with the same potency order as previous results from [(3)H]-angiotensin II and [(3)H]-candesartan binding to human AT(1)-receptors. Whereas the dissociation rate of [(3)H]-irbesartan was essentially independent of the radioligand concentration, it was much slower at 12 degrees C when compared with 37 degrees C. Moreover, the dissociation rate was similar, as determined in washout experiments in the absence or presence of unlabelled AT(1) antagonists. At 37 degrees C the dissociation rate constant corresponded to a half-life of approximately seven minutes, which is sufficient to explain the partially insurmountable inhibition by irbesartan in previous studies. In contrast, other phenomena such as the plasma half life and tissue-related factors are necessary to explain its sustained in vivo antihypertensive effect.


Towards assessing corticospinal excitability bilaterally: Validation of a double-coil TMS method.
For several decades, Transcranial magnetic stimulation (TMS) has been used to monitor corticospinal excitability (CSE) changes in various contexts. Habitually, single-coil TMS is applied over one primary motor cortex (M1), eliciting motor-evoked potentials (MEPs) in a contralateral limb muscle, usually a hand effector. However, in many situations, it would be useful to obtain MEPs in both hands simultaneously, to track CSE bilaterally. Such an approach requires stimulating both M1 concurrently while avoiding interference between the two descending stimuli. We examined MEPs obtained at rest using a double-coil TMS approach where the two M1 are stimulated with a 1ms inter-pulse interval (double-coil1ms). MEPs were acquired using double-coil1ms (MEPdouble) or single-coil (MEPsingle) TMS, at five different intensities of stimulation (100, 115, 130, 145 or 160% of the resting motor threshold, rMT). Given the 1ms inter-pulse interval in double-coil1ms trials, MEPdouble were either evoked by a 1st (MEPdouble-1) or a 2nd (MEPdouble-2) TMS pulse. All MEPTYPE (MEPTYPE=MEPsingle, MEPdouble-1 and MEPdouble-2) were equivalent, regardless of the hand within which they were elicited, the intensity of stimulation or the pulse order. This method allows one to observe state-related CSE changes for the two hands simultaneously on a trial-by-trial basis. These results infer the absence of any neural interactions between the two cortico-spinal volleys with double-coil1ms TMS. Hence, this technique can be reliably used to assess CSE bilaterally, opening new research perspectives for scientists interested in physiological markers of activity in the motor output system.


Caring for children affected by disaster.
The child and adolescent psychiatrist must play an essential role in the wake of disaster. The focus of the community and the world understandably turns to the physical devastation wrought, and emergency and medical efforts take center stage. Physical evidence of the past may be lost, but the child psychiatrist is able to maintain focus on what cannot be seen. He or she may be the only one to advocate the child's emotional needs. It may be too difficult for others who lack the specialized expertise of mental health training to attend to both the child's physical and emotional needs, and it may be impossible for those without medical training to impress on medical personnel the importance of emotional issues. The child and adolescent psychiatrist, with his or her understanding of medical, mental health, and developmental concerns, is well positioned to support the child, the child's community, and the helpers whose own responses may complicate recovery.


On-line cloud point extraction combined with electrothermal vaporization inductively coupled plasma atomic emission spectrometry for the speciation of inorganic antimony in environmental and biological samples.
A new method for the determination of inorganic Sb species by on-line cloud point extraction combined with electrothermal vaporization inductively coupled plasma atomic emission spectrometry (ETV-ICP-AES) is presented and evaluated. The method is based on the complexation of Sb(III) with pyrrolidine dithiocarbamate (PDC) which form an hydrophobic complex at pH 5.5 and subsequently enter surfactant-rich phase at pH 5.5, whereas Sb(V) remained in aqueous solutions. The preconcentration step is mediated by micelles of the non-ionic surfactant Triton X-114 with ammonium pyrrolidine dithiocarbamate (APDC). The micellar system containing the complex was loaded into the FIA manifold at a flow rate of 2.5 mL min(-1), and the surfactant-rich phase was retained in a microcolumn packed with absorbent cotton, at pH 5.5. After the surfactant-rich phase was eluted with 100 microL acetonitrile, it was determined by ETV-ICP-AES. Sb(V) is reduced to Sb(III) by l-cysteine prior to determined total Sb, and its assay is based on subtracting Sb(III) from total antimony. The main factors affecting separation/preconcentration and the vaporization behavior of analyte in graphite tube were investigated in detail. Under the optimized conditions, the precision relative standard deviation (R.S.D.) for eight replicate measurements of 0.2 microg mL(-1) Sb(III) was 4.3%. The apparent concentration factor, which is defined as the concentration ratio of the analyte in the final diluted surfactant-rich extract ready for ETV-ICP-AES detection and in the initial solution, was 872 for Sb(III). The limit of detection (LOD) for Sb(III) was 0.09 microg L(-1). The proposed method was successfully applied for the speciation of inorganic antimony in different water samples and urine sample with satisfactory results.


Genome-wide DNA methylation study of hip and knee cartilage reveals embryonic organ and skeletal system morphogenesis as major pathways involved in osteoarthritis.
Evidence suggests that epigenetics plays a role in osteoarthrits (OA). The aim of the study was to describe the genome wide DNA methylation changes in hip and knee OA and identify novel genes and pathways involved in OA by comparing the DNA methylome of the hip and knee osteoarthritic cartilage tissues with those of OA-free individuals. Cartilage samples were collected from hip or knee joint replacement patients either due to primary OA or hip fractures as controls. DNA was extracted from the collected cartilage and assayed by Illumina Infinium HumanMethylation450 BeadChip array, which allows for the analysis of >480,000 CpG sites. Student T-test was conducted for each CpG site and those sites with at least 10 % methylation difference and a p value <0.0005 were defined as differentially methylated regions (DMRs) for OA. A sub-analysis was also done for hip and knee OA separately. DAVID v6.7 was used for the functional annotation clustering of the DMR genes. Clustering analysis was done using multiple dimensional scaling and hierarchical clustering methods. The study included 5 patients with hip OA, 6 patients with knee OA and 7 hip cartilage samples from OA-free individuals. The comparisons of hip, knee and combined hip/knee OA patients with controls resulted in 26, 72, and 103 DMRs, respectively. The comparison between hip and knee OA revealed 67 DMRs. The overall number of the sites after considering the overlaps was 239, among which 151 sites were annotated to 145 genes. One-fifth of these genes were reported in previous studies. The functional annotation clustering of the identified genes revealed clusters significantly enriched in skeletal system morphogenesis and development. The analysis revealed significant difference among OA and OA-free cartilage, but less different between hip OA and knee OA. We found that a number of CpG sites and genes across the genome were differentially methylated in OA patients, a remarkable portion of which seem to be involved in potential etiologic mechanisms of OA. Genes involved in skeletal developmental pathways and embryonic organ morphogenesis may be a potential area for further OA studies.


[Studies on DNA content of tissues and organs. 2nd communication: findings on DNA content in various rat organs 1. during maturation and aging and 2. during experimental pathological models and their therapy (author's transl)].
In this paper the DNA content as a quantitative parameter of the cell content was analyzed on selected rat organs. Aging changes in parenchymatous and connective tissue (= mesenchymal) organs were examined. Further, some pilot studies on experimental animal models of human diseases (experimental shock and liver fibrosis) and their therapy were carried out. In these simulations of human diseases only some preliminary indications about changes in cell or DNA content, resp., of the various organs could be obtained. The results show that these pilot studies justify intensified continuation (in larger series).


Encapsulated papillary carcinoma of breast; a clinicopathological study of 25 cases and literature review with emphasis on high grade variant.
Encapsulated Papillary Carcinoma (EPC) is a rare breast tumor with excellent prognosis. Treatment and stage of EPC is influenced by invasion and high nuclear grade. Our aim was to study the clinicopathological features of EPC, especially high grade tumors and to compare the features of invasive and non-invasive tumors. We reviewed clinicopathological features of 25 cases of EPC diagnosed at our institution from 2006 till 2020. Patients' age ranged from 21 to 75 years (median 55 years). Tumor size ranged from 1 to 9 cm (median 3.5 cm). Overall, invasion was present in 44% cases. High nuclear grade was observed in 24% cases. Majority of these high grade tumors were below 40 years. All of these tumors were 4 cm or larger in size. Two third of these tumors were invasive. Hormone receptor negativity and lymph node involvement was observed in 1 out of 3 cases, when performed. Clinicopathological and histological features of invasive and non-invasive tumors were compared and only lymph node involvement was found to be significantly more frequent in invasive tumors (p = 0.049). Median follow up duration was 18 months. All patients were alive and disease free except for a single patient who died of cerebrovascular accident. EPC has excellent clinical course. Invasion and high nuclear grade should be carefully searched for as these features determine tumor stage and treatment.


Two-Step Azidoalkenylation of Terminal Alkenes Using Iodomethyl Sulfones.
The radical azidoalkylation of alkenes that was initially developed with α-iodoesters and α-iodoketones was extended to other activated iodomethyl derivatives. By using iodomethyl aryl sulfones, the preparation of γ-azidosulfones was easily achieved. Facile conversion of these azidosulfones to homoallylic azides using a Julia-Kocienski olefination reaction is reported, making the whole process equivalent to the azidoalkenylation of terminal alkenes.


Industrial water consumption forecasting based on combined CEEMD-ARIMA model for Henan province, central chain: A case study.
Industrial water consumption is a major component of the total regional water consumption. Accurate and scientific prediction of industrial water consumption is an essential guide to the rational use of natural resources. In this paper, we proposed a combined model of CEEMD (collective empirical modal decomposition) and ARIMA (autoregressive integrated moving average) for forecasting industrial water consumption to establish an accurate and efficient forecasting model, because of the poor generalization ability of most current industrial water consumption forecasting models. The influencing factors of industrial water consumption are complex, and the data are non-stationary. "Decomposition-prediction-reconstruction" is one of the significant methods for forecasting time series data, and the data decomposition has a suppressive influence on the modal mixing problem in the EMD decomposition procedure. Based on the smoothing ability of CEEMD for non-smooth signals and the better adaptation of the autoregressive moving average prediction model (ARIMA), a combined CEEMD-ARIMA model was established for industrial water consumption forecasting. This study was conducted for industrial water consumption in Henan Province in central China. The results suggest the combined CEEMD-ARIMA model has a favorable forecasting effect, with an average relative percentage error of 1.96%, and mean square error (MSE) of 0.35, a Nash efficiency coefficient (NSE) of 0.95, a prediction pass rate of 100%, and a better prediction accuracy than the ARIMA model and the combined EEMD-ARIMA model. It provides an effective prediction method for the prediction of industrial water consumption and has good application prospects.