No cost but high performance-An alternative open source solution for 3D-visualizations in morphology.
3D-visualization has become common courtesy in science and also found its way into teaching in schools and universities. Nevertheless, the way to high performance 3D-visualization and analyses remains difficult and is often also a matter of budget. Due to the obvious advantages of presenting morphological and anatomical datasets with the help of 3D-figures, all in one software solutions usually come along with high rental and maintenance fees. For that reason, it is more than overdue to establish and use open source software solutions with all their obvious advantages - as other disciplines already do. Here we provide a modular, highly adaptive and freely available software pipeline for high performance 3D-visualizations of (not only) morphological datasets by combining features of ImageJ, MeshLab and Blender, without any additional costs. Exemplarily using serial-block face SEM data as well as serial AZAN-stained histological sections, the herein presented step-by-step protocol allows for a fast and efficient analysis, visualization and animation of large, anatomical datasets. Regardless which type of serial, morphological datasets needs to be analyzed, our open source guide provides an easy to handle and promptly adaptable solution. Therefore, our pipeline for 3D-visualization represents a valuable alternative to conventional, commercial packages. RESEARCH HIGHLIGHTS: We provide a highly modular and easy to learn open source solution for multiple 3D-visualizations. The step-by-step-guide make it easy to start, and advanced users can replace software, add others and such build your own individual software pipeline.


Whole-Exome Sequencing in Papillary Microcarcinoma: Potential Early Biomarkers of Lateral Lymph Node Metastasis.
Early identification of patients with high-risk papillary thyroid microcarcinoma (PTMC) that is likely to progress has become a critical challenge. We aimed to identify somatic mutations associated with lateral neck lymph node (LN) metastasis (N1b) in patients with PTMC. Whole-exome sequencing (WES) of 14 PTMCs with no LN metastasis (N0) and 13 N1b PTMCs was performed using primary tumors and matched normal thyroid tissues. The mutational burden was comparable in N0 and N1b tumors, as the median number of mutations was 23 (range, 12 to 46) in N0 and 24 (range, 12 to 50) in N1b PTMC (P=0.918). The most frequent mutations were detected in PGS1, SLC4A8, DAAM2, and HELZ in N1b PTMCs alone, and the K158Q mutation in PGS1 (four patients, Fisher's exact test P=0.041) was significantly enriched in N1b PTMCs. Based on pathway analysis, somatic mutations belonging to the receptor tyrosine kinase-RAS and NOTCH pathways were most frequently affected in N1b PTMCs. We identified four mutations that are predicted to be pathogenic in four genes based on Clinvar and Combined Annotation-Dependent Depletion score: BRAF, USH2A, CFTR, and PHIP. A missense mutation in CFTR and a nonsense mutation in PHIP were detected in N1b PTMCs only, although in one case each. BRAF mutation was detected in both N0 and N1b PTMCs. This first comprehensive WES analysis of the mutational landscape of N0 and N1b PTMCs identified pathogenic genes that affect biological functions associated with the aggressive phenotype of PTMC.


Feasibility of cerebral near-infrared spectroscopy monitoring in the pre-hospital environment.
Traumatic brain injury (TBI) is a significant cause of death and severe disability from trauma. Pre-hospital care of patients with TBI may be aided by non-invasive monitoring of cerebral tissue oxygenation. This pilot observational study was designed to assess if cerebral tissue oximetry using near-infrared spectroscopy (NIRS) is feasible in the pre-hospital and transport environment. After ethics committee review, we undertook a feasibility trial in healthy volunteers, transported by road ambulance or helicopter, to assess if monitoring signals could be obtained in the outside environment and during patient transport. A total of 33 road ambulance transports and 32 helicopter transports were undertaken. For monitoring commenced outdoors, 33 of 66 probes applied (50%) provided adequate monitoring signal. For road transports, 33 out of 33 transports (100%) resulted in successful bilateral monitoring for more than 70% of the sampling period. For helicopter transports, four transports were cut short by battery failure during the mission and 24 of 28 transports (85.7%) resulted in successful bilateral monitoring for more than 70% of the sampling period. While patient and transport platform movement did not impact on monitoring signals, exposure to ambient light provided a challenge in obtaining monitoring signals that is nevertheless manageable with increased probe shielding. NIRS monitoring is feasible in the pre-hospital environment, opening up the possibility for further research of the role of this modality in this setting.


Transcriptional activation of the MICA gene with an engineered CRISPR-Cas9 system.
Major histocompatibility complex class I polypeptide-related sequence A (MICA) is a prototypical NKG2D ligand. Because immune cells, such as natural killer (NK) cells, recognize virally infected or transformed cells and eliminate them through the interaction between NKG2D receptors on NK cells and NKG2D ligands on pathogenic cells, MICA expression levels are associated with NK cell-mediated immunity. Here, we report that an engineered clustered regularly interspaced short palindromic repeats-Cas9-related complex targeting MICA gene promoter sequences activates transcription of the MICA gene from its endogenous locus. Inhibiting microRNA function, which targets the 3' untranslated region of the MICA gene, enhances this activation. These results demonstrate that the combination of Cas9-based transcriptional activators and simultaneous modulation of microRNA function may be a powerful tool for enhancing MICA protein expression and efficient anti-pathogenic cell immunity.


Effect of the Antimicrobial Peptide LL-37 on Gene Expression of Chemokines and 29 Toll-like Receptor-Associated Proteins in Human Gingival Fibroblasts Under Stimulation with Porphyromonas gingivalis Lipopolysaccharide.
The antimicrobial peptide LL-37 neutralizes the biological activity of lipopolysaccharide (LPS), while it upregulates the expression of several immune-related genes. We investigated the effect of LL-37 on gene regulation of human gingival fibroblasts (HGFs), stimulated with or without Porphyromonas gingivalis-derived LPS, a ligand for Toll-like receptor (TLR). LL-37 was non-toxic to HGFs up to a concentration of 10 μg/ml. P. gingivalis LPS upregulated the expression of IL8, CXCL10, and CCL2, whereas LL-37 reduced this upregulation. In absence of LPS, LL-37 itself upregulated the expression of IL8 and CCL2. LL-37 increased the expression of P2X7, which was constitutively expressed in HGFs. The P2X7 antagonist A-438079 suppressed the cytotoxicity and upregulatory effect of LL-37 on chemokine response, but not its downregulatory effect on P. gingivalis LPS-induced chemokine response. Whether LL-37 alters the expression of 29 genes that encode TLR-associated proteins, including TLRs, co-receptors, signaling molecules, and negative regulators, in HGFs, under stimulation with LPS, was examined. Among TLRs, P. gingivalis LPS upregulated the level of TLR4, whereas LL-37 reduced it. In co-receptors, LL-37 downregulated the level of CD14. Among signaling molecules, LL-37 augmented the LPS-upregulated expression of IRAK1. Similar effects were observed in the specific negative regulators TNFAIP3, RNF216, TOLLIP, and SIGIRR. Our results suggest that LL-37 exerts cytotoxicity and upregulation of chemokine response via the P2X7 receptor, while it induces downregulation of P. gingivalis LPS-induced chemokine response through alteration in the expression of 7 specific TLR-associated genes: downregulation of TLR4 and CD14 and upregulation of IRAK1, TNFAIP3, RNF216, TOLLIP, and SIGIRR.


Association between polyneuritis and multiple sclerosis.
We report two cases in which multiple sclerosis and inflammatory polyneuritis occurred separately, and suggest that this association supports the idea that the two conditions may have an aetiological link.


Why the HIV Reservoir Never Runs Dry: Clonal Expansion and the Characteristics of HIV-Infected Cells Challenge Strategies to Cure and Control HIV Infection.
Antiretroviral therapy (ART) effectively reduces cycles of viral replication but does not target proviral populations in cells that persist for prolonged periods and that can undergo clonal expansion. Consequently, chronic human immunodeficiency virus (HIV) infection is sustained during ART by a reservoir of long-lived latently infected cells and their progeny. This proviral landscape undergoes change over time on ART. One of the forces driving change in the landscape is the clonal expansion of infected CD4 T cells, which presents a key obstacle to HIV eradication. Potential mechanisms of clonal expansion include general immune activation, antigenic stimulation, homeostatic proliferation, and provirus-driven clonal expansion, each of which likely contributes in varying, and largely unmeasured, amounts to maintaining the reservoir. The role of clinical events, such as infections or neoplasms, in driving these mechanisms remains uncertain, but characterizing these forces may shed light on approaches to effectively eradicate HIV. A limited number of individuals have been cured of HIV infection in the setting of bone marrow transplant; information from these and other studies may identify the means to eradicate or control the virus without ART. In this review, we describe the mechanisms of HIV-1 persistence and clonal expansion, along with the attempts to modify these factors as part of reservoir reduction and cure strategies.


Human mesenchymal stem cells abrogate experimental allergic encephalomyelitis after intraperitoneal injection, and with sparse CNS infiltration.
Multiple sclerosis is a currently incurable inflammatory demyelinating syndrome. Recent reports suggest that bone marrow derived mesenchymal stem cells may have therapeutic potential in experimental models of demyelinating disease, but various alternative mechanisms, ranging from systemic immune effects to local cell replacement, have been proposed. Here we used intraperitoneal delivery of human mesenchymal stem cells to help test (a) whether human cells can indeed suppress disease, and (b) whether CNS infiltration is required for any beneficial effect. We found pronounced amelioration of clinical disease but profoundly little CNS infiltration. Our findings therefore help confirm the therapeutic potential of mesenchymal stem cells, show that this does indeed extend to human cells, and are consistent with a peripheral or systemic immune effect of human MSCs in this model.


Labeling stem cells in vitro for identification of their differentiated phenotypes after grafting into the CNS.
Labeling stem cells for CNS grafting is an empirical process. Specific protocols cannot be given that will work for all cell types and all applications. We have provided the range of conditions under which various labels have been successfully used in CNS grafting studies, and delineated the parameters that have to be empirically established. Given a clear understanding of the limitations of the respective labels, and the expected outcome of the grafting experiment, these labeling guidelines should enable any investigator to develop a successful labeling approach. Our own personal bias is to use labels that cannot be transferred to host cells. We prefer BrdU, or more often, retrovirally delivered EGFP or lacZ. However, each investigator will have to decide what is optimal for their own cell population and experimental design.


High amylase content of neoplastic pleural and pericardial effusion probably secondary to amylase producing tumor cells: report of 2 cases.
We report two cases of malignant pleural and pericardial effusion respectively secondary to bronchogenic carcinomas. In both effusions, a significant elevation of the Salivary-type-amylase fraction was found, while the corresponding values were normal in serum and urine. Electronmicroscopy of the malignant tumor cells from the pleural effusion showed typical electron-dense granules, suggesting zymogen granules. It is concluded that the high amylase content of the effusions was due to secretion of S-type-isoamylase by the tumor cells.


Multifactorial Model of Dyspnea in Patients With Cancer.
Dyspnea is a common and distressing symptom for patients with cancer. Although the risk factors for dyspnea in patients with cancer are likely to be multifactorial, a comprehensive description of these risk factors and associated mechanisms is not available in the extant literature. A search of all relevant databases, including Cochrane Library, PubMed®, Embase®, Web of Science, and CINAHL®, was done from January 2009 to May 2022. Case-control and cohort studies that had either a cross-sectional or longitudinal design, as well as randomized controlled trials, were included in the review. Peer-reviewed, full-text articles in English were included. Nineteen studies reported on risk factors for dyspnea. The methodologic quality of each study was examined using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. A number of factors can influence the occurrence and severity of dyspnea. Using the Mismatch Theory of Dyspnea as the central core of this Multifactorial Model of Dyspnea in Patients With Cancer, the factors included in this conceptual model are person, clinical, and cancer-related factors, as well as respiratory muscle weakness, co-occurring symptoms, and stress. The Multifactorial Model of Dyspnea in Patients With Cancer can be used by clinicians to evaluate for multiple factors that contribute to dyspnea and to develop individualized and multilevel interventions for patients experiencing this symptom.


Visual Tracking: Hot Pursuit with Tiny Eyes.
Flying insect predators intercept their aerial prey with deadly precision. New research reveals that a tiny robber fly, with a brain smaller than a pinhead, achieves this using the same visual mechanism that we ourselves employ to catch a passing ball.


Intramolecular reorganization energy in zinc phthalocyanine and its fluorinated derivatives: a joint experimental and theoretical study.
We report a high-resolution gas-phase UPS spectrum of zinc phthalocyanine (ZnPc) together with a detailed analysis of the vibronic structure of the first ionization band, showing that presents the lowest value of the intramolecular reorganization energy experimentally reported for a molecular organic semiconductor.


Sepsis awareness and understanding in Australian parents: A National Child Health Poll survey.
The primary aim of the study was to assess parental awareness and understanding of childhood sepsis. Secondary aims included parental knowledge of the signs and symptoms of sepsis, and what parents would do if they suspected sepsis in their own child. An online questionnaire was administered as part of The Royal Children's Hospital National Child Health Poll. The Poll is a quarterly online survey of a sample of Australian families with at least one child aged 0-17 years old, representative by age, sex and state of residence. The questionnaire collected information on parental sepsis awareness, and for those defined as sepsis aware, information was gathered on sepsis knowledge, signs and symptoms, and how they would respond if they thought their child had sepsis. Signs and symptoms highly likely to be suggestive of sepsis were predefined based on published sepsis guidelines and awareness campaigns. The questionnaire was completed by 3352 parents. Of those, 2065 (61.6%) had heard of the term sepsis and 2818 (84.1%) had heard of at least one alternate term for sepsis and were classified as 'sepsis aware'. Of the 'sepsis aware' parents, 82.9% knew that sepsis was a life-threatening condition, but only 33.8% knew that once diagnosed, sepsis may not be curable. Only 27.8% thought that they could recognise the signs of sepsis in their own child. Less than half of respondents correctly identified signs and symptoms that were highly likely to be suggestive of sepsis. Seventy-one per cent of parents said they would seek urgent care at a hospital emergency department or other facility if they thought their child had sepsis, but only 37.3% said they would consider calling an ambulance. There are considerable knowledge gaps in parental awareness and knowledge of sepsis, particularly sepsis recognition. Parental education should target these knowledge gaps in order to improve healthcare-seeking behaviour and communication between parents and healthcare providers in order to facilitate early sepsis diagnosis and treatment.


Characterization of cell death in Escherichia coli mediated by XseA, a large subunit of exonuclease VII.
Exonuclease VII (ExoVII) of Escherichia coli is a single strandspecific DNA nuclease composed of two different subunits: the large subunit, XseA, and the small subunit, XseB. In this study, we found that multicopy single-stranded DNAs (msDNAs), Ec83 and Ec78, are the in vivo substrates of ExoVII; the enzyme cuts the phosphodiester bond between the fourth and fifth nucleotides from the 5'end. We used this msDNA cleavage to assess ExoVII activity in vivo. Both subunits were required for enzyme activity. Expression of XseA without XseB caused cell death, even though no ExoVII activity was detected. The lethality caused by XseA was rescued by surplus XseB. In XseA-induced death, cells were elongated and multinucleated, and their chromosomes were fragmented and condensed; these are the morphological hallmarks of apoptotic cell death in bacteria. A putative caspase recognition sequence (FVAD) was found in XseA, and its hypothetical caspase product with 257 amino acids was as active as the intact protein in inducing cell death. We propose that under ordinary conditions, XseA protects chromosome as a component of the ExoVII enzyme, but in some conditions, the protein causes cell death; the destruction of cell is probably carried out by the amino terminal fragment derived from the cleavage of XseA by caspase-like enzyme.


Hazard assessment of global warming around the world using GIS.
Global warming is among the important environmental problems of the earth. The present research aims to study temperature variations around the world. For this purpose, the monthly temperature data of 178 points from the NOAA site were studied from 1950 to 2019. In this study, the temperature changes were investigated in terms of its increase, decrease, and significance level by the Mann-Kendall method. Geographic Information System (GIS) and interpolation methods were used to determine the changes in temperature in global warming maps. According to the obtained results, except for 3.8% of the designated area, other parts of the world show change toward warmer conditions. Overall, the world's land temperature has increased by 1.08℃ during the study period. Also, about 85% of the designated area shows moderate and severe hazardous conditions in terms of global warming. The spatial analysis showed higher change and hazardous conditions for global warming in mid-longitude and high-latitude close to both poles.


Oxaziclomefone, a new herbicide, inhibits wall expansion in maize cell-cultures without affecting polysaccharide biosynthesis, xyloglucan transglycosylation, peroxidase action or apoplastic ascorbate oxidation.
Oxaziclomefone (OAC), a new herbicide, inhibits cell expansion, especially in roots and cell-cultures of gramineous monocots. OAC does not affect turgor in cultured maize cells, and must therefore inhibit wall-loosening or promote wall-tightening. The effects of OAC in living cultured maize cells on various biochemical processes thought to influence wall extension were studied. OAC did not affect 14C-incorporation from D-[U-14C]glucose into the major sugar residues of the cell wall (cellulosic glucose, non-cellulosic glucose, arabinose, xylose, galactose, mannose or uronic acids). OAC had no effect on 14C-incorporation from trans-[U-14C]cinnamate into wall-bound ferulate or its oxidative coupling-products. OAC did not influence the secretion or in-vivo action of peroxidase or xyloglucan endotransglucosylase activities-proposed wall-tightening and -loosening activities, respectively. The herbicide did not affect the consumption of extracellular L-ascorbate, an apoplastic solute proposed to act as an antioxidant and/or to generate wall-loosening hydroxyl radicals. OAC decreased wall extensibility without influencing the synthesis or post-synthetic modification of major architectural wall components, or the redox environment of the apoplast. The possible value of OAC as a probe to explore aspects of primary cell wall physiology is discussed.


Racial disparity in survival of patients with uterine serous carcinoma: Changes in clinical characteristics, patterns of care and outcomes over time from 1988 to 2011.
To determine if the disparities in the outcome between white (W) and African American (AA) patients with uterine serous carcinoma (USC) have changed over time. Women with USC were identified using the SEER database from 1988 to 2011 (N=7667). Years of the study were divided into three periods (1988-1997, 1998-2004 and 2005-2011). Overall (OS) and disease-specific survivals (DSS) was estimated. Over the three time periods, African American patients continued to be younger and less likely to have cancer directed surgery and extensive lymphadenectomy when compared to white patients. In multivariable analysis adjusting for age, race, marital status, stage, cancer-directed surgery, extent of lymphadenectomy, adjuvant radiation, and geographic location, AA was significantly associated with worse DSS and OS in the three time periods compared to white race. African American patients were 29% (95% CI 1.03-1.62, p=0.027) in 1988-1997, 40% in 1998-2004 (95% CI 1.21-1.63, p<0.0001) and 34% in 2005-2011 (95% CI 1.13-1.59, p=0.0008) more likely to die from uterine cancer compared to their white counterparts. A slight improvement in the difference in OS over time was noted comparing African American and white patients. African American patients were 46% (95% CI 1.23-1.73, p<0.0001) in 1988-1997, 39% in 1998-2004 (95% CI 1.23-1.56, p<0.0001) and 26% in 2005-2011 (95% CI 1.10-1.45, p<0.0001) more likely to die from any cause compared to their white counterparts. Significant improvement in outcome was noted in both racial groups over time. However, African American patients continued to have worse outcome than white patients over time.


Prosaposin knockdown in Caco-2 cells decreases cellular levels of coenzyme Q10 and ATP, and results in the loss of tight junction barriers.
Coenzyme Q10 (CoQ10) is a key component of the mitochondrial electron transfer chain and is one of the most important antioxidants. We previously found that glycoprotein prosaposin (Psap) binds CoQ10 in human cells. Although Psap is expressed in the intestines, its role in the gastrointestinal tract is not clear. To elucidate the role of Psap in the intestines, we established Psap knockdown (KD) Caco-2 cells, which are an intestinal epithelial cell line. Cellular CoQ10 levels decreased significantly in Psap KD Caco-2 cells as compared to parental Caco-2 cells. Cellular ATP levels also decreased significantly in Psap KD Caco-2 cells as compared to parental Caco-2 cells. Lower ATP levels in the intestines have been reported to result in the failure of tight junction formation. As expected, Psap KD Caco-2 monolayers did not produce transepithelial electrical resistance, while parental Caco-2 monolayers did. Moreover, a fluorescent dye, lucifer yellow, leaked out through Psap KD Caco-2 monolayers, whereas it did not through parental Caco-2 monolayers. These results indicate that Psap is essential to maintain cellular levels of CoQ10 and ATP, and consequently to form tight junctions in the gastrointestinal tract.


Level of urinary catecholamine in children with Sleep Disordered Breathing: A systematic review and meta-analysis.
To compare the levels of different urinary catecholamines amongst paediatric patients with and without sleep-disordered breathing (SDB). Literature searches were conducted on PubMed and EMBASE until 25/06/2022. Inclusion criteria were original human studies, English language, paediatric subjects diagnosed with SDB/obstructive sleep apnoea (OSA). The quality of studies was assessed by the Newcastle-Ottawa Quality Assessment (NOSGEN). The registered number of this study on the International Prospective Register of Systematic Reviews (PROSPERO) is CRD42022332939. The main outcome measured was standardised mean difference (SMD) of urinary catecholamine between subjects with and without SDB, between those with and without OSA, and also between subjects with mild OSA and those with moderate/ severe OSA. Sensitivity analyses were performed to avoid bias. 9 studies (8 cross-sectional and 1 cohort study) with a total of 838 subjects, were included in the quantitative analysis. Urine level of noradrenaline was higher in patients with SDB, which included primary snoring (PS), when compared to controls: SMD = 0.86 (95%CI=0.32-1.41; I2=85%, P=0.002). The levels of urinary noradrenaline and adrenaline were higher in children with OSA when compared to controls: SMD = 1.45 (95%CI=0.91-2.00; I2=75%, P < 0.001); SMD = 1.84 (0.00-3.67; I2=97%, P=0.05). Urine level of noradrenaline was higher in subjects with moderate/severe OSA compared to the mild OSA: SMD = 0.55 (95%CI=0.10-1.00; I2=0%, P=0.02). Urinary dopamine was not associated with SDB regardless of severity. Urinary noradrenaline was higher in all patients with SDB. Subjects with OSA, a more severe form of SDB, had higher urine levels of noradrenaline and adrenaline. Hence, noradrenaline and adrenaline may be markers of sympathetic overtone in patients with SDB and could potentially act as surrogate markers for SDB complications. Further studies are needed to assess this association.


Synthetic cathinones (bath salts): legal status and patterns of abuse.
To review the current legal status and patterns of abuse of bath salts. A literature search was conducted through MEDLINE (1950-December 2011), PubMed (1966-December 2011), EMBASE (1966-December 2011), and International Pharmaceutical Abstracts (1970-December 2011) using the search terms bath salts, mephedrone, and methylenedioxypyrovalerone to identify articles on the legal status of bath salts and on studies focusing on patterns of abuse of bath salts. The GovTrack.us Web site was searched to determine the status of federal bills regarding bath salts. The National Association of Boards of Pharmacy and Drug Enforcement Administration Web sites and the Federal Register were also examined to identify legislation on bath salts. Case reports and studies regarding bath salts were examined. Federal laws involving bath salts were also evaluated. The Department of Justice issued a final order in the Federal Register, temporarily placing the 3 synthetic stimulants, mephedrone, methylenedioxypyrovalerone, and methylone, under Schedule I of the Controlled Substances Act. Literature evaluated included case reports, retrospective studies, surveys, toxicology data, and chemical analyses studies. Information in the literature demonstrated that bath salts are highly abused, and common adverse effects include hypertension, tachycardia, and psychiatric symptoms. Psychoactive substances recently sold as bath salts have been placed in Schedule I of the Controlled Substances Act. Pharmacists can play an important role in raising awareness on the dangers of bath salts abuse through patient counseling and community outreach programs. The evidence on legal status and patterns of abuse clearly demonstrates that bath salts contain dangerous substances that should be permanently controlled.


Synthesis of beta-(S-methyl)thioaspartic acid and derivatives.
Beta-(S-Methyl)thioaspartic acid occurs as a posttranslational modification at position 88 in Escherichia coli ribosomal protein S12, a position that is a mutational hotspot resulting in both antibiotic-resistant and antibiotic-sensitive phenotypes. Critical to research designed to determine the biological function of beta-(S-methyl)thioaspartic acid will be the availability of synthetic beta-(S-methyl)thioaspartic acid as well as derivatives designed for peptide incorporation. We report here the synthesis of beta-(S-methyl)thioaspartic acid and derivatives. The installation of the beta-methylthio moiety into the aspartic acid structure was accomplished by electrophilic sulfenylation of N-protected-l-aspartic acid derivatives with 2,4-dinitrophenyl methyl disulfide. Following this key transformation, we were able to prepare protected beta-(S-methyl)thioaspartic acid derivative suitable for peptide coupling.


Antioxidant and cytotoxic effects of hexane extract of Morinda pubescens leaves in human liver cancer cell line.
To evaluate the antioxidant and cytotoxic effects of hexane extract of Morinda pubescens leaves and to find the primary bioactive compound responsible for antioxidant and cytotoxic activities. The individual compounds were isolated using column chromatography and were characterized by spectroscopic techniques. The antioxidant activity was evaluated for all individual isolated compounds by DPPH method using L-Ascorbic acid as standard and cytotoxicity was assessed for the extract and the hyoscyamine by MTT assay, caspase test and RT-PCR study. The antioxidant activity of the isolated compounds and the extract increased as the concentration increased. One of the isolated compound hyoscyamine showed the high antioxidant activity. The extract and the hyoscyamine dose-dependently decreased the cell viability in HepG2 cells. Hyoscyamine induced caspase-3 mediated apoptosis. Up regulation of p53 gene expression provides cue for apoptotic activity of hyoscyamine. The results indicate that hexane extract possessed potent antioxidant and cytotoxic activity and hyoscyamine is the principal bioactive compound in hexane extract.


Evolution of the Flow Patterns After Endovascular Treatment in Patients with High-Grade Carotid Artery Stenosis - the Clinical Value of Insonation of the Supratrochlear Artery and Alternating Flow.
We aimed to describe the evolution of flow pattern in the ophthalmic artery (OA) and supratrochlear artery (SA) by transcranial Doppler (TCD) ipsilateral to a severe proximal carotid artery stenosis before and after staged endovascular treatment (EVT). We insonated and recorded the flow patterns of OA and SA in 63 patients with ≥ 80% carotid artery stenosis before and after staged carotid angioplasty and stenting at 2-4 weeks apart. Based on the direction of OA and SA blood flow, we categorized patients into (1) reversed, (2) alternating, or (3) forward flow, groups. We evaluated the evolving sonographic flow patterns in OA and SA at the 3-time points and correlated them with the stenotic and flow velocity change. Despite the disconcordance between OA and SA, the evolution of flow direction were evoluted from reversed to alternating or from alternating to forward in both OA and SA. OA and SA's disagreement rate at three-time points was 19.1%, 49.2%, and 28.6%, respectively. After angioplasty alone, we detected an alternating flow in 21 (33.3%) and 46 (73.0%) patients in OA and SA, respectively. Alternating flow patterns in SA persisted in 20 patients (31.7%) after stenting. The post-angioplasty residual stenosis did not differ between the three flow pattern groups (p>0.05). An alternating flow in OA or SA might mark the hemodynamic recovery after EVT. Insonation of SA may provide supporting evidence for hemodynamic change in patients with carotid artery stenosis undergoing EVT.


Regulation of ITGA3 by the dual-stranded microRNA-199 family as a potential prognostic marker in bladder cancer.
Based on the microRNA (miRNA) signature of bladder cancer (BC) by deep sequencing, we recently found that several double-stranded mature miRNAs derived from the same pre-miRNAs were sufficiently expressed and acted as tumour suppressors by regulating common target genes in BC. Our deep-sequencing signature of BC showed that all miR-199 family members (miR-199a-3p/-5p and miR-199b-3p/-5p) were also downregulated. We hypothesised that these miRNAs may function as tumour suppressors by regulating common target genes. Functional assays of BC cells were performed using transfection of mature miRNA. In silico analyses and luciferase reporter analyses were applied to identify target genes of these miRNAs. The overall survival of patients with BC in The Cancer Genome Atlas (TCGA) database was evaluated by the Kaplan-Meier method. Restoration of these miRNAs significantly inhibited cell migration and invasion in BC cells. Integrin α3 (ITGA3) was directly regulated by these miRNAs. The Cancer Genome Atlas database showed that patients with low pre-miR-199 family (miR-199a-1/-2 and miR-199b) expression exhibited significantly poorer overall survival compared with patients with high pre-miR-199 family expression. miR-199 family miRNAs functioned as tumour suppressors in BC cells by targeting ITGA3 and might be good prognostic markers for predicting survival in patients with BC.


Interleukin 1 and rheumatoid arthritis.
The erosive changes seen in the joint structures of the rheumatoid arthritic patient can be attributed to the consequences of the action of interleukin 1. Mononuclear leukocytes have been much studied as a source of the interleukin 1, while polymorphonuclear leukocytes have been largely ignored. The hypothesis promulgated here is that polymorphonuclear leukocytes are the source of the interleukin 1 in the joint space in amounts to be arthritogenic in the susceptible patient. It is proposed that the role of the mononuclear leukocytes, which are activated in the systemic circulation, is to induce infiltration of polymorphonuclear leukocytes into the joint space.


Prolonged severe hypercapnia complicating near fatal asthma in a 35-year-old woman.
We describe a patient with a prolonged and severe hypercapnia occurring during an episode of status asthmaticus induced by ophthalmic instillation of carteolol. Prehospital Emergency Medical Service and Pulmonary Intensive Care Unit in a university hospital. A 35-year-old female developed an acute asthma attack while at home, which required advanced life support. On hospital admission, arterial blood gases revealed a PaCO2 of 208 mmHg. Hypercapnia persisted with a PaCO2 of more than 190 mmHg for 10 h, with pH always less than 7.00. The patient was finally discharged after 26 days without sequelae. This case illustrates the cerebral and cardiovascular tolerance of severe and prolonged hypercapnia associated with major acidosis.


Low radiation coronary calcium scoring by dual-source CT with tube current optimization based on patient body size.
Reducing tube voltage from 120 kV to 100 kV during noncontrast CT for the detection of coronary artery calcium reduces patient radiation exposure. We investigated whether coronary calcium scoring by multidetector row CT can be performed at reduced tube current, resulting in lower radiation dose to the patient. Sixty-six outpatients were scanned on the same visit by dual-source CT (DSCT) with a standard protocol (120 kVp, 150 mAs), followed by a scan with reduced tube current: 85 mAs for patients with body mass index (BMI) ≤ 30 kg/m(2) and weight ≤ 85 kg, and 120 mAs for patients with BMI > 30 kg/m(2) or weight > 85 kg. Low-dose scans were scored by an experienced reader blinded to the standard scan. Agatston scores (ASs) and calcium volume for standard versus low-dose scans were 236 ± 581 versus 234 ± 586 (P = 0.65, NS), and 189 ± 460 mm(3) versus 184 ± 455 mm(3) with excellent correlation (r = 1.0, P < 0.0001), and no significant difference (P = 0.14, NS). Effective radiation dose for the low-dose protocol (1.0 ± 0.2 mSv) was significantly lower than for the standard protocol (1.7 ± 0.2 mSv; P < 0.0001). Image noise was higher for the low-dose scan (18.8 ± 5.5 HU vs 15.2 ± 4.8 HU; P < 0.0001), but both were within target limits. Noncontrast CT for measurement of coronary artery calcium with lower tube current optimized for patient body size is equivalent to standard methods at 40% lower radiation dose, indicating that radiation dose can be lowered for coronary calcium scanning.


Interleukin-4 receptor signalling mechanisms and their biological significance.
These studies describe key elements of the means through which the IL-4 receptor transduces functions of IL-4 and show relationships between these biochemical events and the major biological consequences of IL-4 action. In large measure, the control of IL-4-mediated growth and gene activation are segregated to different regions of the cytosolic domain of the receptor. These regions function by interacting with specific signaling molecules, leading to the activation of these molecules and the intracellular signaling pathways that result in the observed biological effects of IL-4.


Rehabilitation of dysphagia following head and neck cancer.
Patients who have cancers of the oral cavity, pharynx, or larynx may be treated with surgery, radiotherapy, chemotherapy, or a combination of these modalities. Each treatment type may have a negative impact on posttreatment swallowing function; these effects are presented in this article. A number of rehabilitative procedures are available to the clinician to reduce or eliminate swallowing disorders in patients treated for cancer of the head and neck. The various procedures-including postures, maneuvers, modifications to bolus volume and viscosity, range-of-motion exercises, and strengthening exercises-and their efficacy in patients treated for head and neck cancer are discussed.


Triple heterozygosity of a hemoglobin variant: hemoglobin Pyrgos with other hemoglobinopathies.
This article is the first report of hemoglobin (Hb) Pyrgos along with other Hbs forming triple-heterozvgous patterns. Of 2 cases, the first occurred in a Thai girl with thalassemic facies, marked anemia, and hepatosplenomegaly, who had Hb Pyrgos in association with Hb H disease with Hb Constant Spring (CS). This case represents a triple heterozygosity comprising Hb Pyrgos, alpha-thalassemia 1, and Hb CS. Hb electrophoresis revealed an abnormal Hb in addition to Hbs CS, A2, A, Bart's, and H. This abnormal Hb moved slightly faster than Hb A but more slowly than Hb Bart's. Polymerase chain reaction revealed that the abnormal Hb was caused by a missense mutation within codon 83 of the beta-globin gene (GGC to GAC) resulting in a glycine-to-aspartic acid substitution, which corresponds to Hb Pyrgos. The patient required blood transfusions by the age of 3 years. A splenectomy was performed when she was 5 years old, after which her hematocrit level remained above 32%. The second case was the patient's older sister who was also triple heterozygous (Hb Pyrgos, E, and CS) but was healthy.


Both early-onset and late-onset ventilator-associated pneumonia are caused mainly by potentially multiresistant bacteria.
To compare the causative pathogens of early-onset and late-onset ventilator-associated pneumonia (VAP) diagnosed by bronchoalveolar lavage quantitative cultures. Most previous reports have been based on endotracheal aspirate cultures and gave uncertain findings. Prospective evaluation of consecutive patients with clinical suspicion for VAP. Multidisciplinary intensive care unit of a university hospital. During a 3-year period 473 patients with clinical suspicion of VAP entered the study. Diagnosis of VAP was confirmed by cultures of bronchoalveolar lavage (> 10(4) cfu/ml) specimens in 408 patients. Protected bronchoalveolar lavage samples were taken. Initial antibiotic therapy was modified upon bronchoalveolar lavage culture results. Among 408 patients 191 had early-onset (< 7 days mechanical ventilation) and 217 late-onset (> or = 7 days) VAP. Potentially multiresistant bacteria, mainly Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA), were the most commonly isolated pathogens in both types of VAP. No difference was noted in the contribution of potentially multiresistant pathogens (79% vs. 85%), P. aeruginosa (42% vs. 47%), or MRSA (33% vs. 30%) between early-onset and late-onset VAP. Initial antibiotic therapy was modified in 58% of early-onset VAP episodes and in 36% of late-onset VAP episodes. No difference in mortality was found between the two types of VAP. Both early-onset and late-onset VAP were mainly caused by potentially multiresistant bacteria, most commonly P. aeruginosa and MRSA. Antimicrobial agents against these pathogens should be prescribed empirically, at least in our institution.


Comparative profiling of ovarian and testicular piRNAs in the mud crab Scylla paramamosain.
PIWI-interacting RNAs (piRNAs) are abundantly found in germ cells and involved in gametogenesis and gonadal development. Information on the regulatory roles of piRNAs in crustacean reproduction, however, is scarce. Thus, we identified gonadal piRNAs of mud crab Scylla paramamosain. Of the 115,491 novel piRNAs, 596 were differentially expressed. Subsequently, 389,887 potential piRNA-target genes were predicted. The expression of 4 piRNAs and 9 genes with high piRNA interactions were validated with the inclusion of additional immature specimens, including LRP2 that is involved in growth and reproduction, MDN1 in ribosome biogenesis pathway and gametogenesis, and PRKDC, a DNA repair gene involved in gonadal differentiation and maturation. KEGG analysis further revealed the involvement of predicted piRNA target genes in gametogenesis- and reproduction-related pathways. Our findings provide baseline information of mud crab piRNAs and their differential expression between testes and ovaries suggests that piRNAs play an essential role in regulating gametogenesis and gonadal development.


Rapid Normalization of High Glutamic Acid Decarboxylase Autoantibody Titers and Preserved Endogenous Insulin Secretion in a Patient with Diabetes Mellitus: A Case Report and Literature Review.
A 59-year-old Japanese woman developed diabetes mellitus without ketoacidosis in the presence of glutamic acid decarboxylase autoantibody (GADA) (24.7 U/mL). After the amelioration of her hyperglycemia, the patient had a relatively preserved serum C-peptide level. Her endogenous insulin secretion capacity remained almost unchanged during 5 years of insulin therapy. The patient's GADA titers normalized within 15 months. The islet-related autoantibodies, including GADA, are believed to be produced following the autoimmune destruction of pancreatic beta cells and are predictive markers of type 1 diabetes mellitus. Therefore, the transient appearance of GADA in our patient may have reflected pancreatic autoimmune processes that terminated without progression to insulin deficiency.


Pharmacokinetic and pharmacoimmunodynamic interactions between prednisolone and sirolimus in rabbits.
To assess pharmacokinetic and pharmacoimmunodynamic interactions between prednisolone (Pred, I1 mg/kg) and sirolimus (Sir, 0.25 mg/kg) in rabbits. After intravenous administration, plasma concentrations of Pred and corticosterone, and Sir blood concentrations were followed for 24 hours along with blood granulocyte and T-helper cell counts. Ex vivo and in vitro whole blood lymphocyte proliferation marked lymphocyte reactivity. Pred terminal half-life and clearance were 1.1 hr and 0.72 l/hr/kg with no difference after Sir. Sir values were 13 hr and 0.16 l/hr/kg and Pred produced no changes. Corticosterone production (0-12hr) was suppressed by 55% after Pred alone or combined, while Sir did not cause adrenal suppression. Blood T-helper cells and granulocytes displayed circadian rhythms after placebo. Over 12 hr, T-helper cell counts were decreased by Pred (40%) and Sir (19%) while granulocyte numbers increased by 56% and 23%. After coadministration, cell numbers were similar to Pred alone. Pred and Sir decreased lymphocyte reactivity by 41% and 56% over 24 hr and their combination reached 85% inhibition with additive interaction. In vitro studies showed antagonistic or synergistic interactions depending on drug concentration ratios. At therapeutic concentrations, Sir and Pred do not significantly interact pharmacokinetically and have additive pharmacoimmunodynamics. Thus, the therapeutic application of this combination is promising.


Effect of COVID-19 vaccination and booster on maternal-fetal outcomes: a retrospective cohort study.
COVID-19 in pregnant people increases the risk for poor maternal-fetal outcomes. However, COVID-19 vaccination hesitancy remains due to concerns over the vaccine's potential effects on maternal-fetal outcomes. Here we examine the impact of COVID-19 vaccination and boosters on maternal SARS-CoV-2 infections and birth outcomes. This was a retrospective multicentre cohort study on the impact of COVID-19 vaccination on maternal-fetal outcomes for people who delivered (n=106 428) at Providence St Joseph Health across seven western US states from Jan 26, 2021 to Oct 26, 2022. Cohorts were defined by vaccination status at delivery: vaccinated (n=35 926; two or more doses of mRNA-1273 Moderna or BNT162b2 Pfizer-BioNTech), unvaccinated (n=55 878), unvaccinated propensity score matched (n=16 771), boosted (n=10 927; three or more doses), vaccinated unboosted (n=13 243; two doses only), and vaccinated unboosted with propensity score matching (n=4414). We built supervised machine learning classification models, which we used to determine which people were more likely to be vaccinated or boosted at delivery. The primary outcome was maternal SARS-CoV-2 infection. COVID-19 vaccination status at delivery, COVID-19-related health care, preterm birth, stillbirth, and very low birthweight were evaluated as secondary outcomes. Vaccinated people were more likely to conceive later in the pandemic, have commercial insurance, be older, live in areas with lower household composition vulnerability, and have a higher BMI than unvaccinated people. Boosted people were more likely to have more days since receiving the second COVID-19 vaccine dose, conceive earlier in the pandemic, have commercial insurance, be older, and live in areas with lower household composition vulnerability than vaccinated unboosted people. Vaccinated pregnant people had lower rates of COVID-19 during pregnancy (4·0%) compared with unvaccinated matched people (5·3%; p<0·0001). COVID-19 rates were even lower in boosted people (3·2%) compared with vaccinated unboosted matched people (5·6%; p<0·0001). Vaccinated people were also less likely to have a preterm birth (7·9%; p<0·0001), stillbirth (0·3%; p<0·0002), or very low birthweight neonate (1·0%; p<0·0001) compared with unvaccinated matched people (preterm birth 9·4%; stillbirth 0·6%; very low birthweight 1·5%). Boosted people were less likely to have a stillbirth (0·3%; p<0·025) and have no differences in rates of preterm birth (7·6%; p=0·090) or very low birthweight neonates (0·8%; p=0·092) compared with vaccinated unboosted matched people (stillbirth 0·5%; preterm birth 8·4%; very low birthweight 1·1%). COVID-19 vaccination protects against adverse maternal-fetal outcomes, with booster doses conferring additional protection. Pregnant people should be high priority for vaccination and stay up to date with their COVID-19 vaccination schedule. National Institute for Child Health & Human Development and the William O and K Carole Ellison Foundation.


Physical activity, sedentary time, and fitness in relation to brain shapes in children with overweight/obesity: Links to intelligence.
To examine the association between physical activity, sedentary time, and physical fitness with the shapes of subcortical brain structures in children with overweight/obesity. Further, we analyzed whether differences in the shapes of subcortical brain structures were related to intelligence. We hypothesized that those children with higher physical activity levels, lower sedentary time, and better fitness, would show greater expansion of the brain regions analyzed, and these expansions would be associated with higher intelligence. 100 children (10.0 ± 1.1 years, 40 girls) were included in the analyses. Physical activity and sedentary time were measured by accelerometry, and physical fitness was evaluated by a fitness battery. Shapes of subcortical brain structures were assessed by magnetic resonance imaging. Intelligence was measured by the Kaufmann Brief Intelligence test. Physical activity was related to expansion of the right/left pallidum, right/left putamen, and right thalamus (p < 0.05). Higher sedentary time was related to contraction of the left thalamus and right nucleus accumbens (p < 0.05). Higher levels of cardiorespiratory fitness were associated with expansion of the right amygdala (p = 0.022). Greater strength in the upper-limb was related to expansion of the right/left pallidum and the left nucleus accumbens (p < 0.038), and contraction of the left amygdala (p = 0.030). Better speed-agility was associated with expansion of the left nucleus accumbens (p = 0.036). Physical activity- and fitness-related expansion of the right pallidum was associated with higher intelligence (all p < 0.05). Physical activity, sedentary time, and physical fitness were significantly related to the shapes of subcortical brain structures, which in turn were related to intelligence in children with overweight/obesity.


The quality of nifedipine studies used to assess tocolytic efficacy: a systematic review.
To assess the quality of studies of nifedipine used to treat spontaneous preterm labor. A systematic review of study quality using a novel validity assessment tool, examining method-specific and topic-specific items in the domains of selection, performance and measurement biases. Medline (1996-2003), EMBASE (1996-2003), BIOSIS (1993-2003), Current Contents (1995-2003), DERWENT DRUGFILE (1983-2003), Cochrane Database of Systematic Reviews. Bibliographies of existing meta-analyses and systematic reviews of nifedipine as a tocolytic. Forty-five studies evaluating the effectiveness of nifedipine were identified. Each study was assessed for 40 method-specific and topic-specific items of quality in duplicate using piloted data extraction forms. Disagreements between assessors were settled by consensus/arbitration. Very few of the studies complied with adequacy criteria of quality for either method-specific or topic-specific items. There was no improvement in quality over time. The quality of method-specific items was significantly poorer when compared with topic-specific items of quality overall (P<0.0001) and in the domains of selection bias (P<0.0001) and performance bias (P<0.0001). Studies of the effectiveness of nifedipine as a tocolytic are of poorer quality with respect to method-specific items than topic-specific items. These deficiencies should be highlighted in meta-analyses or systematic reviews which measure efficacy and should influence the generation of guideline statements or recommendations for the use of nifedipine as a tocolytic. A large randomized trial fulfilling the quality items is necessary to assess the real efficacy of nifedipine in preterm labor.


The acute effects of repetitive transcranial magnetic stimulation on laminar diffusion anisotropy of neocortical gray matter.
Repetitive transcranial magnetic stimulation (rTMS) is increasingly used to treat neuropsychiatric disorders. Inhibitory and excitatory regimens have been both adopted but the exact mechanism of action remains unclear, and investigating their differential effects on laminar diffusion profiles of neocortex may add important evidence. Twenty healthy participants were randomly assigned to receive a low-frequency/inhibitory or high-frequency/excitatory rTMS targeting the left dorsolateral prefrontal cortex (DLPFC). With the brand-new submillimeter diffusion tensor imaging of whole brain and specialized surface-based laminar analysis, fractional anisotropy (FA) and mean diffusion (MD) profiles of cortical layers at different cortical depths were characterized before/after rTMS. Inhibitory and excitatory rTMS both showed impacts on diffusion metrics of somatosensory, limbic, and sensory regions, but different patterns of changes were observed-increased FA with inhibitory rTMS, whereas decreased FA with excitatory rTMS. More importantly, laminar analysis indicated laminar specificity of changes in somatosensory regions during different rTMS patterns-inhibitory rTMS affected the superficial layers contralateral to the DLPFC, while excitatory rTMS led to changes in the intermediate/deep layers bilateral to the DLPFC. These findings provide novel insights into acute neurobiological effects on diffusion profiles of rTMS that may add critical evidence relevant to different protocols of rTMS on neocortex.


Cruciferous Vegetable Intake and Risk of Prostate Cancer: A Systematic Review and Meta-Analysis.
The relationship between cruciferous vegetables and prostate cancer (PCa) risk remains contentious. This study aimed to assess the association between consuming cruciferous vegetables and PCa risk. We carried out a systematic search through PubMed, Embase, Web of Science, and the Cochrane Library until September 20, 2022. The results of the article will be analyzed using the Stata 14 software. This meta-analysis was reported as directed by the PRISMA guidance, and the study protocol was recorded in PROSPERO (CRD42022361556). 7 case-control studies and 9 cohort studies were eventually included, including 70,201 PCa cases and 1,264,437 members. The higher the intake of cruciferous vegetables, the lower the risk of PCa. In comparison to the lowest dose of cruciferous vegetables, the overall relative risk (RR) of cruciferous vegetables having the highest dose was 0.87 (95% confidence interval [CI]: 0.80-0.95; I2 = 59.2%). A significant linear trend (p = 0.002) was observed for the association, with a combined RR of 0.955 (95% CI: 0.928-0.982) for every 15 g of cruciferous vegetables per day. The study revealed that consumption of cruciferous vegetables may be linked to reduced PCa risk.


New 23-valent pneumococcal vaccine in relation to pneumococcal serotypes in systemic and non-systemic disease.
The serotype distribution of 3631 strains of Streptococcus pneumoniae, isolated from various specimens obtained from patients was determined by coagglutination and included serotyping within a total of 13 serogroups. The results of serotyping of isolates from Scotland demonstrated that the new 23-valent pneumococcal vaccine includes serotypes which accounted for 91% strains associated with systemic disease and 79% strains isolated from other anatomical sites. Altogether, 114 strains (3.1%) were not typable because they did not possess a type-specific capsule; these were commonly isolated from eyes (12%).


CT demonstration of extension of renal angiomyolipoma into the inferior vena cava in a patient with tuberous sclerosis.
The authors present a case of tumor thrombus in the inferior vena cava produced by angiomyolipoma in a young woman with tuberous sclerosis. Diagnosis was made by computed tomography (CT) by measuring the attenuation values of the tumor thrombus. The values obtained were characteristic of fat, demonstrating that tumoral invasion was the cause of the thrombus. To our knowledge, this is the first description of such an association shown by CT in the literature.


Bolting induction in Oenothera erythrosepala Borbás in relation to rosette size, vernalization, and photoperiod.
The relationships between rosette size, vernalization, and photoperiod in bolting induction of Oenothera erythrosepala (a facultative biennial) were examined. A natural population of O. erythrosepala in a sand dune system at Azigaura, Japan, behaves as a monocarpic perennial, while a population treated with fertilizer showed the life cycle of a winter annual. In both natural and fertilized populations, bolting was restricted to size classes with rosette diameter greater than 9 cm, regardless of the chronological age and the amount of food reserves accumulated in the tap root. Pot culture experiments showed that the species requires both vernalization and long-day photoperiod for bolting induction, and has a critical leaf area for receiving photoperiodic stimuli. The amount of food reserves in the plant per se does not contribute to the size-dependent flowering of the species.


Review of Podothrips from China (Thysanoptera, Phlaeothripidae), with one new species and three new records.
Podothrips species occur on the leaves of various Poaceae, including bamboo and grasses. An illustrated identification key is given here to the six Podothrips species recorded from China. These include P. femoralis Dang & Qiao, sp. nov., and P. sasacola Kurosawa, P. odonaspicola (Kurosawa), and P. semiflavus Hood that are newly recorded from China.


Aspects of Program Engagement in an Online Physical Activity Intervention and Baseline Predictors of Engagement.
Participant engagement in an online physical activity (PA) intervention is described and baseline factors related to engagement are identified. Longitudinal Study Within Randomized Controlled Trial. Online/Internet. Primary care patients (21-70 years). ActiveGOALS was a 3-month, self-directed online PA intervention (15 total lessons, remote coaching support, and a body-worn step-counter). Engagement was measured across six outcomes related to lesson completion (total number and time to complete), coach contact, and behavior tracking (PA, sedentary). Self-reported baseline factors were examined from seven domains (confidence, environment, health, health care, demographic, lifestyle, and quality of life). General linear and nonlinear mixed models were used to examine relationships between baseline factors and engagement outcomes within and across all domains. Seventy-nine participants were included in the sample (77.2% female; 74.7% white non-Hispanic). Program engagement was high (58.2% completed all lessons; PA was tracked ≥3 times/week for 11.3 ± 4.0 weeks on average). Average time between completed lessons (days) was longer than expected and participants only contacted their coach about 1 of every 3 weeks. Individual predictors related to health, health care, demographics, lifestyle, and quality of life were significantly related to engagement. Examining multiple aspects of engagement and a large number of potential predictors of engagement is likely needed to determine facilitators and barriers for high engagement in multi-faceted online intervention programs.


Hyaluronate binding and degradation by cultured embryonic chick cardiac cushion and myocardial cells.
Cultured cells obtained from developing chick heart valvular and septal primordial tissues (cardiac cushions) and myocardium were tested for their capacity to bind, internalize, and degrade hyaluronate. A presumptive lysosomal hyaluronidase capable of hyaluronate degradation has been previously isolated and partially characterized from cultures enriched in either cushion tissue cells or myocardial cells (D. H. Bernanke and R. W. Orkin, 1984, Dev. Biol. 106, 351-359). In this study, both types of cultures were found to bind hyaluronate, but only the myocardial cultures could degrade the hyaluronate substrate. The lack of hyaluronate degradative capacity in the mesenchymal cushion tissue cells appears to result from their inability to internalize the macromolecule, thus failing to make it available to the lysosomal hyaluronidase. The data suggest that hyaluronate clearance from the extracellular matrix of the developing cushion is a complex process, involving more than simple extracellular degradation adjacent to the migrating mesenchymal cushion tissue cells. Instead, a sequence of events may be indicated which includes binding of hyaluronate to the cushion tissue cell surfaces and its transport by these cells across the cushion matrix toward the myocardium. The myocardium may be involved in the ultimate removal of hyaluronate from the cardiac jelly.


Radiofrequency identification tag system improves the efficiency of closed vitrification for cryopreservation and thawing of bovine ovarian tissues.
A radiofrequency identification (RFID) tag system was designed to streamline cryopreservation and thawing procedures. This study evaluated the usefulness of the RFID tag system for improving the efficiency of cryopreserving/thawing bovine ovarian tissue by the closed vitrification protocol. Six participants carried out closed vitrification and thawing of bovine ovarian tissues procedures using either the conventional or the new RFID tag method, and the time required to perform each step of the respective methods was measured. After normality of data was confirmed by the Shapiro-Wilk test, the significance of differences was assessed by the unpaired t test. When closed vitrification was performed, the time required for each step showed a significant difference between the two methods (t(4) = 2.938, p = 0.042, d = 2.40), and the total cryopreservation time was 11 min shorter using the RFID tag system. When thawing was performed, the time required for each step also showed a significant difference between the two methods (t(4) = 2.797, p = 0.049, d = 2.28), and the total thawing time was 2 min shorter using the RFID tag system. The RFID tag system tested in this study seems to be suitable for managing biological samples stored in liquid nitrogen. Adoption of an RFID tag system by fertility centers may not only improve the efficiency of cryopreserving/thawing reproductive tissues but could also reduce human error.


From representation to mediation: the shaping of collective mobilization on muscular dystrophy in France.
How, and to what extent, do patient organisations renew traditional forms of social participation and protest? This question is examined, drawing on a socio-historical case study of the Association Française contre les Myopathies--French Muscular Dystrophy Organisation (AFM). The originality of the AFM is that it has not been content to endorse the classic role of representation of people with muscular dystrophy (MD) and their families. It has also articulated and structured different social spaces that allow people suffering from genetic diseases and severe disabilities to be considered as fully-fledged human beings, persons, and citizens within those spaces. Based on quantitative data and methods, this paper aims to characterize this reconfiguration of social spaces that the AFM has undertaken. My contention is that it has given shape to a different form of collective mobilization, one in which the patient organisation is a mediator between different social actors, as much as a patients' representative. It helps a new issue, here MD, to emerge so that the largest possible collective designate it as a general public concern. As we shall discuss, this renews the question of patients' collective identity and citizenship.


Synthesis of Ribo-Azanucleosides by Anodic Oxidation: Reactivity Control of Intermediate for Efficient Access to Pharmacophores.
Azanucleosides, the sugar-modified nucleoside analogues, have various biological activities, while their efficient synthetic strategy is still under development. Herein, a novel method for the synthesis of pharmaceutically relevant azanucleosides, β-anomers of ribo-azanucleosides, by means of site-specific anodic C-H activation by using a nitroalkane-lithium perchlorate medium is reported. A mechanistic study of the electrochemical reaction and the armed/disarmed concept from traditional glycochemistry revealed that the 2'-substituent has a significant effect on the reactivity of prolinol derivative, and suitable carboxylic acid additives can control the reactivity of the intermediate species, an iminium cation equivalent. Finally, this method was demonstrated to be applicable for the synthesis of β-anomers of ribo-azanucleosides with all four nucleobases in a stereoselective manner.


Increased myelosuppression during cytostatic treatment and pleural effusion in patients with small cell lung cancer.
30 patients with small cell lung cancer (SCLC) and malignant pleural effusion were compared with 30 matched patients with SCLC but without pleural effusion. In the 30 with pleural effusion, white blood cell and platelet counts fell significantly after initial chemotherapy, necessitating dose reduction. Of the patients with pleural effusion, 16 developed severe (WHO grade IV) leukopenia, 7 had severe thrombocytopenia, and 2 patients died of infection. Accordingly, exhaustive aspiration of radiologically verified pleural effusion before starting chemotherapy in patients with SCLC is recommended.


WITHDRAWN: Laterality and frequency settings of subthalamic nucleus DBS for Parkinson's disease: A systematic review and network meta-analysis.
This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/policies/article-withdrawal.


Comparison of two aerosol-based detectors for the analysis of gabapentin in pharmaceutical formulations by hydrophilic interaction chromatography.
Comparison of hydrophilic interaction chromatography (HILIC) columns coupled with an evaporative light scattering detector (ELSD) or charged aerosol detector (CAD) was done for the detection of gabapentin in pharmaceutical formulations. The chromatographic separations were achieved on four HILIC columns: ZIC HILIC, ZIC pHILIC, Luna HILIC, and Atlantis HILIC. Experimental factors such as mobile phase composition, acetonitrile content, and mobile phase pH were evaluated. Validation of method was done in terms of linearity, sensitivity, accuracy, and precision. The performance of ELSD detection method is comparable to that of CAD. The intra-day and inter-day variations were below 1.7% and 3.2% for CAD and 2.8%, and 3.4% for ELSD, respectively. In addition, detection sensitivities of ELSD, CAD, and UV detectors were also compared for HILIC and reversed phase (RP) modes and the highest sensitivities were obtained in the HILIC mode when connected with CAD and ELSD. The developed HILIC aerosol based detection methods were successfully applied to the analysis of gabapentin in commercial tablets and capsules.


[Localization of a 1-anilinonaphthalen-8-sulfonate fluorescent probe on the surface monolayer of low density lipoproteins].
A decay of fluorescence probe 1-anilino-8-naphtalene sulfonate (ANS) sorbed on low density lipoproteins (LDL) surface obtained from human plasma was described. It was demonstrated that on the LDL surface the ANS probe is allocated among two pools of molecules with the time of fluorescence decay 4-7 ns and 12-16 ns. One may conclude that 75-90% of the probe is connected with lipid LDL matrix.


Molecular epidemiology of Bartonella species from sympatric mammals collected in urban and rural areas of Punjab, Pakistan.
Bartonella can infect a variety of mammals including humans and has been detected in the Americas, Europe, Africa, and Asia. Roughly two-thirds of identified Bartonella species are found and maintained in rodent reservoirs, with some of these species linked to human infections. Rodents (N=236) were caught from the Sahiwal division of Punjab, Pakistan and tested for Bartonella using PCR targeting gltA and rpoB genes, followed by sequencing of rpoB-positive samples. Genetic relatedness to other published Bartonella spp. rpoB gene sequences were examined using BLAST and phylogenetic analysis. Overall, 7.62% (18/236) of rodents were positive for both gltA and rpoB fragments. Rattus rattus and R. norvegicus had 7.94% (12/151) and 7.05% (6/85) positivity rates for Bartonella DNA, respectively. Phylogenetic analysis revealed a close relatedness between Bartonella spp. from Pakistan to Bartonella spp. from China, Nepal, and Malaysia. This study is the first reported detection of Bartonella spp. in R. rattus and R. norvegicus from the Sahiwal area of Punjab, Pakistan.


Behavioral Engagement With Playable Objects Resolves Stress-Induced Adaptive Changes by Reshaping the Reward System.
The reward system regulates motivated behavior, and repeated practice of specific motivated behavior might conversely modify the reward system. However, the detailed mechanisms by which they reciprocally regulate each other are not clearly understood. Mice subjected to chronic restraint stress show long-lasting depressive-like behavior, which is rescued by continual engagement with playable objects. A series of molecular, pharmacological, genetic, and behavioral analyses, combined with microarray, liquid chromatography, and chemogenetic tools, are used to investigate the neural mechanisms of antidepressive effects of playable objects. Here, we show that repeated restraint induces dopamine surges into the nucleus accumbens-lateral shell (NAc-lSh), which cause upregulation of the neuropeptide PACAP in the NAc-lSh. As repeated stress is continued, the dopamine surge by stressors is adaptively suppressed without restoring PACAP upregulation, and the resulting enhanced PACAP inputs from NAc-lSh neurons to the ventral pallidum facilitate depressive-like behaviors. Continual engagement with playable objects in mice subjected to chronic stress remediates reduced dopamine response to new stressors, enhanced PACAP upregulation, and depressive-like behaviors. Overactivation of dopamine D1 receptors over the action of D2 receptors in the NAc-lSh promotes depressive-like behaviors. Conversely, inhibition of D1 receptors or PACAP upregulation in the NAc-lSh confers resilience to chronic stress-induced depressive-like behaviors. Histochemical and chemogenetic analyses reveal that engagement with playable objects produces antidepressive effects by reshaping the ventral tegmental area-to-NAc-lSh and NAc-lSh-to-ventral pallidum circuits. These results suggest that behavioral engagement with playable objects remediates depressive-like behaviors by resolving stress-induced maladaptive changes in the reward system.


Comparison of clot-based, chromogenic and fluorescence assays for measurement of factor VIII inhibitors in the US Hemophilia Inhibitor Research Study.
Detection and validation of inhibitors (antibodies) to hemophilia treatment products are important for clinical care, evaluation of product safety and assessment of population trends. Centralized monitoring for factor VIII (FVIII) inhibitors was conducted for patients in the Hemophilia Inhibitor Research Study using a previously reported modified Nijmegen-Bethesda clotting assay (NBA), a chromogenic Bethesda assay (CBA) and a novel fluorescence immunoassay (FLI). NBA and CBA were performed on 1005 specimens and FLI on 272 specimens. CBA was negative on 880/883 specimens (99.7%) with Nijmegen-Bethesda units (NBU) < 0.5 and positive on 42/42 specimens (100%) with NBU ≥ 2.0 and 43/80 specimens (53.8%) with NBU 0.5-1.9. Among specimens with positive NBA and negative CBA, 58.1% were FLI negative, 12.9% had evidence of lupus anticoagulant, and 35.5% had non-time-dependent inhibition. CBA and FLI were positive on 72.4% and 100% of 1.0-1.9 NBU specimens and 43.1% and 50.0% of 0.5-0.9 NBU specimens. FLI detected antibodies in 98.0% of CBA-positive and 81.6% of NBA-positive specimens (P = 0.004). Among 21 new inhibitors detected by NBA, five (23.8%) with 0.7-1.3 NBU did not react in CBA or FLI. Among previously positive patients with 0.5-1.9 NBU, 7/25 (28%) were not CBA or FLI positive. FLI was positive on 36/169 NBU-negative specimens (21.3%). FVIII specificity could not be demonstrated by CBA or FLI for 26% of inhibitors of 0.5-1.9 NBU; such results must be interpreted with caution. Low titer inhibitors detected in clot-based assays should always be repeated, with consideration given to evaluating their reactivity with FVIII using more specific assays.


Influence of paper electrocardiogram digitizing on T wave and QRS complex morphology parameters.
Many morphological parameters of the electrocardiogram (ECG) can be calculated from a digital ECG and paper prints of ECG after digitizing. However, the digitizing process, including printing, scanning, ECG contour extraction, and alignment, can produce changes to the signals, reducing the reliability of some sensitive parameters of QRS complex and T wave. The influence of the digitizing process on the parameters of T wave and QRS complex morphology was studied by comparing systematically the values of the nine ECG morphology parameters, computed from the digital ECG and the corresponding paper ECG. The robustness of the parameters to the digitizing process and their discrimination ability between healthy subjects and postinfarction patients were investigated. The standard T wave parameters and all selected dipolar loop-parameters retained their robustness and discrimination ability during the digitizing process of the paper ECGs. The non-dipolar parameters distorted strongly, especially those of the QRS complex. The T wave-based non-dipolar parameters retained their discrimination ability during the digitizing process. The selected standard T wave parameters and the dipolar loop-parameters calculated from properly digitized ECG paper prints can be utilized in patient studies. Non-dipolar parameters distort strongly but T wave-based parameters retain discriminatory information.


Distribution and effect of water content on molecular mobility in poly(vinylpyrrolidone) glasses: a molecular dynamics simulation.
This work explores the distribution of water and its effects on molecular mobilities in poly(vinylpyrrolidone) (PVP) glasses using molecular dynamics (MD) simulation technology. PVP glasses containing 0.5% and 10% w/w water and a small amount of ammonia and Phe-Asn-Gly were generated. Physical aging processes and associated structural and dynamic properties were monitored vs. time for periods up to 0.1 micros by MD simulation. Increasing water content from 0.5% to 10% w/w was found to reduce the Tg by about 90 K and increase the rates of volume and enthalpy relaxation. At 0.5% w/w, water molecules are mostly isolated and uniformly distributed while at 10% w/w, water distribution is markedly heterogeneous, with strands of water molecules occupying channels between the polymer chains. At 10% w/w, each water molecule has an average of 2.0 neighboring water molecules. The plasticization effects of water were revealed in diffusion coefficient increases of 3.7-, 7.3-, and 7.6-fold for water, ammonia, and the individual polyvinylpyrrolidone segments, respectively, and in shorter relaxation times (37- to 47-fold) for rotation of polymer segments with an elevation in water content from 0.5% to 10% w/w. Water diffusivity was found to linearly correlate with the number of neighboring water molecules. Rotation of the PVP segments is comprised of a fast wobble motion within a highly restrained cavity and a slow rotation over a wider angular space. Only the slow rotation was shown to be significantly affected by water content. Water distribution in the PVP glass is highly heterogeneous at 10% w/w water, reflecting the formation of water strands or small clusters rather than complete phase separation. Local enhancement of mobility with increasing water content has been demonstrated using MD simulations.


A kinematic comparison of successful and unsuccessful tennis serves across the elite development pathway.
While velocity generation is an obvious prerequisite to proficient tennis serve performance, it is also the only stroke where players are obliged to negotiate a unique target constraint. Therefore, the dearth of research attending to the accuracy component of the serve is surprising. This study compared the body, racquet and ball kinematics characterising successful serves and service faults, missed into the net, in two groups of elite junior female players and one professional female tennis player. Three-dimensional body, racquet and ball kinematics were recorded using a 22-camera VICON motion analysis system. There were no differences in body kinematics between successful serves and service faults, suggesting that service faults cannot be attributed to a single source of biomechanical error. However, service faults missing into the net are characterized by projection angles significantly further below the horizontal, implying that consistency in this end-point parameter is critical to successful performance. Regulation of this parameter appears dependent on compensatory adjustments in the distal elbow and wrist joints immediately prior to impact and also perceptual feedback. Accordingly, coordination of the distal degrees of freedom and a refined perception-action coupling appear more important to success than any isolated mechanical component of the service action.


Filgotinib: First Approval.
Filgotinib (Jyseleca®) is an oral, ATP-competitive, reversible JAK1 preferential inhibitor that is being developed by Galapagos NV and Gilead Sciences for the treatment of inflammatory autoimmune diseases, including inflammatory arthritis and inflammatory bowel disease. The JAK-STAT signalling pathway has been implicated in the pathogenesis of inflammatory and autoimmune diseases, and filgotinib modulates this pathway by preventing the phosphorylation and activation of STATs. In September 2020, filgotinib received its first approvals in the EU and Japan. In the EU, filgotinib is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adults who have responded inadequately to, or who are intolerant to, one or more disease-modifying anti-rheumatic drugs (DMARDs). In Japan, filgotinib is indicated for the treatment of RA in patients who had an inadequate response to conventional therapies (including prevention of structural damage to joints). Clinical studies of filgotinib for the treatment of inflammatory autoimmune diseases are ongoing worldwide. This article summarizes the milestones in the development of filgotinib leading to this first approval.


Diurnal and nutritional adjustments of intracellular Ca2+ release channels and Ca2+ ATPases associated with restricted feeding schedules in the rat liver.
Intracellular calcium is a biochemical messenger that regulates part of the metabolic adaptations in the daily fed-fast cycle. The aim of this study was to characterize the 24-h variations of the liver ryanodine and IP3 receptors (RyR and IP3R) as well as of the endoplasmic-reticulum and plasma-membrane Ca2+-ATPases (SERCA and PMCA) in daytime restricted feeding protocol. A biochemical and immunohistochemical approach was implemented in this study: specific ligand-binding for RyR and IP3R, enzymatic activity (SERCA and PMCA), and protein levels and zonational hepatic-distribution were determined by immunoblot and immunohistochemistry respectively under conditions of fasting, feeding, and temporal food-restriction. Binding assays and immunoblots for IP3R1 and 2 showed a peak at the light/dark transition in the ad-libitum (AL) group, whereas in the restricted-feeding (RF) group the peak shifted towards the food-access time. In the case of RyR binding experiments, both AL and RF groups showed a modest elevation during the dark period, with the RF rats exhibiting increased binding in response to feeding. The AL group showed 24-h rhythmicity in SERCA level; in contrast, RF group showed a pronounced amplitude elevation and a peak phase-shift during the light-period in SERCA level and activity. The activity of PMCA was constant along day in both groups; PMCA1 levels showed a 24-h rhythmicity in the RF rats (with a peak in the light period), meanwhile PMCA4 protein levels showed rhythmicity in both groups. The fasted condition promoted an increase in IP3R binding and protein level; re-feeding increased the amount of RyR; neither the activity nor expression of SERCA and PMCA protein was affected by fasting-re-feeding conditions. Histochemical experiments showed that the distribution of the Ca2+-handling proteins, between periportal and pericentral zones of the liver, varied with the time of day and the feeding protocol. Our findings show that RF influences mainly the phase and amplitude of hepatic IP3R and SERCA rhythms as well as discrete zonational distribution for RyR, IP3Rs, SERCA, and PMCA within the liver acinus, suggesting that intracellular calcium dynamics could be part of the rheostatic adaptation of the liver due to diurnal meal entrainment/food entrained oscillator expression.


Protocol to obtain high-quality single-cell RNA-sequencing data from mouse liver cells using centrifugation.
High-quality single-cell RNA-sequencing data of liver cells, especially hepatocytes, are challenging due to cell death associated with hepatocyte isolation using fluorescence-activated cell sorting (FACS). Here, we present a protocol to obtain viable hepatocytes and nonparenchymal liver cells for scRNA-seq, using centrifugation. We detail steps for liver wash and enzyme perfusion, followed by in vitro dissociation of liver cells and gradient centrifugation. We further describe hepatocytes harvesting for subsequent viability check and scRNA-seq. For complete details on the use and execution of this protocol, please refer to Wang et al. (2021) and Mederacke et al. (2015).


A case report: retigabine induced oral mucosal dyspigmentation of the hard palate.
Dyspigmentation of the oral mucosa has a multitude of aetiological causes. Retigabine, a new antiepileptic drug, has the potential side effect of inducing a blue/purple pigmentation of the oral mucosa in addition to the skin, lips, nails and retina of the eyes. This article presents a unique case of dyspigmentation present in the oral mucosa of the hard palate which has previously been unreported in the dental literature. A 70 year old white male presented to a secondary care oral surgery department with an unusual asymptomatic pigmented lesion present in the hard palate of the oral cavity. The pigmentation was remarkable for its distinct blue/purple colouration which was associated with a similar discolouration of the nail beds of the hands. This is believed to be a side effect of the anti-epileptic medication retigabine. The dental profession and wider healthcare community should be made fully aware of the potential side effect of oral dyspigmentation associated with the novel anti-epileptic medication retigabine. Enhanced knowledge of the causative role of retigabine in dyspigementation of the oral mucosa will allow the practitioner to make an appropriate diagnosis. As far the authors are aware this is reaction is unreported in the dental literature and should be disseminated to the wider oral health professional's community.


The timing of fasting leads to different levels of food consumption and PYY3-36 in nocturnal mice.
The daily circadian cycle is known to modulate both feeding behavior and metabolism. As such, the timing of food consumption can play a role in regulating overall health. The purpose of this study is to determine whether fasting at different times of the day alters subsequent food consumption and levels of PYY3-36, a hormone secreted after a meal which inhibits appetite. Separate groups of mice were fasted at different times of the day: (1) start of the day, (2) middle of the day, (3) start of the night, and (4) middle of the night, and either injected with vehicle or PYY3-36 to assess their subsequent food consumption patterns, PYY3-36 levels, and glucose and insulin levels. We also investigated whether light exposure during the night would alter food consumption and PYY3-36 levels after fasting. Mice fasted during the start of the daytime exhibited increased food consumption post-fast compared to mice fasted during the night. Injections of PYY3-36 during the night were more effective in reducing food consumption compared to PYY3-36 administration during the day. Constant light exposure suppressed food consumption after fasting and increased fasting PYY3-36 levels. These results indicate that mice exhibit distinct food consumption patterns after being presented with a fast at different times of the day. Light exposure also modulates both food consumption after a fast and levels of PYY3-36.


Correction: An acoustofluidic device for efficient mixing over a wide range of flow rates.
Correction for 'An acoustofluidic device for efficient mixing over a wide range of flow rates' by Hunter Bachman et al., Lab Chip, 2020, 20, 1238-1248, DOI: .


Recent Progress on Nanostructured Layered Double Hydroxides for Visible-Light-Induced Photoreduction of CO2.
Photoreduction of CO2 into solar fuels is usually regarded as one of the promising solutions to overcome environmental pollution and the energy crisis. The main challenge in CO2 photoreduction (CO2 PR) is the low efficiency and poor selectivity. Layered double hydroxides (LDHs) are a class of 2D materials, consisting with M(OH)6 octahedra in the host layers and intercalated anions. Owing to the tuneable composition, particle size, morphology, and virtue coordinatively unsaturated active sites, a series of efficient strategies (morphology control, heterostructure, defect control, etc.) in LDH-based photocatalysts have been efficiently developed to enhance the photocatalytic selectivity and activity for CO2 PR. This review summarizes recent progress on the LDH-based photocatalysts for CO2 PR.


Remote monitoring of neuraxial function in anesthetized dogs in compression chambers.
This paper describes the development of an electrophysiological model using spinal and cortical evoked potentials (SEP, CEP), for the diagnosis and monitoring of spinal cord decompression sickness (DCS) in anesthetized dogs. A comparison of alpha-chloralose with sodium pentobarbital showed that the latter caused a reduction in CEP amplitude. Continuous observation of EPs over 5 h showed a small reduction and an increasing variance of amplitude with time. The effectiveness of the method in the diagnosis of DCS and in studies of the adequacy of treatment is illustrated with several examples.


Retrograde transvenous ethanol embolization of high-flow peripheral arteriovenous malformations.
To report the clinical efficiency and complications in patients treated with retrograde transvenous ethanol embolization of high-flow peripheral arteriovenous malformations (AVMs). Retrograde transvenous ethanol embolization of high-flow AVMs is a technique that can be used to treat AVMs with a dominant outflow vein whenever conventional interventional procedures have proved insufficient. This is a retrospective study of the clinical effectiveness and complications of retrograde embolization in five patients who had previously undergone multiple arterial embolization procedures without clinical success. Clinical outcomes were good in all patients but were achieved at the cost of serious, although transient, complications in three patients. Retrograde transvenous ethanol embolization is a highly effective therapy for high-flow AVMs. However, because of the high complication rate, it should be reserved as a last resort, to be used after conventional treatment options have failed.


The leader sequence of the Escherichia coli lysC gene is involved in the regulation of LysC synthesis.
In Escherichia coli and Bacillus subtilis, long leader sequences are found upstream of the lysC coding sequences which encode lysine-sensitive aspartokinase. Highly conserved regions exist between these sequences. Mutations leading to constitutive expression of the E. coli lysC gene have been localised within these conserved regions, indicating that they participate in the lysine-mediated repression mechanism of lysC expression.


Improved effects of a double suicide gene system on prostate cancer cells by targeted regulation of prostate-specific membrane antigen promoter and enhancer.
To explore the specific killing effect on prostate cancer cells of a dual cytosine deaminase (CD) and uracil phosphoribosyltransferase (UPRT) expression plasmid system controlled by the prostate-specific membrane antigen (PSMA) promoter and enhancer. The CD gene was used to construct the recombinant plasmid prostate-specific membrane antigen(promoter/enhancer)-CD (pPSMA(E/P)-CD). The specific regulatory function of the pPSMA(E/P) promoter was demonstrated by detection of enhanced green fluorescent protein (EGFP) expression in the LNCaP cell line. Survival of cells transfected with different plasmids and treated with 5-fluorocytosine (5-FC) was measured by microculture tetrazolium assay. Cell cycle changes were measured by flow cytometry. Target-specific expression of PSMA(E/P) was observed in the prostate cancer cell line. Cytotoxicity of 5-FC was greater against LNCaP cells transfected with pPSMA(E/P)-CD and UPRT and pPSMA(E/P)-CD than control groups. Percentages of cells in S phase were 37.5% (LNCaP) and 30.6% (5-FC treatment) in the un-transfected groups, whereas they were 23.9% and 12.4% in the double and single suicide gene groups, respectively. Our findings confirm the cytotoxic efficacy of the pPSMA(E/P)-CD + 5-FC and pPSMA(E/P)-CD and UPRT + 5-FC suicide gene systems. The CD and UPRT gene system quickly and directly converted 5-FC into 5-FU, and then into toxic metabolites. The CD and UPRT double suicide gene system was more effective in inducing tumor cell apoptosis with 5-FC than the single suicide gene system. Thus, this construct can specifically target prostate cancer cells and might have a role in gene therapy against prostate cancer.


Embryonic develop-associated gene 1 is overexpressed and acts as a tumor promoter in thyroid carcinoma.
Embryonic develop-associated gene 1 (EDAG-1), a hematopoietic tissue-specific protein, is usually highly expressed in the placenta, fetal liver, bone marrow and leukemia cells, but the expression status in normal or solid tumor tissues is rarely reported. In this study, we found that EDAG-1 was up-regulated in thyroid carcinoma tissues and cells. Knockdown of EDAG-1 suppressed proliferation and enhanced cisplatin-induced apoptosis of thyroid carcinoma cells. We also demonstrated that knockdown of EDAG-1 inactivated the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway in vitro and in vivo. Moreover, knockdown of EDAG-1 suppressed tumorigenesis of thyroid carcinoma in vivo. Taken together, these results suggest that EDAG-1 regulates the proliferation and apoptosis of thyroid carcinoma via the PI3K/Akt signaling pathway.


Corneal amyloidosis associated with keratoconus.
Nodular, gray-white, central corneal opacities which extended from the subepithelial zone through the anterior four fifths of the stroma developed in a 50-year-old man with a longstanding history of hard contact lens wear for keratoconus. Results of histopathologic analysis of the corneal button obtained at the time of penetrating keratoplasty disclosed that the opacities were composed of amyloid. Corneal amyloidosis is rarely found in association with keratoconus. Although there were some similarities in the pattern of amyloid deposition to that seen in primary familial amyloidosis of the cornea, the authors believe that their patient is more likely to have had a secondary amyloidosis. Corneal amyloidosis should be considered in keratoconus patients with development of unusual forms of central corneal opacification.


Transcriptome analysis of the endangered Chinese giant salamander (Andrias davidianus): Immune modulation in response to Aeromonas hydrophila infection.
The endangered Chinese giant salamander (Andrias davidianus) is the largest extant amphibian species. Disease outbreaks represent one of the major factors threatening A. davidianus populations in the wild and the viability of artificial breeding programmes. Development of future immune therapies to eliminate infectious disease in A. davidianus is dependent on a thorough understanding of the immune mechanisms elicited by pathogen encounters. To this end we have undertaken, for the first time in amphibians, differential transcriptome analysis of the giant salamander response to Aeromonas hydrophila, one of the most devastating pathogens affecting amphibian populations. Out of 87,204 non-redundant consensus unigenes 19,216 were annotated, 6834 of which were upregulated and 906 down-regulated following bacterial infection. 2058 unigenes were involved with immune system processes, including 287 differentially expressed unigenes indicative of the impact of bacterial infection on several innate and adaptive immune pathways in the giant salamander. Other pathways not directly associated with immune-related activity were differentially expressed, including developmental, structural, molecular and growth processes. Overall, this work provides valuable insights into the underlying immune mechanisms elicited during bacterial infection in amphibians that may aid in the future development of disease control measures in protecting the Chinese giant salamander. With the unique position of amphibians in the transition of tetrapods from aquatic to terrestrial habitats, our study will also be invaluable towards the further understanding of the evolution of tetrapod immunity.


Prostaglandin 9-hydroxydehydrogenase activity in the adult rat kidney. Identification, assay, pathway, and some enzyme properties.
Prostaglandin F2alpha is converted to 15-keto-13,14-dihydroprostaglandin E2 by adult rat kidney homogenates. A variety of substrates labeled as either the 9beta position alone or at several other positions in the prostaglandin molecule were used to define the step at which the crossover from the F type to the E type prostaglandins takes place. Time course studies further confirmed that 15-keto-13,14-dihydroprostaglandin F2alpha is the immediate substrate for this enzyme which we have termed prostaglandin 9-hydroxydehydrogenase. An assay system based on specific loss of tritium from 9beta-tritiated prostaglandin F2alpha is described. Enzyme activity with prostaglandin F2alpha as substrate is linear with time up to 10 min, stimulated by NAD+, saturable at low concentrations of substrate, stable to storage at minus 25 degrees in phosphate buffer (up to 3 weeks), and has a broad pH optimum around 7.5. The product, 15-keto,13,14-dihydroprostaglandin E2 was identified by mass spectrometry through a sodium borohydride-sodium borodeuteride reduction method.


Prevention of infection in open fractures: Where are the pendulums now?
Soft tissue management and fracture fixation including initial external fixation in Gustilo-Anderson type II and type III open fractures are cornerstones in the treatment but details on timing and type of wound closure, irrigation and debridement, systemic and local antibiotics, antimicrobial-coated implants and the use of Bone Morphogenetic Protein-2 remain controversial. This article looks at current clinical evidence of these items for the management of open fractures. Timing of debridement and wound closure remains critical. Early debridement by an experienced team within 24 h seems adequate while gross contamination, a devascularized limb, a multi-injured patient and compartment syndrome require immediate surgical intervention. Wound closure during the first surgery was shown to result in reduced rates for infections and nonunion. If soft-tissue reconstruction is needed, it should be performed within the first 7 days. Regarding types of irrigation fluid, antiseptic and antibacterial solutions did not prove to be superior to saline. High pressure irrigation has not been demonstrated to be beneficial whereas antibiotic administration as soon as possible has been proven to be favorable. Administration of more than 72 h was not superior to shorter systemic antibiotic intervals. For Gustilo-Anderson type I and II, broad spectrum antibiotic therapy is reasonable. Additional aminoglycosides for broader coverage are recommended in Gustilo-Anderson type III fractures. There is newer literature on the beneficial effects of the use of local antibiotics, e.g. by antibiotic beads. Coating of internal fixation devices is a modern approach to improve infection prophylaxis and gentamicin-coated implants have been demonstrated to be safe in clinical application. Vacuum assisted closure (VAC) could not evidence negative pressure wound therapy to reduce infection risk, improve self-rated disability or quality of life in open fractures, however, enhance treatment costs. Recombinant human bone morphogenetic proteins (rhBMP)-2 showed promising data in Gustilo-Anderson type III open tibial shaft fractures with lower rates of invasive secondary procedures. In conclusion, there is evidence for thorough debridement and irrigation with saline, early soft tissue coverage and the use of systemic and local antibiotics. Except for a short-term soft tissue coverage VAC seems not to be beneficial and rhBMP-2 is an additional tool in Gustilo-Anderson type III open fractures.


Low dose tunicamycin enhances atherosclerotic plaque stability by inducing autophagy.
After decades of indolent progression, atherosclerosis may cause unheralded events, such as myocardial infarction, acute coronary syndrome and stroke due to sudden rupture of atherosclerotic plaques, and pharmacologically modulating plaque stability would reduce the risk of cardiovascular diseases. Endoplasmic reticulum stress (ERS) is responsible for the vulnerability of plaques. However, the underlying mechanism has not been fully elucidated. In this work, ApoE(-/-) mice underwent perivascular carotid collar placement surgeries or sham operations were given higher (3.0mg/kg) and lower (0.3mg/kg) doses of tunicamycin (TM), and plaque stability was evaluated. It was shown that lower TM-treated animals exhibited reduced plaque areas and necrotic cores as well as fibrous cap thickness accompanied by a lower percentage of infiltrates and foam cells than the sham-operated and higher TM treated animals. Lower TM had a profound inhibitory effect on plasma inflammatory response and lipid profile in atherosclerotic ApoE(-/-) mice. In addition, we found that the ApoE(-/-) mice presented higher autophagy activity in response to lower TM administration while apoptosis was reduced. An in vitro study in murine macrophages revealed that lower TM could markedly reduce lipid uptake and accumulation and cell apoptosis while significantly upregulated the expression of Atg7. However, higher TM had adverse effects. Finally, mild induction of ERS by lower TM inhibits AKT-TSC-mTOR cascades to increase cellular autophagy. However, high TM failed to enhance autophagy and equilibrate elevated CHOP-mediated cell death in spite of the inhibition of AKT-TSC-mTOR signaling. In conclusion, lower TM stabilized plaques by activating autophagy through AKT-TSC-mTOR signaling.