[The prognostic value of cardio-pulmonary exercise test parameters in patients with asymptomatic ischemic heart dysfunction during 2-years observation].
Measurement of oxygen uptake at the maximal exercise (VO2max) in the cardio-pulmonary exercise test provides the most reliable information about exertion tolerance. Establishment of VO2peak, VE/CO2 and AT value in the early diagnosis of asymptomatic heart dysfunction in patients with coronary disease (CAD) and prognosis during 2-years observation. The study population: 57 patients (35 M) with CAD, without any signs or symptoms of heart dysfunction, without any features of myocardial infarction, in the age 51.08 +/- 4.01. The analysis was performed twice: in the beginning and after 2-years observation. Physical examinations, echocardiographic parameters [(assessment of systolic and diastolic dysfunction of the left ventricle (LV)] and spiroergometric parameters (VO2peak, VE/CO2 at AT). On the basis of echocardiographic examination, there were created groups of patients: Group A--the patients with normal LV function (n=32; 56.2%; 23 M); Group B--the patients with diastolic heart dysfunction (n=22; 38.6%; 10 M); Group A--32 patients in the age of 50.9 +/- 4, 23 men. Values of VO2pe ak :28.8 +/- 6 ml/kg/min, VE/CO2 28.8 +/- 4.9 and AT 18 +/- 2.5. Group B--the patients with diastolic heart dysfunction: 22 (39%) patients; 10 men, in the age of 51.2 +/- 4.3. Values of VO2peak: 26 +/- 3.4 mi/ kg/min, VE/CO2 31.2 +/- 5.1 and AT 16 +/- 2.5. In the beginning of the study was established significantly differences between anaerobic threshold and degree of heart dysfunction (p=0.039). (1) There was observed that VO2 A and VE/CO2 depended on filling LV profile LV and also of systolic LV function. Anaerobic threshold significantly depended on LV filling pattern. (2) In asymptomatic patients with LV diastolic dysfunction and VO2peak < or = 18.4 ml/kg/min was observed progression of LV diastolic dysfunction during two years.


Circ_0001273 downregulation inhibits the growth, migration and glutamine metabolism of esophageal cancer cells via targeting the miR-622/SLC1A5 signaling axis.
Esophageal cancer is a relatively rare cancer. However, its death rate is not to be taken lightly. Accumulating evidence indicates circular RNA (circRNA) is implicated in cancer development. The objective of this study was to unveil the role of circ_0001273 in esophageal cancer (EC). For expression analysis of circ_0001273, miR-622 and solute carrier family 1 member 5 (SLC1A5), quantitative real-time PCR (qPCR) and Western blot were conducted. Cell proliferation was evaluated by cell counting kit-8 (CCK-8), EdU and colony formation assays. Cell apoptosis and cell migration were investigated using flow cytometry assay and wound healing assay. Glutamine metabolism was assessed by glutamine consumption and glutamate production using matched kits. The predicted binding relationship between miR-622 and circ_0001273 or SLC1A5 was validated by dual-luciferase reporter assay. An in vivo xenograft model was established to determine the role of circ_0001273 on tumor growth. Circ_0001273 was upregulated in EC tumor tissues and cells. Knockdown of circ_0001273 repressed EC cell proliferation, migration, epithelial-mesenchymal transition (EMT) and glutamine metabolism. Circ_0001273 knockdown also blocked tumor development in animal models. MiR-622 was targeted by circ_0001273, and its inhibition reversed the functional effects of circ_0001273 knockdown. SLC1A5 was a target gene of miR-622, and circ_0001273 targeted miR-622 to positively regulate SLC1A5 expression. The inhibitory effects of miR-622 enrichment on EC cell proliferation, migration, EMT and glutamine metabolism were recovered by SLC1A5 overexpression. Circ_0001273 high expression contributed to EC progression via modulating the miR-622/SLC1A5 signaling axis.


Generation of a sheep x mouse heterohybridoma cell line (1C6.3a6T.1D7) and evaluation of its use in the production of ovine monoclonal antibodies.
A stable aminopterin-sensitive sheep X mouse heterohybridoma cell line (1C6.3a6T.1D7) for use in the generation of sheep monoclonal antibodies is described. The line was first constructed by fusing the mouse myeloma line, NSO, to normal sheep lymphocytes obtained from the efferent lymphatic vessel of a cannulated popliteal lymph node. The line was rendered sensitive to aminopterin through a combination of irradiation and treatment with the anti-metabolite drug 6-thioguanine. Characterisation of the cloned cell line showed that it did not secrete sheep immunoglobulin (Ig) molecules, express Ig on the surface membrane, or express normal sheep B or T cell surface markers. The 1C6.3a6T.1D7 line has remained stable in tissue culture for over 2 years, showing no signs of reversion to aminopterin resistance. The 1C6.3a6T.1D7 cells have been used as fusion partners with lymphocytes from antigen primed sheep to generate sheep monoclonal antibodies to human chorionic gonadotropin (hCG) or a synthetic peptide analogue of the VP1 capsid protein of foot and mouth disease virus (FMDV). To optimise the efficiency of heterohybridoma generation, comparisons were made of peripheral blood, efferent lymph or excised lymph nodes as sources of antigen-stimulated lymphocytes for fusion. The results showed that lymphocytes prepared from either efferent lymph or lymph node on the fourth day following antigenic stimulation gave similar high fusion efficiencies, and both were vastly superior to peripheral blood lymphocytes. Results were also obtained which showed that the blast cells present in lymphoid tissues due to antigenic stimulation were the major cell types involved in the generation of viable antibody-secreting sheep X sheep X mouse heterohybridomas.


Anti-Frameshifting Ligand Active against SARS Coronavirus-2 Is Resistant to Natural Mutations of the Frameshift-Stimulatory Pseudoknot.
SARS-CoV-2 uses -1 programmed ribosomal frameshifting (-1 PRF) to control expression of key viral proteins. Because modulating -1 PRF can attenuate the virus, ligands binding to the RNA pseudoknot that stimulates -1 PRF may have therapeutic potential. Mutations in the pseudoknot have occurred during the pandemic, but how they affect -1 PRF efficiency and ligand activity is unknown. Studying a panel of six mutations in key regions of the pseudoknot, we found that most did not change -1 PRF levels, even when base-pairing was disrupted, but one led to a striking 3-fold decrease, suggesting SARS-CoV-2 may be less sensitive to -1 PRF modulation than expected. Examining the effects of a small-molecule -1 PRF inhibitor active against SARS-CoV-2, it had a similar effect on all mutants tested, regardless of basal -1 PRF efficiency, indicating that anti-frameshifting activity can be resistant to natural pseudoknot mutations. These results have important implications for therapeutic strategies targeting SARS-CoV-2 through modulation of -1 PRF.


Defining the pathway for Tat-mediated delivery of beta-glucuronidase in cultured cells and MPS VII mice.
We used recombinant forms of human beta-glucuronidase (GUS) purified from secretions from stably transfected CHO cells to compare the native enzyme to a GUS-Tat C-terminal fusion protein containing the 11-amino-acid HIV Tat protein transduction domain for: (1) susceptibility to endocytosis by cultured cells, (2) rate of clearance following intravenous infusion, and (3) tissue distribution and effectiveness in clearing lysosomal storage following infusion in the MPS VII mouse. We found: (1) Native GUS was more efficiently taken up by cultured human fibroblasts and its endocytosis was exclusively mediated by the M6P receptor. The GUS-Tat fusion protein showed only 30-50% as much M6P-receptor-mediated uptake, but also was taken up by adsorptive endocytosis through binding of the positively charged Tat peptide to cell surface proteoglycans. (2) GUS-Tat was less rapidly cleared from the circulation in the rat (t(1/2) = 13 min vs 7 min). (3) Delivery to most tissues of the MPS VII mouse was similar, but GUS-Tat was more efficiently delivered to kidney. Histology showed that GUS-Tat more efficiently reduced storage in renal tubules, retina, and bone. These studies demonstrate that Tat modification can extend the range of tissues corrected by infused enzyme.


Comparison between fluoropyrimidine-hepatic arterial infusion and systemic chemotherapy for unresectable liver metastases: A protocol for systematic review and meta-analysis based on 16 observational studies.
The benefit of loco-regional treatments such as hepatic arterial infusion (HAI) in terms of survival and response rate is unclear. The aim of this work is to quantitatively summarize the results of both randomized controlled trials (RCTs) and non-randomized studies of interventions (NRSIs) comparing fluoropyrimidine-HAI (F-HAI) to systemic chemotherapy (SCT) for the treatment of colorectal liver metastases (CRLMs). We searched the Cochrane Library, PubMed, EMBASE, and Web of Science up to July 1, 2021. The outcome measures were tumor response rate and overall survival (OS). Both RCTs and NRSIs comparing HAI to SCT for patients with unresectable CRLMs were included. The outcome measures were tumor response rate and OS. Two reviewers assessed trial quality and extracted data independently. All statistical analyses were performed using standard statistical procedures provided in Review Manager 5.2. A total of 16 studies including 11 RCTs and 5 NRSIs were identified for the present meta-analysis. Nine RCTs compared F-HAI to SCT for patients with unresectable CRLMs and the pooled result indicated that patients who received F-HAI experienced more than twofold response rate than SCT, with a pooled risk ratio of 2.10 (95%CI 1.59-2.79; P < .00001). In addition, the pooled result based on RCTs showed that F-HAI had a significant benefit regarding OS, with a pooled HR of 0.83 (95% CI 0.70-0.99; P = .04). Similarly, the benefit of F-HAI in terms of OS was also observed in the results of NRSIs. Our results indicated that the F-HAI regimen had a greater tumor response rate and survival advantage than SCT for patients with unresectable CRLMs. Future propensity score-matched analyses with a large sample size should be conducted to support the evidence of our results based on RCTs and NRSIs.


Delayed bronchial stenosis after blunt chest trauma with right aortic arch.
We report a case of delayed bronchial stenosis after blunt chest trauma with right aortic arch. A 21-year-old male passenger was involved in a traffic accident. He was brought to an emergency hospital with severe chest pain and dyspnea, and diagnosed with multiple rib fractures, right hemopneumothorax and chylothorax. He was treated with chest tube drainage and the symptoms subsided. About 9 weeks later, he complained of exertional dyspnea and was referred to our hospital. Bronchoscopy demonstrated circumferential stenosis of the right main bronchus approximately 1 cm distal to the carina. Thoracic computed tomography and magnetic resonance imaging revealed the right aortic arch. Successful resection of the bronchial stenotic lesion was performed followed by end-to-end anastomosis through midsternotomy due to the associated right aortic arch. Postoperative bronchoscopy revealed that the site of the anastomosis was patent and his symptoms were relieved.


Interaction of viscotoxins A3 and B with membrane model systems: implications to their mechanism of action.
Viscotoxins are small proteins that are thought to interact with biomembranes, displaying different toxic activities against a varied number of cell types, being viscotoxin A(3) (VtA(3)) the most cytotoxic whereas viscotoxin B (VtB) is the less potent. By using infrared and fluorescence spectroscopies, we have studied the interaction of VtA(3) and VtB, both wild and reduced ones, with model membranes containing negatively charged phospholipids. Both VtA(3) and VtB present a high conformational stability, and a similar conformation both in solution and when bound to membranes. In solution, the infrared spectra of the reduced proteins show an increase in bandwidth compared to the nonreduced ones indicating a greater flexibility. VtA(3) and VtB bind with high affinity to membranes containing negatively charged phospholipids and are motional restricted, their binding being dependent on phospholipid composition. Whereas nonreduced proteins maintain their structure when bound to membranes, reduced ones aggregate. Furthermore, leakage experiments show that wild proteins were capable of disrupting membranes whereas reduced proteins were not. The effect of VtA(3) and VtB on membranes having different phospholipid composition is diverse, affecting the cooperativity and fluidity of the membranes. Viscotoxins interact with membranes in a complex way, most likely organizing themselves at the surface inducing the appearance of defects that lead to the destabilization and disruption of the membrane bilayer.


Facial Arterial Variations in Asians: A Study on Computed Tomographic Angiography.
A consensus on facial artery anatomy has not been established due to the discrepancies in previous studies. The authors sought to assess the branches, course, and location of the facial artery in Asians by utilizing computed tomographic angiography. The computed tomographic angiography images of 300 facial arteries from 150 Asian patients were evaluated. The FA was classified as follows: type 1, facial artery terminates superior labial or inferior labial artery; type 2, facial artery terminates lateral nasal or inferior alar artery; type 3, facial artery terminates medial canthal artery; or type 4, facial artery is divided into duplex branches with dominant medial canthal artery laterally. The relationship between nasolabial fold and FA was evaluated, and the distances from anatomical landmarks to FA were measured to position the course. Seventy (23.3%), 163 (54.3%), 49 (16.3%), and the other 18 arteries (6.0%) were classified as type 1, 2, 3, and 4, respectively. A total 72.3% of facial arteries were located medially to the nasolabial fold, and only 14.7% of arteries were lateral to the nasolabial fold. The vertical distance between the facial artery and the inner canthus or the midpoint of the inferior orbital rim decreased from type 1 to type 4 facial artery (P < 0.0001). The 4 types did not significantly differ in distance between the mandibular angle (P = 0.1226) or oral commissure (P = 0.1030) and the facial artery at inferior of mandible. Detailed findings of the facial artery will provide a valuable reference for filler injection in cosmetic procedures and flap design in reconstructive surgery.


Scanning electron microscopic studies and growth response of the plants of Helianthus annuus L. grown on tannery sludge amended soil.
The plants of Helianthus annuus L. var. modern were grown in the soil amended with different amounts of tannery sludge (10%, 25%, 35%, 50%, 75% and 100%), collected from Wastewater Treatment Plant Jajmau, Kanpur (Uttar Pradesh, India) under field conditions. The effect of tannery sludge amendments was studied on the growth performance of the plant, i.e. root length, shoot length, leaf area and number of leaves after 30, 60 and 90 days of exposures. The root length of the plant increased up to 35% tannery sludge followed by significant (p<0.01) decrease at higher amendments, whereas the shoot length of the plant increased with increase in sludge amendment ratio at all the exposure periods, compared to their respective controls. The number of leaves and leaf area in the plants of H. annuus increased at all the amendments of tannery sludge at initial exposure periods (30 and 60 days); however, it decreased at higher sludge amendments at highest exposure period (90 days) as compared to their respective controls. The analysis of scanning electron micrographs of the leaf surface of H. annuus grown on 50% and 100% tannery sludge after 90 days showed an increase in the frequency of stomata and trichomes, closure of stomata and degeneration of certain cells in the sludge grown plants.


Calculations of heating patterns of an array of microwave interstitial antennas.
In this paper, the heating (temperature) distribution patterns of an array of uniformly and step-insulated interstitial antennas located in inhomogeneous tissue and cancerous regions of the human body are calculated. Specifically, the bioheat equation, which takes into account various heat exchange mechanisms such as blood flow rate, heat conduction, and metabolic heat generation, was solved using the finite difference method, while the electromagnetic power absorbed (SAR) in the tissue region heated using an array of interstitial antennas was determined using the finite-difference time-domain (FDTD) method. Numerical results showing the validation of the developed computer program are presented, and the effect of varying parameters such as the blood flow rate on the resulting heating rate and patterns are examined. Possible clinical implementation of the developed temperature distribution-EM power deposition pattern computer code in treatment planning is described.


Defining the origin, evolution, and immune composition of SDH-deficient renal cell carcinoma.
Succinate dehydrogenase (SDH)-deficient renal cell carcinoma represents a rare subtype of hereditary kidney cancer. Clinical diagnosis can be challenging and there is little evidence to guide systemic therapeutic options. We performed genomic profiling of a cohort of tumors through the analysis of whole genomes, transcriptomes, as well as flow cytometry and immunohistochemistry in order to gain a deeper understanding of their molecular biology. We find neutral evolution after early tumor activation with a lack of secondary driver events. We show that these tumors have epithelial derivation, possibly from the macula densa, a specialized paracrine cell of the renal juxtaglomerular apparatus. They subsequently develop into immune excluded tumors. We provide transcriptomic and protein expression evidence of a highly specific tumor marker, PAPPA2. These translational findings have implications for the diagnosis and treatment for this rare tumor subtype.


Predicting cognitive impairment in chronic kidney disease patients using structural and functional brain network: An application study of artificial intelligence.
To develop and validate artificial intelligence models for the prediction of cognitive impairment in chronic kidney disease (CKD) patients using structural and functional brain network. This study retrospectively recruited 621 CKD patients and 625 healthy controls in Jinling hospital and 57 CKD patients in Hainan hospital. These CKD patients were divided into cognitive function impairment (CFI) group and non-CFI group based on diagnostic criteria. All patients underwent brain MRI scan, neuropsychological test and laboratory exam. A deep learning model (Attention MLP) based on structural and functional sub-network (determined by the comparison between the patients and healthy controls) topological properties was developed to generate the MRI signature for the discrimination of CFI. Finally, a clinical-topological logistic regression model was built by combining MRI signature and clinical features. The area under curve (AUC), sensitivity and specificity were calculated to evaluate the model performance. Delong test was used to examine the difference of AUCs between models. The integrated discrimination improvement (IDI) and net reclassification index (NRI) between models were calculated. Attention MLP model performed well in both internal test set and external test set (AUC = 0.744 and 0.763, respectively). After combining with the clinical features, the model performance was further improved both in the internal (AUC: 0.748) and external test sets (AUC: 0.774), while both IDI and NRI were significant (all p < 0.05) in the external test set. According to the comprehensive comparison, the AUC of the Attention MLP model was significantly or marginal significantly higher than that of traditional machine learning models (logistic regression: AUC = 0.634; support vector machine: AUC = 0.613; decision tree: AUC = 0.539; XGBoost: AUC = 0.639) in internal test set. The results showed that the model built on the combining of structural and functional networks data outperformed those on the single network, as well as the connection matrix. The result indicated that the integration of the clinical information and the MRI signature generated by artificial intelligence model based on structural and functional network topological properties could help to predict the CFI of CKD patients effectively. Our results provided a set of quantifiable imaging biomarkers for CFI which may be beneficial to CKD patients.


Effects of hydrogen rich water and pure water on periodontal inflammatory factor level, oxidative stress level and oral flora: a systematic review and meta-analysis.
Hydrogen rich water (HRW) was used as an auxiliary treatment for periodontitis and peri-implantitis due to its good antioxidant properties. However, the stability of artificially added active hydrogen was far less than that of pure natural active hydrogen, which greatly reduced active hydrogen molecules number in HRW. Meanwhile, the effect of HRW was relatively slow. Finally, long-term drinking of HRW may cause abnormal liver function. Hence, this study sought to summarize and analyze the effects of HRW on oral inflammation and oral flora in various studies to determine whether HRW can be used to inhibit dental plaque formation and aliviate oral inflammation. Randomized controlled trials (RCTs) of HRW and pure water (PW) in the treatment of periodontal diseases published before March 2022 in the PubMed, Web of science, EMBASE, Cochrane, China Knowledge Resource Integrated, Wanfang, and Weipu databases were searched. Changes in the inflammatory factor levels, oxidative stress response, and oral flora were summarized and used as outcome indicators. The quality of included studies was assessed by Cochrane risk of bias assessment tool, and the standardized mean differences (SMD) and the 95% confidence intervals (CIs) were calculated using Review Manager 5.3. In total, 17 studies, comprising 304 subjects, were included in this meta-analysis. Among them, 5 studies had a high risk of bias, and the rest had a certain risk of bias, thus, the total risk of bias was medium to low. The levels of interleukin (IL)-1β (SMD =-0.73; 95% CI: -1.29 to -0.18; P=0.009), tumor necrosis factor alpha (SMD =-2.51; 95% CI: -3.56 to -1.46; P<0.00001), IL-6 (SMD =-1.31; 95% CI: -1.96 to -0.67; P<0.0001), 8-hydroxyguanosine (SMD =-1.61; 95% CI: -2.35 to -0.87; P<0.0001), and reactive oxygen metabolites (SMD =-0.49; 95% CI: -0.91 to -0.06; P=0.02) in the HRW group decreased significantly, while the glutathione peroxidase level increased (SMD =2.5; 95% CI: 1.85 to 3.15; P<0.00001). Additionally, HRW was shown to effectively inhibit oral pathogenic bacteria activity (SMD =-0.91; 95% CI: -1.16 to -0.66; P<0.00001). HRW effectively inhibits the inflammatory reaction, oxidative stress level, and bacterial proliferation activity in patients with periodontal disease.


Dinuclear manganese(II) complexes of hexaazamacrocycles bearing N-benzoylated pendant separated by aromatic spacers: Antibacterial, DNA interaction, cytotoxic and molecular docking studies.
Three new homodinuclear manganese(II) complexes of the type [Mn2L(1-3)(ClO4)(H2O)](ClO4)3 (1-3) have been synthesized via cyclocondensation of terephthalaldehyde with three different benzoylated pendants in the presence of manganese(II) perchlorate and characterized by spectroscopic methods. Cyclic voltammetric investigation of complexes (1-3) depict two quasi-reversible one electron reduction processes in the cathodic potential region (E(1)pc=-0.73 to-0.83 V, E(2)pc=-1.31 to -1.40 V) and two quasi-reversible one electron oxidation processes in the anodic potential region (E(1)pa=1.03 to 1.10 V, E(2)pa=1.69 to 1.77 V). Electronic absorption spectra of the complexes suggested tetrahedral geometry around the central metal ion. The observed low magnetic moment values (μeff, 5.60-5.68 B.M.) of the complexes indicate the presence of an antiferromagnetic spin-exchange interaction between two metal centers, which was also supported by the broad EPR signal. All the compounds were tested for antibacterial activity against Gram (-ve) and Gram (+ve) bacterial strains. The binding studies of complexes with CT-DNA suggested minor-groove mode of interaction. Molecular docking studies were carried out in order to find the binding affinity of complexes with DNA and protein EGFR Kinase. The complexes are stabilized by additional electrostatic and van der Waals interaction with the DNA, and support minor groove mode of binding. The cleavage activity of complexes on pBR322 plasmid DNA displays efficient activity through a mechanistic pathway involving hydroxyl radicals. The cytotoxicity of complexes 2 and 3 have been tested against human liver adenocarcinoma (HepG2) cell line. Nuclear-chromatin cleavage has also been observed with propidium iodide (PI) staining and alkaline single-cell gel electrophoresis (comet assay) techniques.


The restoration of ATP synthesis may explain the protective effect of calcium antagonists against cyclosporine A nephrotoxicity.
Cyclosporine A at pharmacological doses decreases the rate and yield of ATP synthesis in rat mitochondria. This action seems to be due to the mitochondrial calcium storage induced by the drug. If such an effect occurs in vivo, the ATP deficit will affect calcium extrusion pumps, so triggering vasoconstriction which is the major side effect of Cyclosporine A. Calcium antagonists (Nifedipine and Verapamil) at least partially correct this effect on ATP synthesis: this finding may be related with the beneficial clinical effect conferred on Cyclosporine A toxicity by calcium antagonists. This effect of calcium antagonists may be due to an interaction with Cyclosporine A at the level of mitochondrial calcium efflux.


Genetic Exchange among Bdelloid Rotifers Is More Likely Due to Horizontal Gene Transfer Than to Meiotic Sex.
Although strict asexuality is supposed to be an evolutionary dead end, morphological, cytogenetic, and genomic data suggest that bdelloid rotifers, a clade of microscopic animals, have persisted and diversified for more than 60 Myr in an ameiotic fashion. Moreover, the genome of bdelloids of the genus Adineta comprises 8%-10% of genes of putative non-metazoan origin, indicating that horizontal gene transfers are frequent within this group and suggesting that this mechanism may also promote genetic exchanges among bdelloids as well. To test this hypothesis, we used five independent sequence markers to study the genetic diversity of 576 Adineta vaga individuals from a park in Belgium. Haplowebs and GMYC analyses revealed the existence of six species among our sampled A. vaga individuals, with strong evidence of both intra- and interspecific recombination. Comparison of genomic regions of three allele-sharing individuals further revealed signatures of genetic exchanges scattered among regions evolving asexually. Our findings suggest that bdelloids evolve asexually but exchange DNA horizontally both within and between species.


An improved 3D KiU-Net for segmentation of liver tumor.
It is a challenging task to accurately segment liver tumors from Computed Tomography (CT) images. The widely used U-Net and its variants generally suffer from the issue to accurately segment the detailed edges of small tumors, because the progressive down sampling operations in the encoder module will gradually increase the receptive fields. These enlarged receptive filed have limited ability to learn the information about tiny structures. KiU-Net is a newly proposed dual-branch model that can effectively perform image segmentation for small targets. However, the 3D version of KiU-Net has high computational complexity, which limits its application. In this work, an improved 3D KiU-Net (named TKiU-NeXt) is proposed for liver tumor segmentation from CT images. In TKiU-NeXt, a Transformer-based Kite-Net (TK-Net) branch is proposed to build the over-complete architecture to learn more detailed features for small structures, and an extended 3D version of UNeXt is developed to replace the original U-Net branch, which can effectively reduce computational complexity but still with superior segmentation performance. Moreover, a Mutual Guided Fusion Block (MGFB) is designed to effectively learn more features from two branches and then fuse the complementary features for image segmentation. The experimental results on two public CT datasets and a private dataset demonstrate that the proposed TKiU-NeXt outperforms all the compared algorithms, and it also has less computational complexity. It suggests the effectiveness and efficiency of TKiU-NeXt.


Healthiness and environmental impact of dinner recipes vary widely across developed countries.
Contrary to food ingredients, little is known about recipes' healthiness or environmental impact. Here we examine 600 dinner recipes from Norway, the UK and the USA retrieved from cookbooks and the Internet. Recipe healthiness was assessed by adherence to dietary guidelines and aggregate health indicators based on front-of-pack nutrient labels, while environmental impact was assessed through greenhouse gas emissions and land use. Our results reveal that recipe healthiness strongly depends on the healthiness indicator used, with more than 70% of the recipes being classified as healthy for at least one front-of-pack label, but less than 1% comply with all dietary guidelines. All healthiness indicators correlated positively with each other and negatively with environmental impact. Recipes from the USA, found to use more red meat, have a higher environmental impact than those from Norway and the UK.


Complications of monochorionic twins.
Sonography has made a dramatic impact on the obstetric management of complicated twin pregnancies. This is based in part on the ability to use prenatal US to diagnose syndromes and complications of MC twinning. All twin pregnancies are at high risk for perinatal morbidity and mortality compared with singleton gestations, but when one of the described complications is recognized, the difficulties in management are compounded dramatically. Despite the relative rarity of some of the entities described, it is vitally important to be familiar with these problems and their sonographic evaluation and diagnosis.


Expression of the immune checkpoint molecule V-set immunoglobulin domain-containing 4 is associated with poor prognosis in patients with advanced gastric cancer.
Recent clinical studies on immune checkpoint (IC) inhibitors in the context of advanced gastric cancer (AGC) have failed to show significant survival benefits but have suggested the possible role of IC inhibitors in anti-AGC immunity. Considering the low efficacy of targeted drugs in AGC, there is an urgent need for the discovery of new targets for the development of immunotherapeutics and prognostic markers for patient selection. This study aimed to investigate the expression of a new IC molecule, V-set Ig domain-containing 4 (VSIG4), and its clinical significance in AGC and other major cancers. We analyzed the expression of VSIG4 and its correlation with survival in various carcinomas, including 882 surgically resected samples from patients with stage II-III AGC (two academic hospitals). VSIG4 positivity in AGC was significantly associated with overall survival (OS; Hazard ratio (HR) = 2.661, 95% confidence interval [CI] = 2.012-3.519, P < 0.001) and event-free survival (HR = 2.8, 95% CI = 2.18-3.72, P < 0.001). These findings were successfully validated in independent cohorts. VSIG4 expression was also significantly correlated with low intratumoral CD8 + T-cell infiltration (CD8i) (P = 0.029) and high Foxp3 + /CD8i ratio (P = 0.026), which is consistent with the previously reported immunological function of VSIG4. However, VSIG4 expression was not associated with survival in other cancers (colon, P = 0.459; lung, P = 0.275; kidney, P = 0.121; breast, P = 0.147). Our results suggest that VSIG4 is an independent prognostic factor in AGC and also implies that VSIG4 is a second-tier IC molecule in AGC, thus, providing an important basis for the development of gastric cancer-specific immunotherapeutics.


Data management solutions for protein therapeutic research and development.
Protein therapeutics, including monoclonal antibodies, are a growing focus of drug discovery research organizations. High-throughput screening of large libraries of protein variants is therefore becoming increasingly important in R&D. As a result, there is a need to link large numbers of variant protein sequences with chemical and biological assay data. This integration will allow more efficient data mining and facilitate decision-making regarding hit identification, lead optimization and drug development. In this paper, we present an implementation in which a widely used small-molecule high-throughput screening data management system has been adapted to meet the unique needs of protein drug discovery and development.


DNA synthesis in vitro in human fibroblast preparations.
When confluent cultures of human fibroblasts were ultraviolet irradiated and either permeabilized or lysed, three types of DNA synthesis were subsequently observed during incubation in vitro: (A) a low level of DNA replication, which ceased after 15-30 min incubation at 37 degrees C; (B) radiation-dependent reparative gap-filling, which also ceased after 15 min at 37 degrees C; and (C) radiation-independent DNA synthesis, which was not semiconservative and proceeded at a linear rate for 1 h at 37 degrees C. Normal and xeroderma pigmentosum fibroblasts displayed different rates of radiation-dependent reparative gap-filling after lysis but similar rates of radiation-independent DNA synthesis. The rates of DNA replication and radiation-independent DNA synthesis were less in the permeable cell system than in the lysed cell system, whereas radiation-dependent reparative gap-filling was the same in both. Preparations of permeable and lysed cells activated radiation-dependent reparative gap-filling at about 15% of the rate estimated for intact cells. No radiation-dependent DNA strand breaks, as assayed by alkaline elution, were observed in the lysed cell preparation. Some radiation-dependent breaks were observed in the permeable cell preparation, but radiation-dependent DNA breakage was less than that seen in intact cells. This inability to incise DNA at damaged sites could account for the low rate of activation of reparative gap-filling in vitro. DNA strand breaks were produced in fibroblast preparations nonspecifically during lysis or permeabilization and incubation in vitro, and this breakage of DNA probably was responsible for the radiation-independent DNA synthesis.


Salmonellosis in dogs with lymphosarcoma.
In 6 dogs with multicentric lymphosarcoma, salmonellosis developed shortly after the start of anticancer chemotherapy. Three of the dogs died. Signs of illness in those that died were vomiting, diarrhea, neutropenia, anorexia, and fever, usually within 3 days of the start of chemotherapy.


Between-centre variability in transfer function analysis, a widely used method for linear quantification of the dynamic pressure-flow relation: the CARNet study.
Transfer function analysis (TFA) is a frequently used method to assess dynamic cerebral autoregulation (CA) using spontaneous oscillations in blood pressure (BP) and cerebral blood flow velocity (CBFV). However, controversies and variations exist in how research groups utilise TFA, causing high variability in interpretation. The objective of this study was to evaluate between-centre variability in TFA outcome metrics. 15 centres analysed the same 70 BP and CBFV datasets from healthy subjects (n=50 rest; n=20 during hypercapnia); 10 additional datasets were computer-generated. Each centre used their in-house TFA methods; however, certain parameters were specified to reduce a priori between-centre variability. Hypercapnia was used to assess discriminatory performance and synthetic data to evaluate effects of parameter settings. Results were analysed using the Mann-Whitney test and logistic regression. A large non-homogeneous variation was found in TFA outcome metrics between the centres. Logistic regression demonstrated that 11 centres were able to distinguish between normal and impaired CA with an AUC>0.85. Further analysis identified TFA settings that are associated with large variation in outcome measures. These results indicate the need for standardisation of TFA settings in order to reduce between-centre variability and to allow accurate comparison between studies. Suggestions on optimal signal processing methods are proposed.


Availability of 99Tc in undisturbed soil cores.
Models for safety assessment of radioactive waste repositories need accurate values of the soil-to-plant transfer of radionuclides. In oxidizing environments, (99)Tc is expected to occur as pertechnetate ((99)TcO(4)(-)). Due to its high mobility, leaching of this element in the field might be important, potentially affecting the reliability of estimated transfer parameters of (99)Tc as measured in closed experimental systems such as hydroponics or pot experiments. The aim of this experiment was to measure the leaching of (99)Tc in undisturbed irrigated soil cores under cultivation as well as plant uptake and to study the possible competition between the two transfer pathways. Undisturbed soil cores (50 x 50 cm) were sampled from a Rendzic Leptosol (R), a colluvial Fluvic Cambisol (F) and a Dystric Cambisol (D) using PVC tubes (three cores sampled per soil type). Each core was equipped with a leachate collector at the bottom, allowing the monitoring of (99)Tc leaching through the cores. Cores were placed in a greenhouse and maize (Zea mays L., cv. DEA, Pioneer) was sown. After 135 d, maize was harvested and radioactivity determined in both plant and water samples. Results showed that during the growing period, leaching of (99)Tc was limited, due to the high evapotranspiration rate of maize. After harvest, leaching of (99)Tc went on because of the absence of evapotranspiration. Effective uptake (EU) of (99)Tc in leaves and grains was calculated. EU reached 70% of the input in the leaves and was not significantly different among soils. These results confirmed those obtained from pot experiments, even though leaching was allowed to occur in close-to-reality hydraulical conditions. As a consequence, it was concluded that pot experiments are an adequate surrogate for more complex "close-to-reality" experimental systems for measuring transfer factors.


Protein oligomers studied by solid-state NMR--the case of the full-length nucleoid-associated protein histone-like nucleoid structuring protein.
Members of the histone-like nucleoid structuring protein (H-NS) family play roles both as architectural proteins and as modulators of gene expression in Gram-negative bacteria. The H-NS protein participates in modulatory processes that respond to environmental changes in osmolarity, pH, or temperature. H-NS oligomerization is essential for its activity. Structural models of different truncated forms are available. However, high-resolution structural details of full-length H-NS and its DNA-bound state have largely remained elusive. We report on progress in characterizing the biologically active H-NS oligomers with solid-state NMR. We compared uniformly ((13)C,(15)N)-labeled ssNMR preparations of the isolated N-terminal region (H-NS 1-47) and full-length H-NS (H-NS 1-137). In both cases, we obtained ssNMR spectra of good quality and characteristic of well-folded proteins. Analysis of the results of 2D and 3D (13)C-(13)C and (15)N-(13)C correlation experiments conducted at high magnetic field led to assignments of residues located in different topological regions of the free full-length H-NS. These findings confirm that the structure of the N-terminal dimerization domain is conserved in the oligomeric full-length protein. Small changes in the dimerization interface suggested by localized chemical shift variations between solution and solid-state spectra may be relevant for DNA recoginition.


Novel ALK5 inhibitor TP0427736 reduces TGF-β induced growth inhibition in human outer root sheath cells and elongates anagen phase in mouse hair follicles.
Androgenic alopecia (AGA) occurs as a result of the contraction of the anagen phase because of the action of androgens on hair follicles. TGF-β production from dermal papillae is enhanced by androgens, and growth inhibition of hair-follicle cells is induced by TGF-β, and the hair cycle progresses from the anagen phase to the catagen phase. We investigated both the in vitro and in vivo potency of the newly identified ALK5 inhibitor TP0427736 {6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole}. For in vitro study, kinase inhibitory activity was evaluated with ELISA, and inhibitory activity against TGF-β-induced Smad2/3 phosphorylation in A549 cells and TGF-β-induced growth inhibition of human outer root sheath cells were assayed using ELISA. For in vivo study, we used a mouse model that had been synchronized through dorsal hair depilation. TP0427736 inhibited ALK5 kinase activity with an IC50 of 2.72nM; this effect was 300-fold higher than the inhibitory effect on ALK3. In cell-based assays, TP0427736 inhibited Smad2/3 phosphorylation in A549 cells and decreased the growth inhibition of human outer root sheath cells. The topical application of TP0427736 significantly decreased Smad2 phosphorylation in mouse skin, and its repeated application suppressed the shortening of average hair follicle length during the transition from the late anagen phase to the catagen phase. TP0427736, a potent ALK5 inhibitor with appropriate in vitro and in vivo profiles, may serve as a potential new therapy for AGA. .


Highly efficient genome editing in Xanthomonas oryzae pv. oryzae through repurposing the endogenous type I-C CRISPR-Cas system.
Efficient and modular genome editing technologies that manipulate the genome of bacterial pathogens will facilitate the study of pathogenesis mechanisms. However, such methods are yet to be established for Xanthomonas oryzae pv. oryzae (Xoo), the causal agent of rice bacterial blight. We identified a single type I-C CRISPR-Cas system in the Xoo genome and leveraged this endogenous defence system for high-efficiency genome editing in Xoo. Specifically, we developed plasmid components carrying a mini-CRISPR array, donor DNA, and a phage-derived recombination system to enable the efficient and programmable genome editing of precise deletions, insertions, base substitutions, and gene replacements. Furthermore, the type I-C CRISPR-Cas system of Xoo cleaves target DNA unidirectionally, and this can be harnessed to generate large genomic deletions up to 212 kb efficiently. Therefore, the genome-editing strategy we have developed can serve as an excellent tool for functional genomics of Xoo, and should also be applicable to other CRISPR-harbouring bacterial plant pathogens.


Demonstration of tumor-selective retention of fluorinated nitroimidazole probes by 19F magnetic resonance spectroscopy in vivo.
We have evaluated two fluorinated misonidazole analogues, Ro 07-0741 and CCI-103F, as potential probes for the non-invasive identification of hypoxic tumor cells by 19F magnetic resonance spectroscopy (MRS) in vivo. The equipment used was a 1.9 T Oxford Research Systems TMR-32 spectrometer, fitted with a 15 mm diameter surface coil. Signal was readily detectable, with similar intensity from EMT6 tumor, liver, and brain at early times (1-2 hr) after i.v. injection in BALB/c mice, indicative of an initial uniform biodistribution of parent probes. At later times (5-10 hr) there was a progressive reduction in signal intensity from brain and liver, but tumor levels remained constant or declined more slowly. This is illustrated by tumor/brain ratios at 6-7 hr of 2.9 (Ro 07-0741) and 4.2 (CCI-103F). In 4/5 mice analyzed at 20-24 hr after Ro 07-0741, and 1/2 following CCI-103F, tumor signal remained detectable. This occurred in the absence of parent probe as measured by HPLC, suggesting the involvement of a product of nitroreductive bioactivation. Studies with KHT and RIF-1 tumors in C3H/He mice showed a similar trend but retention in RIF-1 was less dramatic, and this was consistent with the known hypoxic fractions and comparative in vivo nitroreductase activities. These promising results support the continuing development of 19F nitroimidazole probes for non-invasive identification of hypoxic cells in vivo.


Determinants of photosynthetic capacity in six rainforest Piper species.
We examined the dependence of photosynthetic capacity on leaf nitrogen content and light environment in leaf microsites of six rainforest species growing naturally in understory and clearing habitats. All nine descriptors of the light environment in leaf microsites, encompassing canopy openness, potential exposure to sunflecks, and photosynthetically active photon flux density (PFD) integrated over one day, three months, and an entire year, were highly correlated with each other. Among species, A max was strongly dependent on leaf nitrogen and on all descriptors of the light environment in the leaf microsite. Leaf nitrogen was also dependent on all descriptors of the light environment. Simple regressions of A max on all measures of the light environment were significant for plants in the clearing, but not for plants growing in the understory. Regressions of leaf nitrogen on at least one descriptor of the light environment were significant for both clearing and understory plants. Over all species, and for the clearing plants alone, leaf nitrogen and a single descriptor of the light environment together explained significantly more variance in A max than either variable alone. Multiple regressions using leaf nitrogen and all nine descriptors of the light environment did not explain a significantly greater amount of variance in photosynthetic capacity than multiple regressions using leaf nitrogen and a single light descriptor. In most cases, A max was predicted better by the most general descriptors of the light environment, such as canopy openness and long-term photon flux density, and less accurately by shorter-term sensor measurements or descriptors based on the duration of potential sunfleck exposure. The gest predictors of A max were frequently different than the best predictors of leaf nitrogen. In every case examined, A max was less sensitive to variation in the light environment in understory than in clearing plants.


Visual rehabilitation with new-age rigid gas-permeable scleral contact lenses--a case series.
Primary ectatic corneal diseases usually require rigid gas-permeable (RGP) corneal contact lens wear for visual rehabilitation. As the disease progresses, it becomes increasingly difficult to fit these lenses. RGP scleral contact lenses now provide another treatment option before resorting to surgery. Two patients with pellucid marginal degeneration and one with advanced keratoconus had failed treatment with conventional lenses. They were fitted with RGP scleral lenses. Good vision was obtained together with satisfactory fit and comfort. RGP scleral lenses are a viable alternative to surgery in the visual rehabilitation of patients with advanced ectatic corneal disorders.


The structure of high molecular weight ribonucleic acid in solution. A smallangle x-ray scattering study.
Small-angle x-ray scattering studies on an absolute scale have been carried out on isotropic solutions of high molecular weight RNA obtained from ascites tumor cells, E. coli, and yeast. It was found that in all three cases the RNA is composed of short rigid rods (50 to 150A in length) joined by small flexible regions. The rods account for almost the entire structure (at least 90 per cent); their radius of gyration about the axis and their mass per unit length are similar to those of DNA, suggesting a double-stranded helical structure. The rods are joined in an array forming the compact RNA molecule. On thermal degradation, the molecular superstructure disappears while the rods persist.


Recent developments and biological activities of thiazolidinone derivatives: a review.
Thiazolidinone is considered as a biologically important active scaffold that possesses almost all types of biological activities. Successful introduction of ralitoline as a potent anti-convulsant, etozoline as a antihypertensive, pioglitazone as a hypoglycemic agent and thiazolidomycin activity against streptomyces species proved potential of thiazolidinone moiety. This diversity in the biological response profile has attracted the attention of many researchers to explore this skeleton to its multiple potential against several activities. This review is complementary to earlier reviews and aims to review the work reported on various biological activities of thiazolidinone derivatives from year 2000 to the beginning of 2011. Data are presented for active compounds, some of which have passed the preclinical testing stage.


Consecutive percutaneous valve-in-valve replacement late after Ross procedure: A novel approach in an adult with congenital heart disease.
The emergence of transcatheter valve technology over the last decade has made significant impact on the treatment of patients with valvular heart disease. There has been increasing experience with both native and valve-in-valve indications with promising results. We present the case of a young woman with congenital heart disease who underwent the Ross procedure for bicuspid aortic valve endocarditis with subsequent reoperation and surgical aortic valve replacement for neo-aortic root dilation who experienced worsening symptoms related to both pulmonary and aortic valve dysfunction. She was successfully treated with percutaneous pulmonary and aortic valve replacement with excellent early term technical results and marked improvement in symptoms.


Placental transfer of chlorthalidone and its elimination in maternal milk.
A gas chromatographic method has been used to determine chlorthalidone in amniotic fluid, maternal and foetal blood at delivery, and in maternal milk and blood three days after delivery, following the administration of chlorthalidone to nine pregnant women suffering from toxaemia of pregnancy. Placental transfer of chlorthalidone and elimination in maternal milk have been shown and the implications of these factors are discussed. An explanation has been proposed for our observations that foetal blood levels of the drug are about 15% of those in maternal blood.


Integrating Behavioral Healthcare and Primary Care, Appropriate Balance on What Model is Driving Care, and, the Whole Spectrum of Individuals are Coming Through the Door….
With the integration of behavioral health services into primary care and other medical specialties, the community of providers and the public must address a number of questions, including: What models of care are there for these services? What kinds of providers supply these services? Are these providers trained behavioral health providers or extenders in some form? And, as these systems of care are constructed, who makes use of them? The purpose of this study is to address these questions as well as to consider some of the challenges of attending to the spectrum of needs that will arise as integrated healthcare services expand. Consideration of these questions may serve to clarify the impact that these models of healthcare will have in ways that may be readily apparent and, at the same time, in ways that may be subtler and less comprehensible. Addressing these questions is also intended to facilitate discussions within healthcare systems and among providers concerning which models of care best respond to specific populations. In turn, proactively answering these questions will, for the foreseeable future, shape not only behavioral healthcare, in perhaps small or large ways, but also healthcare in general.


Annotation and analysis of malic enzyme genes encoding for multiple isoforms in the fungus Mucor circinelloides CBS 277.49.
Based on the newly-released genomic data of Mucor circinelloides CBS 277.49, we have annotated five genes encoding for malic enzyme: all code for proteins that contain conserved domains/motifs for malic acid binding, NAD(+) binding and NAD(P)(+) binding. Phylogenetic analysis for malic enzyme genes showed that genes ID 78524 and 11639 share ~80% amino acid identity and are grouped in cluster 1; genes ID 182779, 186772 and 116127 share ~66% amino acid identity are grouped in cluster 2. Genes ID 78524, 11639 and 166127 produce proteins that are localized in the mitochondrion, while the products from genes 182779 and 186772 are localized in the cytosol. Based on the comparative analysis published previously by Song et al. (Microbiology 147:1507-1515, 2001), we propose that malic enzyme genes ID 78524, 166127, 182779, 186772, 11639, respectively, represent protein isoforms I, II, III/IV, V, and VI.


Method for Dissecting the Auditory Epithelium (Basilar Papilla) in Developing Chick Embryos.
Chickens are an invaluable model for exploring auditory physiology. Similar to humans, the chicken inner ear is morphologically and functionally close to maturity at the time of hatching. In contrast, chicks can regenerate hearing, an ability lost in all mammals, including humans. The extensive morphological, physiological, behavioral, and pharmacological data available, regarding normal development in the chicken auditory system, has driven the progress of the field. The basilar papilla is an attractive model system to study the developmental mechanisms of hearing. Here, we describe the dissection technique for isolating the basilar papilla in developing chick inner ear. We also provide detailed examples of physiological (patch clamping) experiments using this preparation.


Neuropsychological functions in bipolar disorders I and II with and without comorbid alcohol dependence.
Bipolar disorder (BP) is a mental disorder most likely to co-occur with substance dependence and abuse, especially alcohol dependence (ALD). Whether the effect of comorbid alcoholism is different between the BP-I and BP-II subtypes remains unclear. We aimed to identify the neuropsychological performance of BP patients with and without comorbid ALD in partial remission from depression or mania, and compare it with that of healthy controls (HCs). We recruited 29 HCs and 94 BP patients, whom we categorized into four groups: (1) BP-I without a history of alcohol abuse or dependence (BP-I(-ALD); n=22), (2) BP-II without a history of alcohol abuse and dependence (BP-II(-ALD); n=38), (3) BP-I with comorbid ALD (BP-I(+ALD); n=16), and (4) BP-II with comorbid ALD (BP-II(+ALD); n=18). Only males were recruited in this study. When patients comorbid with ALD were not excluded, there were no significant differences on neuropsychological tests between the BP-I and BP-II groups. However, when patients with comorbid ALD were excluded, there were significant differences between the two BP(-ALD) groups. The BP-I(-ALD) group had lower scores on memory subtests (p≤0.01) than the HC and BP-II(-ALD) groups, but the BP-II(-ALD) and HC groups had similar scores. We found it important to exclude ALD comorbidity when evaluating neuropsychological functions due to our finding that ALD affected the cognitive performance in BP-I more severely than in the BP-II group. ALD not only impairs neuropsychological function, but also worsen the clinical course and leads to a more pernicious status and negative cycle.


Restoration of Ramus Height in Child Patients With Extracapsular Condylar Fractures: Is This Mission Almost Impossible to Accomplish?
This study aimed to assess whether ramus height is restored in children with extracapsular condylar fractures treated by conservative or surgery procedures. The sample consisted of 35 children (collected consecutively) less than 12 years old who presented with extracapsular condylar fractures and treated within an 8-year period (June 2011 to April 2019). Data on the age, gender, date of injury, mechanism of trauma, location and pattern of mandibular condylar fracture, associated injuries and treatment methods were recorded and analyzed. Ramus height restoration is the main evaluation indicator during the follow-up period. Within the 8-year record retrieval, the 35 children sustained 41 extracapsular condylar fractures. For the sample size, 10 (24.4%) and 31 (75.6%) had condylar neck and base fractures, respectively. Deviation and green-stick fracture were the predominant types in condylar neck and base fractures, accounting for more than 3 quarters (31, 75.6%). The majority (33, 80.5%) of patients were treated with nonsurgical treatment, and 8 (19.5%) were treated by open reduction and internal fixation (ORIF). During the follow-up period (1-1419 days, average time of 110.6 days), only 1 patient (with bilateral extracapsular condylar fractures) had their ramus height restored (follow-up period, 256 days). Most members of the ORIF group (5 of 8, 62.5%) postoperatively showed bended ramus (deviated angularly/fragment angulation). Conservative treatment could hardly restore the ramus height of children with extracapsular condylar fractures. Anatomically or totally restoring the ramus height is difficult even with the surgical treatment of ORIF; however, surgical treatment of ORIF can substantially restore the ramus height for dislocated fractures or seriously displaced fractures.


Development of bioluminescent pyrophosphate assay using pyruvate phosphate dikinase and its application to single-nucleotide polymorphism analysis.
DNA analysis is an important technology with respect to diagnosis of infectious disease and tailored medication. In this study, we developed a novel bioluminescent assay for pyrophosphate, and it was applied to single-nucleotide polymorphism (SNP) analysis using one-base extension reaction. The principle of this method is as follows. A specific primer within each aliquot possessing a short 3' end of the base of interest was hybridized to the single-stranded DNA template. Subsequently, (exo-)Klenow DNA polymerase and one of either alpha-thio-dATP, dTTP, dGTP, or dCTP were added and incubated for 1 min. Pyrophosphate released by DNA polymerase is converted to ATP by pyruvate phosphate dikinase (PPDK), and the concentration of ATP is determined using the firefly luciferase reaction. This method, which does not require expensive equipment, can be used to rapidly monitor one point mutation in the gene.


Carbohydrate metabolism in uremia.
Abnormalities of insulin and glucose metabolism, namely glucose intolerance, inhibition of insulin secretion and insulin resistance, are present in children with chronic renal failure. Insulin resistance is universal among children with end-stage renal disease and may be caused by uremic toxins accumulated because of reduced renal function. The normal response of the beta cell is to enhance insulin secretion to overcome the insulin resistance. In patients with secondary hyperparathyroidism, this increase in insulin secretion is inhibited, resulting in glucose intolerance. Presence of glucose intolerance may be responsive for the growth retardation in uremic children. Improvements in glucose tolerance correlate with improvements in linear growth in uremic children. Further research should be directed towards investigation of the mechanisms by which abnormal energy utilization may affect growth in uremia and development of indices of glucose metabolism as predictors of growth in uremia.


Association of low serum albumin with venous thrombosis in pediatric patients.
The incidence of venous thromboembolism (VTE) in children is increasing, attributed in part to increased utilization of central venous catheters (CVCs). Children with protein losing disorders (PLDs) and low serum albumin may have an increased incidence of thrombosis. We sought to determine the prevalence of PLDs and hypoalbuminemia at the time of diagnosis of VTE in pediatric patients and its relationship to central venous catheters. We performed a single institution retrospective study of 65 consecutive hospitalized pediatric patients with an acute VTE. Data collected included clinical diagnoses, type of thrombosis, presence or absence of a CVC, and serum albumin level, if available. Of 65 patients with acute VTE, 51 % (33/65) had catheter-related thrombosis (CRT), including 71 % (19/27) of patients <12 years of age and 37 % (14/38) of patients aged 12 to 23 (P = 0.008). Eleven VTEs occurred in patients with a diagnosis of a PLD; of these, ten (91 %) were CRT and one (9 %) was a non-CRT (P = 0.003). Serum albumin levels obtained within four days of diagnosis of VTE were available for 38 patients. An albumin level below the lower limit of the age-adjusted normal reference range was documented in 27/38 (71 %) patients with VTE compared to 1011/3028 (33 %) of all pediatric patients admitted to the hospital during a two-year period (P < 0.0001). Albumin levels were low in 19/22 (86 %) patients with CRT compared with 8/16 (50 %) patients with non-CRT (P = 0.019). Low serum albumin levels are highly prevalent among pediatric patients with VTE, especially in those patients with CRT.


Rodenticide efficacy in sewers in São Paulo, Brazil.
Rodents infest urban environments, causing damage and acting as vectors for disease transmission. Currently, anticoagulants are the most widely used chemical rodenticides, and their extensive and widespread use can contaminate the environment. To ensure effectiveness and avoid accumulation of rodent baits in the environment, it is important to evaluate how long rodent baits maintain their palatability and efficacy. In rodent control programs, rodent baits are placed in locations such as sewers, but after a few days, baits appear altered, causing doubts about the control efficacy. For this reason, baits are replaced periodically, which increases costs and generation of chemical waste. The objective of this study was to evaluate the palatability and efficacy of commercial paraffin-type rodent bait blocks placed in sewers in São Paulo City over a period of 90 days. Bait blocks were placed in sewers and collected after 30, 60, and 90 days. Additionally, in a laboratory two-choice test, wild-caught urban Norway rats were offered 40-60 g of bait and an equal volume of standard rat pellets. The amount of bait and rat pellet consumed was registered, the palatability was calculated, and the efficacy was measured as the percentage mortality over 14 days. The results showed that, even when they had an altered appearance, bait blocks remained palatable to the rats and were effective after at least 90 days. Leaving bait blocks for longer periods could be an effective strategy for reducing costs and could help to ensure the control of urban rodents in an environmentally sustainable way.


High Prevalence of Functional Gastrointestinal Disorders in Celiac Patients with Persistent Symptoms on a Gluten-Free Diet: A 20-Year Follow-Up Study.
Ongoing symptoms in treated celiac disease (CD) are frequent and are commonly thought of as being due to infractions to a gluten-free diet (GFD) or complications. To study the etiology and natural history of clinically relevant events (CREs) throughout follow-up and identify predictors thereof to guide follow-up. CREs (symptoms/signs requiring diagnostic/therapeutic interventions) occurring in celiac patients between January-2000 and May-2021 were retrospectively collected between June and September 2021 and analysed. One-hundred-and-eighty-nine adult patients (133 F, age at diagnosis 36 ± 13 years, median follow-up 103 months, IQR 54-156) were enrolled. CREs were very common (88/189, 47%), but hardly due to poor GFD adherence (4%) or complications (2%). Interestingly, leading etiologies were functional gastrointestinal disorders (30%), reflux disease (18%) and micronutrient deficiencies (10%). Age at diagnosis ≥ 45 years (HR 1.68, 95%CI 1.05-2.69, p = 0.03) and classical pattern of CD (HR 1.63, 95%CI 1.04-2.54, p = 0.03) were predictors of CREs on a multivariable Cox model. At 5 years, 46% of classical patients ≥ 45 years old at diagnosis were event-free, while this was 62% for non-classical/silent ≥ 45 years, 60% for classical < 45 years, and 80% for non-classical/silent < 45 years. CREs occurred in almost half of CD patients during follow-up, with functional disorders being very common. New follow-up strategies for adult CD may be developed based on age and clinical pattern at diagnosis.


c-Abl tyrosine kinase plays a critical role in β2 integrin-dependent neutrophil migration by regulating Vav1 activity.
The recruitment and migration of neutrophils are critical for innate immunity and acute inflammatory responses. However, the mechanism that regulates the recruitment and migration of neutrophils has not been well characterized. We here reveal a novel function of c-Abl kinase in regulating neutrophil migration. Our results demonstrate that c-Abl kinase is required for neutrophil recruitment in vivo and migration in vitro, and the inhibition of c-Abl kinase activity has a significant impact on neutrophil migratory behavior. Moreover, c-Abl kinase activation depends on β2 integrin engagement, and the activated c-Abl kinase further regulates actin polymerization and membrane protrusion dynamics at the extended leading edges during neutrophil migration. In addition, we identify the Rho GEF Vav1 as a major downstream effector of c-Abl kinase. The C-terminal SH3-SH2-SH3 domain and proline-rich region of Vav1 are required for its interaction with c-Abl kinase, and c-Abl kinase probably regulates the activity of Vav1 by direct phosphorylation at Tyr-267 in the DH domain. Together, these results indicate that c-Abl kinase plays a critical role in β2 integrin-dependent neutrophil migration by regulating Vav1 activity.


Cyclin D3 Governs Clonal Expansion of Dark Zone Germinal Center B Cells.
Germinal center (GC) B cells surge in their proliferative capacity, which poses a direct risk for B cell malignancies. G1- to S-phase transition is dependent on the expression and stability of D-type cyclins. We show that cyclin D3 expression specifically regulates dark zone (DZ) GC B cell proliferation. B cell receptor (BCR) stimulation of GC B cells downregulates cyclin D3 but induces c-Myc, which subsequently requires cyclin D3 to exert GC expansion. Control of DZ proliferation requires degradation of cyclin D3, which is dependent on phosphorylation of residue Thr283 and can be bypassed by cyclin D3T283A hyperstabilization as observed in B cell lymphoma. Thereby, selected GC B cells in the light zone potentially require disengagement from BCR signaling to accumulate cyclin D3 and undergo clonal expansion in the DZ.


Pregnancy-associated plasma protein A in the human endometrium is dependent on the effect of progesterone.
The biotin-avidin immunoperoxidase method was used to study pregnancy-associated plasma protein A (PAPP-A) in the endometrium of 102 pre- or postmenopausal women. Endometria in the proliferative phase (n = 27) or early secretory phase (days 1-3 postovulation; n = 12), cystic glandular hyperplasia (n = 12), and postmenopausal endometria of untreated (n = 7) or estrogen-treated (n = 5) women were all PAPP-A negative. By contrast, PAPP-A was invariably present in the endometrium during the normal secretory phase after day 3 of ovulation (n = 28), during cyclic progestogen treatment of pre-menopausal women (n = 6), and during estrogen-progestogen replacement therapy of postmenopausal women (n = 5). These results suggest that the occurrence of PAPP-A in the endometrium is progesterone dependent.


Spontaneous healing of Langerhans cell histiocytosis (histiocytosis X).
A 3-month-old male infant presented with pallor, hepatomegaly (4.5 cm), splenomegaly (1.5 cm), anaemia (Hb 6 g/dl) and thrombocytopenia (16 X 10(9)/l). A liver biopsy was diagnostic for Langerhans cell histiocytosis (histiocytosis X). The patient's lymphocytes, co-cultured with neonatal lymphocytes, were positive for virus-like particles without reverse transcriptase activity. The hepatomegaly diminished after 6 months and a second liver biopsy showed decreased histiocytic infiltration. A second viral blood culture remained negative. After 14 months, the hepatomegaly had disappeared completely and there were no more abnormal haematological or clinical findings.


Extension of multiple drug resistant Plasmodium falciparum malaria in Africa: report of a Central African case.
A 24-year-old Caucasian male, living in the Central African Republic, presented with fever due to Plasmodium falciparum infection, although he steadily took chloroquine and sulfadoxine-pyrimethamine chemoprophylaxis. Despite treatment with the same drugs at high doses, the parasitaemia persisted. Clinical and parasitological recovery was obtained by the use of quinine. Chloroquine-resistant Plasmodium falciparum strains have spread in all tropical areas. Multiple drug resistance, already described in Asia, has also begun to appear in Africa.


The effect of roasting on the fate of aflatoxin B1 in artificially contaminated green coffee beans.
A study was undertaken to evaluate aflatoxin B1 contamination in coffee beans. 41 samples of green coffee were collected from large lots of material by representative sampling. The raw samples were analyzed and showed no detectable levels of aflatoxin B1. In order to establish the heat stability of the toxin, 3 artificially contaminated samples (average level 10/μg/kg) were roasted atca 200°C for different operation times periods so as to reproduce light and dark roasting procedures. Each sample was roasted both electrically and by gas.The percentage of toxin destruction was up to 93% for light roasted and 99% for dark roasted coffee with a slightly higher rate up to 100% for the electrically roasted coffee for light and dark roasting. In order to evaluate the potential migration of the aflatoxin B1 into the coffee beverage, 1 sample found contaminated after roasting treatment (0.8/°g/kg) was extracted using each of the 3 most common types of coffee makers. Additional destruction of the toxin was observed (up to 99%) in two cases while only 75% of fate was obtained in the third.The process from raw coffee beans to beverage showed a meaningful destruction of aflatoxin B1, ranging from 97 to 100% depending on the extraction technique adopted in the preparation of the beverages.


Psychosocial effects of intensive care on infants and families after discharge.
The neonatal intensive care environment exposes the developing immature newborn to many sources of stress and pain at a time when the infant is developmentally least able to cope with it. Animal and human evidence suggest that effects of stress, mediated through permanent changes in the brain and neuroendocrine responses, may result in changes in behaviour and information processing, which persist throughout childhood. These changes impact on the dynamics of the mother infant dyad and infant learning. Interactional styles arising in the newborn period tend to persist throughout childhood but may be amenable to intervention focusing on maternal recognition of infant cues, social stimulation of the infant, and family integration. Developmental care may promote better family, infant and child outcomes by both reducing neonatal stress and its neurobiological sequelae, and fostering an appropriate interactional relationship between mother and infant.


Heparin-induced thrombocytopenia in neurologic disease treated with unfractionated heparin.
The risk for immune-mediated heparin-induced thrombocytopenia (HIT) in neurologic patients receiving unfractionated heparin (UFH) is not known. In a prospective study of 200 patients, the authors found a 2.5% rate of HIT and a 2% rate of HIT-associated thromboses, suggesting that neurologic patients treated with UFH are at considerable risk for development of HIT and its complications. Prevalence of heparin-induced antibodies was 20.5% and was dependent on heparin dose. It was higher in cerebrovascular than in noncerebrovascular (29.4% versus 11.2%, p < 0.01) patients.


Hard and glossy-colored films composed of micropatterned organic dots and electrodeposited honeycomb-shaped nickel walls.
This paper proposes a novel approach for the preparation of colored films with a metallic luster and high hardness. The colored organic films were patterned as microdots by photolithography, and then honeycomb-shaped Ni walls were electrodeposited between the micropatterning. The organic/inorganic composite films showed the hardest grade in a pencil hardness test and high durability in wear resistance tests because the honeycomb-shaped Ni walls protected the colored organic dots.


On the characterization of a non-Newtonian blood analog and its response to pulsatile flow downstream of a simplified stenosis.
Particle image velocimetry (PIV) was used to investigate the influence of a non-Newtonian blood analog of aqueous xanthan gum on flow separation in laminar and transitional environments and in both steady and pulsatile flow. Initial steady pressure drop measurements in laminar and transitional flow for a Newtonian analog showed an extension of laminar behavior to Reynolds number (Re) ~ 2900 for the non-Newtonian case. On a macroscale level, this showed good agreement with porcine blood. Subsequently, PIV was used to measure flow patterns and turbulent statistics downstream of an axisymmetric stenosis in the aqueous xanthan gum solution and for a Newtonian analog at Re ~ 520 and Re ~ 1250. The recirculation length for the non-Newtonian case was reduced at Re ~ 520 resultant from increased viscosity at low shear strain rates. At Re ~ 1250, peak turbulent intensities and turbulent shear stresses were dampened by the non-Newtonian fluid in close proximity to the blockage outlet. Although the non-Newtonian case's recirculation length was increased at peak pulsatile flow, turbulent shear stress was found to be elevated for the Newtonian case downstream from the blockage, suggesting shear layer fragmentation and radial transport. Our findings conclude that the xanthan gum elastic polymer prolongs flow stabilization, which in turn emphasizes the importance of non-Newtonian blood characteristics on the resulting flow patterns in such cardiovascular environments.


Lethality of SARS-CoV-2 infection-a comparative autopsy study focusing on COVID-19 development and virus variants.
Different SARS-CoV-2 variants are driving various waves of infection of the corona pandemic. Official statistics provide no information on who died due to coronavirus disease 2019 (COVID-19) or an alternative disease during which SARS-CoV-2 infection was detected. The current study aims at addressing the effect of the different variants evolving during the pandemic on fatal outcomes. Standardised autopsies were performed on 117 people who died of a SARS-CoV-2 infection and the findings were interpreted in clinical and pathophysiological contexts. The typical histological sequence of COVID-19-related lung injury was detected independently of the disease-causing virus variant, but was significantly less common (50 versus 80-100%) and less severe in cases infected by omicron variants compared to precedent variants (P < 0.05). COVID-19 was less often the leading cause of death following omicron infection. Extrapulmonary manifestations of COVID-19 did not contribute to death in this cohort. Lethal COVID-19 may occur after complete SARS-CoV-2 vaccination. Reinfection was not the cause of death in any of the autopsies of this cohort. Autopsies represent the gold standard in determining the cause of death after SARS-CoV-2 infection and autopsy registers are currently the only available data source allowing for evaluation of which patients died of COVID-19 or with SARS-CoV-2 infection. Compared to previous variants, infection with an omicron variant affected the lungs less frequently and resulted in less severe lung disease.


Salivary markers of kidney function - Potentials and limitations.
Saliva can be collected non-invasively, repeatedly and without trained personnel. It is a promising diagnostic body fluid with clinical use in endocrinology and dentistry. For decades, it is known that saliva contains also urea, creatinine and other markers of renal function. Clinical studies have shown that the salivary concentrations of these markers could be useful for the assessment of kidney function without the need of blood collection. This article summarizes the clinical and experimental data on the use of saliva as a diagnostic fluid in nephrology and points out the advantages, pitfalls, technical requirements and future perspective for the use of saliva as a novel potential diagnostic biofluid.


Increased susceptibility to ultraviolet-B and carcinogens of mice lacking the DNA excision repair gene XPA.
Xeroderma pigmentosum patients with a defect in the nucleotide-excision repair gene XPA are characterized by, for example, a > 1,000-fold higher risk of developing sunlight-induced skin cancer. Nucleotide-excision repair (NER) is involved in the removal of a wide spectrum of DNA lesions. The XPA protein functions in a pre-incision step, the recognition of DNA damage. To permit the functional analysis of the XPA gene in vivo, we have generated XPA-deficient mice by gene targeting in embryonic stem cells. The XPA-/-mice appear normal, at least until the age of 13 months. XPA-/-mice are highly susceptible to ultraviolet (UV)-B-induced skin and eye tumours and to 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin tumours. We conclude that the XPA-deficient mice strongly mimic the phenotype of humans with xeroderma pigmentosum.


Prognostic validity of auditory brainstem evoked response screening in newborn infants.
The effectiveness of the auditory brainstem evoked response (ABR) test as a screening test for permanent hearing loss in neonates is examined in 32 published studies including 4,945 infants. Follow-up studies validating initial test failure were available for only 658 infants. Significant differences in methodology exist among these studies, and these differences may have affected their outcomes. Despite this problem, data from these studies were pooled, and they revealed that 16.5 per cent of neonates failed the initial ABR test. Of these, 5.1 per cent were later confirmed to be hearing-impaired or otherwise neurologically impaired. This implies that many of the false-positive results occurred in neonates who had transient disorders, such as conductive hearing loss or neurologic abnormalities, at the time of the screening test, or that the pass/fail criterion was too stringent. Lack of data on false-negative results or the rate of correct identification of normal infants makes it impossible to assess the sensitivity of the test accurately. Firm estimates of the prognostic validity of the neonatal ABR screening in identifying the impaired population can be achieved only when the actual impairment rate can be estimated, and when the distributions of ABR latencies and thresholds for both normal and impaired populations are known. These data could be obtained by following groups of high-risk infants longitudinally and by pooling raw ABR data from the normal and impaired populations that are collected using standardized procedures and similar equipment.


Comparison of 99Tcm-pyrophosphate, 201T1 perfusion, 123I-labelled methyl-branched fatty acid and sympathetic imaging in acute coronary syndrome.
Among a group of patients (n = 15) with acute coronary syndrome, the results of using two new myocardial radiopharmaceuticals--123I-labelled 15-(p-iodo-phenyl)-3,R,S-methylpentadecanoic acid (BMIPP) and 123I-meta-iodobenzyl guanidine (MIBG)--were compared with dual 201Tl/99Tcm-pyrophosphate (Tl-PYP) imaging using single photon emission tomography (SPET). Defect scores were evaluated on a segment-by-segment basis for a total of 270 segments. For the 201Tl, BMIPP, and early and delayed MIBG studies, the mean (+/- S.D.) sums of defect scores were 9 +/- 8, 18 +/- 9, 22 +/- 12 and 29 +/- 9, respectively, revealing significantly higher scores for BMIPP and MIBG than 201Tl (P < 0.005). This was the case irrespective of various functional conditions, such as successful recanalization, failure of coronary angioplasty or restenosis. The culprit coronary artery was best identified using BMIPP, while MIBG SPET showed the most extensive defects. Normal perfusion with decreased BMIPP and MIBG uptake was frequently observed and associated with hypokinesis. 123I-BMIPP and MIBG are more sensitive for the detection of damaged myocardium, and the difference between perfusion and metabolism seems to reflect myocardial stunning.


Investigation of layered structure SAW devices fabricated using low temperature grown AlN thin film on GaN/sapphire.
Epitaxial AlN films have been grown on GaN/sapphire using helicon sputtering at 300 degrees C. The surface acoustic wave (SAW) filters fabricated on AlN/GaN/sapphire exhibit more superior characteristics than those made on GaN/sapphire. This composite structure of AlN on GaN may bring about the development of high-frequency components, which integrate and use their semiconducting, optoelectronic, and piezoelectric properties.


A Cys 23-Ser 23 substitution in the 5-HT(2C) receptor gene influences body weight regulation in females with seasonal affective disorder: an Austrian-Canadian collaborative study.
Most females with seasonal affective disorder (SAD) exhibit atypical vegetative symptoms such as overeating, and weight gain when depressed. The serotonin 2C receptor (5-HT(2C)) plays a key role in control of appetite and satiety. A 5-HT(2C) Cys 23 Ser substitution, coded for by a single nucleotide polymorphism (Cys 23 Ser) within the 5-HT(2C) gene, has been shown to influence 5-HT(2C) function. We hypothesized that Cys 23 Ser influences weight regulation in females with SAD. Two independent samples from Austria (162 females with SAD, 119 controls), and Canada (90 females with SAD, 42 controls) were genotyped for Cys 23 Ser. Influence on weight regulation was analyzed within patients with atypical features. In Austrians, genotype distribution differed between patients and controls (p=0.044) and Cys 23 Ser was associated with weight (p=0.039), body mass index (BMI; p=0.038), and seasonal appetite change (p=0.031). All values were highest in Cys/Cys, intermediate in Cys/Ser, and lowest in Ser/Ser carriers. In Canadian patients, Cys 23 Ser was associated with minimum lifetime BMI (p=0.046), with lowest values in Ser/Ser carriers. Our data provide evidence that Cys 23 Ser mediates severity of weight regulation disturbances in females with SAD, and the gene-dose effect-like differences suggest a direct functional role of Cys 23 Ser in the behavioral regulation of body weight.


Engineering of Escherichia coli to facilitate efficient utilization of isomaltose and panose in industrial glucose feedstock.
Industrial glucose feedstock prepared by enzymatic digestion of starch typically contains significant amounts of disaccharides such as maltose and isomaltose and trisaccharides such as maltotriose and panose. Maltose and maltosaccharides can be utilized in Escherichia coli fermentation using industrial glucose feedstock because there is an intrinsic assimilation pathway for these sugars. However, saccharides that contain α-1,6 bonds, such as isomaltose and panose, are still present after fermentation because there is no metabolic pathway for these sugars. To facilitate more efficient utilization of glucose feedstock, we introduced glvA, which encodes phospho-α-glucosidase, and glvC, which encodes a subunit of the phosphoenolpyruvate-dependent maltose phosphotransferase system (PTS) of Bacillus subtilis, into E. coli. The heterologous expression of glvA and glvC conferred upon the recombinant the ability to assimilate isomaltose and panose. The recombinant E. coli assimilated not only other disaccharides but also trisaccharides, including alcohol forms of these saccharides, such as isomaltitol. To the best of our knowledge, this is the first report to show the involvement of the microbial PTS in the assimilation of trisaccharides. Furthermore, we demonstrated that an L-lysine-producing E. coli harboring glvA and glvC converted isomaltose and panose to L-lysine efficiently. These findings are expected to be beneficial for industrial fermentation.


Utility of FDG-PET Imaging for Risk Stratification of Pancreatic Neuroendocrine Tumors in MEN1.
Patients with multiple endocrine neoplasia type 1 (MEN1) are at high risk of malignant pancreatic neuroendocrine tumors (pNETs). Structural imaging is typically used to screen for pNETs but is suboptimal for stratifying malignant potential. To determine the utility of fluorodeoxyglucose (18F) positron emission tomography/computed tomography (18F-FDG PET/CT) for predicting the malignant potential of pNETs in MEN1. Retrospective observational study. Tertiary referral hospital. Forty-nine adult patients with MEN1 carrying a common MEN1 mutation who underwent 18F-FDG PET/CT for MEN1 surveillance between 1 January 2010 and 30 September 2016. Structural and functional imaging (magnetic resonance imaging, CT, ultrasonography, and 18F-FDG PET/CT) and surgical histopathology. pNET size, behavior, and histopathology. Twenty-five (51.0%) of 49 patients studied had pancreatic lesions on structural imaging. Five (25%) of these had 18F-FDG-PET-avid lesions. In addition, two had solitary FDG-avid liver lesions, and one a pancreatic focus without structural correlate. Eight patients with pNETs underwent surgery (three FDG-avid lesions and five nonavid pNETs). The Ki-67 index was ≥5% in FDG-avid pNETs and <2% in nonavid pNETs. Overall, six of the eight (75%) patients with FDG-avid hepatopancreatic lesions harbored aggressive or metastatic NETs compared with one of 41 patients (2.4%) without hepatopancreatic FDG avidity [P < 0.001; sensitivity; 85.7% (95% confidence interval [CI], 48.7% to 99.3%); specificity, 95.2% (95% CI, 84.2% to 99.2%)]. 18F-FDG PET/CT is an effective screening modality in MEN1 for identifying pNETs of increased malignant potential. Surgical resection is recommended for FDG-avid pNETs.


Maternal drinking and the outcome of pregnancy: implications for child mental health.
Research since identification in 1973 of the fetal alcohol syndrome indicates that offspring of alcoholic women who drink heavily during pregnancy are at high risk for physical and mental deficiencies, and that even "social drinking" during pregnancy may have detrimental effects on birthweight and behavior of infants. While further research and remediation efforts are needed, primary prevention and active intervention in counseling and obstetrical clinics seem clearly and urgently called for.


Metabolomics reveals spoilage characteristics and interaction of Pseudomonas lundensis and Brochothrix thermosphacta in refrigerated beef.
Pseudomonas lundensis and Brochothrix thermosphacta are key spoilage microorganisms in aerobically stored chilled meat. The present study aimed to investigate the physicochemical and metabolomic profiles of refrigerated ground beef inoculated P. lundensis (PL) and B. thermosphacta (BT) as mono- or co-culture (BP). P. lundensis was the dominant spoilage strain in the co-culture of ground beef. A large amount of TCA-soluble peptide, TVB-N and TBA were formed in the PL and BP, while acetion was mainly produced in the BT, as accompanied by the different sensory and color changes. Meat metabolome indicated that 95, 396, and 409 metabolites with significant differences, were identified in ground beef inoculated BT, PL, and BP, respectively. These differential metabolites covered 58 metabolic pathways, in which histidine metabolism was identified as an important pathway related to spoilage in the three groups. Specifically, creatine, inosine, anserine, uracil, alanine, glutamine, 3-methylhistidine and 3-hydroxycapric acid were enriched as potential spoilage biomarkers. Taken together, those findings reveal the complex and competitive interactions of their co-culture of B. thermosphacta and P. lundensis, which provided a comprehensive insight into microbial spoilage mechanism in chilled beef.


[Contribution to the diagnosis of cortical atrophy: evaluation of computer tomograms and angiograms of patients over 70 years old (author's transl)].
To find evidence of cortical atrophy, 112 computer tomograms and 40 angiograms of patients above the age of 70 were evaluated. In the CT the width of the interhemispheric and of the sylvian fissure, in the angiograms the distance between the vessels extending into the interhemispheric fissure (anteroposterior view) and the distance between the cortical branches and the inner table (lateral view) were measured. The same measurements were performed in 100 normal computer tomograms and in 100 normal angiograms of patients between 20 and 40 years old. Statistically significant differences could be ascertained between the mean values for the patients over 70 and those for the younger ones, indicating that age-induced cerebral atrophy can be neuroradiologically demonstrated. The radiologic findings, however, do not necessarily correspond to the grade of intellectual impairment in the elderly. Neuropathologic and molecular biological research could bring us closer to the solution of this correlative problem.


What Is the Role of the Inflammation in the Pathogenesis of Heart Failure?
In heart failure, whether it is associated with reduced or preserved ejection fraction, the immune system is activated and contributes to heart remodeling and impaired function. Studies indicate that cells of the immune system not only play a role in the pathology but are also critical regulators of heart function. Knowledge about the role of the immune system driving heart failure will lead to the development of new targets to this system, particularly in those patients that, despite the apparent wellness, relapse and worsen. In this review, we will address the diverse mechanisms that trigger inflammation and their impact on heart failure progression.


Validity and internal consistency of a Hausa version of the Ibadan Knee/Hip Osteoarthritis Outcome Measure.
The Ibadan Knee/Hip Osteoarthritis Outcome Measure (IKHOAM) was developed for measuring end results of care in patients with knee or hip OA in Nigeria. The purpose of this study was to validate a Hausa translation of IKHOAM in order to promote its use among the Hausa populations of Nigeria and other West African countries. Sixty-seven patients with knee OA, literate in Hausa and English, recruited consecutively from all government hospitals in Kano were assessed on both English and Hausa versions of IKHOAM. The order of assessment with the versions was randomized and separated by 24 hours. Participants also rated their pain intensity on the Visual Analogue Scale. Data was analyzed using the Spearman Rank Order correlation and Cronbach's alpha. The participants (17 males, 50 females) were aged 55.7 +/- 13.4 years. Participants' scores on the Hausa version correlated significantly with the original version (r = 0.67, p = 0.000) and with pain intensity scores on the Visual Analogue Scale (r = -0.24, p = 0.005). The Cronbach's alpha for correlation on the different parts of the Hausa version ranged between 0.28 and 0.95. The Hausa version of IKHOAM meets the criteria for validity and internal consistency and may be used in the Hausa speaking parts of Nigeria and other West African countries.


[Studies of antimycin-A-resistant respiration of erythroid cells].
In bone marrow of rabbits and in erythroid cells of other species there exists an Antimycin A-resistant respiration. Its mechanism corresponds to that postulated for the Antimycin A-resistant respiration of rabbit reticulocytes.


Central precocious puberty following the diagnosis and treatment of paediatric cancer and central nervous system tumours: presentation and long-term outcomes.
To estimate the prevalence of central precocious puberty (CPP) after treatment for tumours and malignancies involving the central nervous system (CNS) and examine repercussions on growth and pubertal outcomes. Retrospective study of patients with tumours near and/or exposed to radiotherapy to the hypothalamus/pituitary axis (HPA). Patients with CPP were evaluated at puberty onset, completion of GnRH agonist treatment (GnRHa) and last follow-up. Multivariable analysis was used to test associations between tumour location, sex, age at CPP, GnRHa duration and a diagnosis of CPP with final height <-2SD score (SDS), gonadotropin deficiency (LH/FSHD) and obesity, respectively. Eighty patients (47 females) had CPP and were followed for 11·4 ± 5·0 years (mean ± SD). The prevalence of CPP was 15·2% overall, 29·2% following HPA tumours and 6·6% after radiotherapy for non-HPA tumours. Height <-2SDS was more common at the last follow-up than at the puberty onset (21·4% vs 2·4%, P = 0·005). Obesity was more prevalent at the last follow-up than at the completion of GnRHa or the puberty onset (37·7%, 22·6% and 20·8%, respectively, P = 0·03). Longer duration of GnRHa was associated with increased odds of final height <-2SDS (OR = 2·1, 95% CI 1·0-4·3) and longer follow-up with obesity (OR = 1·3, 95% CI 1·1-1·6). LH/FSHD was diagnosed in 32·6%. There was no independent association between CPP and final height <-2SDS, and LH/FSHD and obesity in the subset of patients with HPA low-grade gliomas. Patients with organic CPP experience an incomplete recovery of growth and a high prevalence of LH/FSHD and obesity. Early diagnosis and treatment of CPP may limit further deterioration of final height prospects.


S-sulfhydration of SIRT3 combats BMSC senescence and ameliorates osteoporosis via stabilizing heterochromatic and mitochondrial homeostasis.
Senescence of bone marrow mesenchymal stem cells (BMSCs) is one of the leading causes of osteoporosis. SIRT3, an essential NAD-dependent histone deacetylase, is highly correlated with BMSC senescence-mediated bone degradation and mitochondrial/heterochromatic disturbance. S-sulfhydration of cysteine residues favorably enhances SIRT3 activity by forming persulfides. Nevertheless, the underlying molecular mechanism of SIRT3 S-sulfhydration on mitochondrial/heterochromatic homeostasis involved in BMSC senescence remains unknown. Here, we demonstrated that CBS and CSE, endogenous hydrogen sulfide synthases, are downregulated with BMSC senescence. Exogenous H2S donor NaHS-mediated SIRT3 augmentation rescued the senescent phenotypes of BMSCs. Conversely, SIRT3 deletion accelerated oxidative stress-induced BMSC senescence through mitochondrial dysfunction and the detachment of the heterochromatic protein H3K9me3 from the nuclear envelope protein Lamin B1. H2S-mediated SIRT3 S-sulfhydration modification rescued the disorganized heterochromatin and fragmented mitochondria induced by the S-sulfhydration inhibitor dithiothreitol, thus leading to elevated osteogenic capacity and preventing BMSC senescence. The antisenescence effect of S-sulfhydration modification on BMSCs was abolished when the CXXC sites of the SIRT3 zinc finger motif were mutated. In vivo, aged mice-derived BMSCs pretreated with NaHS were orthotopically transplanted to the ovariectomy-induced osteoporotic mice, and we proved that SIRT3 ameliorates bone loss by inhibiting BMSC senescence. Overall, our study for the first time indicates a novel role of SIRT3 S-sulfhydration in stabilizing heterochromatin and mitochondrial homeostasis in counteracting BMSC senescence, providing a potential target for the treatment of degenerative bone diseases.


Gender discrimination of veterinary students and its impact on career aspiration: A mixed methods approach.
As the veterinary profession has become feminised, gender discrimination and its effects have been documented in practicing veterinary surgeons. However, research on gender discrimination experienced by veterinary students and its effects on recruitment and retention remains limited. This study aimed to increase understanding of veterinary students' experiences of gender discrimination and its impact on their career aspirations. A questionnaire including statements with Likert-style response options and free-text questions was distributed to students studying veterinary medicine and science at a UK veterinary school in September 2020 (28% response rate). Two focus groups were carried out following the questionnaire to gain a deeper insight into student experiences. Gender discrimination in a veterinary setting had been experienced by 34% of respondents, the majority (77%) on animal husbandry placements. Female students were more likely to report that their experiences of gender discrimination affected their career aspirations. Seven themes were identified from both the questionnaire and focus group data: stereotyping of certain fields, gender inequality on placements, the lesbian, gay, bisexual, transgender, queer and intersex, plus (LGBTQI+) community, encouraging reporting behaviours, barriers to reporting, education and the placement allocation. This study highlighted that gender discrimination was prevalent during animal husbandry placements, although reporting was infrequent and perceived negatively by students. Recommendations on how veterinary schools and the wider veterinary profession can support veterinary students are made as an outcome of this work.


Poly[[μ4-3,4,8,10,11,13-hexa-hydro-1H,6H-bis-([1,4]di-thio-cino)[6,7-b:6',7'-e]pyrazine]di-μ-iodido-dicopper(I)]: a two-dimensional copper(I) coordination polymer.
The reaction of ligand 3,4,8,10,11,13-hexa-hydro-1H,6H-bis-([1,4]di-thio-cino)[6,7-b:6',7'-e]pyrazine (L) with CuI led to the formation of a two-dimensional coordination polymer, incorporating a [Cu2I2] motif. These units are linked via the four S atoms of the ligand to form the title two-dimensional coordination poly-mer, poly[[μ4-3,4,8,10,11,13-hexa-hydro-1H,6H-bis-([1,4]di-thio-cino)[6,7-b:6',7'-e]pyrazine]di-μ-iodido-dicopper(I)], [Cu2I2(C12H16N2S4)] n , (I). The asymmetric unit is composed of a ligand mol-ecule, two copper(I) atoms and two I- ions. Both copper(I) atoms are fourfold S2I2 coordinate with almost regular trigonal-pyramidal environments. In the crystal, the layers, lying parallel to (102), are linked by C-H⋯I hydrogen bonds, forming a supra-molecular framework.