Pyrotinib plus antiangiogenic agents for HER2-altered advanced non-small cell lung cancer: A retrospective real-world study.
Although some targeted therapies have been shown to be effective in treating HER2-altered non-small cell lung cancer (NSCLC), the survival demands have not yet been met due to the high cost and limited availability. This study aimed to assess the effectiveness and safety of pyrotinib plus antiangiogenic agents, including apatinib, anlotinib, and bevacizumab, in previously treated patients with HER2-altered advanced NSCLC. In this retrospective real-world study, patients with HER2-altered NSCLC who received pyrotinib plus antiangiogenic agents as a second- or later-line treatment between November 2015 and January 2022 were reviewed. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety profiles of patients were analyzed. A total of 107 patients were included in the analysis, of which 59 patients (55.1%) had received at least two lines of prior chemotherapy or tyrosine kinase inhibitors. Most of them (87.9%) were identified as harboring HER2 exon 20 insertions. At the data cutoff date (May 13, 2022), the ORR, DCR, median PFS, and median OS were 19.6% (21/107), 94.4% (101/107), 7.13 months (95% confidence interval [CI]: 6.26-8.01), and 19.50 months (95% CI: 12.83-26.17), respectively. There was no difference in the PFS between patients receiving apatinib or anlotinib/bevacizumab (median PFS, 7.13 vs. 6.27 months, hazard ratio [HR] = 1.49, 95% CI: 0.87-2.54, p = 0.15). The most frequent grade 3 or higher treatment-related adverse events was diarrhea (17.6%), followed by hypertension (11.0%) and nausea (3.3%). No treatment-related death occurred. In this study, pyrotinib plus antiangiogenic agents demonstrated promising efficacy and were tolerable in HER2-altered NSCLC patients.


Effects of granulocyte colony simulating factor on functional activities of endothelial progenitor cells in patients with chronic ischemic heart disease.
Bone marrow-derived circulating endothelial progenitor cells (EPCs) may contribute to regeneration of infarcted myocardium and enhance neovascularization. Granulocyte colony-stimulating factor (G-CSF) is well-established to mobilize hematopoietic stem cells (HSCs) and might, thereby, also increase the pool of endogenously circulating EPC. Therefore, we investigated the effects of G-CSF administration on mobilization and functional activities of blood-derived EPC in patients with chronic ischemic heart disease (CIHD). Sixteen patients with CIHD received 10 microg/kg per day subcutaneous G-CSF injection for 5 days. Leukocyte counts, the number of HSCs and EPCs, and the migratory response to VEGF and SDF-1 were analyzed before and after G-CSF-therapy. At day 5 of G-CSF treatment, the number of circulating leukocytes, CD34+ CD45+ and CD34+ CD133+ cells was significantly increased. Likewise, G-CSF treatment augmented the numbers of colony forming units with endothelial cell morphology (EC-CFU). However, the functional activity of the EPC as assessed by the migratory response to VEGF and SDF-1 was significantly reduced after G-CSF treatment (P<0.01). Because G-CSF was previously shown to cleave the CXCR4 receptor, we determined the surface expression of the 6H8 epitope of the CXCR4 receptor by fluorescence-activated cell sorter (FACS) analysis. Consistent with the reduced migratory capacity, the surface expression of the functionally active CXCR4 receptor was significantly reduced. To test the functional activity of the cultivated EPCs in vivo, cells were intravenously infused in nude mice after hind limb ischemia. EPCs, which were cultivated before G-CSF administration, increased blood flow recovery and prevented limb necrosis. However, infusion of EPCs, which were isolated 5 days after G-CSF treatment from the same patient, showed a reduced capacity to augment blood flow recovery and to prevent necrosis by 27%. G-CSF treatment effectively mobilizes HSCs and EPCs. However, the migratory response to SDF-1 and in vivo capacity of G-CSF-mobilized EPCs was significantly reduced.


A cancer stem cell-like phenotype is associated with miR-10b expression in aggressive squamous cell carcinomas.
Cutaneous squamous cell carcinomas (cSCC) are the primary cause of premature deaths in patients suffering from the rare skin-fragility disorder recessive dystrophic epidermolysis bullosa (RDEB), which is in marked contrast to the rarely metastasizing nature of these carcinomas in the general population. This remarkable difference is attributed to the frequent development of chronic wounds caused by impaired skin integrity. However, the specific molecular and cellular changes to malignancy, and whether there are common players in different types of aggressive cSCCs, remain relatively undefined. MiRNA expression profiling was performed across various cell types isolated from skin and cSCCs. Microarray results were confirmed by qPCR and by an optimized in situ hybridization protocol. Functional impact of overexpression or knock-out of a dysregulated miRNA was assessed in migration and 3D-spheroid assays. Sample-matched transcriptome data was generated to support the identification of disease relevant miRNA targets. Several miRNAs were identified as dysregulated in cSCCs compared to control skin. These included the metastasis-linked miR-10b, which was significantly upregulated in primary cell cultures and in archival biopsies. At the functional level, overexpression of miR-10b conferred the stem cell-characteristic of 3D-spheroid formation capacity to keratinocytes. Analysis of miR-10b downstream effects identified a novel putative target of miR-10b, the actin- and tubulin cytoskeleton-associated protein DIAPH2. The discovery that miR-10b mediates an aspect of cancer stemness - that of enhanced tumor cell adhesion, known to facilitate metastatic colonization - provides an important avenue for future development of novel therapies targeting this metastasis-linked miRNA.


HDL/LDL ratio: a useful parameter for separation of pleural transudates from exudates.
The first diagnostic step in pleural effusions is the separation of transudates from exudates. We aimed in present study to investigate the value of HDL/LDL ratio for distinguishing between pleural exudates and transudates. Pleural fluids (PF)from 121 patients, including 28 transudates and 93 exudates were analyzed. The levels of cholesterol, HDL cholesterol and LDL cholesterol in PF were measured. The HDL/LDL ratio was calculated. HDL/LDL ratio found significantly higher in transudates than exudates (p= 0.001). Receiver operating characteristic (ROC) curves were generated and the cut off points determined to the highest level of accuracy and precision. The HDL/LDL ratio was to maximize sensitivity over specificity in the diagnosis of a transudative effusion. The usefulness of HDL/LDL ratio for identifying transudates was evaluated in terms of sensitivity and specificity. The value of pleural HDL/LDL ratio that best differentiated between transudates and exudates was 0.6 (sensitivity 89%, and specificity of 79%). Measurement of HDL and LDL in PF and calculating of HDL/LDL ratio can be proposed to aid for differentiation between pleural exudates and transudates with advantage of not requiring serum levels.


Deregulation of miR-34a and Its Chaperon Hsp70 in Hepatitis C virus-Induced Liver Cirrhosis and Hepatocellular Carcinoma Patients
Background: MicroRNA deregulation may occur during hepatocellular carcinoma (HCC) genesis and progression stages. MicroRNA-34a (miR-34a) functions as a tumor suppressor and is down-regulated or silenced in a variety of human cancers, while heat shock proteins (Hsps) play important roles in assisting protein folding and preventing both protein aggregation and transport across membranes. The present study aimed to evaluating serum expression of miR-34a and its target Hsp70 for early detection of HCC in patients with liver cirrhosis (LC), focusing on correlations with clinicopathological features. Methods: A total of 180 patients were included: 120 with HCC on top of LC (60 with either early or late HCC) and 60 patients with HCV-related LC. In addition, 60 healthy individuals were considered as controls. Real-time polymerase chain reactions were performed for expression profiling of serum miR-34a and Hsp70 and for allelic discrimination of the promotor variant (rs2763979, C/T). In addition, in silico analysis was carried out. Results: All participants were heterozygote for the promotor polymorphism. miR-34a serum levels were significantly under-expressed in LC and especially HCC patients as compared to controls. Associations with a high Child-Turcotte- Pugh (CTP) score, advanced cancer stage, and number of masses were noted. In contrast the target Hsp70 was significantly overexpressed in cancer patients but not in LC group and inversely correlated with miR-34a levels. Conclusion: Utility of circulating miRNAs as biomarkers for early detection of HCC was raised. Future large-scale studies are warranted to confirm the current findings.


The year 2013 in the European Heart Journal--Cardiovascular Imaging: Part II.
The new multi-modality cardiovascular imaging journal, European Heart Journal - Cardiovascular Imaging, was created in 2012. Here we summarize the most important studies from the journal's second year in two articles. Part I of the review has summarized studies in myocardial function, myocardial ischaemia, and emerging techniques in cardiovascular imaging. Part II is focussed on valvular heart diseases, heart failure, cardiomyopathies, and congenital heart diseases.


Cisplatin-induced nephrotoxicity in children: what is the best protective strategy?
Platinum compounds, which are considerably effective for the treatment of childhood malignancies, have significantly contributed to the increase in long-term survival of children with cancer. Unfortunately, children receiving cisplatin-based chemotherapy have been known to be at risk for severe disabling adverse effects, such as nephrotoxicity. A literature research of the MEDLINE PubMed database was conducted to identify articles published between 1980 and 2019 reviewing "Cisplatin AND mannitol." The primary pharmacodynamics and clinical characteristics of cisplatin were described, focusing on its renal toxic effects and potential preventive strategies, in order to improve clinical outcomes among children with cancer aged 1 to 14 years. Currently, selecting either hydration alone or hydration plus mannitol for preventing nephrotoxicity has been controversial considering the lack of guidelines to provide treatment recommendations both among adults and children. Appropriate knowledge regarding the pharmacokinetics and toxicological profile of cisplatin may help physicians prevent renal toxicity. Unfortunately, published data regarding the nephroprotective utility of adding mannitol appear to be inconclusive. As such, appropriate hydration remains the main fundamental strategy for reducing the risk of cisplatin-induced nephrotoxicity. Considering the increasing number of children safely cured of their tumours, it is imperative that those treated with cisplatin receive the most appropriate nephroprotective strategy for reducing the negative impact of platinum compounds on quality of life.


Single-Cell RNA Sequencing (scRNA-seq) Identifies L1CAM as a Key Mediator between Epithelial Tuft Cell and Innate Lymphoid Cell in the Colon of Hnrnp I Knockout Mice.
(1) Background: Knockout (KO) of heterogeneous nuclear ribonucleoprotein I (Hnrnp I) in mouse intestinal epithelial cells (IECs) induced a severe inflammatory response in the colon, followed by hyperproliferation. This study aimed to investigate the epithelial lineage dynamics and cell-cell communications that underlie inflammation and colitis. (2) Methods: Single cells were isolated from the colons of wildtype (WT) and KO mice and used in scRNA-seq. Whole colons were collected for immunofluorescence staining and cytokine assays. (3) Results: from scRNA-seq, the number of DCLK1 + colonic tuft cells was significantly higher in the Hnrnp I KO mice compared to the WT mice. This was confirmed by immunofluorescent staining of DCLK1. The DCLK1 + colonic tuft cells in KO mice developed unique communications with lymphocytes via interactions between surface L1 cell adhesion molecule (L1CAM) and integrins. In the KO mice colons, a significantly elevated level of inflammatory cytokines IL4, IL6, and IL13 were observed, which marks type-2 immune responses directed by group 2 innate lymphoid cells (ILC2s). (4) Conclusions: This study demonstrates one critical cellular function of colonic tuft cells, which facilitates type-2 immune responses by communicating with ILC2s via the L1CAM-integrins interaction. This communication promotes pro-inflammatory signaling pathways in ILC2, leading to the increased secretion of inflammatory cytokines.


Development of a novel nanoparticle by dual modification with the pluripotential cell-penetrating peptide PepFect6 for cellular uptake, endosomal escape, and decondensation of an siRNA core complex.
Development of novel devices for effective nucleotide release from nanoparticles is required to improve the functionality of nonviral delivery systems, because decondensation of nucleotide/polycation complexes is considered as a key step for cytoplasmic delivery of nucleotides. Previously, PepFect6 (PF6) comprised chloroquine analog moieties and a stearylated cell-penetrating peptide to facilitate endosomal escape and cellular uptake, respectively, was developed as a device for efficient siRNA delivery. As PF6 contains bulky chloroquine analog moieties, the polyplexes are expected to be loose structure, which facilitates decondensation. In the present study, siRNA was electrostatically condensed by PF6, and the PF6/siRNA complexes were coated with lipid membranes. The surface of the nanoparticles encapsulating the PF6/siRNA core (PF6-NP) was modified with PF6 for endosomal escape (PF6/PF6-NP). The RNAi effect of PF6/PF6-NP was compared with those of stearylated cell-penetrating peptide octaarginine (R8)-modified PF6-NP, R8-modified nanoparticles encapsulating the R8/siRNA core (R8-NP) and PF6-modified R8-NP. Nanoparticles encapsulating the PF6 polyplex, especially PF/PF-NP, showed a significant knockdown effect on luciferase activity of B16-F1 cells stably expressing luciferase. siRNA was widely distributed within the cytoplasm after transfection of the nanoparticles encapsulating the PF6 polyplex, while siRNA encapsulated in the R8-presenting nanoparticles was localized within the nuclei. Thus, the siRNA distribution was dependent on the manner of peptide-modification. In conclusion, we have successfully developed PF6/PF6-NP exhibiting a potent RNAi effect resulting from high cellular uptake, efficient endosomal escape and decondensation of the polyplexes based on the multifunctional cell penetrating peptide PF6. PF6 is therefore a useful pluripotential device for siRNA delivery.


Structural basis of specificity and cross-reactivity in T cell receptors specific for cytochrome c-I-E(k).
T cells specific for the cytochrome c Ag are widely used to investigate many aspects of TCR specificity and interactions with peptide-MHC, but structural information has long been elusive. In this study, we present structures for the well-studied 2B4 TCR, as well as a naturally occurring variant of the 5c.c7 TCR, 226, which is cross-reactive with more than half of possible substitutions at all three TCR-sensitive residues on the peptide Ag. These structures alone and in complex with peptide-MHC ligands allow us to reassess many prior mutagenesis results. In addition, the structure of 226 bound to one peptide variant, p5E, shows major changes in the CDR3 contacts compared with wild-type, yet the TCR V-region contacts with MHC are conserved. These and other data illustrate the ability of TCRs to accommodate large variations in CDR3 structure and peptide contacts within the constraints of highly conserved TCR-MHC interactions.


Indication, surgical technique and results of endoscopic fascial release in plantar fasciitis (E FRPF).
The purpose of the present study is to present the surgical technique for, and review our indications and results after, endoscopic fascial release in patients with plantar fasciitis. In five thiel-embalmed human specimens, a biportal technique for endoscopic release of the plantar fascia was established. The aim was here to evaluate the relation between the plantar fascia and the heel spur and to perform a release that would not exceed 50-70% of the diameter of the calcaneoplantar fascia. The endoscopic technique was performed within the last 5 years in ten male and seven female patients. All patients with the clinical entity of plantar fasciitis underwent conservative treatment for at least 6 months. The average age at surgery was 35 years (24-56 years). In the first five patients, surgery was performed under c-arm control. In all patients the operation could be finished endoscopically. The endoscopic portals healed without complications. The time for surgery during the learning curve ranged between 21 and 74 min (average 41 min) and was still longer compared to the open technique. The clinical follow-up ranged between 4 and 48 months (average 18.5 months). Out of 17 patients, 13 improved clinically, and they would choose the treatment option again. In the Ogilvie-Harris score, seven patients showed good and six excellent results. In two patients, the initial results were not satisfactory, because of a bony stress reaction of the calcaneus. This complication was treated by 6 weeks of partial weight bearing, without any further problems. Two other patients developed secondary pain in the lateral column. In spite of the minimal invasive approach it seems to be important to be careful in increasing the weight bearing in early rehabilitation. The technique of the endoscopic plantar fascia release (E FRPF) can be performed in a standardised and reproducible procedure. The follow-up examination showed good midterm results, but a loss of stability of the plantar arch has to be strictly avoided.


Self-documentary in the emergency department: Perspectives on patients recording their own procedures.
Patients often bring their smartphones to the emergency department (ED) and want to record their procedures. There was no clear ED recording policy in the Saskatoon Health Region nor is there in the new Saskatchewan Health Authority. With limited literature on the subject, clinicians currently make the decision to allow/deny the request to record independently. The purpose of this study was to examine and compare patient and clinician perspectives concerning patients recording, in general, and recording their own procedures in the ED. Surveys were developed for patients and clinicians with respect to history and opinions about recording/being recorded. ED physicians and nurses, and patients>17 years old who entered the ED with a laceration requiring stitches were recruited to participate; 110 patients and 156 staff responded. There was a significant difference between the proportion of patients (61.7% [66/107]) and clinicians (28.1% [41/146]) who believed that patients should be allowed to video record their procedure. There was also a significant difference between clinicians and patients with regard to audio recording, but not "selfies" (pictures). However, with no current policy, 47.8% (66/138) of clinicians said that they would allow videos if asked, with caveats about staff and patient privacy, prior consent, and procedure/patient care. Contrary to patients' views, clinicians were not in favour of allowing audio or video recordings in the ED. Concerns around consent, staff and patient privacy, and legal issues warrant the development of a detailed policy if the decision is made in favour of recording.


Sex hormone changes in chronic liver disease: a matched study of alcoholic versus non-alcoholic liver disease.
Men with liver disease are hypogonadal and feminized. European workers consider the liver disease itself to be the major factor but American workers blame alcohol consumption. We studied sexual dysfunction and sex hormones in three matched groups of men; controls (n = 22), those with alcoholic liver disease (n = 21), and those with non-alcoholic liver disease (n = 21). Men with alcoholic liver disease had more sexual dysfunction. Testosterone and androstenedione concentrations were lower and oestradiol and dehydroepiandrosterone sulphate levels were raised in the liver disease groups. The changes were greatest in the alcoholic liver disease group. In this, the first controlled study, liver disease per se appears to cause sexual dysfunction and sex hormone changes but these changes are amplified by ethanol.


An algorithm for fast adaptive image binarization with applications in radiotherapy imaging.
Locally adaptive image binarization with a sliding-window threshold can be an effective tool for various image processing tasks. We have used the method for the detection of bone ridges in radiotherapy portal images. However, a straight-forward implementation of sliding-window processing is too time consuming for routine use. Therefore, we have developed a new thresholding criterion suitable for incremental update within the sliding window, and we show that our algorithm gives better results on difficult portal images than various publicly available adaptive thresholding routines. For small windows, the routine is also faster than an adaptive implementation of the Otsu algorithm that uses interpolation between fixed tiles, and the resulting images are equally good.


Characterization of substance P- and [Met]enkephalin-immunoreactive neurons in the caudate nucleus of cat and ferret by a single section Golgi procedure.
Modifications of the single-section Golgi-impregnation procedure of Gabbott and Somogyi are described. The modifications allow easier and more rapid preparation of the sections for Golgi-impregnation and easier handling of large numbers of serial sections. The technique consists of placing a section that has been treated with osmium tetroxide and potassium dichromate on a microscope slide and "sandwiching" it with a second microscope slide. The two slides are held together at one end by tape and the assembly is dipped into a solution of silver nitrate. Golgi-impregnation of neurons occurs within a few hours and is generally complete within 12 h. The technique has been applied to sections through the caudate nucleus of the cat and ferret in order to define the morphological characteristics of striatal substance P- and methionine enkephalin-immunoreactive neurons. Sections were first incubated to reveal the immunoreactive structures and then subjected to the Golgi method. Golgi-impregnated neurons that were immunoreactive for either substance P or methionine enkephalin had medium-size perikarya from which several dendrites emerged. The dendrites branched close to the perikaryon; secondary and higher order dendrites were densely laden with spines, as many as 15 spines per 10 microns of dendrite. It is concluded that both striatal substance P-containing and methionine enkephalin-containing neurons are of the medium-size densely spiny type. Medium-size densely spiny neurons may be homogeneous with respect to their somatodendritic morphology but heterogeneous with respect to their chemical characteristics and axonal morphology.


Cost-effective clinical trial design: Application of a Bayesian sequential model to the ProFHER pragmatic trial.
There is growing interest in the use of adaptive designs to improve the efficiency of clinical trials. We apply a Bayesian decision-theoretic model of a sequential experiment using cost and outcome data from the ProFHER pragmatic trial. We assess the model's potential for delivering value-based research. Using parameter values estimated from the ProFHER pragmatic trial, including the costs of carrying out the trial, we establish when the trial could have stopped, had the model's value-based stopping rule been used. We use a bootstrap analysis and simulation study to assess a range of operating characteristics, which we compare with a fixed sample size design which does not allow for early stopping. We estimate that application of the model could have stopped the ProFHER trial early, reducing the sample size by about 14%, saving about 5% of the research budget and resulting in a technology recommendation which was the same as that of the trial. The bootstrap analysis suggests that the expected sample size would have been 38% lower, saving around 13% of the research budget, with a probability of 0.92 of making the same technology recommendation decision. It also shows a large degree of variability in the trial's sample size. Benefits to trial cost stewardship may be achieved by monitoring trial data as they accumulate and using a stopping rule which balances the benefit of obtaining more information through continued recruitment with the cost of obtaining that information. We present recommendations for further research investigating the application of value-based sequential designs.


Microarray analysis of active cardiac remodeling genes in a familial hypertrophic cardiomyopathy mouse model rescued by a phospholamban knockout.
Familial hypertrophic cardiomyopathy (FHC) is a disease characterized by ventricular hypertrophy, fibrosis, and aberrant systolic and/or diastolic function. Our laboratories have previously developed two mouse models that affect cardiac performance. One mouse model encodes an FHC-associated mutation in α-tropomyosin: Glu → Gly at amino acid 180, designated as Tm180. These mice display a phenotype that is characteristic of FHC, including severe cardiac hypertrophy with fibrosis and impaired physiological performance. The other model was a gene knockout of phospholamban (PLN KO), a regulator of calcium uptake in the sarcoplasmic reticulum of cardiomyocytes; these hearts exhibit hypercontractility with no pathological abnormalities. Previous work in our laboratories shows that when mice were genetically crossed between the PLN KO and Tm180, the progeny (PLN KO/Tm180) display a rescued hypertrophic phenotype with improved morphology and cardiac function. To understand the changes in gene expression that occur in these models undergoing cardiac remodeling (Tm180, PLN KO, PLN KO/Tm180, and nontransgenic control mice), we conducted microarray analyses of left ventricular tissue at 4 and 12 mo of age. Expression profiling reveals that 1,187 genes changed expression in direct response to the three genetic models. With these 1,187 genes, 11 clusters emerged showing normalization of transcript expression in the PLN KO/Tm180 hearts. In addition, 62 transcripts are highly involved in suppression of the hypertrophic phenotype. Confirmation of the microarray analysis was conducted by quantitative RT-PCR. These results provide insight into genes that alter expression during cardiac remodeling and are active during modulation of the cardiomyopathic phenotype.


Role of plasmacytoid dendritic cells and inducible costimulator-positive regulatory T cells in the immunosuppression microenvironment of gastric cancer.
Regulatory T cells (Tregs) and plasmacytoid dendritic cells (pDCs) play important roles in the immune escape of cancer. In this study, we investigated pDCs and pDC-induced inducible costimulator (ICOS)(+) Treg populations in peripheral blood from gastric cancer (GC) patients and healthy donors by flow cytometry. The distribution of these cells in carcinoma tissue, peritumor tissue, and normal gastric mucosa was detected by immunohistochemistry. Plasma and tissue concentration of the cytokines such as interleukin-10 and transforming growth factor-β1 were also measured. We found that the numbers of pDCs, Tregs, and ICOS(+) Tregs in peripheral blood were increased in GC patients compared with healthy donors. In tissue, Tregs and ICOS(+) Tregs were found distributing mainly in carcinoma tissue, whereas pDCs were mainly found in peritumor tissue. Moreover, the Foxp3(+) ICOS(+) /Foxp3(+) cell ratio in carcinoma and peritumor tissue were higher than that in normal tissue. There were more ICOS(+) Tregs in tumor and peritumor tissue of late-stage GC patients. There was a positive correlation between pDCs and ICOS(+) Tregs in peripheral blood and peritumor tissue from GC patients. In conclusion, pDCs may play a potential role in recruiting ICOS(+) Tregs, and both participate in the immunosuppression microenvironment of GC.


Can Economic Analysis Contribute to Disease Elimination and Eradication? A Systematic Review.
Infectious diseases elimination and eradication have become important areas of focus for global health and countries. Due to the substantial up-front investments required to eliminate and eradicate, and the overall shortage of resources for health, economic analysis can inform decision making on whether elimination/eradication makes economic sense and on the costs and benefits of alternative strategies. In order to draw lessons for current and future initiatives, we review the economic literature that has addressed questions related to the elimination and eradication of infectious diseases focusing on: why, how and for whom? A systematic review was performed by searching economic literature (cost-benefit, cost-effectiveness and economic impact analyses) on elimination/eradication of infectious diseases published from 1980 to 2013 from three large bibliographic databases: one general (SCOPUS), one bio-medical (MEDLINE/PUBMED) and one economic (IDEAS/REPEC). A total of 690 non-duplicate papers were identified from which only 43 met the inclusion criteria. In addition, only one paper focusing on equity issues, the "for whom?" question, was found. The literature relating to "why?" is the largest, much of it focusing on how much it would cost. A more limited literature estimates the benefits in terms of impact on economic growth with mixed results. The question of how to eradicate or eliminate was informed by an economic literature highlighting that there will be opportunities for individuals and countries to free-ride and that forms of incentives and/or disincentives will be needed. This requires government involvement at country level and global coordination. While there is little doubt that eliminating infectious diseases will eventually improve equity, it will only happen if active steps to promote equity are followed on the path to elimination and eradication. The largest part of the literature has focused on costs and economic benefits of elimination/eradication. To a lesser extent, challenges associated with achieving elimination/eradication and ensuring equity have also been explored. Although elimination and eradication are, for some diseases, good investments compared with control, countries' incentives to eliminate do not always align with the global good and the most efficient elimination strategies may not prioritize the poorest populations. For any infectious disease, policy-makers will need to consider realigning contrasting incentives between the individual countries and the global community and to assure that the process towards elimination/eradication considers equity.


Scanning electron microscopic observations of common carotid artery endothelium in the rat. I. Crater artifacts.
Changes in the endothelial surface of the common carotid artery of the Sprague-Dawley rat were observed by scanning electron microscopy after vessels were removed prior to sacrifice or after gluteraldehyde cardiac perfusion. Rates were classified according to whether the vessels was 1) untouched prior to removal, 2) dissected and observed for a period of time, and 3) clamped and observed. Changes consisted of small 1-6 micron craters as well as smooth or cross-striated endothelial ridges or folds. Clamped arteries appeared to exhibit more frequent craters. In contrast, vessels removed prior to death and briefly washed with saline exhibited craters different morphologically from those vessels perfused with gluteraldehyde. Background endothelial folds also differed from the gluteraldehyde-perfused group, exhibiting a cobblestoned or breaded appearance with distorted endothelial bridges. This supports the suggestion of Nelson that premortem perfusion of heart and ascending aorta with gluteraldehyde is necessary to reduce artifact in arterial endothelial structures.


Vacuum Rabi spectra of a single quantum emitter.
We report the observation of the vacuum Rabi splitting of a single quantum emitter by measuring its direct spontaneous emission into free space. We use a semiconductor quantum dot inside a photonic crystal nanocavity, in conjunction with an appropriate cavity design and filtering with a polarizer and an aperture, enabling the extraction of the inherently weak emitter's signal. The emitter's vacuum Rabi spectra exhibit clear differences from those measured by detecting the cavity photon leakage. Moreover, we observe an asymmetric vacuum Rabi spectrum induced by interference between the emitter and cavity detection channels. Our observations lay the groundwork for accessing various cavity quantum electrodynamics phenomena that manifest themselves only in the emitter's direct spontaneous emission.


Extending the Microtubule/Microfibril paradigm. Cellulose synthesis is required for normal cortical microtubule alignment in elongating cells
The cortical microtubule array provides spatial information to the cellulose-synthesizing machinery within the plasma membrane of elongating cells. Until now data indicated that information is transferred from organized cortical microtubules to the cellulose-synthesizing complex, which results in the deposition of ordered cellulosic walls. How cortical microtubules become aligned is unclear. The literature indicates that biophysical forces, transmitted by the organized cellulose component of the cell wall, provide a spatial cue to orient cortical microtubules. This hypothesis was tested on tobacco (Nicotiana tabacum L.) protoplasts and suspension-cultured cells treated with the cellulose synthesis inhibitor isoxaben. Isoxaben (0.25-2.5 m) inhibited the synthesis of cellulose microfibrils (detected by staining with 1 g mL-1 fluorescent dye and polarized birefringence), the cells failed to elongate, and the cortical microtubules failed to become organized. The affects of isoxaben were reversible, and after its removal microtubules reorganized and cells elongated. Isoxaben did not depolymerize microtubules in vivo or inhibit the polymerization of tubulin in vitro. These data are consistent with the hypothesis that cellulose microfibrils, and hence cell elongation, are involved in providing spatial cues for cortical microtubule organization. These results compel us to extend the microtubule/microfibril paradigm to include the bidirectional flow of information.


At Least Two Genes Encode Many Variants of Irak3 in Rainbow Trout, but Neither the Full-Length Factor Nor Its Variants Interfere Directly With the TLR-Mediated Stimulation of Inflammation.
The interleukin-1-receptor-associated kinase 3 (IRAK3) is known in mammals as a negative feedback regulator of NF-κB-mediated innate-immune mechanisms. Our RNA-seq experiments revealed a prototypic 1920-nt sequence encoding irak3 from rainbow trout (Oncorhynchus mykiss), as well as 20 variants that vary in length and nucleotide composition. Based on the DNA-sequence information from two closely related irak3 genes from rainbow trout and an irak3-sequence fragment from Atlantic salmon retrieved from public databases, we elucidated the underlying genetic causes for this striking irak3 diversity. Infecting rainbow trout with a lethal dose of Aeromonas salmonicida enhanced the expression of all variants in the liver, head kidney, and peripheral blood leucocytes. We analyzed the functional impact of the full-length factor and selected structural variants by overexpressing them in mammalian HEK-293 cells. The full-length factor enhanced the basal activity of NF-κB, but did not dampen the TLR2-signaling-induced levels of NF-κB activation. Increasing the basal NF-κB-activity through Irak3 apparently does not involve its C-terminal domain. However, more severely truncated factors had only a minor impact on the activity of NF-κB. The TLR2-mediated stimulation did not alter the spatial distribution of Irak3 inside the cells. In salmonid CHSE-214 cells, we observed that the Irak3-splice variant that prominently expresses the C-terminal domain significantly quenched the stimulation-dependent production of interleukin-1β and interleukin-8, but not the production of other immune regulators. We conclude that the different gene and splice variants of Irak3 from trout play distinct roles in the activation of immune-regulatory mechanisms.


Biomaterial and Stem Cell Interactions: Histological Biocompatibility.
Advancements in biomaterials and stem cell technology have lead current medical technology to tissue engineering and regenerative medicine. Human engineered cartilage, bone, fascia, tendon, nerve and skin tissues have been used for the treatment of tissue injuries and degenerative diseases in combination with embryonic, fetal or adult stem and progenitor cells. Mesenchymal stem cells are one of the most extensively studied adult stem cell population and are widely utilized in cell therapies. Regeneration and 3-dimensional reconstruction of specialized connective tissues by combining differently originated micro and nanoscaled, natural or synthetic scaffolds with stem or progenitor cells are highly expected to guarantee patients to maintain acceptable life quality. In this review we discuss the important issues in biomaterial and stem cell interactions based on histological biocompatibility, updating recent basic research in this field and addressing possible future perspectives.


Characterization of the traD operon of naphthalene-catabolic plasmid NAH7: a host-range modifier in conjugative transfer.
Pseudomonas putida G7 carries a naphthalene-catabolic and self-transmissible plasmid, NAH7, which belongs to the IncP-9 incompatibility group. Adjacent to the putative origin of conjugative transfer (oriT) of NAH7 are three genes, traD, traE, and traF, whose functions and roles in conjugation were previously unclear. These three genes were transcribed monocistronically and thus were designated the traD operon. Mutation of the three genes in the traD operon resulted in 10- to 10(5)-fold decreases in the transfer frequencies of the plasmids from Pseudomonas to Pseudomonas and Escherichia coli and from E. coli to E. coli. On the other hand, the traD operon was essential for the transfer of NAH7 from E. coli to Pseudomonas strains. These results indicated that the traD operon is a host-range modifier in the conjugative transfer of NAH7. The TraD, TraE, and TraF proteins were localized in the cytoplasm, periplasm, and membrane, respectively, in strain G7 cells. Our use of a bacterial two-hybrid assay system showed that TraE interacted in vivo with other essential components for conjugative transfer, including TraB (coupling protein), TraC (relaxase), and MpfH (a channel subunit in the mating pair formation system).


A prognostic model and pre-discharge predictors of post-COVID-19 syndrome after hospitalization for SARS-CoV-2 infection.
Post-COVID-19 syndrome (PCS) has been increasingly recognized as an emerging problem: 50% of patients report ongoing symptoms 1 year after acute infection, with most typical manifestations (fatigue, dyspnea, psychiatric and neurological symptoms) having potentially debilitating effect. Early identification of high-risk candidates for PCS development would facilitate the optimal use of resources directed to rehabilitation of COVID-19 convalescents. To study the in-hospital clinical characteristics of COVID-19 survivors presenting with self-reported PCS at 3 months and to identify the early predictors of its development. 221 hospitalized COVID-19 patients underwent symptoms assessment, 6-min walk test, and echocardiography pre-discharge and at 1 month; presence of PCS was assessed 3 months after discharge. Unsupervised machine learning was used to build a SANN-based binary classification model of PCS development. PCS at 3 months has been detected in 75% patients. Higher symptoms level in the PCS group was not associated with worse physical functional recovery or significant echocardiographic changes. Despite identification of a set of pre-discharge predictors, inclusion of parameters obtained at 1 month proved necessary to obtain a high accuracy model of PCS development, with inputs list including age, sex, in-hospital levels of CRP, eGFR and need for oxygen supplementation, and level of post-exertional symptoms at 1 month after discharge (fatigue and dyspnea in 6MWT and MRC Dyspnea score). Hospitalized COVID-19 survivors at 3 months were characterized by 75% prevalence of PCS, the development of which could be predicted with an 89% accuracy using the derived neural network-based classification model.


[Trypanosome sensitivity to polyene antibiotics].
Swelling of the plasma membrane is one of the mechanisms of resistance to damages in pathogenic Protozoa. Polyenic antibiotics induce reconstruction of the cytoplasma membrane of unicellular eukaryotic organisms, i. e. fungi and Protozoa by binding the membrane lipids. The effect of 5 heptaene polyenic antibiotics, such as amphotericin B, mycoheptin, levorin, its sodium salt and levoridone on the growth of trypanosomides of Trypanosoma lewisi and Crithidia oncopelti was studied. The MIC and IC50 of these antibiotics were determined. It was found that these antibiotics were inhibitors of the trypanosomide growth and development. Levorin and amphotericin were most active with respect to C. oncopelti and levorin was most active with respect to T. lewisi. Physiological and morphological changes in the trypanosomides induced by the polyenic antibiotics were noted. The effect of levorin and amphotericin B on the content of lipids in the trypanosomide cells was studied. A decrease in the total content of the intracellular lipids due to the effect of the polyenes was shown. Differences in the rate of the inhibitory effect as dependent on the structure of the hydrophile part of the lactone ring of the heptaene polyenic antibiotics were found.


Prolongation of hemodialysis access survival with elective revision.
153 hemodialysis accesses (56 fistulas and 97 PTFE grafts) were followed from placement to see if elective intervention prolonged access survival. The mean follow-up was 772 days (minimum 14 days, maximum 2755 days). Patients who expired, were transplanted or transferred were excluded. The groups of fistulas and grafts were subdivided into those whose first intervention was an episode of clotting versus those whose first intervention was an elective revision (either surgical repair or angioplasty of an area of stenosis within the access or run-off). These groups were compared to see whether electively revising an access prior to clotting would change the ultimate longevity of the access when compared to repairing the access after clotting. PTFE grafts with an initial elective intervention had an improved survival compared to grafts that clotted first (1023 days vs 689 days, p = 0.01). The electively revised grafts had fewer subsequent clotting episodes (1.1 clots per patient year vs 3.6, p = 0.02) and fewer interventions (1.8 interventions per patient year vs 3.7, p = 0.06). In fistulas, an initial elective revision increased access longevity when compared to repair after the fistula clotted (999 days vs 358 days, p = 0.005). Clotting episodes were decreased in those electively revised (0.5 clots per patient year vs 4.8, p = 0.014). Total interventions per patient year were also lower in those electively revised (1.2 vs 5.3, p = 0.028). In conclusion, elective correction of abnormalities in PTFE grafts and in AV fistulas prolongs access life when compared to repair after an initial episode of clotting. Elective revision also decreased the subsequent number of clotting episodes per patient year and the total number of interventions (revisions and declottings) per patient year in both grafts and fistulas.


ICAM-1 and SRD5A1 gene polymorphisms in symptomatic peripheral artery disease.
The genotype distribution of two gene polymorphisms, previously associated with peripheral artery disease (PAD), has been evaluated in a population of diabetic (DPAD) and non-diabetic (NDPAD) patients affected by symptomatic PAD (stages II-IV). A decreased frequency of the AA genotype of rs5498 (ICAM-1) was observed in the PAD subjects compared to controls but this result did not reach statistical significance (p=0.06 by chi-squared test). On the contrary, a significant increase in the frequency of the GG homozygous genotype of rs248793 (SRD5A1) was observed in the PAD patient group in comparison to controls (p=0.01). These data confirm that the GG genotype of rs248793 in the SRD5A1 gene is significantly associated with symptomatic PAD and show a trend towards a stronger association with the non-diabetic status.


Substrate metabolism during different exercise intensities in endurance-trained women.
We have studied eight endurance-trained women at rest and during exercise at 25, 65, and 85% of maximal oxygen uptake. The rate of appearance (R(a)) of free fatty acids (FFA) was determined by infusion of [(2)H(2)]palmitate, and fat oxidation rates were determined by indirect calorimetry. Glucose kinetics were assessed with [6,6-(2)H(2)]glucose. Glucose R(a) increased in relation to exercise intensity. In contrast, whereas FFA R(a) was significantly increased to the same extent in low- and moderate-intensity exercise, during high-intensity exercise, FFA R(a) was reduced compared with the other exercise values. Carbohydrate oxidation increased progressively with exercise intensity, whereas the highest rate of fat oxidation was during exercise at 65% of maximal oxygen uptake. After correction for differences in lean body mass, there were no differences between these results and previously reported data in endurance-trained men studied under the same conditions, except for slight differences in glucose metabolism during low-intensity exercise (Romijn JA, Coyle EF, Sidossis LS, Gastaldelli A, Horowitz JF, Endert E, and Wolfe RR. Am J Physiol Endocrinol Metab 265: E380-E391, 1993). We conclude that the patterns of changes in substrate kinetics during moderate- and high-intensity exercise are similar in trained men and women.


Endovascular repair of ruptured abdominal aortic aneurysms: logistics and short-term results.
To report our experience in establishing a treatment protocol for endovascular aneurysm repair (EVAR) of ruptured abdominal aortic aneurysms (rAAA), including an investigation of the reasons for patient exclusion and a report of our short-term results. Between 1997 and July 2002, 21 patients with rAAA underwent endovascular repair according to our protocol and were followed prospectively. A retrospective analysis was also conducted of 23 rAAA patients treated with open repair from January 2001 through June 2002. Procedural and clinical data from this sample were compared to 14 contemporaneous emergent EVAR cases and analyzed to determine why the open repair patients were not treated with an endovascular approach. Among the 21 patients treated with emergent EVAR since the beginning of this protocol, 6 (29%) procedures were performed under local anesthesia and 6 were performed percutaneously. Thirty-day mortality was 19%. In the comparison of 14 emergent EVAR cases to 23 open rAAA repairs, the mean duration of symptoms prior to intervention was 12 hours for the EVAR patients and <1 hour for OR patients. No significant difference was found in operating time, but the EVAR group had significantly less blood loss (p=0.0001) and transfusion needs (p=0.02); duration of intensive care unit stay was significantly shorter in the EVAR group (p=0.02). Thirty-day mortality was 29% (4/14) for EVAR and 35% for OR (8/23) (p>0.05). Reasons for not performing EVAR were unavailability of adequate equipment (n=11) or trained staff (n=7), hemodynamically unstable patient (n=2), mycotic aneurysm (n=2), and unfavorable anatomy in a 60-year old patient with a <5-mm-long, sharply angled infrarenal neck. Endovascular repair of ruptured aortic aneurysms is feasible, and short-term results are promising. Good logistics, adequate training of physicians and staff in an elective setting, and versatile endografts are prerequisites for this type of treatment program.


An assessment of interactions between global health initiatives and country health systems.
Since 2000, the emergence of several large disease-specific global health initiatives (GHIs) has changed the way in which international donors provide assistance for public health. Some critics have claimed that these initiatives burden health systems that are already fragile in countries with few resources, whereas others have asserted that weak health systems prevent progress in meeting disease-specific targets. So far, most of the evidence for this debate has been provided by speculation and anecdotes. We use a review and analysis of existing data, and 15 new studies that were submitted to WHO for the purpose of writing this Report to describe the complex nature of the interplay between country health systems and GHIs. We suggest that this Report provides the most detailed compilation of published and emerging evidence so far, and provides a basis for identification of the ways in which GHIs and health systems can interact to mutually reinforce their effects. On the basis of the findings, we make some general recommendations and identify a series of action points for international partners, governments, and other stakeholders that will help ensure that investments in GHIs and country health systems can fulfil their potential to produce comprehensive and lasting results in disease-specific work, and advance the general public health agenda. The target date for achievement of the health-related Millennium Development Goals is drawing close, and the economic downturn threatens to undermine the improvements in health outcomes that have been achieved in the past few years. If adjustments to the interactions between GHIs and country health systems will improve efficiency, equity, value for money, and outcomes in global public health, then these opportunities should not be missed.


Analysis of performance and robustness against jitter of various search methods for acquiring optical links in space.
We discuss various methods for acquiring optical links in space using a dedicated acquisition sensor. Statistical models are developed and simple analytical equations derived that compare the performance between a single- and dual-spiral scan approach as well as between sequential and parallel acquisition of link chains. Simple derived analytical equations allow relating essential search parameters such as track width, variance of the uncertainty distribution, capture radius, and scan speed to the probabilities of acquiring the links within a specific time. We also assess the probability of failing to acquire a link due to beam jitter and derive a simple analytical model that allows determining the maximum tolerable jitter for a given beam overlap and required probability of success. All results are validated by Monte Carlo simulations and applied to the concrete example of the GRACE FO mission.


Physicochemical characterization of nedocromil bivalent metal salt hydrates. 3. Nedocromil calcium.
A crystalline pentahydrate and a crystalline 8/3 hydrate of nedocromil calcium (NC) were prepared. The relationships between these solid phases and the nature of the water interactions in their structures were studied through characterization by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Karl Fischer titrimetry (KFT), hot-stage microscopy (HSM), ambient- or variable-temperature powder X-ray diffraction (PXRD), Fourier-transform infrared (FTIR) spectroscopy, solid-state nuclear magnetic resonance (SSNMR) spectroscopy, water uptake at various relative humidities (RH), intrinsic dissolution rate (IDR) and solubility measurements. The solubility and intrinsic dissolution rate of the pentahydrate in water at 25 degrees C are approximately 17% greater than the corresponding values for the 8/3 hydrate, corresponding to a greater Gibbs free energy of only 380 J.mol-1 (91 cal.mol-1) for the pentahydrate. The results of DSC, TGA, and FTIR and SSNMR spectroscopy indicate that the water of hydration is more loosely bound in the pentahydrate than in the 8/3 hydrate. On increasing the temperature in open-pan DSC and TGA, the water in the pentahydrate is released in four steps (three steps in crimped pans), whereas the water in the 8/3 hydrate is released in three steps (three steps also in crimped pans). These three stepwise dehydrations are fundamentally explained by their different water environments in the crystal structure of the 8/3 hydrate, which was determined by single-crystal XRD [crystal data: triclinic, space group P1, a = 13.2381(3) A, b = 13.3650(2) A, c = 17.8224(2) A, alpha = 68.202(1) degrees, beta = 86.894(1) degrees, gamma = 82.969(1) degrees, Z = 6]. The asymmetric unit contains three nedocromil anions and three calcium cations associated with eight water molecules. The nedocromil anions act as polyfunctional ligands to the Ca2+ ions, coordinating through both the carbonyl oxygen and the carboxylate oxygen atoms. The molecular conformations of the three nedocromil anions in the asymmetric unit are almost identical. However, the crystal structure contains two different calcium environments, one of which has the Ca2+ ion hydrated by four water molecules in the equatorial plane and by two carbonyl oxygens in its axial coordination sites. In the second environment, the Ca2+ ion has four carboxylate oxygen atoms in its equatorial plane and two water molecules in its axial coordination sites. Two of the carboxylate ligands are twisted out of the tricyclic ring, and the other two carboxylate ligands are nearly coplanar with the tricyclic ring. All of the eight water molecules in the 8/3 hydrate are linked to calcium and carboxylate ions and none are linked to other water molecules.


Resuscitative endovascular balloon occlusion of the aorta induced myocardial injury is mitigated by endovascular variable aortic control.
The cardiac effects of resuscitative endovascular balloon occlusion of the aorta (REBOA) are largely unknown. We hypothesized that increased afterload from REBOA would lead to cardiac injury, and that partial flow using endovascular variable aortic control (EVAC) would mitigate this injury. Eighteen anesthetized swine underwent controlled 25% blood volume hemorrhage. Animals were randomized to either Zone 1 REBOA, Zone 1 EVAC, or no intervention (control) for 45 minutes. Animals were then resuscitated with shed blood, observed during critical care, and euthanized after a 6-hour total experimental time. Left ventricular function was measured with a pressure-volume catheter, and blood samples were drawn at routine intervals. The average cardiac output during the intervention period was higher in the REBOA group (9.3 [8.6-15.4] L/min) compared with the EVAC group (7.2 [5.8-8.0] L/min, p = 0.01) and the control group (6.8 [5.8-7.7] L/min, p < 0.01). At the end of the intervention, the preload recruitable stroke work was significantly higher in both the REBOA and EVAC groups compared with the control group (111.2 [102.5-148.6] and 116.7 [116.6-141.4] vs. 67.1 [62.7-87.9], p = 0.02 and p < 0.01, respectively). The higher preload recruitable stroke work was maintained throughout the experiment in the EVAC group, but not in the REBOA group. Serum troponin concentrations after 6 hours were higher in the REBOA group compared with both the EVAC and control groups (6.26 ± 5.35 ng/mL vs 0.92 ± 0.61 ng/mL and 0.65 ± 0.38 ng/mL, p = 0.05 and p = 0.03, respectively). Cardiac intramural hemorrhage was higher in the REBOA group compared with the control group (1.67 ± 0.46 vs. 0.17 ± 0.18, p = 0.03), but not between the EVAC and control groups. In a swine model of hemorrhagic shock, complete aortic occlusion resulted in cardiac injury, although there was no direct decrease in cardiac function. EVAC mitigated the cardiac injury and improved cardiac performance during resuscitation and critical care.


A novel missense mutation (C30S) in the gene encoding tumor necrosis factor receptor 1 linked to autosomal-dominant recurrent fever with localized myositis in a French family.
To characterize both phenotypic (clinical features and magnetic resonance imaging [MRI] findings) and genotypic aspects of autosomal-dominant recurrent fever, also known as tumor necrosis factor receptor (TNFR)-associated periodic syndrome (TRAPS), in a French family and to investigate the role of the mutated 55-kd tumor necrosis factor alpha (TNFalpha) receptor (TNFR1) in the pathogenesis of the disease. The coding region of TNFR1 was sequenced in 2 individuals with TRAPS (the propositus and her grandfather) and in 3 clinically unaffected relatives. Expression of soluble TNFR1 (sTNFR1) was investigated in 3 of the family members carrying a C30S mutation in TNFR1, and was compared with the levels of soluble TNFR2 (sTNFR2) by enzyme-linked immunosorbent assay. The membrane TNFR1 expression was then compared with membrane TNFR2 levels at the surface of peripheral blood mononuclear cells by flow cytometric analysis. The clinical heterogeneity in this French family was investigated by searching polymorphic variants in the TNFalpha promoter by DNA sequencing. Both the disease course and the clinical presentation in the propositus were highly indicative of TRAPS. MRI study of the segmental inflammatory process in the limbs showed abnormal signals in the muscle and subcutaneous tissue without involvement of adjacent joints or fascia. A novel missense mutation, C30S, in the first extracellular N-terminal cysteine-rich domain (CRD1) of TNFR1 was characterized in the propositus, her affected grandfather, and her clinically unaffected father. Expression of membrane TNFR1 at the surface of monocytes and polymorphonuclear leukocytes, as well as the levels of sTNFR1 in serum when the disease was not active were not modified in the 3 individuals carrying the TNFR1 C30S mutation. In contrast, during attacks, sTNFR1 levels remained abnormally low, as compared with the levels in unrelated patients with active adult-onset systemic Still's disease. The clinical heterogeneity could not be explained by a polymorphic variant in the TNFalpha promoter. TRAPS is a distinct clinical and radiologic disease entity that is responsible for recurrent fever and migratory cellulitis-like processes with localized myositis. We have identified a novel TNFR1 mutation, C30S, that is located in the CRD1 domain in a French family affected by the disease. This mutation seems to affect the level of sTNFR1, which did not increase in the propositus during inflammatory attacks.


łGradation of sideropneumoconiosis.
Pathological-anatomical analyses of biopsy and autopsy samples of 43 men with anamnestically established occupational exposure to welding fumes showed in 38 specimens (88%) characteristic alterations of varying degrees of sidero pneumokonioses. Based on recurrent histological findings of increase and activation of iron storing macrophages (siderophages) and varying degrees of fibrosis, sidero pneumokonioses are classified into three grades. Intraindividually and also toporegionally different degrees may well be present. Based on morphological criteria of the three grades, seven samples were classified as grade I, 21 specimens as grade II, and 10 samples as grade III. The results show that exposure to welding fumes may well cause pulmonary alterations reaching an impairment level, depending on length, extent and special circumstances of the respective exposure. In cases of so-called welders lungs, an obliging statement in an expert's opinion on the degree of functional impairment, however, can only be given when histological findings, detailed information on the occupational history and clinical functional parameters are combined.


TcCYS4, a cystatin from cocoa, reduces necrosis triggered by MpNEP2 in tobacco plants.
In Brazil, most cocoa bean production occurs in Southern Bahia. Witches' broom disease arrived in this area in 1989 and has since caused heavy losses in production. The disease is caused by the basidiomycete fungus Moniliophthora perniciosa, a hemibiotrophic fungus that produces the necrosis and ethylene-inducting protein (MpNEP2) during infection; this protein can activate cysteine proteases and induce programmed cell death. Cysteine proteases can be modulated by cystatin. In this study, we overexpressed TcCYS4, a cocoa cystatin, in tobacco plants and evaluated the effect on MpNEP2 in model plants. Tccys4 cDNA was cloned into the pCAMBIA 1390 vector and inserted into the tobacco plants via Agrobacterium tumefaciens. Transgene expression was analyzed by reverse transcription-quantitative PCR and Western blot analysis. Transcript and protein levels in Tcccys4:tobacco lines were 8.9- and 1.5-fold higher than in wild-type plants (wt). Tcccys4:tobacco lines showed no change in growth compared to wt plants. CO2 net assimilation (A) increased in Tcccys4:tobacco lines compared to wt plants. Only one line showed statistically significant stomatal conductance (gs) and transpiration rate (E) changes. MpNEP2 was infiltered into the foliar mesophyll of Tcccys4:tobacco lines and wt plants, and necrotic lesions were attenuated in lines highly expressing Tccys4. Our results suggest that cocoa cystatin TcCYS4 affects MpNEP2 activity related to the progression of programmed cell death in tobacco plants. This may occur through the action of cystatin to inhibit cysteine proteases activated by MpNEP2 in plant tissues. Further studies are necessary to examine cystatin in the Theobroma cacao-M. perniciosa pathosystem.


[Role of active forms of oxygen in the induction of phytoalexin synthesis in Allium cepa cells].
The results of studies on the role of plant superoxidesynthase signal system in elicitation of antimicrobial phytoalexin (PA) synthesis in cultured Allium cepa cells are presented. Exogenic application of O2- and H2O2 generators results in formation of PA--Tcibulins 1D and 2 [symbol: see text] in A. cepa cells. The mechanism of PA elicitation does not require peroxidase activity. However, the inhibition of one of the possible sources of the reactive oxygen, HADPH oxidase, suppresses elicitor-stimulated PA production. "Oxidative burst" modulation by different chemical compounds in A. cepa cells results in changes of PA synthesis elicitation. The results obtained suggest the tough correlation between "oxidative burst" and elicitation of defense responses, PA synthesis in particular.


Characterization of carbon-coated magnetic nanoparticles using clinical blood coagulation assays: effect of PEG-functionalization and comparison to silica nanoparticles.
Intravascular application of magnetic nanocarriers is a critical step in the development of new therapeutic strategies, including magnetic drug targeting or hyperthermia. However, injection of particulate matter bears the intrinsic risk of contact activation of the blood coagulation cascade. In this work, we use point-of-care assays to study coagulation dynamics and clotting parameters in blood samples exposed to relevant concentrations of surface-functionalized carbon-coated iron carbide nanomagnets using unmodified nanomagnets and poly(ethylene)glycol-functionalized nanomagnets with different end-groups, including -OCH3, -NH2, -COOH, -IgG, and -ProteinA-protected-IgG (-IgG-ProtA). Silica nanoparticles with a comparable surface area are used as a reference material. For magnetic nanoparticles, we observe a decrease in clotting time by 25% compared to native blood at concentrations of 1 mg mL-1, independent of the surface functionalization, and only minor differences in receptor expression on platelets (GP-IIb-IIIa, CD62, and CD63) relative to control samples were observed. Interestingly, the inter-subject variance of the clotting time is similar to the nanoparticle-induced effect in a single subject with average clotting time. Whilst the present study is based on in vitro assays and a small group of healthy blood donors, the comparison to broadly used silica nanoparticles, and the fact that experimental intergroup variability is comparable to the observed effects from the carbon-coated nanomagnets suggests continuing investigations on their potential clinical use.


[Late sequelae of the effect of electromagnetic field on animals].
Simple and complex forms of behaviour, gas composition and acid-alkaline blood status in rats following exposure to the electro-static field (ESF) and iraionization, as well as in their offspring were studied. It has been found out, that ESF combined with the negative polarity air ionization damage motor and sex activity, conditioned-reflectory activity, changes blood indices. The observed disturbances in the organism of parent animals influenced fetus development.


Di-(2-ethylhexyl) phthalate and bisphenol A exposure impairs mouse primordial follicle assembly in vitro.
Bisphenol-A (BPA) and diethylhexyl phthalate (DEHP) are estrogenic compounds widely used in commercial plastic products. Previous studies have shown that exposure to such compounds have adverse effects on various aspects of mammalian reproduction including folliculogenesis. The objective of this study was to examine the effects of BPA and DEHP exposure on primordial follicle formation. We found that germ cell nest breakdown and primordial follicle assembly were significantly reduced when newborn mouse ovaries were exposed to 10 or 100 μM BPA and DEHP in vitro. Moreover, BPA and DEHP exposure increased the number of TUNEL positive oocytes and the mRNA level of the pro-apoptotic gene Bax in oocytes. These effects were associated with decreased expression of oocyte specific genes such as LIM homeobox 8 (Lhx8), factor in the germline alpha (Figla), spermatogenesis and oogenesis helix-loop-helix (Sohlh2), and newborn ovary homeobox (Nobox). Interestingly, BPA and DEHP exposure also prevented DNA demethylation of CpG sites of the Lhx8 gene in oocytes, a process normally associated with folliculogenesis. Finally, folliculogenesis was severely impaired in BPA and DEHP exposed ovaries after transplantation into the kidney capsules of immunodeficient mice. In conclusion, BPA and DEHP exposures impair mouse primordial follicle assembly in vitro.


Reevaluation of radiation reaction and consequences for light-matter interactions at the nanoscale.
In the context of electromagnetism and nonlinear optical interactions, damping is generally introduced as a phenomenological, viscous term that dissipates energy, proportional to the temporal derivative of the polarization. Here, we follow the radiation reaction method presented in [Phys. Lett. A157, 217 (1991)], which applies to non-relativistic electrons of finite size, to introduce an explicit reaction force in the Newtonian equation of motion, and derive a hydrodynamic equation that offers new insight on the influence of damping in generic plasmas, metal-based and/or dielectric structures. In these settings, we find new damping-dependent linear and nonlinear source terms that suggest the damping coefficient is proportional to the local charge density and nonlocal contributions that stem from the spatial derivative of the magnetic field. We discuss the conditions that could modify both linear and nonlinear electromagnetic responses.


Ethanol disrupts and decreases the regulated body temperature differentially in C57BL/6J and DBA/2J mice.
Two inbred mouse strains, C57BL/6J (B6) and DBA/2J (D2), were evaluated for effects of ethanol on thermoregulation. Continuous recording of core temperature (Tc) from undisturbed animals at an ambient temperature (Ta) of 27 degrees C indicated Tc was similar for both strains during active (approximately 38.0 degrees C) and inactive (approximately 36.7 degrees C) periods. Ethanol-injections of 1.5, 2.5, 3.5, and 4.5 g/kg in an environment where Ta rose and fell at 6-min intervals, reaching extremes of 14 and 42 degrees C, produced dose-dependent falls in Tc for both strains. The changes in Ta produced fluctuations in Tc under all conditions. The amplitude of these fluctuations in Tc was used as a measure of physiological disruption. Dose-dependent increases in disruption were found for both strains. At a constant 26 degrees C Ta, ethanol produced dose-related increases in tail temperature. Responses after ethanol administration were different for B6 and D2 mice. The results indicate regulated temperature is similar for B6 and D2 strains. Regulated temperature is decreased more by ethanol for B6 mice, whereas disruption of thermoregulation by ethanol is greater for D2 mice.


Superficial radial nerve compression caused by a parosteal lipoma of proximal radius: a case report.
The superficial radial nerve might be compressed or injured at various anatomical sites along its course in the forearm. Most of the superficial radial nerve neuropathy are caused by pathological lesions such as trauma, a mass or tight band at the distal third of the forearm. Wartenberg's syndrome is the most common cause of sensory radial entrapment at the distal forearm. Compression of superficial radial nerve occurring at the proximal third of forearm is unusual. We present a rare case of superficial radial nerve compression due to a parosteal lipoma of proximal radius. Results of complete physical and radiological examinations are also presented. Surgical intervention of the tumour mass was performed for nerve decompression. The patient reported total relief of the neurological symptom post-operatively. This rare case demonstrates the unique characteristics of parosteal lipoma with unusual superficial radial nerve neuropathy at the proximal radius. This report reminds us that there is the possibility of superficial nerve compression caused by tumour mass over the proximal third of forearm.


Transperitoneal robot-assisted partial nephrectomy: a comparison of posterior and anterior renal masses.
Robot-assisted partial nephrectomy (RAPN) for posterior renal masses necessitates access to the posterior surface of the kidney either via a transperitoneal (TP) or retroperitoneal (RP) approach. While advocates of an RP approach claim reduced morbidity for posterior tumors, it is a less familiar approach to many urologists. In our institution, a TP approach is used for all patients undergoing RAPN. We compared demographics and perioperative outcomes of TP RAPN for posterior and anterior/lateral renal masses. Our institutional renal mass database was queried for patients with available preoperative imaging who underwent TP RAPN from 2007 to 2013. Posterior masses were accessed by opening the Gerota fascia and rotating the kidney anteromedially. Demographic and perioperative outcomes were compared for patients with posterior masses and anterior/lateral masses. Overall, 260 TP RAPN were identified. Of these, 92 were for posterior tumors and 168 were for anterior and lateral tumors. Renal-cell carcinoma (RCC) was found in 77.3% of cases. Patient demographic and tumor characteristics were similar between groups. Among operative characteristics, warm ischemia time (17 vs 16.5, min P=0.70), operative time (160 vs 159 min, P=0.82), estimated blood loss (100 vs 100 mL, P=0.44), RCC positive surgical margins (1.4% vs 1.5%), and postoperative complications (19.6% vs 16.1%, P=1.0) were similar for posterior and anterior/lateral tumors, respectively. TP RAPN is a safe, effective treatment option for patients with posterior renal masses with no additional morbidity compared with anterior/lateral renal masses. RP PN remains an alternative treatment option.


Individualized Ultrasound-Guided Intervention Phantom Development, Fabrication, and Proof of Concept.
Commercial ultrasound vascular phantoms lack the anatomic diversity required for robust pre-clinical interventional device testing. We fabricated individualized phantoms to test an artificial intelligence enabled ultrasound-guided surgical robotic system (AI-GUIDE) which allows novices to cannulate deep vessels. After segmenting vessels on computed tomography scans, vessel cores, bony anatomy, and a mold tailored to the skin contour were 3D-printed. Vessel cores were coated in silicone, surrounded in tissue-mimicking gel tailored for ultrasound and needle insertion, and dissolved with water. One upper arm and four inguinal phantoms were constructed. Operators used AI-GUIDE to deploy needles into phantom vessels. Two groin phantoms were tested due to imaging artifacts in the other two phantoms. Six operators (medical experience: none, 3; 1-5 years, 2; 5+ years, 1) inserted 27 inguinal needles with 81% (22/27) success in a median of 48 seconds. Seven operators performed 24 arm injections, without tuning the AI for arm anatomy, with 71% (17/24) success. After excluding failures due to motor malfunction and a defective needle, success rate was 100% (22/22) in the groin and 85% (17/20) in the arm. Individualized 3D-printed phantoms permit testing of surgical robotics across a large number of operators and different anatomic sites. AI-GUIDE operators rapidly and reliably inserted a needle into target vessels in the upper arm and groin, even without prior medical training. Virtual device trials in individualized 3-D printed phantoms may improve rigor of results and expedite translation.Clinical Relevance- Individualized phantoms enable rigorous and efficient evaluation of interventional devices and reduce the need for animal and human subject testing.


Site of hospital readmission and mortality: a population-based retrospective cohort study.
Unplanned hospital readmission is a complex process, particularly if the patient is readmitted to an acute care institution other than the original hospital. This study tested the hypothesis that readmission to an alternative hospital is associated with increased mortality compared with readmission to the original hospital. We performed a population-based retrospective cohort analysis set between 1995 and 2010 for all 21 acute care adult general hospitals in the Greater Toronto and Hamilton Area. Participants were consecutive adults (age ≥ 18 yr) readmitted through the emergency department within 30 days after hospital discharge. The primary outcome measure was all-cause mortality within 30 days after readmission. Of the 198 149 patients included in the study, 38 134 (19.2%) died within 30 days after readmission. Patients readmitted to an alternative hospital were more likely than those readmitted to the original hospital to be older, reside in a chronic-care facility and arrive by ambulance. Alternative-hospital readmission was associated with a higher risk of death within 30 days (22.3% v. 18.6%, p < 0.001; odds ratio [OR] 1.26, 95% confidence interval [CI] 1.23-1.30). The increased risk was substantially less after adjustment for patient- and hospital-level covariables (adjusted OR 1.06, 95% CI 1.02-1.10). Unadjusted Kaplan-Meier survival curves separated early and the absolute difference in mortality continued throughout the entire 1-year follow-up period, but no difference between groups was observed based on adjusted survival analyses. Among patients readmitted within 30 days after discharge, readmission to an alternative hospital was associated with a higher risk of death than readmission to the original hospital. Whether this adverse prognosis reflects a true causal relation or residual confounding is unknown.


Nitrite Accumulation Is Required for Microbial Anaerobic Iron Oxidation, but Not for Arsenite Oxidation, in Two Heterotrophic Denitrifiers.
Phylogenetically diverse species of bacteria can mediate anaerobic oxidation of ferrous iron [Fe(II)] and/or arsenite [As(III)] coupled to nitrate reduction, impacting the biogeochemical cycles of Fe and As. However, the mechanisms for nitrate-dependent anaerobic oxidation of Fe(II) and As(III) remain unclear. In this study, we isolated two bacterial strains from arsenic-contaminated paddy soils, Ensifer sp. ST2 and Paracoccus sp. QY30. Both strains were capable of anaerobic As(III) oxidation, but only QY30 could oxidize Fe(II) under nitrate-reducing conditions. Both strains contain the As(III) oxidase gene aioA, whose expression was induced greatly by As(III) exposure. Both strains contain the whole suite of genes for complete denitrification, but the nitrite reductase gene nirK was not expressed in QY30 and nitrite accumulated under nitrate-reducing conditions. When the functional nirK gene was knocked out in strain ST2, its nitrite reduction ability was completely abolished and nitrite accumulated in the medium. Moreover, the ST2ΔnirK mutant gained the ability to oxidize Fe(II). When nirK gene from ST2 was introduced to QY30, the recombinant strain QY30::nirK gained the ability to reduce nitrite but lost the ability to oxidize Fe(II). These genetic manipulations did not affect the ability of both strains to oxidize As(III). Our results indicate that nitrite accumulation is required for anaerobic oxidation of Fe(II) but not for As(III) oxidation in these strains. The results suggest that anaerobic Fe(II) oxidation in the two bacterial strains is primarily driven by abiotic reaction of Fe(II) with nitrite, while reduction of nitrate to nitrite is sufficient for redox coupling with anaerobic As(III) oxidation catalyzed by Aio. Deletion of nirK gene in denitrifiers can enhance anaerobic Fe(II) oxidation.


Hemadsorption immunosorbent technique for determination of mumps immunoglobulin M antibody.
We used hemadsorption immunosorbent technique (HIT) to detect mumps immunoglobulin M (IgM) antibody. IgM from human sera was adsorbed into anti-human IgM-coated wells in plates, and mumps-specific IgM was detected by adding mumps virus hemagglutinin and guinea pig erythrocytes consecutively. Specific IgM-positive sera showed hemadsorption, whereas negative sera showed hemagglutination. All 81 patients with current mumps infections tested showed mumps-specific IgM antibody, with titers ranging from 160 to 327,680. In most cases IgM antibody was already present on day 1 or 2 after the onset of illness. IgM antibody persisted for 6 to 10 weeks. Of 57 patients with acute respiratory illnesses caused by parainfluenza virus, 5 showed cross-reactions in the hemadsorption immunosorbent technique assay for mumps IgM. The hemadsorption immunosorbent technique assay is specific for the IgM class of antibody and avoids false-positive results due to rheumatoid factor. This test is an efficient and sensitive method for rapid and early diagnosis of mumps infections.


Differences and similarities in rheumatology specialty training programmes across European countries.
To analyse the similarities and discrepancies between the official rheumatology specialty training programmes across Europe. A steering committee defined the main aspects of training to be assessed. In 2013, the rheumatology official training programmes were reviewed for each of the European League Against Rheumatism (EULAR) countries and two local physicians independently extracted data on the structure of training, included competencies and assessments performed. Analyses were descriptive. 41 of the 45 EULAR countries currently provide specialist training in rheumatology; in the remaining four rheumatologists are trained abroad. 36 (88%) had a single national curriculum, one country had two national curricula and four had only local or university-specific curricula. The mean length of training programmes in rheumatology was 45 (SD 19) months, ranging between 3 and 72 months. General internal medicine training was mandatory in 40 (98%) countries, and was performed prior to and/or during the rheumatology training programme (mean length: 33 (19) months). 33 (80%) countries had a formal final examination. Most European countries provide training in rheumatology, but the length, structure, contents and assessments of these training programmes are quite heterogeneous. In order to promote excellence in standards of care and to support physicians' mobility, a certain degree of harmonisation should be encouraged.


Medullary thyroid carcinoma: role of high-resolution US.
Medullary thyroid carcinoma accounts for 10% of thyroid malignancies. Accurate determination of the extent of disease is important because surgery is required for initial treatment and recurrence. High-resolution (10-MHz) ultrasonography (US) of the neck was used to study 15 patients with medullary thyroid carcinoma; nine of the 15 had undergone thyroidectomy but had biochemical evidence of tumor recurrence. Metastatic cervical lymph nodes were detected with US in all 12 patients who had metastatic nodes at surgery, although these nodes were palpable in only four. Punctate bright echogenic foci were seen within some of the nodes in nine of the 12 patients (75%). Similar bright echogenic foci were seen within the primary intrathyroid tumor in five of the six patients who had not yet undergone thyroidectomy (83%). Pathologically, these foci correlated with deposits of calcium surrounded by amyloid, which is characteristic of medullary thyroid carcinoma. US is useful for the detection of nonpalpable recurrence of cervical metastatic lymph nodes, and because it is noninvasive and relatively inexpensive, it should be the first imaging investigation performed after thyroidectomy.


Survival in lung cancer. An analysis of the effects of age, sex, resectability, and histopathologic type.
Records of 6,686 patients with primary lung malignancies were retrieved from a tumor registry. Survival curves according to histopathologic type demonstrated that patients with anaplastic tumors have a lower cumulative survival than those with either squamous cell cancers or adenocarcinomas (p less than 0.001), but survival for the latter two histologic types is similar. Age at diagnosis influences survival, and women with squamous or anaplastic tumors have a better prognosis than men with the same cell types (p less than 0.001). Although selection for resection is strongly associated with lower early mortality, all patients alive 2 yr after diagnosis have a similar prognosis is regardless of initial resectability. Each survival curve shows a high early mortality and a lower late mortality, indicating that each group can be considered to consist of 2 subgroups with different risks of dying of lung cancer. A mathematical model is described that closely approximates the actuarial survival.


Malonyl coenzyme A decarboxylase deficiency: early dietary restriction and time course of cardiomyopathy.
Malonyl coenzyme A (CoA) decarboxylase (MCD) deficiency is a rare autosomal recessive organic acidemia characterized by varying degrees of organ involvement and severity. MCD regulates fatty acid biosynthesis and converts malonyl-CoA to acetyl-CoA. Cardiomyopathy is 1 of the leading causes of morbidity and mortality in this disorder. It is unknown if diet alone prevents cardiomyopathy development based in published literature. We report a 10-month-old infant girl identified by newborn screening and confirmed MCD deficiency with a novel homozygous MLYCD mutation. She had normal echocardiogram measurements before transition to high medium-chain triglycerides and low long-chain triglycerides diet. Left ventricular noncompaction development was not prevented by dietary interventions. Further restriction of long-chain triglycerides and medium-chain triglycerides supplementation in combination with angiotensin-converting enzyme inhibitors helped to improve echocardiogram findings. Patient remained asymptomatic, with normal development and growth. Our case emphasizes the need for ongoing cardiac disease screening in patients with MCD deficiency and the benefits and limitations of current dietary interventions.


Pharmacological and ultrastructural maturation of serotonergic synapses during ontogeny.
Studies were made on the course of maturation of serotonergic synapses during ontogeny in rat brain. Mature synaptosomes containing the same five types of synatic vesicles as in the adult, including small dense core vesicles, could be isolated in low proportion from the brain of 1-day-old rats. Although the buoyant density of these synaptosomes varied more than in the adult, the 5-hydroxytryptamine (5-HT) synaptosomes at the two age groups had similar sedimentation characteristics. Ouabain and imipramine, which block active transport of 5-HT, and reserpine, which blocks its granular storage, resulted respectively in a similar slight inhibition of uptake and accumulation of (-14C)5-HT in synaptosomes of 19-day foetuses. Transport and storage of (-14C)5-HT in the brain stem matured simultaneously with endogenous 5-HT content. In subcellular fractionation of the brain 5-HT content, the percentage of 5-HT in the supernatant was significantly lower in neonatal than in adult rats. After treatments with monoamine oxidase inhibitors (MAOIs) and reserpine plus MAOI, respectively, the maximum brain content and subcellular distribution of 5-HT were similar in 1-day-old and adult rats; the result suggests the existence of some other binding mechanism besides the Mg++-ATP-dependent granular storage. Imipramine and N,N-dimethyltryptamine, which cause stimulation of 5-HT receptors, decreased the turnover of brain 5-HT by 40% in adults but had no effect in neonatal rats. Immobilization increased the turnover of brain 5-HT by 35% in adults but had no effect in neonatal rats, whereas fasting increased it by 20% in adults and by 150% in neonatal rats. At 3 weeks of age the responses to imipramine, immobilization and fasting resembled those seen in adults. These responses occurred later than the appearance of the endogenous content, transport and storage of 5-HT and may require maturation of synaptic junctions, the latest neuronal structures to develop.


Inferring the Sign of Kinase-Substrate Interactions by Combining Quantitative Phosphoproteomics with a Literature-Based Mammalian Kinome Network.
Protein phosphorylation is a reversible post-translational modification commonly used by cell signaling networks to transmit information about the extracellular environment into intracellular organelles for the regulation of the activity and sorting of proteins within the cell. For this study we reconstructed a literature-based mammalian kinase-substrate network from several online resources. The interactions within this directed graph network connect kinases to their substrates, through specific phosphosites including kinasekinase regulatory interactions. However, the "signs" of links, activation or inhibition of the substrate upon phosphorylation, within this network are mostly unknown. Here we show how we can infer the "signs" indirectly using data from quantitative phosphoproteomics experiments applied to mammalian cells combined with the literature-based kinase-substrate network. Our inference method was able to predict the sign for 321 links and 153 phosphosites on 120 kinases, resulting in signed and directed subnetwork of mammalian kinase-kinase interactions. Such an approach can rapidly advance the reconstruction of cell signaling pathways and networks regulating mammalian cells.


Argonaute2 and LaminB modulate gene expression by controlling chromatin topology.
Drosophila Argonaute2 (AGO2) has been shown to regulate expression of certain loci in an RNA interference (RNAi)-independent manner, but its genome-wide function on chromatin remains unknown. Here, we identified the nuclear scaffolding protein LaminB as a novel interactor of AGO2. When either AGO2 or LaminB are depleted in Kc cells, similar transcription changes are observed genome-wide. In particular, changes in expression occur mainly in active or potentially active chromatin, both inside and outside LaminB-associated domains (LADs). Furthermore, we identified a somatic target of AGO2 transcriptional repression, no hitter (nht), which is immersed in a LAD located within a repressive topologically-associated domain (TAD). Null mutation but not catalytic inactivation of AGO2 leads to ectopic expression of nht and downstream spermatogenesis genes. Depletion of either AGO2 or LaminB results in reduced looping interactions within the nht TAD as well as ectopic inter-TAD interactions, as detected by 4C-seq analysis. Overall, our findings reveal coordination of AGO2 and LaminB function to dictate genome architecture and thereby regulate gene expression.


Recurrent Streptococcus equi subsp. zooepidemicus Bacteremia in an Infant.
We describe a case of an infant with recurrent bacteremia caused by Streptococcus equi subsp. zooepidemicus, likely transmitted from mother to infant. Our case highlights the importance of an epidemiological history and molecular diagnostics in ascertaining insights into transmission, pathogenesis, and optimal management.


Use of Three-dimensional Printing in the Development of Optimal Cardiac CT Scanning Protocols.
Three-dimensional (3D) printing is increasingly used in medical applications with most of the studies focusing on its applications in medical education and training, pre-surgical planning and simulation, and doctor-patient communication. An emerging area of utilising 3D printed models lies in the development of cardiac computed tomography (CT) protocols for visualisation and detection of cardiovascular disease. Specifically, 3D printed heart and cardiovascular models have shown potential value in the evaluation of coronary plaques and coronary stents, aortic diseases and detection of pulmonary embolism. This review article provides an overview of the clinical value of 3D printed models in these areas with regard to the development of optimal CT scanning protocols for both diagnostic evaluation of cardiovascular disease and reduction of radiation dose. The expected outcomes are to encourage further research towards this direction.


Conserved regions of budding yeast Tim22 have a role in structural organization of the carrier translocase.
Mitochondrial biogenesis requires efficient sorting of various proteins into different mitochondrial sub-compartments, mediated by dedicated protein machinery present in the outer and inner membrane. Among them, the TIM22 complex enables the integration of complex membrane proteins with internal targeting signals into the inner membrane. Although the Tim22 protein forms the core of the complex, the dynamic recruitment of subunits to the channel is still enigmatic. In this study, we highlight that the intermembrane space (IMS) and transmembrane 4 (TM4) regions of Tim22 are critically required for interactions with the membrane-embedded subunits, including Tim54, Tim18, and Sdh3, and thereby maintain the functional architecture of the TIM22 translocase. Furthermore, we find that the TM1 and TM2 regions of Tim22 are important for association with Tim18, whereas TM3 is exclusively required for the interaction with Sdh3. Moreover, impairment of TIM22 complex assembly influences its translocase activity, the mitochondrial network, and the viability of cells lacking mitochondrial DNA. Overall, our findings provide compelling evidence highlighting the significance of conserved regions of Tim22 that are important for the maintenance of the TIM22 complex and mitochondrial integrity.


Utilization of genetic counseling by parents of a child or fetus with congenital malformation in North-East Italy.
Congenital malformations (CM) affect 2-3% of all births, the cause of which, when known, is genetic in 80-90% of cases. A genetic consultation (GC) is indicated for the parents of a child affected by a CM. This study analyzes the parental utilization of genetic counseling (GCU) and its possible influencing factors after termination of pregnancy (TOP) because of fetal anomalies or after the birth of a child affected by a major malformation. The study concerns cases in North-East Italy where there is a CM registry and a center-satellite system for genetic counseling. The results of this analysis are also compared to other similar studies, which address the same topic. Between 1981 and 2000, 1,235 out of 14,888 GC were performed because of the presence of a CM in a child/fetus. In the same period, 4,933 births and 1,112 TOPs were registered. The overall GCU was 19%, with significant differences according to malformative phenotype, severity of the malformative condition, type of birth, and viability. Genetic counseling was performed significantly sooner following TOP than after the birth of a malformed child. GCU showed an unequal distribution according to the parents' place of residence, suggesting that easy and equal access to the genetic service was probably not well provided for. Our results suggest that genetic services should be integrated with related services, and that the public and physicians need a greater awareness of these services.


Genetic and biochemical interactions between an essential kinetochore protein, Cbf2p/Ndc10p, and the CDC34 ubiquitin-conjugating enzyme.
CBF2/NDC10/CTF14 encodes the 110-kDa subunit of CBF3, a key component of the yeast centromere/kinetochore. Overexpression of yeast CDC34 specifically suppresses the temperature-sensitive growth phenotype of the ndc10-1 mutation. Mutations in CDC34, which specifies a ubiquitin-conjugating enzyme, arrest yeast cells in the G1 phase of the cell cycle, with no intact spindles formed (M. G. Goebl, J. Yochem, S. Jentsch, J. P. McGrath, A. Varshavsky, and B. Byers, Science 241:1331-1335, 1988). The cdc34-2 mutation drastically alters the pattern of Cbf2p modification. Results of experiments using antibodies against Cbf2p and ubiquitin indicate that Cbf2p is ubiquitinated in vivo. Purified Cdc34p catalyzes the formation of Cbf2p-monoubiquitin conjugate in vitro. These data suggest that Cbf2p is an endogenous substrate of the CDC34 ubiquitin-conjugating enzyme and imply that ubiquitination of a kinetochore protein plays a regulatory role in kinetochore function.


Young cohorts of Russians drink less: age-period-cohort modelling of alcohol use prevalence 1994-2016.
Young Russians have been drinking less alcohol, and fewer strong spirits in particular, in recent years. This study aimed to disentangle age, period and birth cohort effects for the first time in Russia to improve our understanding of these trends. Age, period and cohort analysis of annual nationally representative repeated cross-sectional surveys [Russian Longitudinal Monitoring Survey- Higher School of Economics (RLMS-HSE)] using separate logistic models for each gender. Russia 1994-2016. A total of 195 234 respondents aged 14-85 years. Age (14 groups: 14-17 to 76+ years), period (21 years: 1994-2016) and birth cohorts (17 groups: 1920-24 to 2000-02). Outcome measures were 30-day overall and beverage-specific alcohol use prevalence accounting for vodka, moonshine, beer and wine. Controls were per capita income, education, marital status, ethnicity, residence type and regional climate. Controlling for age and period effects, the most recent cohorts had lower rates of participation than older cohorts. Findings were valid for females born in 1995-2002 (P = 0.000) and males born in 1990-94 (P = 0.002) and 1995-2002 (P = 0.000). The period effects were strong in 1994-2003 due to intensive substitution of beer in place of vodka. Period effects were also important in determining a decline of prevalence in 2008-15 due to restrictive alcohol policy. Age effects showed an inverse U-shaped trend in both genders, except for moonshine and wine. Overall, drinking profiles were beverage-specific. Models indicated diverse beverage-specific effects of income, ethnicity, education, marital status and residence on the prevalence of alcohol use. The recent downward trend in alcohol use in Russia appears to be attributable to reduced participation rates among younger cohorts born after 1990.


The Regulatory Functions of a New Tetrapeptide from the Bursa of Fabricius on AIV Vaccine Immunization and Antibody Production.
Understanding the regulatory functions of the biological peptide from the humoral central immune organ bursa of Fabricius on vaccine immune responses and antibody production is of vital importance. Here we thoroughly verified the immunomodulatory functions of the new tetrapeptide BP4 from the bursa of Fabricius on vaccine immune responses in mice and chicken immunizaiton model, and on potential intracellular signaling during antibody production. BP4 was isolated and identified by Reverse Phase High Performance Liquid Chromatography and matrix-assisted laser desorption ionization time of flight mass spectrometry. immunomodulatory functions of BP4 was verified by AIV vaccine immunization on mice and chickens regarding roles in vivo, by monitoring the impact of signalling inhibitors in hybridoma cells on antibody production in vitro. Our investigation revealed the strong inducing roles of new isolated BP4 on immune responses in mice immunization, the immunomodulatory effects in the immunized chicken, four potential key intracellular signaling during antibody production in hybrdoma cells. The new bursal-derived peptide BP4 was isolated and identified, and the immunomodulatory effects on antigen-specific immune responses in vivo and in vitro were verified, suggesting BP4 might be highly relevant to the humoral immune responses, and PI3K/Akt, p38 MAPK, NF-κB and tyrosine phosphorylation signaling might be the key activated intracellular signaling during antibody production during BP4 stimulation, which provided a novel potential adjuvant candidate for vaccine immunization improvement and precaution on animal epidemic disease.