Two types of murine helper T cell clone. II. Delayed-type hypersensitivity is mediated by TH1 clones.
We have previously shown that at least two types of Lyt-1+, Lyt-2-, L3T4+ helper T cell clones can be distinguished in vitro by different patterns of lymphokine secretion and by different forms of B cell help. Evidence is presented here to show that one type of helper T cell clone (TH1) causes delayed-type hypersensitivity (DTH) when injected with the appropriate antigen into the footpads of naive mice. The antigen-specific, major histocompatability complex (MHC)-restricted footpad swelling reaction peaked at approximately 24 hr. Footpad swelling was induced by all TH1 clones tested so far, including clones specific for soluble, particulate, or allogeneic antigens. In contrast, local transfer of TH2 cells and antigen did not produce a DTH reaction, even when supplemented with syngeneic spleen accessory cells. Similarly, local transfer of an alloreactive cytotoxic T lymphocyte clone into appropriate recipients did not produce DTH. The requirements for the DTH reaction induced by TH1 cells were investigated further by using TH1 clones with dual specificity for both foreign antigens and M1s antigens. Although these clones responded in vitro to either antigen + syngeneic presenting cells, or M1s disparate spleen cells, they responded in vivo only to antigen + MHC and did not cause footpad swelling in an M1s-disparate mouse in the absence of antigen. Moreover, in vitro preactivation of TH1 or TH2 cells with the lectin concanavalin A was insufficient to induce DTH reactions upon subsequent injection into footpads. From these results, we conclude that the lack of DTH given by TH2 clones in vivo could be due to the inability of the TH2 cells to produce the correct mediators of DTH, or to a lack of stimulation of TH2 clones in the footpad environment.


Knee tuberculosis masquerading as pigmented villonodular synovitis.
Tuberculosis (TB), once a disease confined to undeveloped or developing nations is currently in resurgence, which is attributable to pandemic human immunodeficiency virus (HIV) infection and immigration from endemic areas. Tuberculous arthritis is difficult to diagnose early because of its atypical insidious clinical manifestations and nonspecific imaging findings. TB is also known as the 'great mimicker'. Specifically, monoarticular tuberculosis of the knee may mimic pigmented villonodular synovitis (PVNS). The present report describes a young patient with tuberculous arthritis of knee joint. Accurate diagnosis and appropriate management was delayed due to magnetic resonance imaging (MRI) findings, such as, hemosiderin deposits and a nodular mass around the knee joint, suggestive of a diffuse type of PVNS. Our findings suggest that the first step in the diagnosis of tuberculous knee arthritis is to have a high index of suspicion.


Imaging of inflammatory cellular protagonists in human atherosclerosis: a dual-isotope SPECT approach.
Atherosclerotic plaque development and progression signifies a complex inflammatory disease mediated by a multitude of proinflammatory leukocyte subsets. Using single photon emission computed tomography (SPECT) coupled with computed tomography (CT), this study tested a new dual-isotope acquisition protocol to assess each radiotracer's capability to identify plaque phenotype and inflammation levels pertaining to leukocytes expressing leukocyte function-associated antigen-1 (LFA-1) and the leukocyte subset of proinflammatory macrophages expressing somatostatin receptor subtype-2 (SST2). Individual radiotracer uptake was quantified and the presence of corresponding immunohistological cell markers was assessed. Human symptomatic carotid plaque segments were obtained from endarterectomy. Segments were incubated in dual-isotope radiotracers [111In]In-DOTA-butylamino-NorBIRT ([111In]In-Danbirt) and [99mTc]Tc-[N0-14,Asp0,Tyr3]-octreotate ([99mTc]Tc-Demotate 2) before scanning with SPECT/CT. Plaque phenotype was classified as pathological intimal thickening, fibrous cap atheroma or fibrocalcific using histology sections based on distinct morphological characteristics. Plaque segments were subsequently immuno-stained with LFA-1 and SST2 and quantified in terms of positive area fraction and compared against the corresponding SPECT images. Focal uptake of co-localising dual-radiotracers identified the heterogeneous distribution of inflamed regions in the plaques which co-localised with positive immuno-stained regions of LFA-1 and SST2. [111In]In-Danbirt and [99mTc]Tc-Demotate 2 uptake demonstrated a significant positive correlation (r = 0.651; p = 0.001). Fibrous cap atheroma plaque phenotype correlated with the highest [111In]In-Danbirt and [99mTc]Tc-Demotate 2 uptake compared with fibrocalcific plaques and pathological intimal thickening phenotypes, in line with the immunohistological analyses. A dual-isotope acquisition protocol permits the imaging of multiple leukocyte subsets and the pro-inflammatory macrophages simultaneously in atherosclerotic plaque tissue. [111In]In-Danbirt may have added value for assessing the total inflammation levels in atherosclerotic plaques in addition to classifying plaque phenotype.


The specificity of extracellular glycoprotein complexes in mediating cellular adhesion.
Complexes containing glycoproteins and glycosaminoglycans were released into the culture medium by both smooth and skeletal muscle cells. The particles, termed adherons, from three smooth muscle cell lines promoted cell-substratum adhesion of a clonal sympathetic nerve cell line, PC12. In contrast, the glycoprotein complexes from three skeletal muscle preparations inhibited the adhesion of PC12 cells to Petri dish surfaces. The skeletal muscle adherons all sedimented in calcium-free sucrose gradients with an S value of 16, while the smooth muscle particles had a sedimentation value of 12. Although both classes of adherons contained fibronectin and collagen, hyaluronic acid was present only in those from skeletal muscle. An antiserum prepared against skeletal muscle adherons blocked myoblast adhesion to skeletal muscle adherons but did not alter PC12 adhesion to smooth muscle adherons. These data suggest that the glycoprotein complexes released by muscle have some intrinsic specificity with respect to their ability to mediate cellular adhesion.


Suprascapular nerve block (using bupivacaine and methylprednisolone acetate) in chronic shoulder pain.
Shoulder pain from inflammatory arthritis and/or degenerative disease is a common cause of morbidity in the community. It is difficult to treat and there are limited data on the efficacy of most interventions. Suprascapular nerve block has shown promise in limited trials in reducing shoulder pain. There have been no large randomised placebo controlled trials examining the efficacy of suprascapular nerve block for shoulder pain in arthritis and/or degenerative disease using pain and disability end points. To perform a randomised, double blind, placebo controlled trial of the efficacy of suprascapular nerve block for shoulder pain in rheumatoid arthritis (RA) and/or degenerative disease of the shoulder. 83 people with chronic shoulder pain from degenerative disease or RA took part in the trial. If a person had two painful shoulders, these were randomised separately. A total of 108 shoulders were randomised. Patients in the group receiving active treatment had a single suprascapular nerve block following the protocol described by Dangoisse et al, while those in the other group received a placebo injection of normal saline administered subcutaneously. The patients were followed up for 12 weeks by an observer who was unaware of the randomisation and reviewed at weeks 1, 4, and 12 after the injection. Pain, disability, and range of movement data were gathered. Clinically and statistically significant improvements in all pain scores, all disability scores, and some range of movement scores in the shoulders receiving suprascapular nerve block compared with those receiving placebo were seen at weeks 1, 4, and 12. There were no significant adverse effects in either group. Suprascapular nerve block is a safe and efficacious treatment for the treatment of shoulder pain in degenerative disease and/or arthritis. It improves pain, disability, and range of movement at the shoulder compared with placebo. It is a useful adjunct treatment for the practising clinician to assist in the management of a difficult and common clinical problem.


Activation of polyamine catabolism in transgenic rats induces acute pancreatitis.
Polyamines are required for optimal growth and function of cells. Regulation of their cellular homeostasis is therefore tightly controlled. The key regulatory enzyme for polyamine catabolism is the spermidine/spermine N(1)-acetyltransferase (SSAT). Depletion of cellular polyamines has been associated with inhibition of growth and programmed cell death. To investigate the physiological function SSAT, we generated a transgenic rat line overexpressing the SSAT gene under the control of the inducible mouse metallothionein I promoter. Administration of zinc resulted in a marked induction of pancreatic SSAT, overaccumulation of putrescine, and appearance of N(1)-acetylspermidine with extensive depletion of spermidine and spermine in transgenic animals. The activation of pancreatic polyamine catabolism resulted in acute pancreatitis. In nontransgenic animals, an equal dose of zinc did not affect pancreatic polyamine pools, nor did it induce pancreatitis. Acetylated polyamines, products of the SSAT-catalyzed reaction, are metabolized further by the polyamine oxidase (PAO) generating hydrogen peroxide, which might cause or contribute to the pancreatic inflammatory process. Administration of specific PAO inhibitor, MDL72527 [N(1),N(2)-bis(2,3-butadienyl)-1,4-butanediamine], however, did not affect the histological score of the pancreatitis. Induction of SSAT by the polyamine analogue N(1),N(11)-diethylnorspermine reduced pancreatic polyamines levels only moderately and without signs of organ inflammation. In contrast, the combination of N(1), N(11)-diethylnorspermine with MDL72527 dramatically activated SSAT, causing profound depletion of pancreatic polyamines and acute pancreatitis. These results demonstrate that acute induction of SSAT leads to pancreatic inflammation, suggesting that sufficient pools of higher polyamine levels are essential to maintain pancreatic integrity. This inflammatory process is independent of the production of hydrogen peroxide by PAO.


Bias and accuracy in close relationships: an integrative review.
Intimates typically are positively biased in their relationship evaluations. Given this fact, how can intimates regulate their esteem needs about their relationships and still function effectively, without risking later regret and disappointment? We address this issue by first reviewing work showing that because bias and accuracy are independent, they can co-exist. We next show how bias and accuracy are subject to different evaluative motives, relationship evaluations, and situations. It is argued that the pursuit of important goals is a time when people are motivated to feel good about their relationships. This is a time when relationship judgments are positively biased and relatively inaccurate. However, important choice points in the relationship are times when people are motivated to both accurately understand their relationships and to feel good about their relationships. These dual needs can be simultaneously met by becoming more accurate in epistemic-related relationship judgments while being more positively biased in esteem-related relationship judgments.


Senescent Phenotype Induced by p90RSK-NRF2 Signaling Sensitizes Monocytes and Macrophages to Oxidative Stress in HIV-Positive Individuals.
The incidence of cardiovascular disease is higher in HIV-positive (HIV+) patients than it is in the average population, and combination antiretroviral therapy (cART) is a recognized risk factor for cardiovascular disease. However, the molecular mechanisms that link cART and cardiovascular disease are currently unknown. Our study explores the role of the activation of p90RSK, a reactive oxygen species-sensitive kinase, in engendering senescent phenotype in macrophages and accelerating atherogenesis in patients undergoing cART. Peripheral whole blood from cART-treated HIV+ individuals and nontreated HIV-negative individuals was treated with H2O2 (200 µmol/L) for 4 minutes, and p90RSK activity in CD14+ monocytes was measured. Plaque formation in the carotids was also analyzed in these individuals. Macrophage senescence was determined by evaluating their efferocytotic ability, antioxidation-related molecule expression, telomere length, and inflammatory gene expression. The involvement of p90RSK-NRF2 signaling in cART-induced senescence was assessed by p90RSK-specific inhibitor (FMK-MEA) or dominant-negative p90RSK (DN-p90RSK) and NRF2 activator (NRF2A). Further, the severity of atherosclerosis was determined in myeloid cell-specific wild-type and DN-p90RSK transgenic mice. Monocytes from HIV+ patients exhibited higher levels of p90RSK activity and were also more sensitive to reactive oxygen species than monocytes from HIV-negative individuals. A multiple linear regression analysis involving cART, Reynolds cardiovascular risk score, and basal p90RSK activity revealed that cART and basal p90RSK activity were the 2 significant determinants of plaque formation. Many of the antiretroviral drugs individually activated p90RSK, which simultaneously triggered all components of the macrophage senescent phenotype. cART inhibited antioxidant response element reporter activity via ERK5 S496 phosphorylation. NRF2A reversed the H2O2-induced overactivation of p90RSK in cART-treated macrophages by countering the induction of senescent phenotype. Last, the data obtained from our gain- or loss-of-function mice conclusively showed the crucial role of p90RSK in inducing senescent phenotype in macrophages and atherogenesis. cART increased monocyte/macrophage sensitivity to reactive oxygen species- in HIV+ individuals by suppressing NRF2-ARE activity via p90RSK-mediated ERK5 S496 phosphorylation, which coordinately elicited senescent phenotypes and proinflammatory responses. As such, our report underscores the importance of p90RSK regulation in monocytes/macrophages as a viable biomarker and therapeutic target for preventing cardiovascular disease, especially in HIV+ patients treated with cART.


Severe TUBB4A-Related Hypomyelination With Atrophy of the Basal Ganglia and Cerebellum: Novel Neuropathological Findings.
Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare hypomyelinating leukodystrophy characterized by infantile or childhood onset of motor developmental delay, progressive rigidity and spasticity, with hypomyelination and progressive atrophy of the basal ganglia and cerebellum due to a genetic mutation of the TUBB4A gene. It has only been recognized since 2002 and the full spectrum of the disorder is still being delineated. Here, we review a case report of a severely affected girl with a thorough neuropathological evaluation demonstrating novel clinical and pathological findings. Clinically, our patient demonstrated visual dysfunction and hypodontia in addition to the typical phenotype. Morphologically, more severe and widespread changes in the white matter were observed, including to the optic tracts; in gray structures such as the caudate nucleus, thalamus, globus pallidus, and substantia nigra; as well as an area of focal cortical dysplasia. Overall this case offers further insight into the broad range of clinical and neuropathological findings that may be associated with H-ABC and related TUBB4A gene mutations.


Fluorinated organic materials for electronic and optoelectronic applications: the role of the fluorine atom.
In this article we highlight, by means of selected examples drawn from work performed in our or other laboratories, the features of some classes of fluorinated conjugated materials and their use in electronic devices such as electroluminescent diodes or field effect transistors. A variety of fluorinated conjugated systems, either molecular or polymeric, such as poly(phenylenevinylene)s, poly(phenyleneethynylene)s, polythiophenes, polyphenylenes, are dealt with. Attention is also focused on a different class of electroluminescent compounds, represented by the cyclometalated iridium complexes with various forms (mer and fac). In particular, fluorine atoms lower both the HOMO and LUMO energy levels. Consequently, the electron injection is made easier, the materials display a greater resistance against the degradative oxidation processes and organic n-type or ambipolar semiconducting materials may result. Moreover, the C-H...F interactions play an important role in the solid state supramolecular organization, originating a typical pi-stack arrangement which enhances the charge carrier mobility.


Assessing outcome in postoperative pain trials: are we missing the point? A systematic review of pain-related outcome domains reported in studies early after total knee arthroplasty.
The management of acute postoperative pain remains suboptimal. Systematic reviews and Cochrane analysis can assist with collating evidence about treatment efficacy, but the results are limited in part by heterogeneity of endpoints in clinical trials. In addition, the chosen endpoints may not be entirely clinically relevant. To investigate the endpoints assessed in perioperative pain trials, we performed a systematic literature review on outcome domains assessing effectiveness of acute pain interventions in trials after total knee arthroplasty. We followed the Cochrane recommendations for systematic reviews, searching PubMed, Cochrane, and Embase, resulting in the screening of 1590 potentially eligible studies. After final inclusion of 295 studies, we identified 11 outcome domains and 45 subdomains/descriptors with the domain "pain"/"pain intensity" most commonly assessed (98.3%), followed by "analgesic consumption" (88.8%) and "side effects" (75.3%). By contrast, "physical function" (53.5%), "satisfaction" (28.8%), and "psychological function" (11.9%) were given much less consideration. The combinations of outcome domains were inhomogeneous throughout the studies, regardless of the type of pain management investigated. In conclusion, we found that there was high variability in outcome domains and inhomogeneous combinations, as well as inconsistent subdomain descriptions and utilization in trials comparing for effectiveness of pain interventions after total knee arthroplasty. This points towards the need for harmonizing outcome domains, eg, by consenting on a core outcome set of domains which are relevant for both stakeholders and patients. Such a core outcome set should include at least 3 domains from 3 different health core areas such as pain intensity, physical function, and one psychological domain.


Linear and extended: a common polyglutamine conformation recognized by the three antibodies MW1, 1C2 and 3B5H10.
A long-standing pathomechanistic model proposes that the polyglutamine (polyQ)-length-dependent toxicity threshold observed in all polyQ diseases is triggered by a conformational change within the monomer that occurs only above a certain polyQ length. If true, this yet undefined and elusive mutant-specific toxic conformation would constitute a direct therapeutic target. Three anti-polyQ antibodies-MW1, 1C2 and 3B5H10-have been extensively used to probe the conformation of polyQ. The crystal structure of the MW1 epitope reveals a linear, non-pathogenic polyQ. In contrast, although the detailed structure of its epitope is unknown, the 3B5H10 antibody is widely advertised and used as a conformational antibody that recognizes the toxic conformation of expanded polyQ. We solved the crystal structure of the 1C2 antigen-binding domain (1C2-Fab) and performed a direct comparison between the 1C2, MW1 and 3B5H10 structures. The MW1 and 1C2 antibodies have similar sequences and structures, consistent with their binding to short polyQ and their polyQ length-discrimination properties. Unexpectedly, the 3B5H10 antibody also shares striking features with MW1 and 1C2, which prompted us to revisit its binding properties. We show that the 3B5H10 epitope is actually a short, non-pathogenic polyQ. All three antibodies MW1, 1C2 and 3B5H10 interact similarly with polyQ of various lengths, and bind small polyQ epitopes in similar linear and extended conformations. Together with studies published during the recent years, our work argues against the hypothesis that a mutant-specific conformation in monomeric polyQ molecules is the toxic entity responsible for polyQ diseases.


Baseline sacroiliac joint magnetic resonance imaging abnormalities and male sex predict the development of radiographic sacroiliitis.
We evaluated the relationship between the baseline sacroiliac joint (SIJ) magnetic resonance imaging (MRI) findings and the development of radiographic sacroiliitis and tested their prognostic significance in cases of ankylosing spondylitis. Patients who had undergone an SIJ MRI at the rheumatology department were identified. Individuals for whom pelvic X-rays were available after at least 1 year of MRI were included in the analysis. All radiographs and MRI examinations were scored by two independent readers. Medical records of the patients were reviewed to obtain potentially relevant demographic and clinical data. We identified 1,069 SIJ MRIs, and 328 fulfilled our inclusion criteria. Reliability analysis revealed moderate to good inter- and intra-observer agreement. On presentation data, 14 cases were excluded because they had unequivocal radiographic sacroiliitis at baseline. After a mean of 34.8 months of follow-up, 24 patients developed radiographic sacroiliitis. The presence of active sacroiliitis (odds ratio (OR) 15.1) and structural lesions on MRI (OR 8.3), male sex (OR 4.7), fulfillment of Calin's inflammatory back pain criteria (P = 0.001), and total MRI activity score (P < 0.001) were found to be related to the development of radiographic sacroiliitis. By regression modeling, the presence of both active inflammatory and structural damage lesions on MRI and male sex were found to be predictive factors for the development of radiographic sacroiliitis. Our present results suggest that the occurrence of both active inflammatory and structural lesions in SIJs revealed by MRI is a significant risk factor for radiographic sacroiliitis, especially in male patients with early inflammatory back pain.


Functional outcome after inpatient rehabilitation in postintensive care unit COVID-19 patients: findings and clinical implications from a real-practice retrospective study.
Coronavirus disease 2019 (COVID-19) pandemic is quickly spreading worldwide, with survivors that suffer functional impairments with a consequent key role of rehabilitation in this context. To date, there is a lack of findings on the role of rehabilitation in postacute COVID-19 patients. Thus, we aimed at describing the role of a patient-tailored rehabilitation plan on functional outcome in hospitalized COVID-19 patients. Real-practice retrospective study. Inpatients Rehabilitation Unit. Postacute COVID-19 patients. Medical records of patients referred to an Italian COVID-19 Rehabilitation Unit from March 10th, 2020 to April 30th, 2020 were collected. All patients underwent a rehabilitative (30 minutes/set, 2 times/day), aimed to improve gas exchanges, reducing dyspnoea, and improving muscle function. At the admission (T0) and at the discharge (T1), we evaluated as outcome measures: Barthel Index (BI), modified Medical Research Council Dyspnea Scale, 6-Minute Walking Test (6-MWT) and Borg Rating of Perceived Exertion (RPE) scale. We also assessed: type of respiratory supports needed, pulmonary function, coagulation and inflammation markers and length of stay (LOS) in Rehabilitation Unit. We included 41 postacute COVID-19 patients (25 male and 19 female), mean aged 72.15±11.07 years. Their mean LOS in the Rehabilitation Unit was 31.97±9.06 days, as 39 successfully completed the rehabilitation treatment and 2 deceased. We found statistically significant improvement in BI (84.87±15.56 vs. 43.37±26.00; P<0.0001), 6-MWT (303.37±112.18 vs. 240.0±81.31 meters; P=0.028), Borg RPE scale (12.23±2.51 vs. 16.03±2.28; P<0.0001). These findings suggest that postacute COVID-19 patients might beneficiate of a motor and respiratory rehabilitation treatment. However, further studies are advised to better understand long-term sequelae of the disease. This study provides evidence on the role of rehabilitation COVID-19 postacute inpatients through a patient-tailored treatment.


Oxidative Stress Markers in Tuberculosis and HIV/TB Co-Infection.
Dysfunction of redox homeostasis has been implicated in many pathological conditions. An imbalance of pro- and anti-oxidants have been observed in Tuberculosis (TB) and its co-morbidities especially HIV/AIDS. The pro inflammatory milieu in either condition aggravates the physiological balance of the redox mechanisms. The present study therefore focuses on assessing the redox status of patients suffering from TB and HIV-TB co-infection. To assess the oxidative stress markers in the HIV-TB and TB study cohort. The current prospective study was conducted in Haffkine Institute, Parel, Maharashtra, India, during January 2013 to December 2015. Blood samples from 50 patients each suffering from active TB and HIV-TB co-infection were collected from Seth G.S.Medical College and KEM Hospital Mumbai and Group of Tuberculosis Hospital, Sewree Mumbai. Samples were processed and the experiments were carried out at the Department of Biochemistry, Haffkine Institute. Samples from 50 healthy volunteers were used as controls. Serum was assessed for pro-oxidant markers such as Nitric Oxide (NO), Thiobarbituric Acid Reactive Species (TBARS), C-Reactive Protein (CRP), superoxide anion. Antioxidant markers such as catalase and Superoxide Dismutase (SOD) were assessed. Total serum protein, was also assessed. Among the pro-oxidants, serum NO levels were decreased in TB group while no change was seen in HIV-TB group. TBARS and CRP levels showed significant increase in both groups; superoxide anion increased significantly in HIV-TB group. Catalase levels showed decreased activities in TB group. SOD activity significantly increased in HIV-TB but not in TB group. The total serum proteins were significantly increased in HIV-TB and TB groups. The values of Control cohort were with the normal reference ranges. In the present study, we found the presence of oxidative stress to be profound in the TB and HIV-TB co-infection population.


Amyloid Positivity in the Alzheimer/Subcortical-Vascular Spectrum.
We investigated the frequency of β-amyloid (Aβ) positivity in 9 groups classified according to a combination of 3 different cognition states and 3 distinct levels of white matter hyperintensities (WMH) (minimal, moderate, and severe) and aimed to determine which factors were associated with Aβ after controlling for WMH and vice versa. A total of 1,047 individuals with subjective cognitive decline (SCD, n = 294), mild cognitive impairment (MCI, n = 237), or dementia (n = 516) who underwent Aβ PET scans were recruited from the memory clinic at Samsung Medical Center in Seoul, Korea. We investigated the following: (1) Aβ positivity in the 9 groups, (2) the relationship between Aβ positivity and WMH severity, and (3) clinical and genetic factors independently associated with Aβ or WMH. Aβ positivity increased as the severity of cognitive impairment increased (SCD [15.7%], MCI [43.5%], and dementia [76.2%]), whereas it decreased as the severity of WMH increased (minimal [54.5%], moderate [53.9%], and severe [41.0%]) or the number of lacunes (0 [59.0%], 1-3 [42.0%], and >3 [23.4%]) increased. Aβ positivity was associated with higher education, absence of diabetes, and presence of APOE ε4 after controlling for cognitive and WMH status. Our analysis of Aβ positivity involving a large sample classified according to the stratified cognitive states and WMH severity indicates that Alzheimer and cerebral small vessel diseases lie on a continuum. Our results offer clinicians insightful information about the association among Aβ, WMH, and cognition.


The Use of Bayesian Networks to Assess the Quality of Evidence from Research Synthesis: 2. Inter-Rater Reliability and Comparison with Standard GRADE Assessment.
The grades of recommendation, assessment, development and evaluation (GRADE) approach is widely implemented in systematic reviews, health technology assessment and guideline development organisations throughout the world. We have previously reported on the development of the Semi-Automated Quality Assessment Tool (SAQAT), which enables a semi-automated validity assessment based on GRADE criteria. The main advantage to our approach is the potential to improve inter-rater agreement of GRADE assessments particularly when used by less experienced researchers, because such judgements can be complex and challenging to apply without training. This is the first study examining the inter-rater agreement of the SAQAT. We conducted two studies to compare: a) the inter-rater agreement of two researchers using the SAQAT independently on 28 meta-analyses and b) the inter-rater agreement between a researcher using the SAQAT (who had no experience of using GRADE) and an experienced member of the GRADE working group conducting a standard GRADE assessment on 15 meta-analyses. There was substantial agreement between independent researchers using the Quality Assessment Tool for all domains (for example, overall GRADE rating: weighted kappa 0.79; 95% CI 0.65 to 0.93). Comparison between the SAQAT and a standard GRADE assessment suggested that inconsistency was parameterised too conservatively by the SAQAT. Therefore the tool was amended. Following amendment we found fair-to-moderate agreement between the standard GRADE assessment and the SAQAT (for example, overall GRADE rating: weighted kappa 0.35; 95% CI 0.09 to 0.87). Despite a need for further research, the SAQAT may aid consistent application of GRADE, particularly by less experienced researchers.


Molecular Detection of a Novel Fowl Adenovirus Serotype-4 (FadV-4) from an Outbreak of Hepatitis Hydropericardium Syndrome in Commercial Broiler Chickens in Egypt.
Hepatitis hydropericardium syndrome (HHS) is an acute infectious disease caused by fowl adenovirus serotype-4 (FAdV-4), which mainly affects broilers aged 4-5 wk. During the winter of January 2021, a 32-day-old broiler flock (Cobb-500) suffered from unusually high mortality (15%) in the Alexandria Governorate, Egypt. The chickens showed depression, ruffled feathers, and greenish diarrhea besides the typical pathologic features of suspected HHS involving flabby hearts, accumulation of a straw-colored fluid in the pericardial sacs, and pale, enlarged hemorrhagic and friable livers with necrotic foci. The kidneys exhibited edema with uric acid depositions. Histopathologic examination of bird livers naturally infected with HHS showed multifocal areas of necrosis, vascular changes, and basophilic intranuclear inclusion bodies (INIB) in the hepatocytes. Molecular identification of the causative agent was accomplished by PCR and sequence analysis of the hyper-variable regions of loop 1 of the hexon gene of fowl aviadenovirus. A pathogenic strain of the novel genotype-4 (FAdV-4) was demonstrated, closely similar to the Israeli strain IS/1905/2019, with an identity of 98%. This is the first report to identify FADV-4 in Egypt, prompting further studies to elucidate its epidemiologic role in all poultry sectors and associated economic losses to provide insights to its control and prevention.


Going DEEP: guidelines for building simulation-based team assessments.
Whether for team training, research or evaluation, making effective use of simulation-based technologies requires robust, reliable and accurate assessment tools. Extant literature on simulation-based assessment practices has primarily focused on scenario and instructional design; however, relatively little direct guidance has been provided regarding the challenging decisions and fundamental principles related to assessment development and implementation. The objective of this manuscript is to introduce a generalisable assessment framework supplemented by specific guidance on how to construct and ensure valid and reliable simulation-based team assessment tools. The recommendations reflect best practices in assessment and are designed to empower healthcare educators, professionals and researchers with the knowledge to design and employ valid and reliable simulation-based team assessments. Information and actionable recommendations associated with creating assessments of team processes (non-technical 'teamwork' activities) and performance (demonstration of technical proficiency) are presented which provide direct guidance on how to Distinguish the underlying competencies one aims to assess, Elaborate the measures used to capture team member behaviours during simulation activities, Establish the content validity of these measures and Proceduralise the measurement tools in a way that is systematically aligned with the goals of the simulation activity while maintaining methodological rigour (DEEP). The DEEP framework targets fundamental principles and critical activities that are important for effective assessment, and should benefit healthcare educators, professionals and researchers seeking to design or enhance any simulation-based assessment effort.


Selenium compounds are substrates for glutaredoxins: a novel pathway for selenium metabolism and a potential mechanism for selenium-mediated cytotoxicity.
The Grx (glutaredoxin) proteins are oxidoreductases with a central function in maintaining the redox balance within the cell. In the present study, we have explored the reactions between selenium compounds and the glutaredoxin system. Selenite, GS-Se-SG (selenodiglutathione) and selenocystine were all shown to be substrates of human Grx1, implying a novel role for the glutaredoxins in selenium metabolism. During the past few years, selenium has further evolved as a potential therapeutic agent in cancer treatment, and a leading mechanism of cytotoxicity is the generation of ROS (reactive oxygen species). Both selenite and GS-Se-SG were reduced by Grx1 and Grx2 in a non-stoichiometric manner due to redox cycling with oxygen, which in turn generated ROS. The role of Grx in selenium toxicity was therefore explored. Cells were treated with the selenium compounds in combination with transient overexpression of, or small interfering RNA against, Grx1. The results demonstrated an increased viability of the cells during silencing of Grx1, indicating that Grx1 is contributing to selenium toxicity. This is in contrast with TrxR (thioredoxin reductase), which previously was shown to protect cells from selenium cytotoxicity, verifying a diverse role between Grx and TrxR in selenium-mediated cytotoxicity. Furthermore, selenium treatment led to a marked increase in protein glutathionylation and cysteinylation that potentially can influence the activity and function of several proteins within the cell.


Multiple forms of genes in pyelonephritogenic Escherichia coli encoding adhesins binding globoseries glycolipid receptors.
Earlier studies have shown that the majority of Escherichia coli isolates from urinary tract infections which possess a D-mannose-resistant adhesin contain gene sequences homologous to the pap pilus gene sequences encoded on the recombinant plasmid pRHU845. In this report, several E. coli isolates from urinary tract infections were examined to determined the arrangement of pap-related sequences. Copies of gene sequences homologous to the entire pap operon were found to exist at multiple sites in the chromosomes of some strains. The position of the pap operon(s) with respect to adjacent sequences was also found to be variable.


Sparganosis in the lumbar spine : report of two cases and review of the literature.
Sparganosis is a rare parasitic infection affecting various organs, including the central nervous system, especially the lumbar epidural space. This report describes the identification of disease and different strategies of treatments with preoperative information. A 42-year-old man presented with a 2-year history of urinary incontinence and impotence. He had a history of ingesting raw frogs 40 years ago. Magnetic resonance (MR) imaging showed an intramedullary nodular mass at conus medullaris and severe inflammation in the cauda equina. A 51-year-old woman was admitted with acute pain in the left inguinal area. We observed a lesion which seemed to be a tumor of the lumbar epidural space on MR imaging. She also had a history of ingesting inadequately cooked snakes 10 years ago. In the first patient, mass removal was attempted through laminectomy and parasite infection was identified during intra-operative frozen biopsy. Total removal could not be performed because of severe arachnoiditis and adhesion. We therefore decided to terminate the operation and final histology confirmed dead sparganum infection. We also concluded further surgical trial for total removal of the dead worm and inflammatory grannulation totally. However, after seeing another physician at different hospital, he was operated again which resulted in worsening of pain and neurological deficit. In the second patient, we totally removed dorsal epidural mass. Final histology and enzyme-linked immunosorbent assay (ELISA) confirmed living sparganum infection and her pain disappeared. Although the treatment of choice is surgical resection of living sparganum with inflammation, the attempt to remove dead worm and adhesive granulation tissue may cause unwanted complications to the patients. Therefore, the result of preoperative ELISA, as well as the information from image and history, must be considered as important factors to decide whether a surgery is necessary or not.


A computer-assisted method for pathogenicity assessment and genetic reporting of variants stored in the Australian Inherited Retinal Disease Register.
The assignment of pathogenicity to variants suspected of causing an inherited retinal disease and the subsequent creation of molecular genetic reports sent to clinical geneticists and ophthalmologists has traditionally been time-consuming and subject to error and ambiguity. The purpose of this paper is to describe a computer-assisted method we have developed for (1) assessment of the predicted pathogenicity of genetic variants identified in patients diagnosed with an inherited retinal disease and (2) the incorporation of these results into the Australian Inherited Retinal Disease Register and DNA Bank's databases, for the production of molecular genetics reports. This method has significantly accelerated the assessment of variant pathogenicity prediction and subsequent patient report generation for the Australian Inherited Retinal Disease Register and DNA Bank, and has reduced the potential for human error. The principles described in this paper may be applied in any situation where genetic variants and patient information are stored in a well-organised database.


Probing Antibody-Antigen Interactions.
Antibodies are biological molecules generated by the host immune system in response to the invasion of foreign bodies or antigens. Therefore, antibodies must possess high specificity toward target antigens in order for the antigen to be recognized and subsequently destroyed. Because of this specificity, antibodies or antibody fragments that maintain binding specificity are heavily used in diagnostic assays and are becoming increasingly important in many therapeutic applications. Classical immunoassays such as radioimmunoassay and enzyme-linked immunosorbent assay are effective analytical techniques that have been widely used to screen and determine antibody specificity. Because of increased demands for antibodies with well-defined specificities, other techniques have been developed that facilitate generation and characterization of antibody-binding specificities under different conditions, such as when the protein is expressed on a cell surface or the target antigen is hard to isolate. Here, we describe three alternate techniques that provide unique abilities to characterize antibody-antigen binding events: (i) surface plasmon resonance, (ii) fluorescence activated cell sorting, and (iii) atomic force microscopy. These different techniques take advantage of various changes in physical and/or chemical properties of the analytes that occur upon binding, such as refractive index, surface charge, and changes in structure. These techniques provide unique powerful advantages over traditional immunoassays including real-time and label-free detection, low sample volume and concentration requirements, and molecular-level detection sensitivity. This article provides an overview of how these alternate approaches to studying antibody-antigen interactions can be used to facilitate rapid development of new antibody-based reagents for diagnostic and therapeutic applications.


Prevalence and Antimicrobial Resistance of Salmonella Isolates from Chicken Carcasses in Retail Markets in Yangon, Myanmar.
A cross-sectional investigation was conducted concerning prevalence, antimicrobial resistance, multidrug resistance patterns, and serovar diversity of Salmonella in chicken meat sold at retail in Yangon, Myanmar. The 141 chicken meat samples were collected at 141 retail markets in the Yangon Region, Myanmar, 1 November 2014 to 31 March 2015. Information on hygienic practices (potential risk factors) was retrieved via checklists. Salmonella was isolated and identified according to International Organization for Standardization methods (ISO 6579:2002) with minor modifications. Twelve antimicrobial agents belonging to eight pharmacological groups were used for antimicrobial susceptibility testing (disk diffusion method). Salmonella was recovered from 138 (97.9%) of the 141 samples. The isolates were most frequently resistant to trimethoprim-sulfamethoxazole (70.3% of isolates), tetracycline (54.3%), streptomycin (49.3%), and ampicillin (47.1%). Resistance was also found to chloramphenicol (29.7%), amoxicillin-clavulanic acid (17.4%), ciprofloxacin (9.4%), tobramycin (8.7%), gentamicin (8%), cefazolin (7.2%), lincomycin-spectinomycin (5.8%), and norfloxacin (0.7%). Among the 138 Salmonella isolates, 72 (52.2%) were resistant to three or more antimicrobial agents. Twenty-four serovars were identified among the 138 Salmonella-positive samples; serovars Albany, Kentucky, Braenderup, and Indiana were found in 38, 11, 10, and 8% of samples, respectively. None of the potential risk factors were significantly related to Salmonella contamination of chicken carcasses. This study provides new information regarding prevalence and antimicrobial resistance and Salmonella serovar diversity in retail markets in Yangon, Myanmar.


Inflammatory stimuli alter bone marrow composition and compromise bone health in the malnourished host.
Inflammation has a role in the pathogenesis of childhood malnutrition. We investigated the effect of malnutrition and inflammatory challenge on bone marrow composition and bone health. We studied an established murine model of moderate acute malnutrition at baseline and after acute inflammatory challenge with bacterial lipopolysaccharide (LPS), a surrogate of Gram-negative bacterial sepsis, or Leishmania donovani, the cause of visceral leishmaniasis. Both of these infections cause significant morbidity and mortality in malnourished children. Of the 2 stimuli, LPS caused more pronounced bone marrow changes that were amplified in malnourished mice. LPS challenge led to increased inflammatory cytokine expression (Il1b, Il6, and Tnf), inflammasome activation, and inflammatory monocyte accumulation in the bone marrow of malnourished mice. Depletion of inflammatory monocytes in Csfr1-LysMcre-DT malnourished mice significantly reduced the inflammasome activation and IL1-ß production after LPS challenge. The inflammatory challenge also led to increased expansion of mesenchymal stem cells (MSCs), bone marrow adiposity, and expression of genes (Pparg, Adipoq, and Srbp1) associated with adipogenesis in malnourished mice. This suggests that inflammatory challenge promotes differentiation of BM MSCs toward the adipocyte lineage rather than toward bone-forming osteoblasts in the malnourished host. Concurrent with this reduced osteoblastic potential there was an increase in bone-resorbing osteoclasts, enhanced osteoclast activity, upregulation of inflammatory genes, and IL-1B involved in osteoclast differentiation and activation. The resulting weakened bone formation and increased bone resorption would contribute to the bone fragility associated with malnutrition. Lastly, we evaluated the effect of replacing lipid rich in omega-6 fatty acids (corn oil) with lipid-rich in omega-3 fatty acids (fish oil) in the nutrient-deficient diet. LPS-challenged malnourished mice that received dietary fish oil showed decreased expression of inflammatory cytokines and Rankl and reduced osteoclast differentiation and activation in the bone marrow. This work demonstrates that the negative effect of inflammatory challenge on bone marrow is amplified in the malnourished host. Increasing dietary intake of omega-3 fatty acids may be a means to reduce inflammation and improve bone health in malnourished children.


The Distribution and Role of M1 and M2 Macrophages in Aneurysm Healing after Platinum Coil Embolization.
Impairment of macrophage polarization from a proinflammatory macrophage type 1 (M1) population to an anti-inflammatory macrophage type 2 (M2) population is a hallmark of poor wound healing. In this study, we aimed to evaluate the distribution of M1 and M2 macrophages and to analyze their association with healing in aneurysms embolized by endovascular coiling. Elastase-induced aneurysms were created in female rabbits and subsequently embolized with platinum coils. Aneurysm occlusions were evaluated with angiographic imaging at 1 (n = 6), 3 (n = 5), or 6 (n = 6) months. Aneurysm tissues were harvested for histologic analysis, quantification of M1 and M2 macrophages by immunofluorescence, and collagen deposition determined by Masson trichrome staining. Histologic grading of aneurysm healing was also performed. Untreated aneurysms were used as controls (n = 6). The M1 macrophage population was highest at 1 month posttreatment, progressively decreasing at 3 and 6 months. The M2 macrophage population progressively increased at 3 and 6 months posttreatment. The highest collagen deposition was at 6 months posttreatment. We found a moderate-to-weak direct correlation between the percentage of M2 macrophages and collagen deposition, as well as total histologic scores overall, and a strongly positive direct correlation between the percentage of M2 macrophages and total histologic scores at 6 months posttreatment. Our data support the direct correlation between M2 macrophage polarization and healing in aneurysm tissues. Our results show a positive relationship between M2 macrophage populations and total histologic scores at later stages of healing after endovascular coiling. We conclude that interventions aimed at stimulating M2 macrophage expression locally may improve aneurysm healing after coil embolization.


Intermolecular interactions during complex coacervation of pea protein isolate and gum arabic.
The nature of intermolecular interactions during complexation between pea protein isolate (PPI) and gum arabic (GA) was investigated as a function of pH (4.30-2.40) by turbidimetric analysis and confocal scanning microscopy in the presence of destabilizing agents (100 mM NaCl or 100 mM urea) and at different temperatures (6-60 degrees C). Complex formation followed two pH-dependent structure-forming events associated with the formation of soluble and insoluble complexes and involved interactions between GA and PPI aggregates. Complex formation was driven by electrostatic attractive forces between complementary charged biopolymers, with secondary stabilization by hydrogen bonding. Hydrophobic interactions were found to enhance complex stability at lower pH (pH 3.10), but not with its formation.


Antigenic heterogeneity in subunit S1 of pertussis toxin.
Culture supernates containing pertussis toxin (PT) from four strains of Bordetella pertussis were examined for both immunological reactivity and biological activity. PT from all four strains sensitized mice to histamine and toxin was detectable in supernates of all strains when examined by Western blotting with polyclonal antiserum to PT. In supernates of three of the four strains, PT was detectable by an enzyme-linked immunosorbent assay (ELISA) using mouse monoclonal antibody to subunit S1 of PT as the third antibody layer. However, supernates from one strain, 18323, failed to react in ELISA. Electroblots probed with the monoclonal antibody labelled subunit S1 of PT from all strains except that of strain 18323. PT of strain 18323, whilst retaining histamine-sensitizing activity, differed antigenically from that of other strains.


Quantitative changes in T-cell populations after left ventricular assist device implantation: relationship to T-cell apoptosis and soluble CD95.
Left ventricular assist devices (LVADs) are currently being evaluated as permanent therapy for end-stage heart failure. Because life-threatening infections limit successful long-term device implantation, we investigated the relationship between quantitative T-cell defects in LVAD recipients and CD95-mediated T-cell apoptosis. Immunological studies were performed in NYHA class IV patients awaiting cardiac transplantation who received either a TCI Heartmate left ventricular assist device (LVAD) or medical management. Fluorochrome-labeled Mabs were used in T-cell phenotypic analyses. T-cell apoptosis was measured by annexin V binding of T cells cultured in medium for 24 hours. Circulating serum levels of soluble CD95 were measured by ELISA. LVAD recipients had a relative lymphopenia and reduction in CD4 T-cell levels compared with NYHA class IV heart failure controls. These observations were confirmed in a longitudinal study in LVAD recipients, which showed that device implantation was accompanied by progressive and sustained reductions in circulating CD4 T-cell levels. These abnormalities in LVAD recipients were accompanied by increased levels of circulating soluble CD95 and by excessive CD4 and CD8 T-cell apoptosis. Susceptibility to induction of apoptosis was >2-fold greater for CD4 T cells than for CD8 T cells. These results suggest that the reduction in CD4 T-cell levels accompanying LVAD implantation is a consequence of an augmented pathway of CD95-mediated apoptosis. The clinical consequences of these abnormalities may include increased prevalence of systemic infections.


Pulmonary function in workers exposed to tobacco dust.
Exposure to vegetable dusts is probable in many industrial and agricultural industries. The aim of this study was to investigate the relation between exposure to tobacco dusts and lung capacities and airflows. Two hundred thirty-one individuals who were exposed to tobacco dusts in a cigarette-manufacturing company were included in the study. One hundred individuals who were working in the same area but in other industries and were not exposed to harmful dusts were also selected as controls. Spirometry with American Thoracic Society (ATS) standards was performed for both groups. Spirometry results were compared between the two groups using SPSS software by 't' test. The mean age of the exposed and unexposed groups was 36 +/- 7 and 35 +/- 7 years, respectively. Spirometry results showed that lung capacities and airflows in the exposed group were significantly less than those of controls (P< 0.001). Considering relative variation, the highest reduction was seen in peak expiratory flow (PEF), forced expiratory flow (FEF25%) and peak inspiratory flow (PIF). The results of this study show that exposure to tobacco dust would decrease lung capacities and airflows during the years.


Biochemical characterization of the respiratory syncytial virus N0-P complex in solution.
As all the viruses belonging to the Mononegavirales order, the nonsegmented negative-strand RNA genome of respiratory syncytial virus (RSV) is encapsidated by the viral nucleoprotein N. N protein polymerizes along the genomic and anti-genomic RNAs during replication. This requires the maintenance of the neosynthesized N protein in a monomeric and RNA-free form by the viral phosphoprotein P that plays the role of a chaperone protein, forming a soluble N0-P complex. We have previously demonstrated that residues 1-30 of P specifically bind to N0 Here, to isolate a stable N0-P complex suitable for structural studies, we used the N-terminal peptide of P (P40) to purify truncated forms of the N protein. We show that to purify a stable N0-P-like complex, a deletion of the first 30 N-terminal residues of N (NΔ30) is required to impair N oligomerization, whereas the presence of a full-length C-arm of N is required to inhibit RNA binding. We generated structural models of the RSV N0-P with biophysical approaches, including hydrodynamic measurements and small-angle X-ray scattering (SAXS), coupled with biochemical and functional analyses of human RSV (hRSV) NΔ30 mutants. These models suggest a strong structural homology between the hRSV and the human metapneumovirus (hMPV) N0-P complexes. In both complexes, the P40-binding sites on N0 appear to be similar, and the C-arm of N provides a high flexibility and a propensity to interact with the N RNA groove. These findings reveal two potential sites to target on N0-P for the development of RSV antivirals.


Risk of loco-regional recurrence and distant metastases of patients with invasive breast cancer up to ten years after diagnosis - results from a registry-based study from Germany.
Population-based estimates of the long-term risk of loco-regional recurrence and distant metastases of breast cancer (BRC) patients are scant, as most published studies used hospital-based cohorts or participants of clinical trials. This work aims to extend available knowledge by providing population-based long-term estimates of the cumulative risk of BRC recurrence up to 10 years after diagnosis. Data from the population-based Saarland Cancer Registry were used and included 9359 female patients with primary invasive BRC diagnosed between 1999 and 2009. Estimates of the cumulative incidence (CI) of BRC recurrence were derived for patients who had received local surgery with free resection margins by type of recurrence and stratified by age, tumor characteristics and major treatment options, taking into account mortality from any cause as a competing risk. The 10-year CI of BRC recurrence was 16%. For loco-regional recurrence and distant metastases alone it was 8 and 11%, respectively. The estimates showed substantial variation and were particularly increased if tumors were advanced (T1/2N+ 23%, T3/4N0 24%, T3/4N+ 34%), of high grade (23%), or of 'HER2/neu positive' (28%) or 'triple negative' subtype (23%), respectively. The derived estimates reflect the risk of 'real world' patients and may therefore extend available knowledge. These data are thus of great relevance for clinicians, their patients and researchers. The study likewise demonstrated the usefulness of cancer registries for a population-based monitoring of the effectiveness of cancer care in terms of disease recurrence as a major treatment related outcome measure.


Why do women live longer than men?
In the contemporary United States, males have 60 percent higher mortality than females. In Part I, published in the previous issue, we showed that 40 percent of this sex differential in mortality is due to a twofold elevation of arteriosclerotic heart disease among men. Major causes of higher rates of arteriosclerotic heart disease in men include greater cigarette smoking among men; probably a greater prevalence of the competitive, aggressive Coronary Prone Behavior Pattern among men; and possibly a protective role of female hormones. In addition, men have higher death rates for lung cancer and emphysema, primarily because more men smoke cigarettes. In Part II we analyze the other major causes of men's higher death rates: accidents, suicide, and cirrhosis of the liver. Each of these is related to behaviors which are encouraged or accepted more in men than in women in our society--for example, using guns, being adventurous and acting unafraid, working at hazardous jobs and drinking alcohol. We conclude with suggestions for reducing male mortality; for example, by changing the social conditions which foster in men the behaviors that elevate their mortality.


Premenopausal Obesity and Breast Cancer Growth Rates in a Rodent Model.
Obese premenopausal women with breast cancer have poorer prognosis for long term survival, in part because their tumors are larger at the time of diagnosis than are found in normal weight women. Whether larger tumor mass is due to obesity-related barriers to detection or to effects on tumor biology is not known. This study used polygenic models for obesity and breast cancer to deconstruct this question with the objective of determining whether cell autonomous mechanisms contribute to the link between obesity and breast cancer burden. Assessment of the growth rates of 259 chemically induced mammary carcinomas from rats sensitive to dietary induced obesity (DS) and of 143 carcinomas from rats resistant (DR) to dietary induced obesity revealed that tumors in DS rats grew 1.8 times faster than in DR rats. This difference may be attributed to alterations in cell cycle machinery that permit more rapid tumor cell accumulation. DS tumors displayed protein expression patterns consistent with reduced G1/S checkpoint inhibition and a higher threshold of factors required for execution of the apoptotic cell death pathway. These mechanistic insights identify regulatory targets for life style modifications or pharmacological interventions designed to disrupt the linkage between obesity and tumor burden.


Cytotoxic activity of some marine brown algae against cancer cell lines.
The aim of this study was to investigate the in vitro cytotoxic activity of total extract of MeOH (70%) and partition fractions of hexan, chloroform (CHCL3), ethylacetate (EtOAc) and MeOH-H2O of brown algae species (Sargassum swartzii, Cystoseira myrica, Colpomenia sinuosa) found in the Persian Gulf against in different cell lines including HT-29, Caco-2, T47D, MDA-MB468 and NIH 3T3 cell lines by MTT and AnnexinV-PI assay. The hexan fraction of S. swartzii and C. myrica showed selective cytotoxicity against proliferation of Caco-2 cells (IC50 < 100 μg/ml) T47D cell line (IC50<100 μg/ml), respectively. S. swartzii and C. myrica were also observed for increasing apoptosis in Caco-2 and T47D cells. Total extract and fractions of C. sinuosa did not show any significant cytotoxicity against the studied cell lines. MDA-MB468 cells were more sensitive to C. myrica than was T47D (IC50 99.9 ± 8.11 vs. 56.50' ± 0.88). This reflects an estrogen receptor independent mechanism for cytotoxicity of the extract. The IC50 of the hexan fraction of C. myrica on T47D parent cells was lower than it was on T47D-TR cells (IC50 99.9 ± 8.11 vs. 143.15 ± 7.80). This finding suggests a role for the MDR-1 in the development of possible future tolerance to the extract.


Economic and Health Predictors of National Postpartum Depression Prevalence: A Systematic Review, Meta-analysis, and Meta-Regression of 291 Studies from 56 Countries.
Postpartum depression (PPD) poses a major global public health challenge. PPD is the most common complication associated with childbirth and exerts harmful effects on children. Although hundreds of PPD studies have been published, we lack accurate global or national PPD prevalence estimates and have no clear account of why PPD appears to vary so dramatically between nations. Accordingly, we conducted a meta-analysis to estimate the global and national prevalence of PPD and a meta-regression to identify economic, health, social, or policy factors associated with national PPD prevalence. We conducted a systematic review of all papers reporting PPD prevalence using the Edinburgh Postnatal Depression Scale. PPD prevalence and methods were extracted from each study. Random effects meta-analysis was used to estimate global and national PPD prevalence. To test for country level predictors, we drew on data from UNICEF, WHO, and the World Bank. Random effects meta-regression was used to test national predictors of PPD prevalence. 291 studies of 296284 women from 56 countries were identified. The global pooled prevalence of PPD was 17.7% (95% confidence interval: 16.6-18.8%), with significant heterogeneity across nations (Q = 16,823, p = 0.000, I2 = 98%), ranging from 3% (2-5%) in Singapore to 38% (35-41%) in Chile. Nations with significantly higher rates of income inequality (R2 = 41%), maternal mortality (R2 = 19%), infant mortality (R2 = 16%), or women of childbearing age working ≥40 h a week (R2 = 31%) have higher rates of PPD. Together, these factors explain 73% of the national variation in PPD prevalence. The global prevalence of PPD is greater than previously thought and varies dramatically by nation. Disparities in wealth inequality and maternal-child-health factors explain much of the national variation in PPD prevalence.


Substrate stiffness affects the immunosuppressive and trophic function of hMSCs via modulating cytoskeletal polymerization and tension.
Mesenchymal stem cells (MSCs) have broad therapeutic potential due to their ability to secrete bioactive factors that are immunomodulatory and trophic (regenerative). In this study, polyacrylamide (PAAm) hydrogels with different stiffness are used as a model to explore the effects of substrate stiffness on the paracrine function of human mesenchymal stem cells (hMSCs). Human MSCs cultured on soft substrates produced significantly higher levels of immunomodulatory and trophic factors compared with hMSCs cultured on rigid substrates. The enhanced paracrine function of hMSCs is further confirmed by the M2 phenotypic polarization observed in macrophages, as well as the accelerated chemotactic migration and angiogenesis capacity observed in human umbilical vein endothelial cells (HUVECs) after treatment with conditioned media (CM) collected from hMSCs cultured on soft substrates. Furthermore, the inhibited secretion of immunosuppressive and trophic factors by hMSCs cultured on rigid substrates is largely rescued by treatment with Lat.A, a cytoskeletal polymerization inhibitor. Similar results are observed after treatment with either myosin (Blebbi) or ROCK (Y27632) inhibitors. These results demonstrate that substrate stiffness is a key modulator of the paracrine function of hMSCs and highlight the potential utility of promoting tissue repair through stiffness-regulated paracrine signaling in MSCs.


L-glutathione chemisorption on gold and acid/base induced structural changes: a PM-IRRAS and time-resolved in situ ATR-IR spectroscopic study.
Adsorption of the tripeptide L-glutathione (gamma-glu-cys-gly) on gold surfaces was investigated by polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS) and attenuated total reflection (ATR) infrared spectroscopy. PM-IRRAS was used to study ex situ the adsorbate layer prepared from aqueous solutions at different pH, whereas ATR-IR was applied to study in situ adsorption from ethanol in the presence and absence of acid and base. ATR-IR was furthermore combined with modulation spectroscopy in order to investigate the reversible changes within the adsorbate layer induced by acid and base stimuli, respectively. The molecule is firmly anchored on the gold surface via the thiol group of the cys part. However, the ATR-IR spectra in ethanol indicate a further interaction with the gold surface via the carboxylic acid group of the gly part of the molecule, which deprotonates upon adsorption. Hydrochloric acid readily protonates the two acid groups of the adsorbed molecule. During subsequent ethanol flow the acid groups deprotonate again, a process which proceeds in two distinct steps: a fast step associated with the deprotonation of the acid in the glu part of the molecule and a considerably slower step associated with deprotonation of the acid in the gly moiety. The latter process is assisted by the interaction of the corresponding acid group with the surface. The spectra furthermore indicate a rearrangement of the hydrogen bonding network within the adsorbate layer upon deprotonation. Depending on the protonation state during adsorption of l-glutathione, the response toward identical protonation-deprotonation stimuli is significantly different. This is explained by the ionic state-dependent shape of the molecule, as supported by density functional theory calculations. The different shapes of the individual molecules during layer formation thus influence the structure of the adsorbate layer.


Crystal structure of human type III collagen Gly991-Gly1032 cystine knot-containing peptide shows both 7/2 and 10/3 triple helical symmetries.
Type III collagen is a critical collagen that comprises extensible connective tissue such as skin, lung, and the vascular system. Mutations in the type III collagen gene, COL3A1, are associated with the most severe forms of Ehlers-Danlos syndrome. A characteristic feature of type III collagen is the presence of a stabilizing C-terminal cystine knot. Crystal structures of collagen triple helices reported so far contain artificial sequences like (Gly-Pro-Pro)(n) or (Gly-Pro-Hyp)(n). To gain insight into the structural properties exhibited by the natural type III collagen triple helix, we synthesized, crystallized, and determined the structure of a 12-triplet repeating peptide containing the natural type III collagen sequence from residues 991 to 1032 including the C-terminal cystine knot region, to 2.3A resolution. This represents the longest collagen triple helical structure determined to date with a native sequence. Strikingly, the Gly(991)-Gly(1032) structure reveals that the central non-imino acid-containing region adopts 10/3 superhelical properties, whereas the imino acid rich N- and C-terminal regions adhere to a 7/2 superhelical conformation. The structure is consistent with two models for the cystine knot; however, the poor density for the majority of this region suggests that multiple conformations may be adopted. The structure shows that the multiple non-imino acids make several types of direct intrahelical as well as interhelical contacts. The looser superhelical structure of the non-imino acid region of collagen triple helices combined with the extra contacts afforded by ionic and polar residues likely play a role in fibrillar assembly and interactions with other extracellular components.


Infrared spectra of (12)CF(2)=(12)CH(2) and (12)CF(2)=(13)CH(2), quantum-chemical calculations of anharmonicity, and analyses of resonances.
Infrared spectra obtained in gas and liquid argon phases are reported for (12)CF(2) horizontal line(12)CH(2) and (12)CF(2) horizontal line(13)CH(2). These spectra firmly establish the positions of nu(3)(A(1)) and nu(6)(A(2)) for both isotopomers. Using anharmonicity constants from MP2 calculations, Fermi resonances affecting nu(1)(A(1)), nu(2)(A(1)), nu(3), and nu(8)(B(1)) are analyzed. Deperturbed fundamental frequencies from these analyses are used in conjunction with unaffected fundamentals and ab initio anharmonicity data to predict all 12 "observed" harmonic frequencies. A Darling-Dennison type resonance between 2nu(6) and nu(11) + nu(12) is diagnosed, the calculation of which from ab initio data requires modification of the existing second-order treatment of such constants, where Fermi resonance type terms are also present. Predictions are made of many overtone and combination band frequencies, aiding assignment of observed spectra. From the isolated CH stretching frequency obtained here of 3125.4 cm(-1), the C-H equilibrium bond length is predicted to be 1.0762(11) A.


MatrixQCvis: shiny-based interactive data quality exploration for omics data.
First-line data quality assessment and exploratory data analysis are integral parts of any data analysis workflow. In high-throughput quantitative omics experiments (e.g. transcriptomics, proteomics and metabolomics), after initial processing, the data are typically presented as a matrix of numbers (feature IDs × samples). Efficient and standardized data quality metrics calculation and visualization are key to track the within-experiment quality of these rectangular data types and to guarantee for high-quality datasets and subsequent biological question-driven inference. We present MatrixQCvis, which provides interactive visualization of data quality metrics at the per-sample and per-feature level using R's shiny framework. It provides efficient and standardized ways to analyze data quality of quantitative omics data types that come in a matrix-like format (features IDs × samples). MatrixQCvis builds upon the Bioconductor SummarizedExperiment S4 class and thus facilitates the integration into existing workflows. MatrixQCVis is implemented in R. It is available via Bioconductor and released under the GPL v3.0 license. Supplementary data are available at Bioinformatics online.


A Rare Case of Mandibular Exostoses and its Review.
Mandibular exostosis is a type of bony prominence caused due to hyperostosis in the mandibular bone. They are benign, broad-based surface masses on the outer or facial aspect of the jaw bones; slowly enlarge over the years to form the bulky masses. During the period between the 10th to 13th week of intrauterine life, changes in the structure of the Meckel's cartilage and the protrusion of the medial lamina of the mandible onto the cartilage can result in the formation of such exostosis. We discuss here a very rare case of a 49-year-old male, in which the buccal exostoses formed underwent changes in size and shape due to certain factors, resulting in a bony bar formation in the mandibular anterior region.


A Delphi study to identify indicators of poorly managed pain for pediatric postoperative and procedural pain.
Adverse health care events are injuries occurring as a result of patient care. Significant acute pain is often caused by medical and surgical procedures in children, and it has been argued that undermanaged pain should be considered to be an adverse event. Indicators are often used to identify other potential adverse events. There are currently no validated indicators for undertreated pediatric pain. To develop a preliminary list of indicators of undermanaged pain in hospitalized pediatric patients. The Delphi technique was used to survey experts in pediatric pain management and quality improvement. The first round used an electronic questionnaire to ask: "In your opinion, what indicators would signify that acute pain in a child has not been adequately controlled?" Responses were grouped together in semantically similar themes, providing a list of possible adverse event indicators. Using this list, an electronic questionnaire was developed for round 2 asking respondents to indicate the importance of each potential indicator. All but one indicator achieved a level of consensus ≥70%. Separate indicators emerged for postoperative and procedural pain. An additional distinction was made between indicators that could be identified by chart review and those requiring observation of practice and assessment from the child or parent. The adverse care indicators developed in the present study require further refinement. There is a need to test their clinical usability and to determine whether these indicators actually identify undermanaged pain in clinical practice. The present study is an important first step in identifying undermanaged pain in hospital and treating it as an adverse event. The adverse care indicators developed in the present study are the first step in conceptualizing mismanaged pain as an adverse event.


Flexible responsive Janus nanosheets.
Flexible Janus nanosheets of molecular scale thickness (3.5 nm) are massively fabricated by a sol-gel process of a self-assembled monolayer of an amphiphilic silane onto a template. Groups of both sides are tuneable, and thus performance of the nanosheets, for example, is pH responsive. As a flexible solid emulsifier, the desired species can be wrapped with an individual nanosheet, which is pH triggered.


Distribution of an intravenous injectable nimodipine nanosuspension in mice.
The distribution of an intravenous injectable nimodipine nanosuspension with mean particle size of both 300 and 650 nm in mice was systemically investigated compared with that of a nimodipine ethanol formulation (Nimotop) and a nanosuspension coated with Tween-80. The results showed that the 650-nm nanoparticles provided significantly higher drug concentrations in the liver, spleen and lungs because of their capture by Kupffer cells in the mononuclear phagocyte system, but lower drug concentrations in the brain compared with Nimotop and smaller nanoparticles. These nanoparticles failed to give increased brain concentrations even when coated with Tween-80. The 300-nm nanoparticles could effectively increase drug concentrations in the brain and remarkably reduce drug concentrations in the liver, spleen and lungs, indicating that the nimodipine nanosuspension may be a promising formulation with no ethanol, but the particle size must be small.


Dial 9-1-1 for p53: mechanisms of p53 activation by cellular stress.
The tumor suppressor protein, p53, is part of the cell's emergency team that is called upon following cellular insult. How do cells sense DNA damage and other cellular stresses and what signal transduction pathways are used to alert p53? How is the resulting nuclear accumulation of p53 accomplished and what determines the outcome of p53 induction? Many posttranslational modifications of p53, such as phosphorylation, dephosphorylation, acetylation and ribosylation, have been shown to occur following cellular stress. Some of these modifications may activate the p53 protein, interfere with MDM2 binding and/or dictate cellular localization of p53. This review will focus on recent findings about how the p53 response may be activated following cellular stress.


A model of the dynamics of retinal activity during natural visual fixation.
During visual fixation, small eye movements keep the retinal image continuously in motion. It is known that neurons in the visual system are sensitive to the spatiotemporal modulations of luminance resulting from this motion. In this study, we examined the influence of fixational eye movements on the statistics of neural activity in the macaque's retina during the brief intersaccadic periods of natural visual fixation. The responses of parvocellular (P) and magnocellular (M) ganglion cells in different regions of the visual field were modeled while their receptive fields scanned natural images following recorded traces of eye movements. Immediately after the onset of fixation, wide ensembles of coactive ganglion cells extended over several degrees of visual angle, both in the central and peripheral regions of the visual field. Following this initial pattern of activity, the covariance between the responses of pairs of P and M cells and the correlation between the responses of pairs of M cells dropped drastically during the course of fixation. Cell responses were completely uncorrelated by the end of a typical 300-ms fixation. This dynamic spatial decorrelation of retinal activity is a robust phenomenon independent of the specifics of the model. We show that it originates from the interaction of three factors: the statistics of natural scenes, the small amplitudes of fixational eye movements, and the temporal sensitivities of ganglion cells. These results support the hypothesis that fixational eye movements, by shaping the statistics of retinal activity, are an integral component of early visual representations.


Cholesterol and triglycerides lowering activities of caraway fruits in normal and streptozotocin diabetic rats.
The purpose of this study was to examine the effect of single and repeated oral administration of the aqueous extract of Carum carvi L. fruits at a dose of (20mg/kg) on lipid metabolism in normal and streptozotocin-induced diabetic rats (STZ). After a single oral administration, Carum carvi extract produced a significant decrease on triglycerides levels in normal rats (p<0.05). In STZ diabetic rats, cholesterol levels were decreased significantly 6h after Carum carvi treatment (p<0.05). On the other hand, repeated oral administration of Carum carvi extract exhibited a significant hypotriglyceridemic and hypocholesterolemic activities in both normal (p<0.01 and <0.001 respectively) and STZ diabetic rats (p<0.001) 15 days after Carum carvi treatment. We conclude that the aqueous extract of Carum carvi (20mg/kg) exhibits a potent lipid lowering activity in both normal and severe hyperglycemic rats after repeated oral administration of Carum carvi aqueous extract.


The Effect of VMoS3 Point Defect on the Elastic Properties of Monolayer MoS2 with REBO Potentials.
Structural defects in monolayer molybdenum disulfide (MoS2) have significant influence on the electric, optical, thermal, chemical, and mechanical properties of the material. Among all the types of structural defects of the chemical vapor phase-grown monolayer MoS2, the VMoS3 point defect (a vacancy complex of Mo and three nearby S atoms) is another type of defect preferentially generated by the extended electron irradiation. Here, using the classical molecular dynamics simulation with reactive empirical bond-order (REBO) potential, we first investigate the effect of VMoS3 point defects on the elastic properties of monolayer MoS2 sheets. Under the constrained uniaxial tensile test, the elastic properties of monolayer MoS2 sheets containing VMoS3 vacancies with defect fraction varying from 0.01 to 0.1 are obtained based on the plane anisotropic constitutive relations of the material. It is found that the increase of VMoS3 vacancy concentration leads to the noticeable decrease in the elastic modulus but has a slight effect on Poisson's ratio. The maximum decrease of the elastic modulus is up to 25 %. Increasing the ambient temperature from 10 K to 500 K has trivial influences on the elastic modulus and Poisson's ratio for the monolayer MoS2 without defect and with 5 % VMoS3 vacancies. However, an anomalous parabolic relationship between the elastic modulus and the temperature is found in the monolayer MoS2 containing 0.1 % VMoS3 vacancy, bringing a crucial and fundamental issue to the application of monolayer MoS2 with defects.


The metabolism of glucose by the rabbit lens in the presence and absence of oxygen.
1. The effect of the absence of oxygen on the metabolism of [U-(14)C]glucose by the rabbit lens has been examined. 2. Protein-free extracts of incubated lens were subjected to electrophoresis followed by chromatography on paper; radioautographs showed 10 compounds substantially labelled. In the absence of oxygen, less radioactivity appeared in glucose, sorbitol, fructose, alanine, glutamic acid, glutathione and nucleotides, and more in lactic acid, alpha-glycerophosphate and glycerol. 3. The radioactivity of lens protein was about two to four times greater after aerobic than after anaerobic incubation. 4. The radioactivity of carbon dioxide was 2- to 4-fold greater after aerobic incubation than after anaerobic incubation. 5. After aerobic incubation of the lens, the radioactivity of all the labelled compounds was higher in the outer part (cortex) than in the inner part (nucleus). 6. Free glycerol has been found to be present in the lens. Its concentration, and that of alpha-glycerophosphate, has been measured in the lens of several species of animal.


Evaluation of a Dual Isolation Width Acquisition Method for Isobaric Labeling Ratio Decompression.
Isobaric labeling is a highly precise approach for protein quantification. However, due to the isolation interference problem, isobaric tagging suffers from ratio underestimation at the MS2 level. The use of narrow isolation widths is a rational approach to alleviate the interference problem; however, this approach compromises proteome coverage. We reasoned that although a very narrow isolation window will result in loss of peptide fragment ions, the reporter ion signals will be retained for a significant portion of the spectra. On the basis of this assumption, we have designed a dual isolation width acquisition (DIWA) method, in which each precursor is first fragmented with HCD using a standard isolation width for peptide identification and preliminary quantification, followed by a second MS2 HCD scan using a much narrower isolation width for the acquisition of quantitative spectra with reduced interference. We leverage the quantification obtained by the "narrow" scans to build linear regression models and apply these to decompress the fold-changes measured at the "standard" scans. We evaluate the DIWA approach using a nested two species/gene knockout TMT-6plex experimental design and discuss the perspectives of this approach.


Traumatised primary teeth in Nigerian children attending University Hospital: the consequences of delays in seeking treatment.
The objectives of this study were to investigate the occurrence, causes, types and severity of trauma to primary teeth in a hospital population, and to evaluate the interval between injury and treatment. The records of 1809 children treated in a two year period at the Ibadan University College Hospital were reviewed. There were 122 children aged one to seven years, with the highest frequency of trauma in the four and five year age groups, with no significant difference between boys and girls. Falls (88 per cent) were the commonest cause, and 57 children (47 per cent) had two injuries per episode of trauma. The majority (94 per cent) were luxation injuries and 6 per cent were fractures. Eighty-nine per cent of the injuries affected the maxilla, and the maxillary central incisors were the most frequently affected teeth, accounting for 68 per cent of all injuries. Only 11 per cent of the injuries presented for treatment on the day of trauma, while 10 per cent presented later than one year after trauma. The results suggest that the parents of these children with dental trauma do not bring the children for early treatment. The findings underscore a need to improve oral health awareness in general, but more importantly they emphasise that parents should obtain treatment for their children as soon as possible following any episode of dental trauma.


CyclOBEAP (cyclophosphamide, vincristine, bleomycin, etoposide, doxorubicin, prednisolone) regimen with granulocyte colony-stimulating factor (G-CSF) for patients with aggressive non-Hodgkin's lymphoma: a pilot study. The Adult Lymphoma Treatment Study Group (ALTSG).
We conducted a multi-institutional collaborative study to examine the usefulness and safety of third-generation chemotherapy CyclOBEAP (cyclophosphamide, vincristine, bleomycin, etoposide, doxorubicin, prednisolone) combined with granulocyte colony-stimulating factor (G-CSF) in the treatment of aggressive non-Hodgkin's lymphoma (NHL). Subjects included patients with aggressive NHL who were 60 yr of age or younger and had been diagnosed as having a low-intermediate, high-intermediate, or high risk using the International Prognostic Index (IPI). A total of 24 patients were enrolled in the study between May 1997 and March 1998, including 9 low-intermediate-risk cases, 13 high-intermediate-risk cases and 2 high-risk cases. Although all 24 patients were originally enrolled in the study, one adult T-cell leukemia/lymphoma case was subsequently excluded. Thus, in the end, 23 cases were evaluated. Evaluation of the efficacy of therapy revealed complete remission in 20 patients (87%). Of these 20 patients, 8 were low-intermediate-risk cases (89%) and 12 were either high-intermediate- or high-risk cases (86%). Partial remission was achieved in 2 patients (8.7%). The 2-yr survival rate was 91.3%, and the 2-yr disease-free survival rate was 81.8%. Grade 3 or higher adverse reactions were granulocytopenia (87%), thrombocytopenia (17.4%) and liver dysfunction (4.3%). CyclOBEAP therapy has been associated with a high remission rate for aggressive NHL. When combined with G-CSF, a high relative dose intensity was maintained for each drug administered (0.94-0.97). Furthermore, although the observation period was short, both the survival rate and disease-free survival rate were good. Hence, we concluded that there were no problems associated with the procedure in terms of safety.


Regulation of lifespan by neural excitation and REST.
The mechanisms that extend lifespan in humans are poorly understood. Here we show that extended longevity in humans is associated with a distinct transcriptome signature in the cerebral cortex that is characterized by downregulation of genes related to neural excitation and synaptic function. In Caenorhabditis elegans, neural excitation increases with age and inhibition of excitation globally, or in glutamatergic or cholinergic neurons, increases longevity. Furthermore, longevity is dynamically regulated by the excitatory-inhibitory balance of neural circuits. The transcription factor REST is upregulated in humans with extended longevity and represses excitation-related genes. Notably, REST-deficient mice exhibit increased cortical activity and neuronal excitability during ageing. Similarly, loss-of-function mutations in the C. elegans REST orthologue genes spr-3 and spr-4 elevate neural excitation and reduce the lifespan of long-lived daf-2 mutants. In wild-type worms, overexpression of spr-4 suppresses excitation and extends lifespan. REST, SPR-3, SPR-4 and reduced excitation activate the longevity-associated transcription factors FOXO1 and DAF-16 in mammals and worms, respectively. These findings reveal a conserved mechanism of ageing that is mediated by neural circuit activity and regulated by REST.


New stains for blood and bone marrow cells.
Traditionally, blood and bone marrow cells have been identified based on their characteristic shapes and colors when stained with one of several panoptic stains including Wright's or Giemsa's. As questions arose regarding the origin of normal and leukemic cells, cytochemical stains were developed. These stains help identify cells on the basis of a distinctive metabolite or enzyme. As part of an ongoing tradition in which textile dyes are used for biological staining, several new stains have been applied to hematologic staining. These include C.I. basic blue 41, basic blue 141, basic blue 93, and an asymmetrical polymethine dye. As additional cell-selective stains are developed, we can anticipate further improvements in our ability to identify normal and malignant hematopoietic cells.


Baseline risk stratification or duration of prior therapy predicts prognosis in patients with metastatic renal cell carcinoma treated with axitinib.
To elucidate the clinical prognostic factors in patients with metastatic renal cell carcinoma (mRCC) treated with axitinib. A total of 58 patients were retrospectively analyzed. All patients received axitinib treatment for mRCC at Keio University hospital in Japan. Baseline clinical factors and on treatment adverse events were assessed to predict survival. The median progression free survival (PFS) for axitinib treatment was 10.9 months (95% CI 5.8-13.5), and the median overall survival (OS) from the start of axitinib treatment was 39.8 months (95% CI 25.9-NR), respectively. The PFS (P < 0.0001) and OS (P = 0.0022) were significantly correlated with the International mRCC Database Consortium (IMDC) classification, respectively. The PFS and OS were significantly longer in patients who received longer prior treatment (P = 0.0424 and 0.0067, respectively). On-treatment hypertension, hand foot syndrome and hypothyroidism were associated with longer PFS (P = 0.0002, 0.0055 and 0.0290, respectively). On-treatment hypertension, diarrhea, and hand foot syndrome were associated with longer OS (P = 0.0004, 0.0036 and 0.0115, respectively). Baseline and on treatment factors are identified as prognostic markers in mRCC patients treated with axitinib. Our findings might be helpful for clinicians to select the best treatment to individual patients.


A proteomic approach reveals new actors of nodule response to drought in split-root grown pea plants.
Drought is considered the more harmful abiotic stress resulting in crops yield loss. Legumes in symbiosis with rhizobia are able to fix atmospheric nitrogen. Biological nitrogen fixation (SNF) is a very sensitive process to drought and limits legumes agricultural productivity. Several factors are known to regulate SNF including oxygen availability to bacteroids, carbon and nitrogen metabolisms; but the signaling pathways leading to SNF inhibition are largely unknown. In this work, we have performed a proteomic approach of pea plants grown in split-root system where one half of the root was well-irrigated and the other was subjected to drought. Water stress locally provoked nodule water potential decrease that led to SNF local inhibition. The proteomic approach revealed 11 and 7 nodule proteins regulated by drought encoded by Pisum sativum and Rhizobium leguminosarum genomes respectively. Among these 18 proteins, 3 proteins related to flavonoid metabolism, 2 to sulfur metabolism and 3 RNA-binding proteins were identified. These proteins could be molecular targets for future studies focused on the improvement of legumes tolerance to drought. Moreover, this work also provides new hints for the deciphering of SNF regulation machinery in nodules.


Characterization of a versatile organometallic pro-drug (CORM) for experimental CO based therapeutics.
The complex fac-[Mo(CO)(3)(histidinate)]Na has been reported to be an effective CO-Releasing Molecule in vivo, eliciting therapeutic effects in several animal models of disease. The CO releasing profile of this complex in different settings both in vitro and in vivo reveals that the compound can readily liberate all of its three CO equivalents under biological conditions. The compound has low toxicity and cytotoxicity and is not hemolytic. CO release is accompanied by a decrease in arterial blood pressure following administration in vivo. We studied its behavior in solution and upon the interaction with proteins. Reactive oxygen species (ROS) generation upon exposure to air and polyoxomolybdate formation in soaks with lysozyme crystals were observed as processes ensuing from the decomposition of the complex and the release of CO.


Integrating Liquification of the Gelated Tumor Interstitium around Nanomedicines with Biconditional GD2-Targeting for Precise and Safe Chemotherapy.
The quick diffusion of nanomedicines in the polysaccharide-gel-filling tumor interstitium and precise active targeting are two major obstacles that have not yet been overcome. Here, a poly(L-glutamyl-L-lysine(EK) (p(EK))-camouflaged, doxorubicin (Dox)-conjugated nanomedicine is developed to demonstrate the underlying mechanism of zwitterionic shell in synchronous barrier-penetration and biconditional active targeting. The zwitterionic p(EK) shell liquifies its surrounding water molecules in the polysaccharide gel of tumor interstitium, leading to five times faster diffusion than the pegylated Doxil with similar size in tumor tissue. Its doped sulfonate groups lead to more precise active tumor-targeting than disialoganglioside (GD2) antibody by meeting the dual requirements of tumor microenvironment (TME) pH and overexpression of GD2 on tumor. Consequently, the concentrations of the nanomedicine in tumor are always higher than in life-supported organs in whole accumulation process, reaching over ten times higher Dox in GD2-overexpressing MCF-7 tumors than in life-supporting organs. Furthermore, the nanomedicine also avoids anti-GD2-like accumulation in GD2-expressing kidney in a mouse model. Thus, the nanomedicine expands the therapeutic window of Doxil by more than three times and eliminates tumors with negligible myocardial and acute toxicity. This new insight paves an avenue to design nanodelivery systems for highly precise and safe chemotherapy.


Bisphenol S dysregulates thyroid hormone homeostasis; Testicular survival, redox and metabolic status: Ameliorative actions of melatonin.
Bisphenol S (BPS) is an incipient threat for reproductive health augmenting societal burden of infertility worldwide. In the present study, we investigated the mechanism of BPS induced testicular dysfunctions and protective actions of melatonin in mice. BPS (150 mg/kg BW) treatment reduced serum T3/T4, testosterone and elevated insulin levels along with adverse effect on thyroid and testicular histoarchitecture. Further, BPS treatment compromised sperm quality, reduced mRNA expression of steroidogenic (StAR/CYP11A1) markers, elevated oxidative load and disrupts metabolic status. However, melatonin (5 mg/kg BW) administration to BPS treated mice showed improved hormonal/histological parameters, enhanced thyroid hormone (TR-α/Dio-2)/melatonin (MT-1) receptor expressions. Further, melatonin treatment modulated the expression of testicular survival/redox (SIRT1/PGC-1α/FOXO-1, Nrf2/HO-1, p-JAK2/p-STAT3), proliferative (PCNA) and metabolic (IR/pAKT/GLUT-1) markers. Furthermore, melatonin treatment enhanced testicular antioxidant status and reduced caspase-3 expression. In conclusion, our results showed that BPS induces endocrine/oxidative and metabolic anomalies while melatonin improved male reproductive health.


Solution processed infrared- and thermo-photovoltaics based on 0.7 eV bandgap PbS colloidal quantum dots.
Harnessing low energy photons is of paramount importance for multi-junction high efficiency solar cells as well as for thermo-photovoltaic applications. However, semiconductor absorbers with the bandgap lower than 0.8 eV have been limited to III-V (InGaAs) or IV (Ge) semiconductors that are characterized by high manufacturing costs and complicated lattice matching requirements in their growth and integration with higher bandgap cells. Here, we have developed solution processed low bandgap photovoltaic devices based on PbS colloidal quantum dots (CQDs) with a bandgap of 0.7 eV suited for both thermo-photovoltaics and low energy solar photon harvesting. By matching the spectral response of those cells to that of the infrared solar spectrum, we report a record high short circuit current (JSC) of 37 mA cm-2 under the full solar spectrum and 5.5 mA cm-2 when placed at the back of a silicon wafer resulting in power conversion efficiencies (PCEs) of 6.4% and 0.7%, respectively. Moreover, the device reached an above bandgap PCE of ∼6% as a thermo-photovoltaic cell recorded under a 1000 °C blackbody radiator.


The DUB/USP17 deubiquitinating enzymes: a gene family within a tandemly repeated sequence, is also embedded within the copy number variable beta-defensin cluster.
The DUB/USP17 subfamily of deubiquitinating enzymes were originally identified as immediate early genes induced in response to cytokine stimulation in mice (DUB-1, DUB-1A, DUB-2, DUB-2A). Subsequently we have identified a number of human family members and shown that one of these (DUB-3) is also cytokine inducible. We originally showed that constitutive expression of DUB-3 can block cell proliferation and more recently we have demonstrated that this is due to its regulation of the ubiquitination and activity of the 'CAAX' box protease RCE1. Here we demonstrate that the human DUB/USP17 family members are found on both chromosome 4p16.1, within a block of tandem repeats, and on chromosome 8p23.1, embedded within the copy number variable beta-defensin cluster. In addition, we show that the multiple genes observed in humans and other distantly related mammals have arisen due to the independent expansion of an ancestral sequence within each species. However, it is also apparent when sequences from humans and the more closely related chimpanzee are compared, that duplication events have taken place prior to these species separating. The observation that the DUB/USP17 genes, which can influence cell growth and survival, have evolved from an unstable ancestral sequence which has undergone multiple and varied duplications in the species examined marks this as a unique family. In addition, their presence within the beta-defensin repeat raises the question whether they may contribute to the influence of this repeat on immune related conditions.


Hexavalent IPV-based combination vaccines for public-sector markets of low-resource countries.
In anticipation of the successful eradication of wild polio virus, alternative vaccination strategies for public-sector markets of low-resource countries are extremely important, but are still under development. Following polio eradication, inactivated polio vaccine (IPV) would be the only polio vaccine available, and would be needed for early childhood immunization for several years, as maintenance of herd immunity will be important for sustaining polio eradication. Low-cost combination vaccines containing IPV could provide reliable and continuous immunization in the post-polio eradication period. Combination vaccines can potentially simplify complex pediatric routine immunization schedules, improve compliance, and reduce costs. Hexavalent vaccines containing Diphtheria (D), Tetanus (T), whole cell pertussis (wP), Hepatitis B (HBV), Haemophilus b (Hib) and the three IPV serotype antigens have been considered as the ultimate combination vaccine for routine immunization. This product review evaluates potential hexavalent vaccine candidates by composition, probable time to market, expected cost of goods, presentation, and technical feasibility and offers suggestions for development of low-cost hexavalent combination vaccines. Because there are significant technical challenges facing wP-based hexavalent vaccine development, this review also discusses other alternative approaches to hexavalent that could also ensure a timely and reliable supply of low-cost IPV based combination vaccines.