Inhibitors of epidermoid growth factor receptor suppress cell growth and enhance chemosensitivity of nasopharyngeal cancer cells in vitro.
Epidermoid growth factor receptor (EGFR, HER1) is overexpressed in a majority of head-and-neck cancers, including nasopharyngeal carcinoma (NPC). Although EGFR inhibitors appear to be effective for some head-and-neck cancers, their efficacy in NPC remains unclear. The effect of EGFR-specific tyrosine kinase inhibitors, including PD153035 and ZD1839, were studied in NPC-TW01, NPC-TW04, and HONE1 cell lines. The effect of combining EGFR inhibitors with cytotoxic agents was evaluated in NPC-TW04 cells. All three NPC cell lines expressed EGFR. PD153035 and ZD1839 inhibited the growth of NPC cells with IC50s around 10 and 20 microM, respectively. These inhibitors, however, effectively suppressed ligand-stimulated EGFR activation in NPC cells with a much lower concentration (> or =0.1 microM). The growth-suppression activity of EGFR inhibitors was closely associated with suppression of AKT phosphorylation. LY294002, a phosphatidylinositol-3 kinase (P13K)/AKT inhibitor, did suppress the growth of NPC cells. Pretreatment of EGFR inhibitors by 24 h significantly enhanced the cytotoxic effect of doxorubicin, paclitaxel, cisplatin, and 5-fluororuacil in NPC-TW04 cells. Our data indicate that inhibition of EGFR activation is not sufficient to induce growth inhibition in NPC cells in vitro. EGFR inhibitors may be useful adjuncts in treating NPC when combined with conventional anticancer drugs.


Dihydroquercetin (DHQ) ameliorates LPS-induced acute lung injury by regulating macrophage M2 polarization through IRF4/miR-132-3p/FBXW7 axis.
Acute lung injury (ALI) is a common complication of sepsis. Dihydroquercetin (DHQ) has been found to attenuate lipopolysaccharide (LPS)-induced inflammation. However, the effect of DHQ on LPS-challenged ALI remains unclear. Pulmonary HE and TUNEL staining and lung wet/dry ratio were detected in LPS-treated Balb/c mice. IL-1β, IL-6 and TNF-α levels were determined utilizing ELISA assay. RAW264.7 cell apoptosis and macrophage markers (CD86, CD206) were tested using flow cytometry. TC-1 viability was analyzed by MTT assay. Western blot measured protein expression of macrophage markers. Interactions of miR-132-3p, IRF4 and FBXW7 were explored utilizing ChIP, RNA pull-down and dual luciferase reporter assays. DHQ alleviated histopathological change, pulmonary edema and apoptosis in LPS-treated mice. DHQ affected LPS-induced M2 macrophage polarization and TC-1 cell injury-related indicators, such as decreased cell activity, decreased LDH levels, and increased apoptosis. LPS inhibited IRF4 and miR-132-3p expression, activated Notch pathway and increased FBXW7 level, which were overturned by DHQ. IRF4 transcriptionally activated miR-132-3p expression. FBXW7 was a downstream target of miR-132-3p. DHQ alleviated LPS-induced lung injury through promoting macrophage M2 polarization via IRF4/miR-132-3p/FBXW7 axis, which provides a new therapeutic strategy for ALI.


Interrelationship between tumour virus receptors, A and C, coded by host cell genes in fowl.
Bryan Standard strain of Rous Sarcoma Virus (BS-RSV) of subgroup A and pseudotype of Bryan high titre RSV(RAV-49) of subgroup C and an equal mixture of subgroup A and subgroup C virus were inoculated to 11-day old embryos of white leghorn (WL), Australorp (AL) and f1 and f2 generations of crosses between WL and AL breeds of fowl to detect and estimate the interrelationship between tumour virus receptor coding host cell genes of tva and tvc loci. Linkage values estimated on a pooled sex basis were 0.08 +/- 0.03 and 0.10 +/- 0.03 for WL and AL breeds respectively and 0.09 on pooled breed basis. This clearly indicates that the tva and tvc loci are indeed closely linked in WL and AL breeds of fowl and supports the concept of using subgroup C virus to raise stocks resistant to subgroup A virus infection.


Pattern of pharmaceutical retailing of anti-diabetic products in Ibadan, Nigeria.
Twenty-four pharmacists in the city of Ibadan were surveyed through a self-administered structured questionnaire as to the extent of their involvement in the pharmaceutical retailing of antidiabetic products and their cost. Oral hypoglycemic agents especially, chlorpropamide (Diabenese) and glibenclamide (Daonil) were the most readily available drugs being obtainable from 21 (87.5%) pharmacies. Insulin was stocked regularly by only 14 (58.3%) of the pharmacists and insulin syringes and needles could be obtained from only 10 (41.6%) of the pharmacies. Among materials for urine testing, clinistix strip was the most readily available and fully one-third of the pharmacies did not stock any such material. The prices of all the products were disturbingly high and between 1983 and 1986 when retail prices were re-assessed, the cost of some materials had escalated by as much as 400%. Scarcity of antidiabetic products and their high cost pose serious challenges for those involved in the care of diabetic patients in Nigeria. Some suggestions have been made as to what steps both the government and the pharmaceutical industry can take in ensuring the availability of these life sustaining products for the increasingly large Nigerian diabetic population.


Zinc and alcoholic liver disease.
Zinc deficiency is one of the most consistent nutritional/biochemical observations in alcoholic liver disease (ALD). The objectives of our research are to determine how alcohol interferes with cellular zinc homeostasis and if zinc deficiency is a causal factor in the development of ALD. Metallothionein (MT) is a major protein responsible for cellular zinc homeostasis. MT-transgenic (MT-TG) mice with hepatic overexpression of MT and elevation of zinc level were resistant to ethanol-induced liver injury. MT-knockout (MT-KO) mice with a reduction of hepatic zinc were more susceptible to alcohol toxicity. However, zinc treatment also provided beneficial effects on alcohol hepatoxicity in MT-KO mice, suggesting a MT-independent action. Dietary zinc supplementation normalized hepatic zinc level and attenuated the pathological changes in the liver of mice chronically fed alcohol. Several mechanisms were involved in zinc action against alcoholic cytotoxicity. Zinc enhanced cellular antioxidant capacity and corrected alcohol metabolic switch from alcohol dehydrogenase to cytochrome P4502E1. Zinc attenuated cytokine production and TNF-α receptor- and Fas-mediated cell death pathways. Zinc restored activities of hepatocyte nuclear factor-4α (HNF-4α) and peroxisome proliferation activator-α (PPAR-α), and enhanced hepatic fatty acid β-oxidation and lipid secretion. Hepatoma cell cultures showed that zinc deprivation induces lipid accumulation via inactivating HNF-4α and PPAR-α. These results suggest that alcohol exposure interferes with hepatic zinc homeostasis, leading to cellular zinc deprivation. Inactivation of zinc proteins due to zinc release is likely an important molecular mechanism in the pathogenesis of ALD.


Carotenoids, Chronic Disease Prevention and Dietary Recommendations.
Carotenoids are C-30, C-40 or C-50 terpenoids produced by a number of bacteria, fungi, and plants. In addition to acting as vitamin A precursors such as β-carotene, their dietary intake and blood plasma/serum and tissue levels have been associated in several epidemiological studies to the reduced incidence of chronic diseases, including the reduction of type 2 diabetes and other cardiometabolic diseases, as well as some types of cancer. Lutein and zeaxanthin also appear to play a role in the amelioration of age-related macular degeneration (AMD), the main cause of blindness in the elderly, and may be regarded as conditionally essential nutrients for the elderly. Furthermore, some studies have proposed that carotenoids may improve cognitive functions. Though the underlying mechanisms remain to be fully elucidated, it is perceived that direct antioxidant effects and protection from UV-light, as well as rather indirect effects, acting on transcription factors such as NF-κB, Nrf-2, and nuclear receptors such as RAR/RXR (retinoic acid receptor/retinoid X receptor), altering gene expression, all can play a role. Despite individual intervention trials suggesting negative effects of high doses of β-carotene on smokers, perhaps due to effects related to cytochrome enzyme activation, there is accumulating evidence that these colourful pigments indeed contribute to a healthy life and well-being. However, further research is warranted to better understand factors influencing variable inter-individual responses following carotenoid consumption and to establish more detailed recommendations regarding their dietary intake and toward establishing health claims.


Serological Determination of Toxoplasma gondii among Sheep (Ovis aries) in Guilan Province, Iran.
Toxoplasma gondii is one of the most common foodborne protozoan parasite causing congenital infection, abortion, and stillbirth in humans and animals. The temperate and humid climate is one of the most important factors in the high prevalence of T. gondii. Sheep are among the important sources of meat production in Guilan province, Iran. Therefore, the consumption of raw and half-cooked meat is one of the major risk factors for T. gondii infection. Toxoplasmosis in patients with intact immune systems is usually asymptomatic; however, it but can be life-threatening in patients with a weak immune system (for example, patients with the human immunodeficiency viruses/acquired immunodeficiency syndrome or cancer and transplant recipients). Guilan is divided into three geographical regions of plains with a temperate climatic condition, hillsides with a semi-humid climate, and heights with cold mountainous climate. Climate situations play a role in the prevalence of toxoplasmosis. The present study aimed to investigate the seroprevalence of T. gondii infection among sheep in Guilan province, north of Iran. In the current cross-sectional study, a total of 400 sheep sera samples were tested for the determination of immunoglobulin G (IgG) antibody against T. gondii using the enzyme-linked immunosorbent assay. The samples were divided into different groups according to the geographical location and animal age. T. gondii antibody (i.e., IgG) was detected in 166 sheep (41.5%). The highest frequency of T. gondii infection (72.7%; n=56) was observed for the age group of > 4 years; the difference was statistically significant in this regard (P=0.0001) in comparison to that reported for other groups. In addition, the seroprevalence of T. gondii was significantly higher in the plains (53.9%) than that of the hillsides and heights (P=0.0001). Consequently, the seroprevalence of T. gondii infection in Guilan was high indicating a significant relationship with geographical location and animal age.


Concomitant information in bioassay and semi-parametric estimation.
This paper presents a flexible modern approach to handling concomitant information for estimating the relative potency parameter in quantitative bioassays. This is accomplished in a semi-parametric framework where the concomitant variable is included non-parametrically. Estimation is then performed using smoothing splines where the point and interval estimators of the relative potency parameter exhibits desirable asymptotic properties.


Simulation Training in Urology: State of the Art and Future Directions.
There has been a major shift from the old paradigm of 'see one, do one, teach one' in medical training due in large part to resident work-hour restrictions and required oversight in the operating room. In response to this, advancements in technology have allowed for the introduction of more objective measures to assess the skill competency and proficiency of surgical trainees. Patient safety and trainee well-being are important drivers for this new model, and so surgical training programs are adopting simulation into their curriculum. Urology is uniquely positioned at the forefront of new emerging technologies in surgery, because of the field's commitment to safe and efficient minimally invasive surgery and endourological procedures. Due to these technically challenging procedures, urological training must incorporate these educational technologies to allow for objective skills assessment, skills transfer, and ultimately providing optimal patient care with the production of proficient and competent urological trainees.


Recruiting human microbiome shotgun data to site-specific reference genomes.
The human body consists of innumerable multifaceted environments that predispose colonization by a number of distinct microbial communities, which play fundamental roles in human health and disease. In addition to community surveys and shotgun metagenomes that seek to explore the composition and diversity of these microbiomes, there are significant efforts to sequence reference microbial genomes from many body sites of healthy adults. To illustrate the utility of reference genomes when studying more complex metagenomes, we present a reference-based analysis of sequence reads generated from 55 shotgun metagenomes, selected from 5 major body sites, including 16 sub-sites. Interestingly, between 13% and 92% (62.3% average) of these shotgun reads were aligned to a then-complete list of 2780 reference genomes, including 1583 references for the human microbiome. However, no reference genome was universally found in all body sites. For any given metagenome, the body site-specific reference genomes, derived from the same body site as the sample, accounted for an average of 58.8% of the mapped reads. While different body sites did differ in abundant genera, proximal or symmetrical body sites were found to be most similar to one another. The extent of variation observed, both between individuals sampled within the same microenvironment, or at the same site within the same individual over time, calls into question comparative studies across individuals even if sampled at the same body site. This study illustrates the high utility of reference genomes and the need for further site-specific reference microbial genome sequencing, even within the already well-sampled human microbiome.


Magnetic i-MXenes: a new class of multifunctional two-dimensional materials.
Based on density functional theory calculations, we investigated two-dimensional in-plane ordered MXenes (i-MXenes), focusing particularly on their magnetic properties. It has been observed that robust two-dimensional magnetism can be achieved by alloying nonmagnetic MXenes with magnetic transition metal atoms. Moreover, both the magnetic ground states and the magnetocrystalline anisotropy energy of i-MXenes can be effectively manipulated by strain, indicating a strong piezomagnetic effect. Further studies on the transport properties reveal that i-MXenes provide an interesting platform to realize large thermoelectric response, antiferromagnetic topological insulators, and spin-gapless semiconductors. Thus, i-MXenes are a new class of multifunctional two-dimensional magnetic materials which are promising for future spintronic applications.


Emergent Management of Tandem Lesions in Acute Ischemic Stroke.
Background and Purpose- Although intracranial thrombectomy represents the standard treatment approach for anterior circulation tandem occlusions, whether the extracranial lesion requires acute stenting remains unclear. Our aim was to investigate differences in clinical and procedural outcomes related to stenting extracranial lesions in a registry of patients undergoing thrombectomy for acute stroke. Methods- Data were analyzed from the STRATIS registry (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke)-a prospective, nonrandomized study of patients undergoing neurothrombectomy with the Solitaire device. A total of 984 patients treated at 55 sites were analyzed. Univariate and multivariable logistic regression was used to assess relationship between outcome and procedural technique. Results- Of 147 (14.9%) patients with tandem lesions treated, stenting of the extracranial lesion during thrombectomy was performed in 80 patients and withheld in 67 patients. There were no differences between groups with respect to age, ASPECTS (Alberta Stroke Program Early CT Score), or intravenous-tPA (tissue-type plasminogen activator) use. However, the patients in the stenting group had lower baseline National Institutes of Health Stroke Scale (16 versus 17.9; P=0.07), shorter onset to arterial puncture time (133.6 versus 163.4 minutes; P=0.04), and lower rates of atrial fibrillation (6.3% versus 25.4%) as compared to the nonstenting group. Good outcomes (modified Rankin Scale, 0-2 at 90 days) were higher in the stenting group (68.5% versus 42.2%; P=0.003) with no difference in mortality or symptomatic hemorrhage. After adjustment for covariates, stenting continued to be associated with superior outcomes. Conclusions- Acute stenting of an extracranial carotid stenosis during neurothrombectomy can be achieved with equal safety compared with no stenting. Carotid stenting in the acute phase may lead to better outcomes; this should ideally be confirmed by randomized trials.


A New Era in Magnetic Resonance Contrast Media.
Next-generation gadolinium-based contrast agents (GBCAs), including both high relaxivity agents and targeted agents, and manganese-based agents with a high probably of commercial success are discussed in some depth. It is highly likely that gadopiclenol and gadoquatrane, both next-generation high relaxivity gadolinium-based compounds, will come in time to replace the current macrocyclic gadolinium chelates, despite the wide acceptance, very high safety profile, and high stability of the latter group. Current research has also made possible the development of 2 new targeted gadolinium chelates, which look very promising, with the potential to improve cancer detection (for both MT218 and ProCA32.collagen) as well as diseases of collagen (for the latter agent). Further work with manganese-based compounds, a topic left fallow for more than 20 years, has also now produced 2 agents with high potential for clinical use, one (manganese chloride tetrahydrate, administered orally) developed primarily for imaging of the liver and the other (Mn-PyC3A, administered intravenously) as a gadolinium-free replacement for the GBCAs. New detail has recently emerged regarding specific circumscribed subregions of the brain with specialized cytoarchitecture and functions in which high gadolinium concentrations are seen following injection of the linear agent gadodiamide. These findings pave the way for tailored functional neurological testing, specifically in patients at potential risk due to the continued wide use in many countries across the world of the linear GBCAs. The impact of artificial intelligence is also critically discussed, with its most likely applications being dose reduction and new clinical indications.


A cluster of acute flaccid paralysis and cranial nerve dysfunction temporally associated with an outbreak of enterovirus D68 in children in Colorado, USA.
Clusters of acute flaccid paralysis or cranial nerve dysfunction in children are uncommon. We aimed to assess a cluster of children with acute flaccid paralysis and cranial nerve dysfunction geographically and temporally associated with an outbreak of enterovirus-D68 respiratory disease. We defined a case of neurological disease as any child admitted to Children's Hospital Colorado (Aurora, CO, USA) with acute flaccid paralysis with spinal-cord lesions involving mainly grey matter on imaging, or acute cranial nerve dysfunction with brainstem lesions on imaging, who had onset of neurological symptoms between Aug 1, 2014, and Oct 31, 2014. We used Poisson regression to assess whether the numbers of cases during the outbreak period were significantly greater than baseline case numbers from a historical control period (July 31, 2010, to July 31, 2014). 12 children met the case definition (median age 11·5 years [IQR 6·75-15]). All had a prodromal febrile illness preceding neurological symptoms by a median of 7 days (IQR 5·75-8). Neurological deficits included flaccid limb weakness (n=10; asymmetric n=7), bulbar weakness (n=6), and cranial nerve VI (n=3) and VII (n=2) dysfunction. Ten (83%) children had confluent, longitudinally extensive spinal-cord lesions of the central grey matter, with predominant anterior horn-cell involvement, and nine (75%) children had brainstem lesions. Ten (91%) of 11 children had cerebrospinal fluid pleocytosis. Nasopharyngeal specimens from eight (73%) of 11 children were positive for rhinovirus or enterovirus. Viruses from five (45%) of 11 children were typed as enterovirus D68. Enterovirus PCR of cerebrospinal fluid, blood, and rectal swabs, and tests for other causes, were negative. Improvement of cranial nerve dysfunction has been noted in three (30%) of ten children. All ten children with limb weakness have residual deficits. We report the first geographically and temporally defined cluster of acute flaccid paralysis and cranial nerve dysfunction in children associated with an outbreak of enterovirus-D68 respiratory illness. Our findings suggest the possibility of an association between enterovirus D68 and neurological disease in children. If enterovirus-D68 infections continue to happen in an endemic or epidemic pattern, development of effective antiviral or immunomodulatory therapies and vaccines should become scientific priorities. National Center for Advancing Translational Sciences, National Institutes of Health.


Water immersion increases urinary excretion of aquaporin-2 in healthy humans.
Many previous studies have shown that aquaporin-2 (AQP2), the vasopressin-regulated water channel, is excreted in the urine and that the excretion increases in response to vasopressin. Moreover, recently a close correlation between AQP2 excretion in urine and kidney AQP2 expression has been demonstrated, showing that urinary excretion of AQP2 is a reliable indicator for AQP-2 function. As head-out water immersion causes an expansion in the central vascular volume equal to that induced by 2 liters of saline, without modifying plasma composition, we used immersion in water to evaluate if the response to acute expansion of the central vascular volume could involve vasporessin (AVP) and AQP2. In healthy subjects, concentrations of plasma atrial natriuretic factor (ANF) and AVP, and urinary AQP2 were measured during a 2-hour immersion period. In all subjects, immersion caused a prompt and marked increase in immunoreactive ANF (23.0 +/- 2.12 pg/ml at second hour vs. 2.17 +/- 0.42 pg/ml at baseline) and in urinary excretion of AQP2 (23.9 +/- 2. 69 pmol/mg creatinine at second hour vs. 4.42 +/- 0.14 pmol/mg creatinine at baseline), while a significant decrease was found in plasma AVP. Recovery was associated with a prompt return to pre-study levels. These findings demonstrate that heat-out water immersion stimulates urinary excretion of AQP2 in absence of an increase in plasma AVP.


Respectful maternity care and its relationship with childbirth experience in Iranian women: a prospective cohort study.
Intrapartum respectful maternity care is defined as a fundamental human right that can affect the mother's experiences. This study aimed to determine the status of respectful maternity care and its relationship with childbirth experience among Iranian women. This prospective cohort study recruited 334 postpartum women in postpartum wards of two public and four private hospitals in Tabriz, Iran. Quota sampling was used based on the number of births in each hospital. Data were collected through interviews with the use of the following tools: sociodemographic and obstetrics characteristics questionnaire, respectful maternity care scale (6 to 18 h postpartum), and childbirth experience questionnaire (30 to 45 days postpartum). The General Linear Model was used to determine the relationship between respectful maternity care and childbirth experience. The mean respectful maternity care score was 62.58 with a range of 15 to 75, and the total childbirth experience score was 3.29 with a range of 1 to 4. After adjusting for sociodemographic and obstetrics characteristics, a statistically significant direct correlation was found between respectful maternity care and a positive childbirth experience (P < 0.001). The findings reveals a direct relationship between respectful maternity care and positive childbirth experience. Therefore, it is recommended that mangers and policy makers in childbirth facilities reinforce facilitating a respectful maternity care to improve women's child birth experience and prevent potential adverse effects of negative childbirth experiences.


TWEAKing the Hippocampus: The Effects of TWEAK on the Genomic Fabric of the Hippocampus in a Neuropsychiatric Lupus Mouse Model.
Neuropsychiatric manifestations of systemic lupus erythematosus (SLE), specifically cognitive dysfunction and mood disorders, are widely prevalent in SLE patients, and yet poorly understood. TNF-like weak inducer of apoptosis (TWEAK) has previously been implicated in the pathogenesis of neuropsychiatric lupus (NPSLE), and we have recently shown its effects on the transcriptome of the cortex of the lupus-prone mice model MRL/lpr. As the hippocampus is thought to be an important focus of NPSLE processes, we explored the TWEAK-induced transcriptional changes that occur in the hippocampus, and isolated several genes (Dnajc28, Syne2, transthyretin) and pathways (PI3K-AKT, as well as chemokine-signaling and neurotransmission pathways) that are most differentially affected by TWEAK activation. While the functional roles of these genes and pathways within NPSLE need to be further investigated, an interesting link between neuroinflammation and neurodegeneration appears to emerge, which may prove to be a promising novel direction in NPSLE research.


The importance of excluding coronary artery vasospasm before percutaneous transluminal coronary angioplasty. A case report.
It is important to exclude coronary vasospasm, the mechanism responsible for so-called 'dynamic' coronary stenosis, when selecting of patients for percutaneous transluminal coronary angioplasty (PTCA). Although cine angiographic demonstration of this frequently fleeting entity can sometimes be difficult, a strong suspicion should be aroused by a carefully taken history. The danger of PTCA in these cases of Prinzmetal's variant angina, as well as the frustration often encountered in drug management, is high-lighted.


Prevention of unintended pregnancy and use of contraception-important factors for preconception care.
Preservation of fertility and optimizing health before pregnancy is becoming increasingly important in societies where childbirth often is postponed. Research shows that as women postpone childbirth they achieve higher levels of education and higher incomes. This leads to advantages for their children and for society. However, as women postpone childbearing they are at risk for contracting conditions which may affect fertility and/or pregnancies, pregnancy outcome, and the newborn child. Preconception counseling is therefore becoming increasingly important. Women are often unaware of the added health benefits of contraception and have the right to be well informed so they can make decisions to fulfill their reproductive desires. Contraception can reduce the risk of unintended pregnancies, ectopic and molar pregnancies, and sexually transmitted infections. In addition, hormonal contraceptives reduce the risk of some types of cancer, dysmenorrhea, heavy menstrual bleeding, and anemia and are a treatment for endometriosis. Contraception should increasingly be looked upon as a means of preserving fertility and optimizing health status before a planned pregnancy. Thus, effective contraception can provide women with a possibility of achieving their long-term reproductive goals, although childbearing is actually postponed. The most effective contraceptive methods are the long-acting reversible contraceptives, which have been shown to be highly effective especially in young women who have difficulties with adherence to user-dependent methods. Therefore, these methods should increasingly be promoted in all age groups.


Search for supersymmetry in events containing a same-flavour opposite-sign dilepton pair, jets, and large missing transverse momentum in [Formula: see text] TeV pp collisions with the ATLAS detector.
Two searches for supersymmetric particles in final states containing a same-flavour opposite-sign lepton pair, jets and large missing transverse momentum are presented. The proton-proton collision data used in these searches were collected at a centre-of-mass energy [Formula: see text] TeV by the ATLAS detector at the Large Hadron Collider and corresponds to an integrated luminosity of 20.3 fb[Formula: see text]. Two leptonic production mechanisms are considered: decays of squarks and gluinos with Z bosons in the final state, resulting in a peak in the dilepton invariant mass distribution around the Z-boson mass; and decays of neutralinos (e.g. [Formula: see text]), resulting in a kinematic endpoint in the dilepton invariant mass distribution. For the former, an excess of events above the expected Standard Model background is observed, with a significance of three standard deviations. In the latter case, the data are well-described by the expected Standard Model background. The results from each channel are interpreted in the context of several supersymmetric models involving the production of squarks and gluinos.


ESHRE PGT Consortium good practice recommendations for the detection of structural and numerical chromosomal aberrations.
The field of preimplantation genetic testing (PGT) is evolving fast, and best practice advice is essential for regulation and standardisation of diagnostic testing. The previous ESHRE guidelines on best practice for PGD, published in 2005 and 2011, are considered outdated, and the development of new papers outlining recommendations for good practice in PGT was necessary. The current paper provides recommendations on the technical aspects of PGT for chromosomal structural rearrangements (PGT-SR) and PGT for aneuploidies (PGT-A) and covers recommendations on array-based comparative genomic hybridisation (aCGH) and next-generation sequencing (NGS) for PGT-SR and PGT-A and on fluorescence in situ hybridisation (FISH) and single nucleotide polymorphism (SNP) array for PGT-SR, including laboratory issues, work practice controls, pre-examination validation, preclinical work-up, risk assessment and limitations. Furthermore, some general recommendations on PGT-SR/PGT-A are formulated around training and general risk assessment, and the examination and post-examination process. This paper is one of a series of four papers on good practice recommendations on PGT. The other papers cover the organisation of a PGT centre, embryo biopsy and tubing and the technical aspects of PGT for monogenic/single-gene defects (PGT-M). Together, these papers should assist everyone interested in PGT in developing the best laboratory and clinical practice possible.


The association of stress-coping variables to quality of life among caregivers of individuals with traumatic brain injury.
The purpose of this study was to determine the degree to which stress-coping variables contribute to quality of life (QOL) among caregivers of individuals with traumatic brain injury (TBI). This study examined the direct effects of the following variables: functional competency, caregiving appraisal, coping, perceived social support, and family needs on QOL. In addition, the unique variance accounted for in QOL by each set was investigated, and whether perceived social support, coping, and family needs mediate or moderate the relationship between caregiving appraisal and QOL. The sample consisted of 108 caregivers recruited from support groups who were predominantly white females. The majority of care-recipients had a severe head injury. Measures administered were the Interpersonal Support Evaluation List, Family Needs Questionnaire, Modified Caregiving Appraisal Scale, and the World Health Organization Quality of Life--Brief Version. Results showed that the full model accounted for 68% of the variance in QOL; caregiving appraisal, perceived social support and family needs remained significant after other stress-coping variables were partialled; and of these sets, emotional social support, social needs, and perceived burden were the significant individual predictors. Emotional social support and social needs mediated the relationship between perceived burden and QOL.


[The understanding of competencies and their application in nursing].
The present article consists of a reflection on competencies and their application at the Nursing. It is part ofa doctoral thesis. It was observe that health organizations have not been adopting the Competency Management either because it is a tool that requires specific knowledge or a fairly unexplored tool. We present some considerations on the understanding of Competency Management and its applicability and main Questioning for the nurse professional at the relation with people. We emphasized the registration of its evolution, analyzing different phases, determinant changes that were capable of allying its organizational strategies to the Human Resources politics on professional development.


Neuropeptide Y plasma levels and immunological changes during academic stress.
Academic stress is a good model of psychological stress in humans for studying psychoneuroimmune correlations. We looked for correlations between psychological scores, immune tests and plasma levels of cortisol and neuropeptide Y (NPY). A group of medical students were evaluated at the beginning of the academic year (Baseline) and the day before an examination (Stress). They underwent evaluation by The Profile of Mood States (POMS), The Malaise Inventory, The Self Efficacy Scale and A Global Assessment of Recent Stress (GARS). The lymphocyte subsets, the lymphocyte proliferative response and the cytokine production were also evaluated. We detected modifications of some psychological test scores between the Baseline and Stress evaluation, a significant reduction of lymphocyte proliferation, IL-2 production and percentage of the lymphocyte CD19, and an increase in plasma cortisol levels during stress. The lymphocyte proliferation negatively correlated with the POMS score as well as the percentage of CD16+ cells with NPY plasma levels. NPY levels were not different from Baseline. The emotional and mood states seem to influence immunity. Copyrightz1999S.KargerAG,Basel


Reaction of the hydroxyl radical with phenol in water up to supercritical conditions.
The rate constants for the reactions of phenol with the hydroxyl radical (OH*) in water have been measured from room temperature to 380 degrees C using electron pulse radiolysis and transient absorption spectroscopy. The reaction scheme designed to fit the data shows the importance of an equilibrium, giving back reactants (OH* radical and phenol) from the dihydroxycyclohexadienyl radical formed by their reaction, and the non-negligible contribution of the hydroxycyclohexadienyl radical absorption from H* atom addition. The accuracy of the reaction scheme and the reaction rate constants determined from it have been determined by the analysis of two different experiments, one under pure N2O atmosphere and the second under a mixture a N2O and O2. We report reaction rates for the H* and OH* radical addition to phenol, the formation of phenoxyl, the second-order recombination, the reaction of dihydroxycyclohexadienyl with O2, and the decay of the peroxyl adduct. Nearly all of the reaction rates deviate strongly from Arrhenius behavior.


Allergic reactions after intravenous injection of methylprednisolone: A case report.
Corticosteroid preparations have anti-inflammatory and immunosuppressive properties and are used widely for the treatment of allergic disorders and asthma. Steroids themselves, however, can induce hypersensitivity reactions. In this study, we report the case of a 66-year-old man with chronic obstructive pulmonary disease who exhibited an allergic reaction (rash, bronchospasm, bradycardia, severe hypotension and cardiac arrest) immediately after the intravenous injection of methylprednisolone sodium succinate. Despite cardiopulmonary resuscitation, sinus rhythm was not restored. The anesthesiologist should be aware that allergic reactions to corticosteroids can occur.


Risk of postpartum depressive symptoms with elevated corticotropin-releasing hormone in human pregnancy.
Postpartum depression (PPD) is common and has serious implications for the mother and her newborn infant. A possible link between placental corticotropin-releasing hormone (pCRH) and PPD incidence has been hypothesized, but empirical evidence is lacking. To determine whether accelerated increases in pCRH throughout pregnancy are associated with PPD symptoms. Pregnant women were recruited into this longitudinal cohort study. Blood samples were obtained at 15, 19, 25, 31, and 37 weeks' gestational age (GA) for assessment of pCRH, cortisol, and adrenocorticotropic hormone (ACTH). Depressive symptoms were assessed with a standardized questionnaire at the last 4 pregnancy visits and post partum. Subjects were recruited from 2 southern California medical centers, and visits were conducted in research laboratories. One hundred adult women with a singleton pregnancy. Main Outcome Measure Symptoms of PPD were assessed at a mean (SD) of 8.7 (2.94) weeks after delivery with the Edinburgh Postnatal Depression Scale. Sixteen women developed PPD symptoms. At 25 weeks' GA, pCRH was a strong predictor of PPD symptoms (R(2) = 0.21; beta = 0.46 [P < .001]), an effect that remained significant after controlling for prenatal depressive symptoms. No significant associations were found for cortisol and ACTH. Receiver operating characteristic curve analyses revealed that pCRH at 25 weeks' GA is a possible diagnostic tool (area under the curve, 0.78 [P = .001]). Sensitivity (0.75) and specificity (0.74) at the ideal cutoff point (pCRH, 56.86 pg/mL) were moderate. Growth curve analyses indicated that the trajectories of pCRH in women with PPD symptoms are significantly accelerated from 23 to 26 weeks' GA. At a critical period in midpregnancy, pCRH is a sensitive and specific early diagnostic test for PPD symptoms. If replicated, these results have implications for the identification and treatment of pregnant women at risk for PPD.


Decoding brain states from fMRI connectivity graphs.
Functional connectivity analysis of fMRI data can reveal synchronised activity between anatomically distinct brain regions. Here, we extract the characteristic connectivity signatures of different brain states to perform classification, allowing us to decode the different states based on the functional connectivity patterns. Our approach is based on polythetic decision trees, which combine powerful discriminative ability with interpretability of results. We also propose to use ensemble of classifiers within specific frequency subbands, and show that they bring systematic improvement in classification accuracy. Exploiting multi-band classification of connectivity graphs is also proposed, and we explain theoretical reasons why the technique could bring further improvement in classification performance. The choice of decision trees as classifier is shown to provide a practical way to identify a subset of connections that distinguishes best between the conditions, permitting the extraction of very compact representations for differences between brain states, which we call discriminative graphs. Our experimental results based on strict train/test separation at all stages of processing show that the method is applicable to inter-subject brain decoding with relatively low error rates for the task considered.


Alcohol Expectancies Mediate the Relationship Between Age of First Intoxication and Drinking Outcomes in College Binge Drinkers.
While prior research has shown that age of first intoxication (AI) is associated with negative alcohol outcomes, limited research has examined factors accounting for this relationship. Alcohol expectancies, or beliefs about the effects of alcohol, may explain such associations as both positive and negative expectancies have been shown to be key predictors of drinking outcomes. The present study examined expectancies as mediators between early AI and alcohol-related outcomes. Data collection occurred in 2012 and 2013. Participants were college students (N = 562, 65.8% women) who completed an online survey including measures of alcohol use history, alcohol expectancies, typical alcohol consumption, and alcohol-related problems. Structural equation modeling was used to test the hypothesized model. Our findings support a model whereby AI is associated with drinking through its influence on both positive and negative expectancies. Specifically, an earlier AI was associated with stronger alcohol expectancies, which in turn, was associated with heavier alcohol use and alcohol-related problems. These findings are consistent with expectancy theory and previous research suggesting that more experienced drinkers hold stronger drinking-related beliefs, be it positive or negative, and these expectancies ultimately explain variability in alcohol use and problems. Our findings further support that expectancies play an important role in the initiation of drinking behavior.


Characterization of the Pharmacokinetic and Pharmacodynamic Profile of Apraglutide, a Glucagon-Like Peptide-2 Analog, in Healthy Volunteers.
Apraglutide (FE 203799) is a glucagon-like peptide-2 (GLP-2) analog under development for the treatment of intestinal failure associated with short bowel syndrome (SBS-IF) and graft-versus-host disease (GvHD). Compared with native GLP-2, apraglutide has slower absorption, reduced clearance, and higher protein binding, enabling once-weekly dosing. This study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) profile of apraglutide in healthy adults. Healthy volunteers were randomized to receive 6 weekly subcutaneous administrations of 1, 5, or 10 mg apraglutide or placebo. PK and citrulline (an enterocyte mass PD marker) samples were collected at multiple time points. Kinetic parameters of apraglutide and citrulline were calculated using noncompartmental analysis; repeated PD measures were analyzed with a mixed model of covariance. A population PK/PD model was developed that also included data from a previous phase 1 study in healthy volunteers. Twenty-four subjects were randomized; 23 received all study drug administrations. Mean estimated apraglutide clearance was 16.5-20.7 l/day, and mean volume of distribution was 55.4-105.0 liters. A dose-dependent increase in citrulline plasma concentration was observed, with 5-mg and 10-mg doses inducing higher citrulline levels than 1-mg doses and placebo. PK/PD analysis showed that weekly 5-mg apraglutide induced the maximal citrulline response. Increased plasma citrulline levels were sustained for 10-17 days after the final apraglutide administration. Apraglutide displays predictable dose-dependent PK and PD profiles, with a 5-mg dose showing significant PD effects. Results suggest that apraglutide has early and enduring effects on enterocyte mass and supports the continued development of weekly subcutaneous apraglutide for SBS-IF and GvHD patient populations. SIGNIFICANCE STATEMENT: Once-weekly subcutaneous apraglutide results in dose-dependent elevations of plasma citrulline (an enterocyte mass pharmacodynamic marker) with parameters suggesting that apraglutide has lasting effects on enterocyte mass and the potential to provide therapeutic benefits. This is the first report of a model relating glucagon-like peptide-2 (GLP-2) agonism and its effects in intestinal mucosa, affording not only the ability to predict pharmacologic effects of GLP-2 analogs but also the exploration of optimal dosing regimens for this drug class across populations with different body weights.


Purification and characterization of a glucoamylase secreted by the plant pathogen Scierotinia sclerotiorum.
Among the lytic enzymes secreted by the phytopathogen fungus Sclerotinia sclerotiorum, a starch-degrading enzyme has been isolated and characterized. This glycoprotein of 72 kDa is composed of several isoforms ranging from pI 4.8 to 5.4. The enzymatic parameters have been determined. Specificity studies together with the analysis of the reaction products show that it is an alpha-1,4-glucanohydrolase. This result is also corroborated by the analysis of the N-terminal and two inner amino acids sequences that are very similar to fungal glucoamylase genes or enzymes so far sequenced.


Trends in oxidative aging theories.
The early observations on the rate-of-living theory by Max Rubner and the report by Gershman that oxygen free radicals exist in vivo culminated in the seminal proposal in the 1950s by Denham Harman that reactive oxygen species are a cause of aging (free radical theory of aging). The goal of this review is to analyze recent findings relevant in evaluating Harman's theory using experimental results as grouped by model organisms (i.e., invertebrate models and mice). In this regard, we have focused primarily on recent work involving genetic manipulations. Because the free radical theory of aging is not the only theorem proposed to explain the mechanism(s) involved in aging at the molecular level, we also discuss how this theory is related to other areas of research in biogerontology, specifically, telomere/cell senescence, genomic instability, and the mitochondrial hypothesis of aging. We also discuss where we think the free radical theory is headed. It is now possible to give at least a partial answer to the question whether oxidative stress determines life span as Harman posed so long ago. Based on studies to date, we argue that a tentative case for oxidative stress as a life-span determinant can be made in Drosophila melanogaster. Studies in mice argue for a role of oxidative stress in age-related disease, especially cancer; however, with regard to aging per se, the data either do not support or remain inconclusive on whether oxidative stress determines life span.


Mind the Gaps: Adoption and Underutilization of Holmium Laser Enucleation of the Prostate in the United States from 2008 to 2014.
Purpose: There is increasing recognition of the advantages of holmium laser enucleation of the prostate (HoLEP) for benign prostatic hypertrophy (BPH) treatment in the United States but relatively little is known about the extent of HoLEP adoption over time. This study aims to assess national HoLEP adoption rates and regional trends from 2008 to 2014. Methods: We retrospectively analyzed a data set of 100% Medicare claims to determine the rate of U.S. HoLEP adoption in 2008, 2011, and 2014. Rates were adjusted by age and race and stratified by hospital referral region (HRR). Linear and logistic regression models were used to assess for trends in HoLEP adoption over time. Results: Total U.S. BPH cases decreased 24% from 2008 to 2014 and HoLEP cases increased significantly from 1086 (2008) to 3368 (2014). Despite this, HoLEP accounted for just 4% of total BPH cases in 2014. In 2008, 28/306 (9%) of HRRs recorded >10 HoLEP cases per year. This increased to 89 HRRs (29%) in 2011 but stabilized at 94 HRRs (31%) in 2014. In 2014, over 50% of states still had only 0 to 1 sites doing 10+ HoLEP cases per year. Conclusions: Based on this 100% sample of Medicare claims from 2008 to 2014, surgical BPH treatment volume has decreased, while HoLEP volume and regional adoption have tripled. However, rates of HoLEP remain extremely low at just 4% of all BPH procedures in 2014, and large regional gaps in care exist. These data indicate that HoLEP remains substantially underutilized and the majority of regions still lack access to centers performing >10 HoLEP cases per year.


Childhood Cognitive Flexibility and Externalizing and Internalizing Behavior Problems: Examination of Prospective Bidirectional Associations.
The goal of this study was to examine reciprocal associations between cognitive flexibility and externalizing and internalizing behavior problems longitudinally using data on four occasions from kindergarten through first grade and test for potential gender differences in these associations. The Dimensional Change Card Sort task was used to assess children's cognitive flexibility as a measure of executive function. Participants were 12,462 kindergarteners (49% female) from the Early Childhood Longitudinal Study (ECLS-K: 2011). Results from multivariate latent curve models with structured residuals revealed that children's cognitive flexibility at the beginning of kindergarten was not associated with their growth in either externalizing (r = -0.01, p = .174), or internalizing (r = -0.03, p = .403) problems between kindergarten and the end of first grade. However, after controlling for individual differences in growth, cognitive flexibility at each assessment directly contributed to subsequent lower levels of internalizing (but not externalizing) behavior problems at the next assessment (b = -0.004, p = 0.013; β = -0.03), suggesting that children who are more flexible in switching from one activity to another may be less prone to developing internalizing problems. At kindergarten entry boys had lower levels of cognitive flexibility (b = -0.31, p < .001, β = -.12) and higher levels of externalizing (b = 0.25, p < .001, β = .23), and internalizing problems(b = 0.04, p = 001, β = .05) compared to girls, but did not differ from girls in their rates of change in cognitive flexibility and externalizing or internalizing behavior problems.


[S35 lipoic acid distribution and its effect on pyruvate dehydrogenase activity in rats with Walker carcinoma].
S35-lipoic acid injected intraperitoneally in rats with Walker carcinosarcoma in a dose of 250 mg/Kg is accumulated in their organs and tissues to much higher concentrations compared with normal animals during all terms of the observation (15 min, 1 hour, 24 hours). Differences were especially great after 24 hours. Pyruvate dehydrogenase activity in tumor rats organs was considerably reduced when calculated per 1 Kg of tissue, but it is practically unchanged when calculated per 1 mg of protein, which amount in 1 g of tissue in them is distinctly lower than in normal animals. Single injections of lipoic acid in tumor-bearing rats do restore the enzyme activity to normal (in 1 hour), while repeated ones (10 days)--prolong animals lifeterms by 25%.


NMR, mass spectrometry and chemical evidence reveal a different chemical structure for methanobactin that contains oxazolone rings.
Methanobactin (mb) is a small copper-binding peptide produced by methanotrophic bacteria and is intimately involved in both their copper metabolism and their role in the global carbon cycle. The structure for methanobactin comprises seven amino acids plus two chromophoric residues that appear unique to methanobactin. In a previously published structure, both chromophoric residues contain a thiocarbonyl attached to a hydroxyimidazolate ring. In addition, one is attached to a pyrrolidine ring, while the other is attached to an isopropyl ester. A published X-ray determined structure for methanobactin shows these two chromophoric groups forming an N2S2 binding site for a single Cu(I) ion with a distorted tetrahedral geometry. In this report we show that NMR, mass spectrometry, and chemical data reveal a chemical structure that is significantly different than the previously published one. Specifically, the 1H and 13C NMR assignments are inconsistent with an N-terminal isopropyl ester and point instead to a 3-methylbutanoyl group. Our data also indicate that oxazolone rings instead of hydroxyimidazolate rings form the core of the two chromophoric residues. Because these rings are directly involved in the binding of Cu(I) and other metals by methanobactin and are likely involved in the many chemical activities displayed by methanobactin, their correct identity is central to developing an accurate and detailed understanding of methanobactin's many chemical and biological roles. For example, the oxazolone rings make methanobactin structurally more similar to other bacterially produced bactins and siderophores and suggest pathways for its biosynthesis.


Pre-vaccine serotype composition within a lineage signposts its serotype replacement - a carriage study over 7 years following pneumococcal conjugate vaccine use in the UK.
Serotype replacement has been reported in carriage and disease after pneumococcal conjugate vaccine (PCV) introductions in the UK and globally. We previously described concurrent expansion and decline of sequence types associated with serotype replacement over 5 years following PCV introductions in the UK. Here we use whole-genome sequencing to fully characterise the population structure of pneumococcal isolates collected over seven winters encompassing PCV7 and PCV13 introductions in the UK, investigating the importance of lineages in serotype replacement. We analysed 672 pneumococcal genomes from colonised children of 4 years old or less. The temporal prevalence of 20 lineages, defined by hierarchical Bayesian analysis of population structure (BAPS), was assessed in the context of serotype replacement. Multiple serotypes were detected in the primary winter of sampling within three vaccine-type (VT) lineages BAPS4, BAPS10 and BAPS11, in which serotype replacement were observed. In contrast, serotype replacement was not seen in the remaining three VT lineages (BAPS1, BAPS13 and BAPS14), that expressed a single serotype (6B, 6A and 3, respectively) in the primary winter. One lineage, BAPS1 serotype 6B was undetectable in the population towards the end of the study period. The dynamics of serotype replacement, in this UK population, was preceded by the presence or absence of multiple serotypes within VT lineages, in the pre-PCV population. This observation could help predict which non-vaccine types (NVTs) may be involved in replacement in future PCV introductions here and elsewhere. It could further indicate whether any antibiotic resistance associated with the lineages is likely to be affected by replacement.


Cytokine kinetics and other host factors in response to pneumococcal pulmonary infection in mice.
There is a need for more insight into the pathogenesis of Streptococcus pneumoniae pneumonia, as the fatality rate associated with this disease remains high despite appropriate antibiotherapy. The host response to pneumococci was investigated after intranasal inoculation of CD1 mice with 10(7) log-phase CFU of bacteria. We identified five major pathogenesis steps from initial infection to death. In step 1 (0 to 4 h), there was ineffective phagocytosis by alveolar macrophages, with concurrent release of tumor necrosis factor alpha (TNF), interleukin-6 (IL-6), and nitric oxide (NO) in bronchoalveolar lavage (BAL) fluid, TNF, IL-6, and interleukin-1 alpha (IL-1) in lung tissues, and IL-6 in serum, which were associated with tachypnea and hemoconcentration. In step 2 (4 to 24 h), bacterial growth in alveoli and polymorphonuclear cell recruitment from bloodstream to lung tissue (high myeloperoxidase levels) to alveoli were associated with high release of all three cytokines and leukotriene B4 (LTB4) in tissue and BAL fluid, as well as transient spillover of IL-1 in serum. In step 3 (24 to 48 h), despite downregulation of TNF and IL-1 in BAL fluid and lungs, there was appearance of injury to alveolar ultrastructure, edema to interstitium, and increase in lung weight as well as regeneration of type II pneumocytes and increased secretion of surfactant; bacteria progressed from alveoli to tissue to blood, and body weight loss occurred. In step 4 (48 to 72 h), strong monocyte recruitment from blood to alveoli was associated with high NO release in tissue and BAL fluid, but there was also noticeable lymphocyte recruitment and leukopenia; bacteremia was associated with TNF and IL-6 release in blood and thrombocytopenia. In step 5 (72 to 96 h), severe airspace disorganization, lipid peroxidation (high malondialdehyde release in BAL fluid), and diffuse tissue damage coincided with high NO levels; there was further increase in lung weight and bacterial growth, loss in body weight, and high mortality rate. Delineation of the sequential steps that contribute to the pathogenesis of pneumococcal pneumonia may generate markers of evolution of disease and lead to better targeted intervention.


C1 esterase inhibitor deficiency in X-linked hypogammaglobulinaemia: an anomaly fostering anaphylactoid reactions following intramuscular gammaglobulin administration.
A patient with apparent X-linked agammaglobulinaemia was found to be inordinately susceptible to anaphylactoid reactions to intramuscular injections of gammaglobulin. The patient was found also to have low levels of C1 esterase inhibitor (C1 INH). The possibility that the C1 INH deficiency and in this patient, whether genetic or acquired, fostered the susceptibility to the production of anaphylactoid reactions after gammaglobulin injections urges further studies of the association of C1 INH deficiency and anaphylactoid reactions to gammaglobulin injections. The possibility that C1 INH levels like C1q levels may be low in hypogammaglobulinaemic patients as a consequence of increased catabolism of this regulator of the complement system when IgG levels are low is considered.


Venous thromboembolism and intracranial hemorrhage in patients undergoing glioblastoma surgery.
In the perioperative management of patients with glioblastoma (GBM), physicians face the question of whether and when to administer prophylactic or therapeutic anticoagulation (AC). In this study, we investigate the effects of the timing of postoperative heparinization on thromboembolic events (TE) and postoperative hemorrhage (bleeding, PH) as well as the interactions between the two in the context of an underlying intracerebral malignancy. For this retrospective data analysis, 222 patients who underwent surgery for grade IV glioblastoma, IDH-wildtype (2016 CNS WHO) between 01/01/2014 and 31/12/2019 were included. We followed up for 12 months. We assessed various biographical and clinical data for risk factors and focused on the connection between timepoint of AC and adverse events. Subgroup analyses were performed for pulmonary artery embolism (PE), deep vein thrombosis, and postoperative intracranial hemorrhage (PH) that either required surgical intervention or was controlled radiologically only. Statistical analysis was performed using Mann-Whitney U-Test, Chi-square test, Fisher's exact test and univariate binomial logistic regression. p values below 0.05 were considered statistically significant. There was no significant association between prophylactic AC within 24 h and more frequent major bleeding (p = 0.350). AC in patients who developed major bleeding was regularly postponed by the physician/surgeon upon detection of the re-bleeding; therefore, patients with PH were anticoagulated significantly later (p = 0.034). The timing of anticoagulant administration did not differ significantly between patients who experienced a thromboembolic event and those who did not (p = 0.634). There was considerable overlap between the groups. Three of the six patients (50%) with PE had to be lysed or therapeutically anticoagulated and thereafter developed major bleeding (p < 0.001). Patients who experienced TE were more likely to die during hospitalization than those with major bleeding (p = 0.022 vs. p = 1.00). Prophylactic AC within 24 h after surgery does not result in more frequent bleeding. Our data suggests that postoperative intracranial hemorrhage is not caused by prophylactic AC but rather is a surgical complication or the result of antithrombotic therapy. However, thromboembolic events worsen patient outcomes far more than postoperative bleeding. The fact that bleeding may occur as a complication of life-saving lysis therapy in the setting of a thromboembolic event should be included in this cost-benefit consideration.


International Society of Urological Pathology (ISUP) Consensus Conference on Current Issues in Bladder Cancer: Working Group 3: Subcategorization of T1 Bladder Cancer.
Emerging data on T1 bladder cancer subcategorization (aka substaging) suggests a correlation with oncological outcomes. The International Society of Urological Pathology (ISUP) organized the 2022 consensus conference in Basel, Switzerland to focus on current issues in bladder cancer and tasked working group 3 to make recommendations for T1 subcategorization in transurethral bladder resections. For this purpose, the ISUP developed and circulated a survey to their membership querying approaches to T1 bladder cancer subcategorization. In particular, clinical relevance, pathological reporting, and endorsement of T1 subcategorization in the daily practice of pathology were surveyed. Of the respondents of the premeeting survey, about 40% do not routinely report T1 subcategory. We reviewed literature on bladder T1 subcategorization, and screened selected articles for clinical performance and practicality of T1 subcategorization methods. Published literature offered evidence of the clinical rationale for T1 subcategorization and at the conference consensus (83% of conference attendants) was obtained to report routinely T1 subcategorization of transurethral resections. Semiquantitative T1 subcategorization was favored (37%) over histoanatomic methods (4%). This is in line with literature findings on practicality and prognostic impact, that is, a shift of publications from histoanatomic to semiquantitative methods or by reports incorporating both methodologies is apparent over the last decade. However, 59% of participants had no preference for either methodology. They would add a comment in the report briefly stating applied method, interpretation criteria (including cutoff), and potential limitations. When queried on the terminology of T1 subcategorization, 34% and 20% of participants were in favor of T1 (microinvasive) versus T1 (extensive) or T1 (focal) versus T1 (nonfocal), respectively.


Ideal homes? Housing effects on rodent brain and behaviour.
Rodents used in biomedical research are typically reared in small cages that lack key features of their natural habitats. These conditions impose constraints on behaviour and brain development, resulting in altered brain functions. In this article, evidence for three different ways in which barren housing conditions interfere with brain development and behaviour is reviewed. Early environmental deprivation, thwarting of behavioral response rules, and disruption of habitat-dependent adaptation processes are shown to result in aberrant or maladaptive brain functions. Current standard housing conditions could therefore compromise the utility of rodents for research, especially in behavioural neuroscience. However, a better understanding of the animals' needs and of the environmental factors involved in the control of behaviour could offer a biological basis for refinement.


Transplantation of Renal Allograft After Removal of Renal Cell Carcinoma: Case Report and Review of the Literature.
With the rising incidence of end-stage renal disease in the United States, patients needing renal transplants are waiting longer for increasingly scarce grafts. Formerly, the general practice was to avoid organs with tumors for transplant because of the risk of malignancy transmission to the recipient. However, with comprehensive donor selection and a small-sized primary tumor, the positive outcomes of transplant outweigh the risks of transmission after a partial nephrectomy. In our case, a 31-year-old woman, the daughter of the recipient, underwent a laparoscopic nephrectomy with an existing 8-mm tumor later confirmed as renal cell carcinoma. An ex vivo tumor enucleation was performed before the allograft was transplanted into the 69-year-old patient with endstage renal disease. At last follow-up, graft function has remained excellent with no evidence of local recurrence or metastasis in both the donor and recipient. Here, we describe our case and perform a literature review on the incidence and management of renal allografts with incidentally detected renal cell carcinoma during transplant.


Domain Specificity or Generality: Assessing the Chinese Implicit Theories Scale of Six Fundamental Psychological Attributes.
Implicit theories have been widely studied in different domains; however, it is still debatable whether these theories are domain-specific or domain-general. Using the Implicit Theories Scale (ITS) about six fundamental psychological attributes, i.e., intelligence, personality, cognition, feeling, behavior, and emotion, we examined domain specificity versus generality using a factor analytic approach; in addition, we investigated associations between implicit theories about these domains and related psychological attributes. In four sequential studies, we translated a Chinese version of the ITS (Study 1), tested inter-item correlations within and between subscales (Studies 1-4), and conducted exploratory factor analysis (Studies 2 and 3) and confirmatory factor analysis (Studies 3 and 4). We tested associations between implicit theory domains and coping, resilience, grit, and school performance (Studies 3 and 4). Results showed that the six ITS subscales were independent, while the implicit theories about cognition, feeling, behavior, and emotion shared a common component. The implicit theories of intelligence and personality were independent and did not share a common component. The six domains presented different patterns of association with psychological variables. Overall, our results suggest that implicit theories are both domain-specific and domain-general. Future studies are needed to examine the mechanism underlying the domain specificity and generality of implicit theories.


Laboratory testing and identification of antiphospholipid antibodies and the antiphospholipid syndrome: a potpourri of problems, a compilation of possible solutions.
The antiphospholipid syndrome (APS) is an autoimmune condition characterized by vascular thromboses and/or pregnancy morbidity, and its diagnosis currently requires laboratory evidence of the presence of antiphospholipid antibodies (aPL). aPL are in turn identified using a large number of laboratory procedures based on one of two distinct test processes, namely solid-phase assays and liquid-phase assays. The former includes anticardiolipin antibodies and anti-beta2 glycoprotein I antibodies, and the latter are centered on clot-based tests that are used to identify the so-called lupus anticoagulant. The current article provides an overview of the laboratory testing and identification of aPL, and in particular the limitations, standardization, and clinical utility of such testing. We also review preanalytical, analytical, and postanalytical issues that compromise the clinical utility of these tests. Finally, we provide a list of recommendations aimed to foster broader international cooperation to assist in the preparation of integrated guidelines, for both solid-phase and liquid-phase assays, and for laboratory testing, clinical ordering, and interpretation.


Chewing lice (phthiraptera) of several species of wild birds in iran, with new records.
Although there are about 520 species of birds in Iran, but only some of them have been checked for ectoparasites so far.The aim of this study was to check some more available species of the birds of Iran for lice. This study was performed between 2008-2010 in northern Iran. For this purpose we tried to check some of the wild bird species available and mostly not checked before to identify the lice of them.The birds were found in some of the houses of hunters keeping as trap for catching more birds, some of the bird keepers and a few dead birds from taxidermists. In this way we could check 79 birds of 6 species. We identified 11 lice species on the birds and overall 15.2 % of the examined birds were infested by the lice. Nine lice species including Aquanirmus podicipis, Pseudomenopon dolium, Ardeicola sp, Ciconiphilus decimfasciatus; Menacanthus sp, Austromenopon transversum, Pectinopygus gyricornis, Colpocephalum turbinatum and Hohorstiella lata were recorded for the first time on the birds in Iran. One specimen of Menacanthus sp was found on the purple Heron (Ardea purpurea) that is a new host report for this lice. Although the infection rate was not very high in the birds, but 11 species of lice in 6 studied birds species in this study, shows there are still other lice species that exist in the birds and should be identified and added to Iran lice fauna list.


Healthy food and determinants of food choice on online food delivery applications.
Online food delivery applications (OFD apps) provide consumers with a wide range of options to choose from. The present study aimed to assess the usage of OFD apps and investigate the factors that affect food choices with a special emphasis on healthy food choices and hygiene. A cross-sectional study among food delivery application users in Jordan was conducted using an online questionnaire between March and May 2022. A total of 675 eligible subjects participated in the study. Consumers' demographic characteristics, data on consumers' use of OFD apps, consumers' perceptions of healthy food availability in OFD apps, and consumers' attitudes toward food safety and delivery hygiene were collected and analyzed. About 64% of the studied sample used OFD apps weekly. Fast food was the most popular option for ordering (87.1%) and lunchtime was the most preferred time to order food (67.3%) for most of the respondents. Respondents' perceptions of a "healthy meal" was associated with the presence of a variety of vegetables in the meal. Food price, food appearance, time of delivery, macronutrient content information, the availability of healthy options, and considering vegetables as part of a healthy meal were determinants of consumer food choice (p<0.05). The findings suggest that the online food environment in Jordan was perceived to be unhealthy. Nevertheless, the convenient nature and the popularity of OFD apps hold great potential to promote healthy eating among consumers.


Intragenic copy number variation within filaggrin contributes to the risk of atopic dermatitis with a dose-dependent effect.
Loss-of-function variants within the filaggrin gene (FLG) increase the risk of atopic dermatitis. FLG also demonstrates intragenic copy number variation (CNV), with alleles encoding 10, 11, or 12 filaggrin monomers; hence, CNV may affect the amount of filaggrin expressed in the epidermis. A total of 876 Irish pediatric atopic dermatitis cases were compared with 928 population controls to test the hypothesis that CNV within FLG affects the risk of atopic dermatitis independently of FLG-null mutations. Cases and controls were screened for CNV and common FLG-null mutations. In this population the 11-repeat allele was most prevalent (allele frequency 51.5%); the 10-repeat allele frequency was 33.9% and the 12-repeat allele frequency was 14.6%. Having excluded FLG mutation carriers, the control group had a significantly higher number of repeats than cases (χ(2) P=0.043), and the odds ratio of disease was reduced by a factor of 0.88 (95% confidence interval 0.78-0.98, P=0.025) for each additional unit of copy number. Breakdown products of filaggrin were quantified in tape-stripped stratum corneum from 31 atopic dermatitis patients and urocanic acid showed a positive correlation with total copy number. CNV within FLG makes a significant, dose-dependent contribution to atopic dermatitis risk, and therefore treatments to increase filaggrin expression may have therapeutic utility.


Population genetics of tandem trypsin inhibitor genes in Arabidopsis species with contrasting ecology and life history.
Duplicated genes are important in the evolution and ecology of plant-defences because herbivore and pathogen attack can be countered via functional diversification at two levels: among duplicated loci and within loci. We explore molecular sequence variation for two members of a defence-related gene family, Arabidopsis thaliana trypsin inhibitors (ATTI), in A. thaliana and a closely related species, A. lyrata subspp. petraea. A worldwide sample of the inbreeding annual A. thaliana had less genetic variation at two ATTI loci (piTOTAL <or= 0.0006) than observed previously at other functional loci. A significant excess of high frequency derived alleles in the signal sequence and 5' UTR of ATTI2 was consistent with a model of positive selection. However, demographic processes such as population subdivision and expansion, both likely to have occurred in A. thaliana during the last 10 000 years, can also give rise to similar deviations from neutrality. A single population of A. lyrata subspp. petraea in Germany had up to an order of magnitude more standing genetic variation at ATTI loci than the species-wide sample of A. thaliana. Although the level of variability for ATTI1 and ATTI2 within this single population was similar to, or even greater than, observed species-wide diversity for other loci in A. lyrata, there was little evidence to reject an equilibrium neutral model. A spatially explicit sample of 87 A. lyrata subspp. petraea individuals detected outbreeding (FIS = -0.16; FIT = -0.15) but little population subdivision (FST = 0.006) in this self-incompatible perennial herb. Genetic differences between Arabidopsis species were consistent with, but not fully explained by, divergence in ecology and life history. Diversification appears to have occurred in different functional domains for the tandemly duplicated ATTI1 and ATTI2 genes; the majority of fixed replacements in ATTI1 surround the enzyme binding site of the mature protein, whereas in ATTI2 most functional evolutionary change is located in the signal peptide. This pattern is consistent with a hypothesis of subfunctionalization in trypsin inhibitory function.


[Comments to dispute about catarrhal appendicitis].
One of the "blind-spots" in the problem of acute appendicitis is uncertainty in treatment policy for catarrhal appendicitis. Present-day pathophysiological approaches support necessity of different medical measures depending on morphological form of appendicitis. In diagnostic difficulties 186 patients underwent laparoscopy for appendicitis form specification. It is established that undestructive forms of vermiform appendix inflammation has characteristic clinico-endoscopic picture presented as primary (true), and secondary (false) appendicitis. Frequency of acute appendicitis when surgical treatment is required does not exceed 10% of total amount of appendectomies.


Dermatological adverse events with taxane chemotherapy.
Taxanes (docetaxel and paclitaxel) are among the most commonly prescribed anticancer drugs approved for the treatment of metastatic or locally advanced breast, non-small cell lung, prostate, gastric, head and neck, and ovarian cancers, as well as in the adjuvant setting for operable node-positive breast cancers. Although the true incidence of dermatological adverse events (AEs) in patients receiving taxanes is not known, and has never been prospectively analysed, they clearly represent one of the major AEs associated with these agents. With an increase in the occurrence of cutaneous AEs during treatment with novel targeted and immunological therapies when used in combination with taxanes, a thorough understanding of reactions attributable to this class is imperative. Moreover, identification and management of dermatological AEs is critical for maintaining the quality of life in cancer patients and for minimizing dose modifications of their antineoplastic regimen. This analysis represents a systematic review of the dermatological conditions reported with the use of these drugs, complemented by experience at comprehensive cancer centres. The conditions reported herein include skin, hair, and nail toxicities. Lastly, we describe the dermatological data available for the new, recently FDA-and EMA- approved, solvent-free nab-paclitaxel.


The spatial-temporal dynamics of respiratory syncytial virus infections across the east-west coasts of Australia during 2016-17.
Respiratory syncytial virus (RSV) is an important human respiratory pathogen. In temperate regions, a distinct seasonality is observed, where peaks of infections typically occur in early winter, often preceding the annual influenza season. Infections are associated with high rates of morbidity and mortality and in some populations exceed that of influenza. Two subtypes, RSV-A and RSV-B, have been described, and molecular epidemiological studies have shown that both viruses mostly co-circulate. This trend also appears to be the case for Australia; however, previous genomic studies have been limited to cases from one Eastern state-New South Wales. As such, the broader spatial patterns and viral traffic networks across the continent are not known. Here, we conducted a whole-genome study of RSV comparing strains across eastern and Western Australia during the period January 2016 to June 2017. In total, 96 new RSV genomes were sequenced, compiled with previously generated data, and examined using a phylodynamic approach. This analysis revealed that both RSV-A and RSV-B strains were circulating, and each subtype was dominated by a single genotype, RSV-A ON1-like and RSV-B BA10-like viruses. Some geographical clustering was evident in strains from both states with multiple distinct sub-lineages observed and relatively low mixing across jurisdictions, suggesting that endemic transmission was likely seeded from imported, unsampled locations. Overall, the RSV phylogenies reflected a complex pattern of interactions across multiple epidemiological scales from fluid virus traffic across global and regional networks to fine-scale local transmission events.


Alcohol use and depression among African-American and Caucasian adolescents.
The purpose of this study was to determine differences in reported alcohol use and depressive symptomatology among a sample of 524 African-American and Caucasian adolescents. Of specific interest was determining if ethnicity, gender, and age predicted severity of scores obtained on the Reynolds Adolescent Depression Scale (RADS) and Adolescent Drinking Index (ADI). Extreme groups were formed using upper (> 75%) and lower (< 25%) quartiles. Three other groups were formed using each instrument's normatively derived cutoff scores: depressed only (RADS > 77), heavy drinking (ADI > 16) and mixed (RADS > 77, ADI > 16). Several results were obtained. First, Caucasians obtained significantly higher scores on the ADI than African-Americans, although no differences were obtained for the RADS. Females scored higher on the RADS but lower on the ADI than males. In terms of extreme scores, females were less likely to belong to the severe depression group, while older adolescents in general and African-Americans in particular had a greater probability of belonging to the heavy-drinking group. Finally, using RADS and ADI cutoff scores, females were less likely than males to belong to the depression only group as were African-Americans. Older adolescents, in general, and African-Americans in particular had a greater probability of belonging to the mixed group than did their counterparts.


Household air pollution from wood burning in two reconstructed houses from the Danish Viking Age.
During 13 winter weeks, an experimental archeology project was undertaken in two Danish reconstructed Viking Age houses with indoor open fireplaces. Volunteers inhabited the houses under living conditions similar to those of the Viking Age, including cooking and heating by wood fire. Carbon monoxide (CO) and particulate matter (PM2.5 ) were measured at varying distances to the fireplace. Near the fireplaces CO (mean) was 16 ppm. PM2.5 (mean) was 3.40 mg/m(3) , however, measured in one house only. The CO:PM mass ratio was found to increase from 6.4 to 22 when increasing the distance to the fire. Two persons carried CO sensors. Average personal exposure was 6.9 ppm, and from this, a personal PM2.5 exposure of 0.41 mg/m(3) was estimated. The levels found here were higher than reported from modern studies conducted in dwellings using biomass for cooking and heating. While this may be due to the Viking house design, the volunteer's lack of training in attending a fire maybe also played a role. Even so, when comparing to today's issues arising from the use of open fires, it must be assumed that also during the Viking Age, the exposure to woodsmoke was a contributing factor to health problems.


Anisakid parasites of two forkbeards (Phycis blennoides and Phycis phycis) from the eastern Mediterranean coasts in Tunisia.
Two gadiform species with a successive bathymetric and an ecological and economical importance in the Mediterranean fishing industry, Phycis blennoides and Phycis phycis, were selected for the present study. A total of 592 fresh specimens belonging to the Gadiformes genus were obtained from local commercial fisheries. The investigation was centred on anisakid parasites of 272 specimens of the greater forkbeard (P. blennoides) and 320 of the forkbeard (P. phycis) captured off the Mediterranean coasts of Tunisia (eastern Mediterranean Sea). Four species of nematodes were identified: Anisakis simplex s.1., Anisakis physeteris, Hysterothylacium aduncum and Hysterothylacium fabri. The total prevalence was 53.75% in the forkbeard and 51.47% in the greater forkbeard. The highest values of prevalence (38.75%, 2-14), mean intensity (6.74+/-3.4) and mean abundance (2.61) were all obtained for H. fabri L4 in the forkbeard. The most frequent parasite in the greater forkbeard was H. aduncum L3 with 32.35% (1-3) prevalence and values of 1.21+/-0.58 and 0.39 for mean intensity and mean abundance, respectively. The infestation parameters were also analysed according to the host length, and prevalence was highest in P. blennoides longer than 35 cm in respect of all anisakid species. Whilst in P. phycis, the highest prevalence, conditioned by H. fabri parasitisation, was found in fish with length reaching a maximum of more than 40 cm. When the data were grouped seasonally, clear patterns were observed for P. blennoides and P. phycis species, with prevalence and mean intensity of all the anisakid species peaking in spring and summer.


Analysis of pharmacological mechanisms and targets mining of Wuzi-Yanzong-Wan for treating non-obstructive oligoasthenospermia.
As a classical traditional Chinese medicine, Wuzi-Yanzong-Wan (WZYZW) has been widely applied for several centuries to treat non-obstructive oligoasthenozoospermia (NOA), although its pharmacological mechanisms remain largely unknown. In this study, both plasma and urine metabolomics profiling was first analysed to explore the therapeutic mechanisms of WZYZW in NOA rats induced by removal of the unilateral testicle. Then, 106 identified compounds comprising WZYZW (our previous work), for which putative targets were discovered using systems pharmacology, were systematically analysed via mRNA microarrays to validate their putative targets. Finally, metabolomics-tested WZYZW-regulated metabolites were connected with validated targets using Spearman correlation analysis to further confirm the targets from a biological perspective. The results suggested that WZYZW plays key roles in modulating the concentrations of 18 metabolites in the metabolism of amino acids, lipids and so on, normalizing the metabolic phenotype and regulating metabolic disorders. Moreover, 27 targets of WZYZW (23 compounds) against NOA were validated, and metabolomics-tested metabolites were also found to be significantly related to these identified targets, suggesting that these targets and compounds are worthy of further research. This work offers the first systematic investigation of the efficacy of WZYZW against NOA and illustrates a practicable approach for explaining the molecular mechanisms of multicomponent drugs.


A review of phytochemistry, metabolite changes, and medicinal uses of the common food mung bean and its sprouts (Vigna radiata).
The seeds and sprouts of mung bean (Vigna radiata), a common food, contain abundant nutrients with biological activities. This review provides insight into the nutritional value of mung beans and its sprouts, discussing chemical constituents that have been isolated in the past few decades, such as flavonoids, phenolic acids, organic acids, amino acids, carbohydrates, and lipids. Moreover, we also summarize dynamic changes in metabolites during the sprouting process and related biological activities, including antioxidant, antimicrobial, anti-inflammatory, antidiabetic, antihypertensive, lipid metabolism accommodation, antihypertensive, and antitumor effects, etc., with the goal of providing scientific evidence for better application of this commonly used food as a medicine.


Antioxidant effect of a Ginkgo biloba extract (EGb 761) on the retina.
Several investigations have recently shown that the retina is very sensitive to oxygenated free radicals (O2-, OH.) at the origin of the membrane phospholipids peroxidation. Peroxy radical (ROO.) release is responsible for the induction of electrophysiological disturbances leading to retinopathy development. As Ginkgo biloba extract (EGb 761, IPSEN, France) was reported to scavenge primary (O2-, OH.) and secondary (ROO.) free radicals, we evaluated its antioxidant effect on retinas of albino rats submitted to different types of aggressors. On isolated rat retina, EGb 761 given orally significantly protected against lipoperoxidation induced by a mixture of ferrous sulfate and sodium ascorbate added to the perfusion solution. With EGb 761, the decrease of the b-wave ERG amplitude was less pronounced and the retina survival was increased. EGb 761 was also effective against ischaemia-reperfusion disorders due to occlusion of the central retinal artery or by intraocular hypertony. Like other antioxidants such as superoxide dismutase tested on these models, EGb 761 significantly attenuated, according to a dose-response effect, the free-radical injury. EGb 761 reduces the decrease of the b-wave amplitude, the oedema, necrosis and ion homeostasis disturbances. Xenobiotics are also responsible for the retinotoxicity partly due to free radicals and PAF release. We noted an EGb 761 dose-dependent protective effect against acute and chronic chloroquine toxicity to the retina. The deleterious effect of chloroquine was characterized by a delayed b-wave and an asymmetry of the signal with slow declining b-wave. After EGb 761 treatment, the ERG aspect was partially normal. In conclusion, EGb 761, by its general free-radical scavenger properties, is an antioxidant that inhibits or reduces the functional and morphological retina impairments observed after lipoperoxide release.


[Effect of change in the occupational structure on extending life expectancy in Germany--a cohort analysis].
Life expectancy in Germany has increased considerably during the 20th century. Simultaneously a considerable change in occupational structure has occurred. Keeping the occupational impact on mortality in mind, the question arises as to what extent the mortality decrease can be contributed to changes in occupation. Based on cohort data this question is analysed with the result that a considerable impact on life expectancy is confirmed. The impact of changes in occupational structure on life expectancy is greater for men than for women. This can be explained by the fact that men benefit from the improvements of general living conditions associated with occupational status, as well as from improved working conditions.


Hybrid nanomaterials for biomedical applications.
Hybrid nanomaterials, composed of both inorganic and organic components, have recently been examined as promising platforms for imaging and therapeutic applications. This unique class of nanomaterials can not only retain beneficial features of both the inorganic and organic components, but also provides the ability to systematically tune the properties of the hybrid material through the combination of functional components. This feature article will summarize recent advances in the design and synthesis of hybrid nanomaterials and their applications in biological and biomedical areas. The hybrid nanomaterials to be discussed fall into two main categories, silica based materials and nanoscale metal-organic frameworks. Their applications as imaging contrast agents and nanotherapeutics will be highlighted.


EGFR inhibition blocks cancer stem cell clustering and lung metastasis of triple negative breast cancer.
Triple-negative breast cancer (TNBC) is one of the most aggressive and metastatic breast cancer subtypes lacking targeted therapy. Our recent work demonstrated that circulating tumor cell (CTC) clusters and polyclonal metastasis of TNBC are driven by aggregation of CD44+ cancer stem cells (CSC) and associated with an unfavorable prognosis, such as low overall survival. However, there is no existing therapeutic that can specifically block CTC or CSC cluster formation. Methods: Using patient-derived xenograft (PDX) models, we established an ex vivo tumor cell clustering assay for a pilot screening of blockade antibodies. After identifying EGFR as a target candidate, we modulated the gene expression and inhibited its kinase activity to determine its functional importance in tumor cell clustering and therapeutic inhibition of lung metastasis. We also examined the molecular regulation network of EGFR and a potential connection to CSC marker CD44 and microRNAs, which regulate CTC clustering. Results: We report here that EGFR inhibition successfully blocks circulating CSC (cCSC) clustering and lung metastasis of TNBC. EGFR enhances CD44-mediated tumor cell aggregation and CD44 stabilizes EGFR. Importantly, blocking EGFR by a novel anti-EGFR monoclonal antibody (clone LA1) effectively blocked cell aggregation in vitro and reduced lung metastasis in vivo. Furthermore, our data demonstrated that the tumor suppressor microRNA-30c serves as another negative regulator of cCSC clustering and lung metastasis by targeting CD44 as well as its downstream effector EGFR. Conclusion: Our studies identify a novel anti-EGFR therapeutic strategy to inhibit cCSC aggregation and therefore abolish cCSC cluster-mediated metastasis of TNBC.


Species concepts in Calonectria (Cylindrocladium).
Species of Calonectria and their Cylindrocladium anamorphs are important plant pathogens worldwide. At present 52 Cylindrocladium spp. and 37 Calonectria spp. are recognised based on sexual compatibility, morphology and phylogenetic inference. The polyphasic approach of integrating Biological, Morphological and Phylogenetic Species Concepts has revolutionised the taxonomy of fungi. This review aims to present an overview of published research on the genera Calonectria and Cylindrocladium as they pertain to their taxonomic history. The nomenclature as well as future research necessary for this group of fungi are also briefly discussed.


Porin-independent accumulation in Pseudomonas enables antibiotic discovery.
Gram-negative antibiotic development has been hindered by a poor understanding of the types of compounds that can accumulate within these bacteria1,2. The presence of efflux pumps and substrate-specific outer-membrane porins in Pseudomonas aeruginosa renders this pathogen particularly challenging3. As a result, there are few antibiotic options for P. aeruginosa infections4 and its many porins have made the prospect of discovering general accumulation guidelines seem unlikely5. Here we assess the whole-cell accumulation of 345 diverse compounds in P. aeruginosa and Escherichia coli. Although certain positively charged compounds permeate both bacterial species, P. aeruginosa is more restrictive compared to E. coli. Computational analysis identified distinct physicochemical properties of small molecules that specifically correlate with P. aeruginosa accumulation, such as formal charge, positive polar surface area and hydrogen bond donor surface area. Mode of uptake studies revealed that most small molecules permeate P. aeruginosa using a porin-independent pathway, thus enabling discovery of general P. aeruginosa accumulation trends with important implications for future antibiotic development. Retrospective antibiotic examples confirmed these trends and these discoveries were then applied to expand the spectrum of activity of a gram-positive-only antibiotic, fusidic acid, into a version that demonstrates a dramatic improvement in antibacterial activity against P. aeruginosa. We anticipate that these discoveries will facilitate the design and development of high-permeating antipseudomonals.


Repeated cessation and resumption of resistance training attenuates increases in arterial stiffness.
Although high-intensity resistance training (RT) increases arterial stiffness, removing weightlifting stimuli returns arterial stiffness to baseline levels within relatively short periods during 4-8 weeks. This study investigates the effects of repeated RT cessation and resumption on arterial stiffness. Eighteen young healthy subjects were randomly assigned to a group that performed continuous RT (CRT, n=9) and a group that performed periodic RT (PRT, n=9). Both groups performed RT at 75% of one repetition maximum for 3 days per week. The CRT group continuously trained for 16 weeks, whereas the PRT group performed 3 cycles of 4 weeks training, with 2 weeks detraining intervals between cycles. The carotid-femoral pulse wave velocity in the CRT group significantly increased (P<0.05) at 4, 6, 10, 12, 16 and 20 weeks from baseline, whereas in the PRT group it significantly increased (P<0.05) after 4, 10 and 16 weeks from baseline, and was significantly lower (P<0.05) than that of the CRT group after 6, 10, 12, 16 and 20 weeks. Muscle mass and strength in the both groups significantly increased after 16 weeks from baseline and persisted for 20 weeks (P<0.05). These results suggest that PRT, including short-term repeated cessation and resumption, attenuates increases in arterial stiffness.


Antithrombotic therapy in children.
Thromboembolic events are an increasingly common secondary complication in children who are successfully treated for serious, life-threatening primary diseases. In contrast to adults, thromboembolic events are rare enough in children to hinder clinical trials assessing optimal use of antithrombotic agents. Currently, pediatric patients are treated according to guidelines extrapolated from adults. However, optimal prevention and treatment of thromboembolic events in children likely differs from such treatment for adults. The following review summarizes the available information on commonly used antithrombotic agents in children, which include standard heparin, low molecular heparin, oral anticoagulants, thrombolytic therapy, antiplatelet agents, antithrombin concentrates, and protein C concentrates. The mechanisms, dosing, monitoring, therapeutic range, factors influencing dose-response relationship, and side effects are discussed.


Identification and Functional Characterization of a Calcium-Sensing Receptor Mutation in an Infant with Familial Hypocalciuric Hypercalcemia.
Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant disorder, associated with inactivating mutations of the calcium-sensing receptor (CaSR). To evaluate the functional significance of a CaSR mutation, identified in a young infant who presented with hypercalcemia and hypocalciuria. The CaSR gene coding sequences were analyzed by polymerase chain reaction amplification and direct sequencing analysis. The mutation identified was introduced by site-directed mutagenesis into a wild-type (WT) CaSR plasmid, and human embryonic kidney 293 T cells were transfected with either the WT or mutant CaSR. The function of the mutated CaSR protein was analyzed by evaluating the free intracellular calcium [(Ca2+)i] response after challenge with extracellular calcium (Ca2+). We identified a heterozygous mutation c.772_773delGTinsA in exon 4 resulting in the substitution of amino acid valine (Val) with amino acid arginine (Arg) and the premature pause of the translation 46 amino acids later (Val258ArgfsTer47). Functional assay showed that cells transfected with the mutant CaSR had a significantly poorer response to extracellular Ca2+ stimulation compared with the WT. We have shown that the c.772_773delGTinsA mutation causes a significant alteration of CaSR function leading to features of FHH in an affected young infant since the first months of life.


Tactile and proprioceptive temporal discrimination are impaired in functional tremor.
In order to obtain further information on the pathophysiology of functional tremor, we assessed tactile discrimination threshold and proprioceptive temporal discrimination motor threshold values in 11 patients with functional tremor, 11 age- and sex-matched patients with essential tremor and 13 healthy controls. Tactile discrimination threshold in both the right and left side was significantly higher in patients with functional tremor than in the other groups. Proprioceptive temporal discrimination threshold for both right and left side was significantly higher in patients with functional and essential tremor than in healthy controls. No significant correlation between discrimination thresholds and duration or severity of tremor was found. Temporal processing of tactile and proprioceptive stimuli is impaired in patients with functional tremor. The mechanisms underlying this impaired somatosensory processing and possible ways to apply these findings clinically merit further research.


Integrated Knowledge Translation for Non-Communicable Diseases: Stories from Sub-Saharan Africa.
Integrated Knowledge Translation (IKT) is a key strategy for contextualising, tailoring, and communicating research for policy and practice. In this viewpoint, we provide examples of how partners from five countries in sub-Saharan Africa used IKT to advance interventions for curbing non-communicable diseases in their contexts and how these strategies were magnified during the COVID-19 pandemic in some cases. The stories highlight the importance of deliberate and reinforced capacity building, authentic relationship enhancement, adaptable and user-informed stakeholder engagement, and agile multi-sectoral involvement.