Menopausal hormone therapy: why we should no longer be afraid of the breast cancer risk.
The threat that women may develop breast cancer is the major reason why both physicians and women are afraid to use menopausal hormone therapy (MHT). The fear pertains to estrogen-progestin replacement therapy (EPRT) as estrogen-alone replacement therapy has no, or even a reduced, breast cancer risk. We reviewed the way breast cancer risk with EPRT was reported in some major publications since 2002 and tried to put the use-risk association in context. We hope this will make it easier for the physician and the menopausal woman to understand the risk involved and allow more confident and more informed decision-making regarding MHT use. We conclude that there are five interrelated reasons why physicians and women should no longer be afraid of the breast cancer risk with EPRT. We submit that breast cancer related to EPRT use is rare because the risk is very low; the reported increase in breast cancer risk with EPRT is not relevant to current practice; modifiable lifestyle factors, not EPRT, are the real risks for breast cancer; breast cancer-specific mortality is reduced in women who develop breast cancer while on EPRT; and avoiding MHT use when indicated puts a woman in harm's way.


Access and issues of equity in remote/rural areas.
This article reports on a workshop in which the major focus was a review of the barriers that prevent access to the array of community-based services available to the rural elderly. The demographics of the elderly were outlined and key components of the service system described. Attention was given to access hospital-based care, the closing of hospitals and the reasons for bypassing rural hospitals for those in large towns or cities. Special emphasis also was given to mental health services and their uneven accessibility. A review of the policy implications closed the workshop.


Effector Th1 cells under PD-1 and CTLA-4 checkpoint blockade abrogate the upregulation of multiple inhibitory receptors and by-pass exhaustion.
Immune checkpoint inhibitor (ICI) immunotherapy relies on the restoration of T-cell functions. The ICI receptors are not only found on exhausted T cells but also upregulated upon activation and reach high levels on effector T cells. In an ex vivo model, this study explored the consequences of PD-1 and cytotoxic T-lymphocyte antigen (CTLA-4) blockade applied during specific time frames of T-cell stimulation that coincide with distinct functional phases in type 1 helper T (Th1) cells. When applied at an early stimulation stage, the checkpoint blockade interfered with the upregulation of multiple inhibitory receptors such as PD-1, LAG3, TIM-3 and CTLA-4. Moreover, extension of the blockade period restricted the hyporesponsiveness in T cells. Alternatively, a short-term ICI treatment was advantageous when applied at late time frames of Th1 cell stimulation. Here, a transition phase from effector to exhausted state, which coincided with the late time frames of Th1 stimulation, was clearly determined together with the transcriptomics data demonstrating the initiation of significant alterations in metabolic pathways, genetic information processes, effector and exhaustion specific pathways. Applied in this transition phase, PD-1 and/or CTLA-4 blockade downregulated the inhibitory receptors which were already present on the effector Th1 cells, potentially through endocytic pathways. Therefore, the efficacy of ICI therapy was modulated by the functional status of T cells and can be improved by modifying the timing and duration of PD-1 and CTLA-4 blockade. In conclusion, the ICI therapy not only supports the reactivation of T cells but can also constrain de novo exhaustion.


Clinical application research: a hermeneutical approach to the appropriation of caring science.
Clinical caring science researchers contribute, by means of various participatory research efforts, to bring clinical practice closer to the ideals of caring. These research efforts have in the main been developed from classical action research rooted in critical theory. In this article, the authors launch an alternative research approach called clinical application research, the basis of which can be traced to the interpretative paradigm, or hermeneutics. The basic cornerstones of this research approach are ontology, context, and appropriation as well as understanding, interpretation, and application. Using an example from ongoing clinical research, the authors demonstrate the utility of this approach. Their aim in this article is to contribute to the development of methods within clinical research.


Nutrition surveillance and intervention, South Africa.
Under the apartheid regime there was no national framework for development in South Africa. Now, for the first time in South Africa, the government of national unity has provided a framework for development. This is a people-centered development strategy that calls for intersectoral collaboration and a vision for community involvement. Within this framework, the Department of Health has developed an integrated nutrition program with a health-based component and a community-based aspect. There is now a movement towards community-based program and nutrition surveillance. Although it is still early, there are some lessons that can be learned from these programs: growth monitoring can be used to promote community-based surveillance and to provide information upon which the communities can act; training, supervision, and information dissemination is essential, and it is also important to identify indicators to monitor success; building on existing infrastructure and capabilities within communities and linking up with NGOs and other organizations who have long-standing relationships with the communities is essential; identifying and capitalizing on indigenous resources and capabilities within countries is important; and there has to be political commitment.


Orthosteric and allosteric potentiation of heteromeric neuronal nicotinic acetylcholine receptors.
Heteromeric nicotinic ACh receptors (nAChRs) were thought to have two orthodox agonist-binding sites at two α/β subunit interfaces. Highly selective ligands are hard to develop by targeting orthodox agonist sites because of high sequence similarity of this binding pocket among different subunits. Recently, unorthodox ACh-binding sites have been discovered at some α/α and β/α subunit interfaces, such as α4/α4, α5/α4 and β3/α4. Targeting unorthodox sites may yield subtype-selective ligands, such as those for (α4β2)2 α5, (α4β2)2 β3 and (α6β2)2 β3 nAChRs. The unorthodox sites have unique pharmacology. Agonist binding at one unorthodox site is not sufficient to activate nAChRs, but it increases activation from the orthodox sites. NS9283, a selective agonist for the unorthodox α4/α4 site, was initially thought to be a positive allosteric modulator (PAM). NS9283 activates nAChRs with three engineered α4/α4 sites. PAMs, on the other hand, act at allosteric sites where ACh cannot bind. Known PAM sites include the ACh-homologous non-canonical site (e.g. morantel at β/α), the C-terminus (e.g. Br-PBTC and 17β-estradiol), a transmembrane domain (e.g. LY2087101) or extracellular and transmembrane domain interfaces (e.g. NS206). Some of these PAMs, such as Br-PBTC and 17β-estradiol, require only one subunit to potentiate activation of nAChRs. In this review, we will discuss differences between activation from orthosteric and allosteric sites, their selective ligands and clinical implications. These studies have advanced understanding of the structure, assembly and pharmacology of heteromeric neuronal nAChRs. This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc.


[From piroplasmosis to babesiosis--problems with classification of Babesia protozoa isolated from dogs].
Babesia and Theileria are the tick-borne parasites belonging to the order Piroplasmida. Both of them cause a severe disease with symptoms of hemolytic anemia. The main etiological factors of canine piroplasmosis are protozoa Babesia. There are two species of this pathogen infective for dogs: Babesia canis and Babesia gibsoni. Based on the results of molecular biology techniques it is possible to distinguish them as well as many subspecies or strains. It is known since quite some time that there are substantial differences in vector specificity, cross-immunity and pathogenicity between isolates of this species. Also the results of molecular analysis of these protozoa indicate that their genetic structure is diversified. On the basis of analysis of Babesia DNA sequences, the new variants of protozoa in dogs were detected. It is possible that, these new variants of Babesia are characterized by high virulence for dogs and resistance to drugs used in babesiosis therapy.


Paraspinal arteriovenous malformations in children.
Arteriovenous malformations (AVMs) within the spinal canal and in the paraspinal region are unusual. Spinal cord and dural AVMs or arteriovenous fistulas have been the subject of numerous reports, but paraspinal malformations causing venous congestion or hemorrhage in the spinal canal are rare and present special diagnosis and management challenges. The authors review previously published reports on 16 children with paraspinal AVMs. They also describe the 17th case of a child with a paraspinal AVM who presented with a spontaneous spinal epidural hematoma. To the best of the authors' knowledge, there has been no other case of a spinal epidural hematoma associated with a paraspinal AVM. In each of the 17 cases, the vascular lesion was successfully obliterated using endovascular therapy. Embolization with permanent occlusive agents is an effective treatment for these rare but potentially debilitating lesions.


Agrin, laminin beta 2 (s-laminin) and ARIA: their role in neuromuscular development.
Development of pre- and postsynaptic specializations at the vertebrate neuromuscular junction is affected by molecules concentrated in the extracellular matrix of the synaptic cleft. Agrin, laminin beta 2 and ARIA are the best characterized proteins known to be involved in particular aspects of synaptic differentiation. Recent advances in defining the domains of these molecules that are crucial for their synapse-organizing activity and their localization to synaptic basal lamina will help our understanding of the molecular mechanisms involved in synapse formation.


Evidence for Hygrometric Pressurization in the Internal Gas Space of Spartina alterniflora.
Higher pressure, up to several hundred pascal relative to ambient, is generated by hygrometric pressurization within the central hollow space of the stem in Spartina alterniflora. Dilution of oxygen and nitrogen by water vapor within the plant's internal gas space results in an influx of nitrogen and oxygen from the air and a net increase in the internal gas pressure at steady state. The nature of the pressure gradient suggests that small pores exist in the plant tissues. Moreover, the compact arrangement of leaf mesophyll cells creates a high resistance for the mass flow of gases and contributes to the higher pressure within leaves. After experimentally venting the internal pressure, outside air diffused through the basal area of the adaxial side of the leaves into the internal space and elevated pressure was restored.


Changing NHS structures: implications for nursing careers.
This article explores what implications the flatter NHS structures (after the restructuring of April 1999) might have for nursing careers. It examines issues of recognition, reward systems and career pathways and the problems these may pose for the retention of qualified staff within nursing. It is seen that flatter structures will offer little in the way of traditional vertical promotion opportunities and readers are invited to explore the possibility of lateral promotion, continuous development, career grids and the rise of the generic nurse. Speculation about the introduction of competency-based pay systems is introduced. The article attempts to progress the debate in the area of the links between structure and supporting human resource infrastructures within the public sector set against background context of severe cash constraints. It seeks to raise the issues and open debate among practitioners.


On the scope of scientific hypotheses.
Hypotheses are frequently the starting point when undertaking the empirical portion of the scientific process. They state something that the scientific process will attempt to evaluate, corroborate, verify or falsify. Their purpose is to guide the types of data we collect, analyses we conduct, and inferences we would like to make. Over the last decade, metascience has advocated for hypotheses being in preregistrations or registered reports, but how to formulate these hypotheses has received less attention. Here, we argue that hypotheses can vary in specificity along at least three independent dimensions: the relationship, the variables, and the pipeline. Together, these dimensions form the scope of the hypothesis. We demonstrate how narrowing the scope of a hypothesis in any of these three ways reduces the hypothesis space and that this reduction is a type of novelty. Finally, we discuss how this formulation of hypotheses can guide researchers to formulate the appropriate scope for their hypotheses and should aim for neither too broad nor too narrow a scope. This framework can guide hypothesis-makers when formulating their hypotheses by helping clarify what is being tested, chaining results to previous known findings, and demarcating what is explicitly tested in the hypothesis.


Guided self-help interventions for mental health disorders in children with neurological conditions: study protocol for a pilot randomised controlled trial.
Rates of mental health disorders are significantly greater in children with physical illnesses than in physically well children. Children with neurological conditions, such as epilepsy, are known to have particularly high rates of mental health disorders. Despite this, mental health problems in children with neurological conditions have remained under-recognised and under-treated in clinical settings. Evidence-based guided self-help interventions are efficacious in reducing symptoms of mental health disorders in children, but their efficacy in reducing symptoms of common mental health disorders in children with neurological conditions has not been investigated. We aim to pilot a guided self-help intervention for the treatment of mental health disorders in children with neurological conditions. A pilot randomised controlled trial with 18 patients with neurological conditions and mental health disorders will be conducted. Participants attending specialist neurology clinics at a National UK Children's Hospital will be randomised to receive guided self-help for common mental health disorders or to a 12-week waiting list control. Participants in the treatment group will receive 10 sessions of guided self-help delivered over the telephone. The waiting list control group will receive the intervention after a waiting period of 12 weeks. The primary outcome measure is reduction in symptoms of mental health disorders. Exclusion criteria are limited to those at significant risk of harm to self or others, the presence of primary mental health disorder other than anxiety, depression or disruptive behaviour (e.g. psychosis, eating disorder, obsessive-compulsive disorder) or intellectual disability at a level meaning potential participants would be unable to access the intervention. The study has ethical approval from the Camden and Islington NHS Research Ethics Committee, registration number 14.LO.1353. Results will be disseminated to patients, the wider public, clinicians and researchers through publication in journals and presentation at conferences. This is the first study to investigate guided self-help interventions for mental health problems in children with neurological conditions, a group which is currently under-represented in mental health research. The intervention is modular and adapted from an empirically supported cognitive behavioural treatment. The generalisability and broad inclusion criteria are strengths but may also lead to some weaknesses. Current Controlled Trials: ISRCTN21184717 . Registered on 25 September 2015.


Beyond ITER: neutral beams for a demonstration fusion reactor (DEMO) (invited).
In the development of magnetically confined fusion as an economically sustainable power source, International Tokamak Experimental Reactor (ITER) is currently under construction. Beyond ITER is the demonstration fusion reactor (DEMO) programme in which the physics and engineering aspects of a future fusion power plant will be demonstrated. DEMO will produce net electrical power. The DEMO programme will be outlined and the role of neutral beams for heating and current drive will be described. In particular, the importance of the efficiency of neutral beam systems in terms of injected neutral beam power compared to wallplug power will be discussed. Options for improving this efficiency including advanced neutralisers and energy recovery are discussed.


Fanconi-Bickel syndrome versus osteogenesis imperfeeta: An Iranian case with a novel mutation in glucose transporter 2 gene, and review of literature.
Fanconi-Bickel syndrome is an extremely rare hereditary metabolic disease, characterized by hepatomegaly due to glycogen storage, refractory hypophosphatemic rickets, marked growth retardation and proximal renal tubular acidosis. Recurrent bone fractures are one of the hallmark findings. It is a single gene disorder; the responsible gene belongs to the facilitative glucose transporters 2 (GLUT2) family gene or (SLC2A2) mapped to the q26.1-26.3 locus on chromosome 3, and encodes the GLUT protein 2. This protein is expressed in pancreatic ί-cells, hepatocytes, renal tubules, and intestinal mucosa. Several mutations in the GLUT2 gene have been reported in different ethnicities. Herein we report an Iranian girl with a missed diagnosis of osteogenesis imperfecta. She was referred with the history of frequent fractures, and severe motor delay and was suspected to osteogenesis imperfecta. Following the case we detected refractory rickets instead of OI, sever growth failure, proximal renal tubulopathy and RTA, and enlarged kidneys, progressive hepatomegaly, and GSD on liver biopsy. Glucose and galactose tolerance tests confirmed abnormal carbohydrate metabolism. Molecular analysis on GLUT2 gene revealed a homozygous novel mutation in exon 5; it was 15 nucleotide deletion and 7 nucleotide insertion and caused a frame shift mutation, produced a premature truncated protein (P.A229QFsX19). This mutation has not been reported before in the relevant literature.


The prognostic value of the antiperinuclear factor, anti-citrullinated peptide antibodies and rheumatoid factor in early rheumatoid arthritis.
To study the prognostic value of the antiperinuclear factor (APF), determined by an indirect immunofluorescence test (IIF) and a recently developed anti-citrullinated cyclic peptide (CCP) ELISA, in combination with rheumatoid factor (RF) status, in early RA (< 1 year). A total of 249 participants in a randomized trial of treatment strategies were divided into 4 groups according to their APF (or CCP) and RF status at baseline. Differences in disability, joint involvement and radiological damage over a 3-year period were analysed. APF-IIF results differed from CCP-ELISA in 42 cases (17%); 38 of the 42 had a positive IIF and negative ELISA value. Disability after 3 years did not differ significantly between the RF and APF groups. APF- patients had significantly lower Thompson joint scores compared to APF+ patients (6 vs 24 for CCP-ELISA; 2 vs 24 for IIF). RF+APF+ patients exhibited more radiological damage compared to RF-APF- patients. RF+APF- and RF-APF+ patients had intermediate scores. Within the RF+ and RF- groups, APF+ was associated with more radiological damage and thus yielded prognostic information in addition to RF. In this respect, the results of ELISA and IIF were comparable. Thirty percent of the RF+APF+ patients had a radiological score higher than 45, compared to 13% of the RF+APF-, none of the RF-APF+, and 2% of RF-APF- patients (p < 0.001). In addition, more large joints were affected in APF+ than in APF- patients, while no difference was observed between RF+ and RF- patients. APF has prognostic value in addition to RF for joint involvement and radiological damage in early RA. The CCP-ELISA technique for APF assessment may facilitate its use in clinical practice. However, the prognostic value of the two tests lies in their ability to predict mild disease. Reliable identification at baseline of individual patients with progressive disease is still not possible.


Validating the Chinese version of the Verbal Learning Test for screening Alzheimer's disease.
Episodic memory tasks are one of the most sensitive tools to discriminate Alzheimer's disease (AD). This study aimed to validate a shorter version verbal memory test that will efficiently assess Chinese elderly with memory complaints. One hundred and eighty-five elderly with normal cognition (NC) and 217 AD patients were evaluated. Each participant received the Chinese Version Verbal Learning Test (CVVLT) consisting of 9 two-character nouns with 4 learning trials, 2 delayed recalls in 30 seconds and 10 minutes, and a word recognition test. In the NC elderly, age and sex had significant effects on recall scores in CVVLT, while education level showed an inverse correlation with 3 different patterns of errors made during the learning, recall, and recognition trials. AD patients had lower scores across all recall tests. In those with lower educational level, NC elderly had higher perseveration errors than AD patients. The cutoff value between the AD and NC groups in the 10-minute recall was 4/5 for those aged >75 years and 5/6 for those aged <75 years. This study has good validity in discriminating AD participants and the data here can help in diagnosing AD and mild cognitive impairment using the CVVLT.


Psychopathological Correlates and Emotion Regulation as Mediators of Approach and Avoidance Motivation in a Chinese Military Sample.
Background: Approach and avoidance motivation have been thoroughly studied in common mental disorders, which are prevalent in the military context. Approach/avoidance motivational dispositions underlie emotion responses and are thought to influence emotion dysregulation. However, studies on the mediating role of emotion regulation (ER) between motivational dispositions and mental disorders have been insufficient. We examined the psychopathological correlates of motivational dispositions and explored the mediating role of ER. Methods: The Behavioral Inhibition System and Behavioral Activation System (BIS/BAS) scales and measures of mood disorders (depression, anxiety, OCD, and PTSD) were administered to a nonclinical sample of 3,146 Chinese military service members. The Emotion Regulation Questionnaire for Armymen (ERQ-A) (Chinese version) was used to measure ER styles. We examined the reliability and construct validity of the BIS/BAS scales. Approach/avoidance motivations were correlated with symptoms of mood disorders. Mediation analysis was conducted to confirm the mediating role of ER between motivation and mood disorders. Results: The results showed acceptable internal reliability and construct validity of the BIS/BAS scales. Gender (female), family status (single-parent family), and social relationships (having fewer good friends) were significant predictors of high BIS sensitivity. More years of education, an older age, being an only child and being in a single-parent family all significantly predicted high BAS sensitivity. The BIS/BAS scales were predictive of various DSM-V-based mental disorders (depression, anxiety, OCD, and PTSD). Immersion exacerbated the impact of BAS/BIS sensitivities on depressive/PTSD symptoms, while reinterpretation and talking out alleviated the impact of BAS/BIS sensitivities on these symptoms. Conclusions: Motivational dispositions have an impact on mood symptoms under specific conditions. ER strategies (immersion, reinterpretation, and talking out) were shown to be partial mediators between approach/avoidance motivation and mood disorders. These findings highlight the importance of ER in altering the impact of motivational dispositions on mood disorders and as a promising target of psychotherapies.


Biomechanics of humerus fracture fixation by locking, cortical, and hybrid plating systems in a cadaver model.
The goal of this study was to discover how locking or cortical screws or a hybrid of both would perform in stabilizing a simulated humerus fracture. We simulated stripping of screw threads or poor bone quality by overdrilling the screw hole, and also studied a control group with no overdrilling. A total of 38 fresh frozen cadaver humeri were divided into 2 groups: 16 undergoing overdrilling with a drill bit 0.3 mm less than the diameter of the screw and 22 undergoing no overdrilling. A 4-point bending test followed torsional fatigue of 1000 cycles with an amplitude of +/-10 degrees. The post-fatigued samples were retested in the same way after tightening the loose screws if necessary. Finally, each fatigued specimen was tested for failure in torsion at 0.5 Hz by applying a maximum rotational displacement of 60 degrees .The bending stiffness values (Nm/mm) of cortical and locking screws, with the exception of the hybrid system, were significantly higher for the overdrilled group than the non-overdrilled (cortical, 6.9 vs 5.6; locking, 9.1 vs 6.3; hybrid, 8.4 vs 6.8). Fatigue had no effect on the bending stiffness of all the screw/plate systems (cortical, 6.9 vs 7.4; locking, 9.1 vs 8.8; hybrid, 8.5 vs 8.1). The overdrilling had no effect on the failure loads and displacements for all the screws except cortical screws, where the failure displacement was significantly higher for the overdrilling group. The torsional stiffness retentions after 1000 cycles were significantly different for overdrilled specimens in the cortical screws group only.Overdrilling had a minimal effect on bending and torsional properties. The results of the locking and hybrid were close, and the cortical screw had only slightly lower bending stiffness.


The rhoptry neck protein RON4 re-localizes at the moving junction during Toxoplasma gondii invasion.
Host cell invasion in the Apicomplexa is unique in its dependency on a parasite actin-driven machinery and in the exclusion of most host cell membrane proteins during parasitophorous vacuole (PV) formation. This exclusion occurs at a junction between host cell and parasite plasma membranes that has been called the moving junction, a circumferential zone which forms at the apical tip of the parasite, moves backward and eventually pinches the PV from the host cell membrane. Despite having been described by electron microscopic studies 30 years ago, the molecular nature of this singular structure is still enigmatic. We have obtained a monoclonal antibody that recognizes the moving junction of invading tachyzoites of Toxoplasma gondii, in a pattern clearly distinct from those described so far for microneme and rhoptry proteins. The protein recognized by this antibody has been affinity purified. Mass spectrometry analysis showed that it is a rhoptry neck protein (RON4), a hypothetical protein with homologues restricted to Apicomplexa. Our findings reveals for the first time the participation of rhoptry neck proteins in moving junction formation and strongly suggest the conservation of this structure at the molecular level among Apicomplexa.


Use of multiple molecular subtyping techniques to investigate a Legionnaires' disease outbreak due to identical strains at two tourist lodges.
A multistate outbreak of Legionnaires' disease occurred among nine tour groups of senior citizens returning from stays at one of two lodges in a Vermont resort in October 1987. Interviews and serologic studies of 383 (85%) of the tour members revealed 17 individuals (attack rate, 4.4%) with radiologically documented pneumonia and laboratory evidence of legionellosis. A survey of tour groups staying at four nearby lodges and of Vermont-area medical facilities revealed no additional cases. Environmental investigation of common tour stops revealed no likely aerosol source of Legionella infection outside the lodges. Legionella pneumophila serogroup 1 was isolated from water sources at both implicated lodges, and the monoclonal antibody subtype matched those of the isolates from six patients from whom clinical isolates were obtained. The cultures reacted with monoclonal antibodies MAB1, MAB2, 33G2, and 144C2 to yield a 1,2,5,7 or a Benidorm 030E pattern. The strains were also identical by alloenzyme electrophoresis and DNA ribotyping techniques. The epidemiologic and laboratory data suggest that concurrent outbreaks occurred following exposures to the same L. pneumophila serogroup 1 strain at two separate lodges. Multiple molecular subtyping techniques can provide essential information for epidemiologic investigations of Legionnaires' disease.


Phosphatidylinositol 3-kinase activity is required for hepatocyte growth factor-induced mitogenic signals in epithelial cells.
Phosphatidylinositol (PI) 3-kinase is an important enzyme implicated in growth factor-stimulated intracellular signaling. In this study we have shown that hepatocyte growth factor (HGF) induces a rapid tyrosine phosphorylation of PI 3-kinase and association with HGF receptor/Met in Mv1Lu epithelial cells. Murine mammary carcinoma (SP1) cells, which co-express HGF and HGF receptor/Met, showed sustained phosphorylation of PI 3-kinase. Wortmannin, a potent inhibitor of PI 3-kinase, inhibited HGF-induced PI 3-kinase activity, proliferation of Mv1Lu cells, and spontaneous growth of SP1 cells in a dose-, and time-dependent manner. Transfection of a dominant negative mutant p85 (Deltap85) subunit of PI 3-kinase into SP1 cells strongly inhibited HGF-stimulated proliferation and PI 3-kinase activity. However, wortmannin did not influence HGF-induced c-Jun expression. Furthermore, HGF stimulated S6 kinase activity, but its activity was not required for HGF-induced proliferation. Overall, these results suggest that HGF-induced PI 3-kinase activity is important for the mitogenic action of HGF in epithelial cells and further demonstrate that expression of c-Jun is not influenced by inhibition of PI 3-kinase activity.


Clinical and prognostic effect of a positive granulocyte scan in infective endocarditis.
Thirty patients with clinical signs of infective endocarditis and pathologic echocardiographic findings indicating vegetations underwent scanning with In-111 or Tc-99m hexamethylpropylene amineoxime (HMPAO) labeled granulocytes. Blood cultures were positive in 60% of the patients. The other cases were negative as a result of antibiotic pretreatment. The results of scintigraphy were correlated with the subsequent clinical course, and in 20 cases with data obtained by histologic examination of the valves. With regard to the degree of the inflammatory process, the nuclear medical procedure provided the following results: true-positive in 6 cases, false-positive in 1 case, true-negative in 19 cases, and false-negative in 3 cases. In this study, positive granulocyte scans correlate with high activity of the inflammatory process and predict a poor prognosis for the patients concerned.


Adiponectin is present in human milk and is associated with maternal factors.
Previous studies have shown that human milk has a role in the gastrointestinal, neural, and immune development of neonates. If present in milk, adiponectin would be a promising candidate for influencing infant development, given its metabolic functions. Our objectives were to determine whether adiponectin is present in human milk and to characterize maternal factors associated with potential variation in milk adiponectin concentrations. We quantified adiponectin concentrations in human milk samples from donors to the Cincinnati Children's Research Human Milk Bank and randomly selected participants in a cohort study in Mexico City funded by the National Institutes of Health. Using cross-sectional and longitudinal data, we examined milk adiponectin concentrations in relation to lactation duration, maternal body mass index (BMI; in kg/m(2)), and ethnicity. Adiponectin was detected in human skim milk (range: 4.2-87.9 ng/mL). In cross-sectional and longitudinal analyses, duration of lactation was negatively associated with milk adiponectin concentrations (beta = -0.059 +/- 0.024 and -0.059 +/- 0.007, respectively; P < 0.02 for both). Maternal postpregnancy BMI was positively associated with milk adiponectin concentrations (beta = 0.08 +/- 0.02, P < 0.0001; longitudinal analysis). Mexican mothers had lower median milk adiponectin concentrations at 1 mo than did the non-Hispanic white subjects from Cincinnati (11.5 and 19.8 ng/mL; P = 0.003). Adiponectin is present in human milk and its concentrations are associated with duration of lactation, maternal adiposity, and ethnicity. Given the importance of adiponectin in inflammation, insulin sensitivity, and fatty acid metabolism, future studies should examine milk adiponectin's role in infant metabolic development.


A Rare Case Report of a Paratesticular Fibrous Pseudotumor Mimicking a Hydrocele.
Tumors arising in the spermatic cord are very rare. The common benign tumors of the spermatic cord include adenomatoid tumor, lipoma, neurofibroma, and leiomyoma. We report a rare case of fibrous pseudotumor of the spermatic cord presenting clinically as a hydrocele. A 28-year-old male presented with the complaint of swelling in the left scrotum, which gradually progressed in size over four years. Clinically, the swelling was soft and fluctuant. The left testis was not separately made out and a diagnosis of left hydrocele was made. On scrotal exploration, a large 12 x 7 cm fleshy mass was seen in the left hemiscrotum with the left testis adherent to the upper pole of the mass. The mass was dissected out from the testis, and the histology showed features of fibrous pseudotumor of the spermatic cord. Fibrous pseudotumor of the spermatic cord is a very rare entity and can pose a diagnostic challenge. Preoperative scrotal ultrasound and intraoperative frozen section assessment can prevent unnecessary orchiectomies in young patients with paratesticular fibrous pseudotumors.


Low-damaged p-type doping of MoS2 using direct nitrogen plasma modulated by toroidal-magnetic-field.
Low damaged doping of two-dimensional (2D) materials proves to be a significant obstacle in realizing fundamental devices such as p-n junction diodes and transistors due to its atom layer thickness. In this work, the defect formation energy and p-type conduction behavior of nitrogen plasma doping are investigated by first principle calculation. Low damaged substitutional p-type doping in MoS2 using low energy nitrogen plasma composed of N+ and N2 + is achieved by a novel toroidal magnetic field (TMF). The TMF helps to raise the concentration of N2 + ions at low RF power condition. The electrical characteristics of double-layer MoS2 field-effect transistors (FETs) clearly show an efficient p-type doping behavior. Atomic force microscope is applied to verify the slight damage in MoS2. X-ray photoelectron spectroscopy, photoluminescence and Raman spectroscopy confirm the effective p-type doping characteristic with weak damage. These findings provide a low damage technology for efficient carrier modulation of MoS2 and other homogeneous TMDC materials, which overcomes barriers in developing 2D electronic and optoelectronic devices.


A preliminary study: is fibulin 1 a friend or an enemy that needs to be silenced with siRNAs for mesothelioma?
The impaired balance between cell proliferation and cell death, followed the inability to receive the death signals, cells push towards the neoplasia pathway. Fibulin 1 (FBLN1) plays a role as a co-factor in the mechanism of action of a protease such as a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-1), which has important roles in angiogenesis, can also act as both tumor suppressor gene (TSG) and an oncogene in the main constituent of the extra-cellular matrix. This preliminary study has investigated the effects of silencing FBLN1 with siRNA on autophagy, proliferation, apoptosis pathways in the MSM cell line. It was transfected siRNA specific to FBLN1 incubated MSM SPC212 cells, and compared with negative control siRNAs by a real-time polymerase chain reaction. It was determined apoptosis, proliferation, autophagy-related genes in mRNA levels. It was observed that increased anti-apoptosis genes, such as CASP2, CASP7, DDFA, and BCL2, anti-apoptotic gene, reduced APAF1, CASP8. Proliferation induced through while increased ADAMTS1, CDH1, CDH6, CLDN7, CSF3, MMP7, MMP13 genes. Autophagy increased via increasing MAP1LC3B, ATG-16L1 genes while decreased via suppressed ULK1, and ATG7 genes by silencing FBLN1 with siRNAs (p < 0.05). Proliferation can be induction with silencing of FBLN1 with siRNA in processing mechanism MSM. It was concluded that FBLN1 could be act as pleiotropic on autophagy, and apoptosis pathways in proliferation processing for MSM. Therefore we think that FBLN1 acts like a TSG. FBLN1 can be considered as a targeted treatment option in advanced stage MSM.


Generation of induced pluripotent stem cells.
Induced pluripotent stem cells (iPSCs) are generated from somatic cells that have been reprogrammed by the ectopic expression of defined embryonic transcription factors. This technology has provided investigators with a powerful tool for modelling disease and developing treatments for human disorders. This chapter provides the researcher with some background on iPSCs and details on how to produce MEF-conditioned medium, prepare mitotically arrested mouse embryonic fibroblasts (MEFs), create iPSCs using viral vectors, passage iPSCs, and cryopreserve iPSCs. The methods offered here have been used in many laboratories around the world and the reader can initially follow these methods. However, not all cell types are easily transduced using viral vectors and other methods of delivering the reprogramming transcription factors may need to be tested.


Longitudinal analysis of vaginal microbiota during IVF fresh embryo transfer and in early pregnancy.
Infertility is a global public health issue which leads many couples to seek fertility treatments, of which in vitro fertilization (IVF) is considered to be the most effective. Still, only about one-third of the women achieve live birth after the first IVF embryo transfer (IVF-ET). Factors affecting embryo implantation are poorly known, but the female reproductive tract microbiota may play a key role. Our study confirms the beneficial role of vaginal lactobacilli, especially Lactobacillus crispatus, in the probability of achieving clinical pregnancy and live birth following IVF-ET. Our findings regarding the intra-individual shift of vaginal microbiota between non-pregnancy and pregnancy states are novel and provide new information about the dynamics of microbiota in the early steps of human reproduction. These findings may help clinicians in their attempts to optimize the conditions for ET by microbiota screening or modulation and timing the ET when the microbiota is the most favorable.


Enhancement of struvite pellets crystallization in a full-scale plant using an industrial grade magnesium product.
A full-scale struvite crystallization system was operated for the treatment of the centrate obtained from the sludge anaerobic digester in a municipal wastewater treatment plant. Additionally, the feasibility of an industrial grade Mg(OH)2 as a cheap magnesium and alkali source was also investigated. The struvite crystallization plant was operated for two different periods: period I, in which an influent with low phosphate concentration (34.0 mg P·L-1) was fed to the crystallization plant; and period II, in which an influent with higher phosphate concentration (68.0 mg P·L-1) was used. A high efficiency of phosphorus recovery by struvite crystallization was obtained, even when the effluent treated had a high level of alkalinity. Phosphorus recovery percentage was around 77%, with a phosphate concentration in the effluent between 10.0 and 30.0 mg P·L-1. The experiments gained struvite pellets of 0.5-5.0 mm size. Moreover, the consumption of Mg(OH)2 was estimated at 1.5 mol Mg added·mol P recovered-1. Thus, industrial grade Mg(OH)2 can be an economical alternative as magnesium and alkali sources for struvite crystallization at industrial scale.


Enterophages, a group of phages infecting Enterococcus faecalis, and their potential as alternate indicators of human faecal contamination.
We have developed a method for the detection of viruses in environmental samples that we have called enterophages, that specifically infect Enterococcus faecalis. This method has allowed us to determine the prevalence and to study the ecology of this group of phages. The enterophages replicate at 37 degrees C, and at 41 degrees C. The presence of NaN(3) in the media inhibits the growth of background microbiota and allows an accurate, specific and rapid detection of these viruses. Enterophages were present in raw domestic sewage at lower concentrations (average 1.8 x 10(2) PFU/100 mL) than those of coliphages (average 1.7 x 10(5) PFU/100 mL). Phages were characterised by transmission electron microscopy showing icosahedral capsids, some with non-contractile tails as well as icosahedral non-tailed capsids. Different isolates had capsid sizes ranging from 20 nm to about 75 nm in diameter. These data describe a new group of phages that may serve as alternate indicators of human faecal pollution, especially in recreational waters. The ecology of these enterophages indicates that these may be strictly of human origin.


Twenty-four hour secretory pattern of prolactin in hyperprolactinaemic patients with pituitary micro- and macroadenomas.
No nocturnal increase of prolactin (Prl) secretion during sleep has reportedly been discernible in most cases of hyperprolactinaemic patients with pituitary tumour. However, subjects previously evaluated, were in the majority, patients with large pituitary tumour. In the present study, 24 h secretory pattern of Prl was evaluated in 4 hyperprolactinaemic women with pituitary microadenoma and in 4 hyperprolactinaemic women with pituitary macroadenoma. Nocturnal increase of Prl secretion was observed in patients with microadenoma, but not in patients with macroadenoma. The nocturnal increase of Prl secretion in patients with microadenoma may reflect the function of the adenoma cells, and may suggest that the basic central nervous system programme governing Prl secretion in normals is qualitatively preserved in these patients. Alternatively, the nocturnal increase of Prl secretion may reflect the function of the normal lactotrophs remaining in these patients.


Coagulase-negative staphylococci isolated from two cases of toxic shock syndrome lack superantigenic activity, but induce cytokine production.
Two strains of Staphylococcus epidermidis isolated from patients with toxic shock symptoms have been reported to carry genes related to S. aureus enterotoxins B and C by dot-blot hybridisation, although the corresponding superantigenic toxins were not detected immunologically. We here show that these strains produce no superantigens capable of stimulating proliferation of human mononuclear leukocytes or rabbit splenocytes, and that no DNA homologous to the seb or sec genes can be detected by PCR. However, stimulation of human monocytes by whole killed bacteria induced dose-dependent production of the cytokines TNF alpha, IL-1 beta and IL-6, which may be responsible for the clinical symptoms in these patients.


Vascular dementia: European perspectives.
Vascular dementia (VaD) is the second most frequent cause of organic acquired cognitive dysfunction in the Western world and is probably the first cause in some Asian countries. Therefore, it represents an important target for drug trials in dementia. This report puts in perspective methodological issues in VaD trials, as opposed to Alzheimer disease (AD), and reproduces in extenso the European Medicinal Products Evaluation Agency (EMEA) guidelines for trials of symptomatic treatments of dementia, particularly in AD. There are no explicit guidelines for VaD trials, but many of the recommendations for AD are already applicable to VaD for drugs aiming at alleviating symptoms of dementia. However, VaD can be viewed as being one of the many possible consequences of cerebrovascular diseases, so that there is more to expect from secondary prevention strategies for VaD than for AD (in which both the etiology and the pathophysiological mechanisms are largely unknown). So it seems logical to put more emphasis on the stabilization of the symptoms of VaD, by preventing progression or recurrence insofar as the vascular risk factors for VaD can often be identified and controlled, than in attempting to improve the existing clinical manifestations of established vascular brain damage. Even if purely symptomatic drugs are developed to improve the symptoms of VaD, they will have to be studied in the context of a tight control of existing vascular risk factors. For secondary prevention, trials of at least 1 year seem advisable.


Biological activity of rhizobial siderophore.
Non-nodulating mutant of Rhizobium leguminosarum biovar trifolli produces the phenolate type of siderophore consisting of 2,3-dihydroxybenzoic acid and threonine. The activity of this compound against the various bacteria was tested. Only, the growth of R. leguminosarum strains was stimulated by siderophore. The other species of Rhizobium, especially R. meliloti, were sensitive to this agent. The growth of R. meliloti was also inhibited by agrobactin and pseudobactin. This effect was reversed by ferric iron.


Dracorhodin perchlorate induces G1/G0 phase arrest and mitochondria-mediated apoptosis in SK-MES-1 human lung squamous carcinoma cells.
Dracorhodin perchlorate (DP) has recently been revealed to induce apoptosis in various types of cancer. However, the antitumor potential and molecular mechanisms of DP in human lung cancer have not been previously reported. Therefore, the present study aimed to investigate the effects of DP on cell viability, the cell cycle and apoptosis, using an MTT assay, flow cytometry and western blot studies. DP was identified to induce cellular and DNA morphological changes, and decreased the viability of SK-MES-1 human lung squamous carcinoma cells. DP significantly inhibited the growth of SK-MES-1 cells by inducing apoptosis and G1/G0 cell cycle arrest in a dose-dependent manner via activation of p53 (P<0.05). Furthermore, DP promoted the significant upregulation of B cell lymphoma-2 (Bcl-2)-activated X protein and significant downregulation of Bcl-2 (P<0.05), inducing dissipation of the mitochondrial membrane potential (MMP). In addition, caspase-3 was activated by DP via the cleavage of its substrate, proteolytic cleavage of poly(ADP-ribose) polymerase. DP also induced caspase-independent apoptosis by significantly increasing the protein expression of the apoptosis-inducing factor (P<0.05), which is localized in mitochondria under the physiological conditions and released into the cytoplasm when MMP is dissipated. Furthermore, the present study demonstrated that DP significantly increased the generation of reactive oxygen species (P<0.05). In conclusion, the current study revealed that DP is able to induce cell cycle arrest and apoptosis in SK-MES-1 cells via activation of the mitochondrial pathway, indicating that DP may be a potential leading compound for the development of future lung cancer therapeutic regimes.


Low prevalence of anti-hepatitis C virus antibodies in female hemodialysis patients without blood transfusion: a multicenter analysis.
To investigate whether nosocomial infection with hepatitis C virus (HCV) in chronic hemodialysis patients is related primarily to hemodialysis procedures, a multicenter analysis was carried out on 2,132 chronic hemodialysis patients (male: 1,274, female: 858) from 23 dialysis units using a second-generation anti-HCV antibody assay. The prevalence of anti-HCV antibodies in patients with blood transfusion (29.9%) was significantly higher (P < .0001) than in those without blood transfusion (7.6%). Although the prevalence of anti-HCV antibodies increased with the length of hemodialysis in males without blood transfusion, it did not increase even after long-term hemodialysis (more than 5 years) in females without blood transfusion, who exhibited a rate (1.9%) similar to that of healthy blood donors in Japan. There was a significant correlation between the presence of anti-HCV antibodies and anti-HBs antibody in males without blood transfusion. In anti-HBs antibody-negative male patients without blood transfusion, the prevalence of anti-HCV antibodies was significantly lower compared with anti-HBs antibody-positive male patients without blood transfusion. There was marked difference in the prevalence rate in patients without blood transfusion among dialysis units, and there was no correlation between the prevalence and the mean period of dialysis of each dialysis unit. Although nosocomial infection with HCV appears to be related to the hemodialysis environment, the low prevalence of anti-HCV antibodies in females suggests that dialysis procedures per se may not present the risk of hepatitis C virus infection.


Circadian rhythms of chloroplast orientation and photosynthetic capacity in ulva.
Ulva lactuca L. var. latissima (L.) Decandolle and var. rigida (C. Agardh) Le Jolis and U. mutabilis Foyn have a circadian rhythm of chloroplast orientation which results in large changes in the light-absorption properties of the thallus. During the day, the chloroplasts cover the outer face of the cells and absorbance is high. At night, the chloroplasts are along the side walls and absorbance is low. Enteromorpha linza (L.) J. Agardh, E. intestinalis (L.) Link, E. sp., and Monostroma grevillei (Thuret) Wittrock, members of the Ulvales, were not observed to have this rhythmic movement. Chloroplasts, when in the face position, could not be induced to move to the sides by high intensity light up to 80,000 lux. Unrelated to chloroplast position per se and light-absorption efficiency, there is a rhythm of photosynthetic capacity which peaks just before midday and which continues in constant darkness.


Temporal features of spectral integration in the inferior colliculus: effects of stimulus duration and rise time.
This report examines temporal features of facilitation and suppression that underlie spectrally integrative responses to complex vocal signals. Auditory responses were recorded from 160 neurons in the inferior colliculus (IC) of awake mustached bats. Sixty-two neurons showed combination-sensitive facilitation: responses to best frequency (BF) signals were facilitated by well-timed signals at least an octave lower in frequency, in the range 16-31 kHz. Temporal features and strength of facilitation were generally unaffected by changes in duration of facilitating signals from 4 to 31 ms. Changes in stimulus rise time from 0.5 to 5.0 ms had little effect on facilitatory strength. These results suggest that low frequency facilitating inputs to high BF neurons have phasic-on temporal patterns and are responsive to stimulus rise times over the tested range. We also recorded from 98 neurons showing low-frequency (11-32 kHz) suppression of higher BF responses. Effects of changing duration were related to the frequency of suppressive signals. Signals<23 kHz usually evoked suppression sustained throughout signal duration. This and other features of such suppression are consistent with a cochlear origin that results in masking of responses to higher, near-BF signal frequencies. Signals in the 23- to 30-kHz range-frequencies in the first sonar harmonic-generally evoked phasic suppression of BF responses. This may result from neural inhibitory interactions within and below IC. In many neurons, we observed two or more forms of the spectral interactions described here. Thus IC neurons display temporally and spectrally complex responses to sound that result from multiple spectral interactions at different levels of the ascending auditory pathway.


Preliminary observations on the effect of glucan in combination with radiation and chemotherapy in four murine tumors.
The efficacy of glucan in combination with local radiation therapy was measured using three solid murine tumors of differing abilities to induce a host defense. Using the KHT fibrosarcoma which induces no measurable host defense, glucan did not improve tumor-free survival over radiation alone; the combination produced a marginal improvement in tumor-free survival in animals bearing the highly immunogenic EMT-6 tumor. The most marked improvement in tumor-free survival was found with the mildly immunogenic 6C3HED lymphosarcoma. The efficacy of glucan in combination with BCNU chemotherapy was measured using the disseminated AKR transplantable leukemia; the combination yielded a high level of cures compared to no survival for either agent alone. Using the AKR transplantable leukemia in an F1 model, the effect of amphotericin B (AmB) alone or in combination with BCNU was tested. AmB or BCNU alone had little or no curative effect when tested in (AKR X DBA)F1 mice, but 56% of mice were cured when combined therapy was employed. When tested in (AKR X C57BL)F1 or (AKR X A)F1 mice, a small fraction was cured with AmB alone while about 90% were cured with either BCNU alone or the combination.


Relationships of serum pro-inflammatory cytokines and vascular endothelial growth factor with liver dysfunction in severe ovarian hyperstimulation syndrome.
The aims of this study were to determine if differences in serum pro-inflammatory cytokines, vascular endothelial growth factor (VEGF) and clinical pregnancy rate, could be observed in women with severe ovarian hyperstimulation syndrome (OHSS) in those who did and did not have liver dysfunction. Twenty-nine in-vitro fertilization patients with severe OHSS were included. The patients were divided into the normal liver function tests (LFT) group (n = 14) and the abnormal LFT group (n = 15) according to the LFT on day of admission. Periodic measurements of serum interleukin (IL)-6, IL-8, tumour necrosis factor-alpha (TNF-alpha), VEGF, oestradiol, progesterone concentrations, and LFT were performed during hospitalization. Concentrations of IL-6 in the active phase of OHSS were significantly higher in the abnormal LFT group than in the normal LFT group (19.7 +/- 15.7 versus 8.1 +/- 7.0 pg/ml, respectively). The severity of liver dysfunction was not correlated with concentrations of oestradiol, progesterone, haematocrit, white blood cell counts, or any studied cytokine. The clinical pregnancy rate was significantly lower in the abnormal LFT group (46.7%) than in the normal LFT group (85.7%). These results suggest that IL-6 cytokine system may play a role in the pathogenesis of liver dysfunction in severe OHSS. Abnormal LFT were associated with lower clinical pregnancy rates.


Complete evaluation of the child identified as a poor listener.
With increasing awareness among educators of the importance of early identification of hearing impairment, growing numbers of children are being referred for evaluation when a teacher or day care supervisor perceives that a child is having difficulty listening. Some children who manifest difficulty listening in a pre-school play group or the classroom may have conductive or sensorineural hearing loss, while others have normal hearing with an underlying and yet-to-be-detected behavioral or psychoeducational disorder. This report presents suggestions for evaluation of the child referred for difficulty listening. The otologist should consider that a child may have an attention deficit disorder when results of initial audiologic assessment indicate there is no hearing loss or when the degree of hearing loss appears to be small in relation to the degree of inattentiveness that has been observed. The features of Attention-deficit Hyperactivity Disorder (ADHD) and Specific Developmental Disorder (SDD) are described, and illustrative case studies are presented. Clues to diagnosis are provided and a distinction between overlapping disorders is made.


[Efficacy of pralsetinib in a patient with advanced lung adenocarcinoma positive for RET rearrangement: the importance of Comprehensive Genomic Profiling.]
Modern gene profiling techniques have allowed in recent years considerable progresses in the knowledge of molecular alterations in the context of non-small cell lung cancer (NSCLC). In some cases, these alterations have been recognized as having a pathogenic role and targeted therapies capable of inhibiting tumor proliferation by selective and specific blocking of the enzymatic activity of the related abnormal proteins have been developed. This has made it possible to improve the effectiveness of the treatments by minimizing toxicity. Today it is essential to apply Comprehensive Genomic Profiling methods also in clinical practice, in order to allow the best treatment available for each patient, possibly also in the context of clinical trials. Below we report the clinical history of a patient with advanced stage adenocarcinoma of the lung with molecular diagnosis of RET fusion, treated with pralsetinib with excellent clinical and radiological response and good tolerability. This clinical case emphasizes the importance of the broader molecular profiling in patients with advanced NSCLC (especially for non-squamous histology) from the diagnosis before starting first-line treatment.


The Contribution of PEG Molecular Weights in PEGylated Emulsions to the Various Phases in the Accelerated Blood Clearance (ABC) Phenomenon in Rats.
PEGylated preparations will be cleared rapidly from blood circulation when they are administrated twice in the same animal at a time interval, referred to as the "accelerated blood clearance" (ABC) phenomenon. Commonly, the study of the ABC phenomenon was investigated in two aspects: induction phase and effectuation phase. Herein, we report the influence of physicochemical properties (PEG molecular weights) in the induction phase and effectuation phase on the ABC phenomenon. In the experiment, on one hand, PEGylated emulsions with different molecular weights of PEG (refer to PEn, n = 400, 600, 800, 1000, 2000, and 5000) were injected for the first dose (induction phase) and induced PE2000 to produce ABC phenomenon. On the other hand, after PE2000 injected, PEn was injected for the second dose (effectuation phase). The results indicated that PE2000 and PE5000 induced an intense ABC phenomenon by their long-circulating characteristic. Interestingly, PE400, PE600, PE800, and PE1000 produced a consistent ABC phenomenon but different circulation time. Apparently, the induction of the ABC phenomenon is not only determined by the circulation time but also by the PEG molecular weights. When PEn is in the effectuation phase, the extent of the ABC phenomenon was not positively related to the molecular weights of PEG, increasing first and then weaken with the increase of molecular weights of PEG. These suggest that the number of -(CH2CH2O)n- repeat units of PE2000 was more conducive to interact with anti-PEG IgM. The results reported here clearly indicate that both the PEG molecular weights of prior dose and the subsequent dose of emulsion strongly influence the extent of the ABC phenomenon. Taken together, our observations in this study complete the effect of PEG molecular weights at a different phase of the ABC phenomenon. Furthermore, our findings have a significant impact on the choice of molecular weights for PEGylated formulations for use in cross-administration.


Walking for health during pregnancy: A literature review and considerations for future research.
Walking is the most commonly chosen type of physical activity (PA) during pregnancy and provides several health benefits to both mother and child. National initiatives have promoted the importance of walking in general, but little emphasis is directed toward pregnant women, the majority of whom are insufficiently active. Pregnant women face a variety of dynamic barriers to a physically active lifestyle, some of which are more commonly experienced during specific times throughout the pregnancy experience. Walking is unique in that it appears resistant to a number of these barriers that limit other types of PA participation, and it can be meaningfully integrated into some transportation and occupational activities when leisure-time options are unavailable. Preliminary intervention work suggests that walking programs can be effectively adopted into a typical pregnancy lifestyle. However, a great deal of work remains to administer successful pregnancy walking interventions, including developing and using validated methods of PA and walking assessment. This narrative review discusses the unique advantages of walking during pregnancy, provides recommendations for future intervention work, and outlines the need for pregnancy-focused community walking initiatives. Standard search procedures were followed to determine sources from the literature specific to walking during pregnancy for use in each section of this review.


Development of a Handheld Line Information Reader and Generator for Efficient Management of Optical Communication Lines.
A handheld line information reader and a line information generator were developed for the efficient management of optical communication lines. The line information reader consists of a photo diode, trans-impedance amplifier, voltage amplifier, microcontroller unit, display panel, and communication modules. The line information generator consists of a laser diode, laser driving circuits, microcontroller unit, and communication modules. The line information reader can detect the optical radiation field of the test line by bending the optical fiber. To enhance the sensitivity of the line information reader, an additional lens was used with a focal length of 4.51 mm. Moreover, the simulation results obtained through BeamPROP® software from Synopsys, Inc. demonstrated a stronger optical radiation field of the fiber due to a longer transmission wavelength and larger bending angle of the fiber. Therefore, the developed devices can be considered as useful tools for the efficient management of optical communication lines.


A novel variant of the immunoglobulin fold in surface adhesins of Staphylococcus aureus: crystal structure of the fibrinogen-binding MSCRAMM, clumping factor A.
We report here the crystal structure of the minimal ligand-binding segment of the Staphylococcus aureus MSCRAMM, clumping factor A. This fibrinogen-binding segment contains two similarly folded domains. The fold observed is a new variant of the immunoglobulin motif that we have called DE-variant or the DEv-IgG fold. This subgroup includes the ligand-binding domain of the collagen-binding S.aureus MSCRAMM CNA, and many other structures previously classified as jelly rolls. Structure predictions suggest that the four fibrinogen-binding S.aureus MSCRAMMs identified so far would also contain the same DEv-IgG fold. A systematic docking search using the C-terminal region of the fibrinogen gamma-chain as a probe suggested that a hydrophobic pocket formed between the two DEv-IgG domains of the clumping factor as the ligand-binding site. Mutagenic substitution of residues Tyr256, Pro336, Tyr338 and Lys389 in the clumping factor, which are proposed to contact the terminal residues (408)AGDV(411) of the gamma-chain, resulted in proteins with no or markedly reduced affinity for fibrinogen.


Effects of 3,4-methylenedioxymethamphetamine administration on retinal physiology in the rat.
3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) is known to produce euphoric states, but may also cause adverse consequences in humans, such as hyperthermia and neurocognitive deficits. Although MDMA consumption has been associated with visual problems, the effects of this recreational drug in retinal physiology have not been addressed hitherto. In this work, we evaluated the effect of a single MDMA administration in the rat electroretinogram (ERG). Wistar rats were administered MDMA (15 mg/kg) or saline and ERGs were recorded before (Baseline ERG), and 3 h, 24 h, and 7 days after treatment. A high temperature (HT) saline-treated control group was also included. Overall, significantly augmented and shorter latency ERG responses were found in MDMA and HT groups 3 h after treatment when compared to Baseline. Twenty-four hours after treatment some of the alterations found at 3 h, mainly characterized by shorter latency, tended to return to Baseline values. However, MDMA-treated animals still presented increased scotopic a-wave and b-wave amplitudes compared to Baseline ERGs, which were independent of temperature elevation though the latter might underlie the acute ERG alterations observed 3 h after MDMA administration. Seven days after MDMA administration recovery from these effects had occurred. The effects seem to stem from specific changes observed at the a-wave level, which indicates that MDMA affects subacutely (at 24 h) retinal physiology at the outer retinal (photoreceptor/bipolar) layers. In conclusion, we have found direct evidence that MDMA causes subacute enhancement of the outer retinal responses (most prominent in the a-wave), though ERG alterations resume within one week. These changes in photoreceptor/bipolar cell physiology may have implications for the understanding of the subacute visual manifestations induced by MDMA in humans.


[Isolated retrograde amnesia following viral encephalitis].
We describe a patient who presented with isolated retrograde amnesia of 2-year duration after recovery from viral encephalitis. The patient was a 29-year-old right-handed male dentist and was admitted to our hospital with a complaint of generalized convulsion. Cerebrospinal fluid (CSF) showed mononuclear pleocytosis. Neuroradiological examinations (X-ray CT, MRI and 123I-IMP SPECT) revealed no significant abnormality. Immunological method showed no specific increase of viral antibody titers. However, with a tentative diagnosis of viral encephalitis, administration of acyclovir was started. After 3 weeks he became comprehensive, and several kinds of neuropsychological tests were performed. His intelligence and immediate memory were normal, and his procedural memory of dentist was intact. On the other hand, he could not recall any information about events, both personal and public, occurred within 2 years before the onset of present illness. His autobiographical memory disorder was also demonstrated using a series of weekly comic. In isolated retrograde amnesia following viral encephalitis like this case, memory of relatively short time duration, acquired prior to the onset of present illness, tend to be disturbed.


The troubled HMO industry: what's next?
The fortunes of health maintenance organizations (HMOs) have been on a roller coaster ride for the last 15 years. Growth rates in the number and total enrollments of HMOs surged in 1973 and 1974 following passage of the federal HMO Act. Growth rates abated over the next 8 years. Several favorable factors converged in 1983 to push growth rates back up. Some 15 for-profit HMO companies went public with initial stock offerings during the 1983-85 period. Their stock prices soared as they compiled astounding records of enrollment, revenue and profit growth. In the next 2 years, however, stock prices dropped as quickly as they had risen. Intense price competition and inexperienced managers were important factors contributing to sharp descents in HMO earnings in 1986 and 1987. Some analysts now see positive signs pointing to an industry recovery. However, investors are not convinced of this as HMO stock prices remain severely depressed.


Aloe vera and ofloxacin incorporated chitosan hydrogels show antibacterial activity, stimulate angiogenesis and accelerate wound healing in full thickness rat model.
Burns are potentially fatal and physically debilitating injuries, causing psychological and physical scars and result in chronic disabilities. A well vascularized wound bed is required to achieve complete and scar free wound closure. For many centuries, a variety of herbal plants have been used for wound healing, among these aloe vera (AV) has been found to be very effective in wound healing. Secondly, the main reason for delayed wound healing is bacterial infections. Ofloxacin (OX) has been reported as an active antibacterial drug for topical infections and it is effective against both positive and negative bacterial strains. In current research three different concentrations of OX (0.5, 2.5, and 5 mg) were loaded into chitosan (CS)/AV based hydrogels prepared by freeze gelation. The surface morphology of prepared CS/AV based OX loaded hydrogels were evaluated by scanning electron microscopy (SEM). In drug release analysis, 0.5 mg OX loaded hydrogel showed a sustained drug release behavior over 3 days period. An effective dose dependent antibacterial activity was exhibited by OX loaded hydrogels. Alamar Blue cells viability assay revealed that 0.5 mg OX hydrogel (CA 0.5 OX) showed comparatively better 3 T3 fibroblast cells proliferation as compared to CA 2.5 OX (2.5 mg OX) and CA 5 OX hydrogel (5 mg OX). Moreover, all OX loaded hydrogels showed good angiogenic activity in CAM bioassay while higher angiogenic potential was observed from CA 0.5 OX containing comparatively lower concentration of OX. These OX incorporated CS/AV based hydrogels are promising wound dressings for future clinical use.


Pib2 and the EGO complex are both required for activation of TORC1.
The TORC1 complex is a key regulator of cell growth and metabolism in Saccharomyces cerevisiae The vacuole-associated EGO complex couples activation of TORC1 to the availability of amino acids, specifically glutamine and leucine. The EGO complex is also essential for reactivation of TORC1 following rapamycin-induced growth arrest and for its distribution on the vacuolar membrane. Pib2, a FYVE-containing phosphatidylinositol 3-phosphate (PI3P)-binding protein, is a newly discovered and poorly characterized activator of TORC1. Here, we show that Pib2 is required for reactivation of TORC1 following rapamycin-induced growth arrest. Pib2 is required for EGO complex-mediated activation of TORC1 by glutamine and leucine as well as for redistribution of Tor1 on the vacuolar membrane. Therefore, Pib2 and the EGO complex cooperate to activate TORC1 and connect phosphoinositide 3-kinase (PI3K) signaling and TORC1 activity.


Development of Endoplasmic Reticulum and Glyoxysomal Membrane Redox Activities during Castor Bean Germination.
Redox activities, NADH:ferricyanide reductase, NAD(P)H:cytochrome reductases, and NADH:ascorbate free-radical reductase, are present in endoplasmic reticulum (ER) and glyoxysomal membranes from the endosperm of germinating castor bean (Ricinus comminus L. var Hale). The development of these functions was followed in glyoxysomes and ER isolated on sucrose gradients from castor bean endosperm daily from 0 through 6 days of germination. On a per seed basis, glyoxysomal and ER protein, glyoxysomal and ER membrane redox enzyme activities, and glyoxylate cycle activities peaked at day 4 as did the ER membrane content of cytochrome P-450. NADH:ferricyanide reductase was present in glyoxysomes and ER isolated from dry seed. This activity increased only about twofold in glyoxysomes and threefold in ER during germination relative to the amount of protein in the respective fractions. The other reductases, NADH:cytochrome reductase and NADH:ascorbate free-radical reductase, increased about 10-fold in the ER relative to protein up to 4 to 5 days, then declined. NADPH:cytochrome reductase reached maximum activity relative to protein at day 2 in both organelles. The increases in redox activities during germination indicate that the membranes of the ER and glyoxysome are being enriched with redox proteins during their development. The development of redox functions in glyoxysomes was found to be coordinated with development of the glyoxylate cycle.


Milk-borne hormones: possible tools of communication between mother and suckling.
Early studies suggested endocrine type mother-pup interaction: 131I administered to suckling rats appeared via the urine of the suckling and mother's milk in the circulation of litter mates who were not injected with iodine; levels of thyroxin in rat milk were influenced by the status of the thyroid gland of the lactating rat. Administration of TRH (thyrotropin releasing hormone) to lactating mothers led to an appearance of unaltered hormones in the milk and stomach content of sucklings. TSH (thyroid stimulating hormone) or ACTH (adrenocorticotropic hormone) when given orogastrically to suckling rats increased thyroid hormones and corticosterone serum levels in suckling rats. Functional effects of gastrointestinal administration of insulin, bombesin (mammalian analog of gastrin-releasing peptide) and epidermal growth factor (EGF) are reviewed in detail (32 references).


Clinical course of the untreated calcified big cerebellar liponeurocytoma.
Cerebellar liponeurocytoma (CLN) is a very rare tumor of central nervous system, classified as glioneuronal tumor by the latest classification of World Health Organization (WHO) in 2016. There are limited data in the literature about biologic behavior, growth pattern and radiological features of this tumor. In this case report, we operated a big calcified CLN patient who had denied any surgical procedures suggested by an another institute and had been followed for 4 years.


Gonadotropins and steroid hormones in older people: their mutual connections and relations to body mass indices.
Aging in mammals, including man, is accompanied by deep changes in hormone secretion. In the majority of cases, hormone secretion (mostly of gonadal steroids and adrenocortical hormone dehydroepiandrosterone - DHEA) undergoes pronounced decrease. This decrease is thought to contribute to the progression of aging. In contrast, the secretion of gonadotropins is sharply increased in older adults, as a result of gonadal deficiency. Recent data indicate that gonadotropin excess may also, by itself, influence the aging process. The aim of the present study was to investigate the mutual relation between steroid hormones and gonadotropins and their effect on body mass indices in older people. In a group of 100 patients (61 women and 39 men) aged over 75 years, blood serum concentrations of folliclestimulating hormone (FSH), luteinising hormone (LH), oestradiol (E2), testosterone, dehydroepiandrosterone sulphate (DHEAs), and cortisol were measured. All the patients were measured for the following: body weight (kg), body mass index (BMI) (kg/m²), and waist-to-height ratio (WtHR). The differences of the numerical data were evaluated by Student's t-test and the correlations between them by means of Pearson's test. The most interesting finding of this study was to show that FSH and LH are negatively correlated with body mass and indices such as BMI and WtHR in older women. Because in older women the mediation of ovary is unlikely, we conclude that gonadotropins may influence the body mass by their direct extra-gonadal action.


Specific detection of mousepox virus by polymerase chain reaction.
Polymerase chain reaction was applied to the rapid identification and detection of mousepox virus. This was accomplished by selection of primers targeting the A-type inclusion body protein gene. By investigating 20 strains belonging to five different species of the genus Orthopoxvirus, amplification was achieved only with the seven mousepox virus strains examined. The size of the resulting DNA fragment accounted for 116 base pairs and contained a recognition site for the restriction enzyme HindII, thus confirming its viral origin. Amplification of mousepox virus specific sequences was also possible from infected mouse lung tissue and serum.


The role of the ventro-lateral prefrontal cortex in idiom comprehension: An rTMS study.
Previous research is equivocal with respect to the neural substrates of idiom processing. Particularly elusive is the role of the left ventro-lateral prefrontal cortex (VLPFC), a region implicated in semantic control generally. Although fMRI studies have shown that the left VLPFC is active during idiom processing (see Rapp et al. (2012), for review), rTMS studies have failed to corroborate a clear role of this prefrontal region (e.g., Oliveri et al., 2004). We investigated this issue using a semantic meaningfulness judgment task that compared idiom comprehension following rTMS-stimulation to the left VLPFC relative to a control site (vertex). We also investigated whether individual differences in general cognitive capacity among comprehenders modulated the effects of rTMS. The results indicate that left VLPFC stimulation particularly affected the processing of low-familiar idioms, possibly because these items involve a maximal semantic conflict between a salient literal and less-known figurative meaning. Of note, this pattern only emerged for comprehenders with higher cognitive control capacity, possibly because they were more likely to activate or maintain multiple semantic representations during idiom processing, which required VLPFC integrity. Taken together, the results support the importance of the left VLPFC to idiom processing.


Cardiac tamponade--a rare complication in acute pancreatitis.
A patient with recurrent acute pancreatitis developed pericardial effusion and cardiac tamponade. His systolic blood pressure fell to 70 mmHg and sinus tachycardia (150/min) developed. The central venous pressure rose from 3 cm H2O to 27 cm H2O. A chest radiograph showed an enlargement of the cardiac shadow. Pericardial paracentesis was performed and 300 ml fluid was aspirated. This produced rapid clinical improvement. The literature related to this uncommon complication is reviewed and possible pathogenetic mechanisms are discussed.


Aryl sulfoxides from allyl sulfoxides via [2,3]-sigmatropic rearrangement and domino Pd-catalyzed generation/arylation of sulfenate anions.
Allylic sulfoxides, via [2,3]-sigmatropic rearrangement and oxidative addition of the resulting allylic sulfenate esters to Pd(0), are found to be excellent precursors of sulfenate anions. This hitherto unknown reactivity is applied in a new Pd(0)-catalyzed domino sequence involving sulfenate anion generation followed by arylation to afford aryl sulfoxides.


Femtomole Infrared Spectroscopy at the Electrified Metal-Solution Interface.
Characterization of surface adsorbed species using infrared (IR) spectroscopy provides valuable information concerning interfacial chemical and physical processes. However, in situ infrared studies of surface areas approaching the IR diffraction limit, such as micrometer scale electrodes, require a hitherto unrealized means to obtain high signal-to-noise (S/N) spectra from femtomole quantities of adsorbed molecules. A major methodological breakthrough is described that couples the high brilliance of synchrotron-sourced infrared microscopy with attenuated total reflection surface enhanced infrared spectroscopy (ATR-SEIRAS). The method is shown to allow the spectral measurement of a monolayer of 4-methoxypyridine (MOP) adsorbed on a surface enhancing gold film electrode under fully operational electrochemistry conditions. A factor of 15 noise improvement is achieved with small apertures using synchrotron IR relative to a thermal IR source. The very low noise levels allow the measurement of high quality IR spectra of 2.5 fmol of molecules confined to a 125 μm2 beam spot.


A Call to Action to Develop Integrated Curricula in Cardiorenal Medicine.
With the adoption of the new definition and classification of cardiorenal syndrome (CRS) and its relevant subtypes, much attention has been placed on elucidating the mechanisms of heart and kidney interactions. Of great interest are the pathophysiological pathways by which acute heart failure may result in acute kidney injury (AKI; type 1), chronic heart failure accelerating the progression of chronic kidney disease (CKD; type 2), AKI provoking cardiac events (type 3), and CKD increasing the risk and severity of cardiovascular disease (type 4). A remarkable interest has also been placed on the acute and chronic systemic conditions, such as sepsis and diabetes, which simultaneously affect heart and kidney function (type 5). Furthermore, the physiology of acute and chronic heart-kidney cross talk is drawing attention to hemodynamics (fluids, pressures, flows, resistances, perfusion), physiochemical (electrolytes, pH, and toxins), and biological (inflammation, immune system activation, neurohormonal signals) processes. Common clinical scenarios call for recognition, knowledge, and skill in managing CRS. There is a clear need for medical and surgical specialists that are well versed in the pathophysiology and the clinical manifestations that arise in the setting of CRS. With this editorial, we are making a call to action to stimulate universities, medical schools, and teaching hospitals to create a core curriculum for cardiorenal medicine to better equip the physicians of the future for these common, serious, and frequently fatal syndromes.


Association between serum cathepsin S and mortality in older adults.
Experimental data suggest that cathepsin S, a cysteine protease, is involved in the complex pathways leading to cardiovascular disease and cancer. However, prospective data concerning a potential association between circulating cathepsin S levels and mortality are lacking. To investigate associations between circulating cathepsin S levels and mortality in 2 independent cohorts of elderly men and women. Prospective study using 2 community-based cohorts, the Uppsala Longitudinal Study of Adult Men (ULSAM; n = 1009; mean age: 71 years; baseline period: 1991-1995; median follow-up: 12.6 years; end of follow-up: 2006) and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; n = 987; 50% women; mean age: 70 years; baseline period: 2001-2004; median follow-up: 7.9 years; end of follow-up: 2010). Serum samples were used to measure cathepsin S. Total mortality. During follow-up, 413 participants died in the ULSAM cohort (incidence rate: 3.59/100 person-years at risk) and 100 participants died in the PIVUS cohort (incidence rate: 1.32/100 person-years at risk). In multivariable Cox regression models adjusted for age, systolic blood pressure, diabetes, smoking status, body mass index, total cholesterol, high-density lipoprotein cholesterol, antihypertensive treatment, lipid-lowering treatment, and history of cardiovascular disease, higher serum cathepsin S was associated with an increased risk for mortality (ULSAM cohort: hazard ratio [HR] for 1-unit increase of cathepsin S, 1.04 [95% CI, 1.01-1.06], P = .009; PIVUS cohort: HR for 1-unit increase of cathepsin S, 1.03 [95% CI, 1.00-1.07], P = .04). In the ULSAM cohort, serum cathepsin S also was associated with cardiovascular mortality (131 deaths; HR for quintile 5 vs quintiles 1-4, 1.62 [95% CI, 1.11-2.37]; P = .01) and cancer mortality (148 deaths; HR for 1-unit increase of cathepsin S, 1.05 [95% CI, 1.01-1.10]; P = .01). Among elderly individuals in 2 independent cohorts, higher serum cathepsin S levels were associated with increased mortality risk. Additional research is needed to delineate the role of cathepsin S and whether its measurement might have clinical utility.


Commitment to a world without cancer.
The author is a layperson, health educator, and political oncologist who is, in addition to her work at the cancer center at UCLA, a long-time volunteer with the American Cancer Society. She has served the National Cancer Institute as a member of the National Cancer Advisory Board and is currently a member of its Board of Scientific Counselors, Division of Cancer Control. In these various roles she was part of the lay leadership that influenced and cooperated with the Nixon administration in its efforts to pass the National Cancer Act of 1971. She has participated continually in the implementation of the National Cancer Program and Act since 1971. This essay reviews the history of our nation's support of cancer research, commencing with the founding of the American Cancer Society. It considers the factors that led to the passage of the National Cancer Act in 1971. It then comments on the interaction between universities, the National Cancer Institute, and the Cancer Act, which has produced the "cancer business" that has come of age since the Cancer Act was passed. This commentary does not review the advances made in research and clinical practice as a result of the passage of the National Cancer Act of 1971. Others, better qualified, will do that in this journal and in other publications as well. These views are concerned with the process, the systems, and ancillary activities that have developed as a consequence of the national will to conquer cancer. They are meant to highlight several portions of the whole. The "seeds" of cancer consciousness sown early by the American Cancer Society and those so firmly planted in research and in the creation of a national network of researchers, patient care institutions, and information systems by the National Cancer Institute and the National Cancer Program Plan and Act of 1971 have reaped a harvest of independent programs and even businesses that have given substance to the hopes of those seeking to achieve a world without cancer.


Early-life social environment predicts social network position in wild zebra finches.
Early-life experience can fundamentally shape individual life-history trajectories. Previous research has suggested that exposure to stress during development causes differences in social behaviour later in life. In captivity, juvenile zebra finches exposed to elevated corticosterone levels were less socially choosy and more central in their social networks when compared to untreated siblings. These differences extended to other aspects of social life, with 'stress-exposed' juveniles switching social learning strategies and juvenile males less faithfully learning their father's song. However, while this body of research suggests that the impacts of early-life stress could be profound, it remains unknown whether such effects are strong enough to be expressed under natural conditions. Here, we collected data on social associations of zebra finches in the Australian desert after experimentally manipulating brood sizes. Juveniles from enlarged broods experienced heightened sibling competition, and we predicted that they would express similar patterns of social associations to stress-treated birds in the captive study by having more, but less differentiated, relationships. We show striking support for the suggested consequences of developmental stress on social network positions, with our data from the wild replicating the same results in 9 out of 10 predictions previously tested in captivity. Chicks raised in enlarged broods foraged with greater numbers of conspecifics but were less 'choosy' and more central in the social network. Our results confirm that the natural range of variation in early-life experience can be sufficient to predict individuals' social trajectories and support theory highlighting the potential importance of developmental conditions on behaviour.


Non-invasive evaluation of liver fibrosis: a comparison of ultrasound-based transient elastography and MR elastography in patients with viral hepatitis B and C.
To compare the diagnostic accuracy of TE and MRE and establish cutoff levels and diagnostic strategies for both techniques, enabling selection of patients for liver biopsy. One hundred three patients with chronic hepatitis B or C and liver biopsy were prospectively included. Areas under curves (AUROC) were compared for TE and MRE for METAVIR fibrosis grade ≥ F2 and ≥F3. We defined cutoff values for selection of patients with F0-F1 (sensitivity >95%) and for significant fibrosis F2-F4 (specificity >95%). Following exclusions, 85 patients were analysed (65 CHB, 19 CHC, 1 co-infected). Fibrosis stages were F0 (n = 3), F1 (n = 53), F2 (n = 15), F3 (n = 8) and F4 (n = 6). TE and MRE accuracy were comparable [AUROCTE ≥ F2: 0.914 (95% CI: 0.857-0.972) vs. AUROCMRE ≥ F2: 0.909 (0.840-0.977), P = 0.89; AUROCTE ≥ F3: 0.895 (0.816-0.974) vs. AUROCMRE ≥ F3: 0.928 (0.874-0.982), P = 0.42]. Cutoff values of <5.2 and ≥8.9 kPa (TE) and <1.66 and ≥2.18 kPa (MRE) diagnosed 64% and 66% of patients correctly as F0-F1 or F2-F4. A conditional strategy in inconclusive test results increased diagnostic yield to 80%. TE and MRE have comparable accuracy for detecting significant fibrosis, which was reliably detected or excluded in two-thirds of patients. A conditional strategy further increased diagnostic yield to 80%. • Both ultrasound-based transient elastography and magnetic resonance elastography can assess hepatic fibrosis. • Both have comparable accuracy for detecting liver fibrosis in viral hepatitis. • The individual techniques reliably detect or exclude significant liver fibrosis in 66 %. • A conditional strategy for inconclusive findings increases the number of correct diagnoses.


Inhibiting autophagy promotes endoplasmic reticulum stress and the ROS‑induced nod‑like receptor 3‑dependent proinflammatory response in HepG2 cells.
Inflammation and endoplasmic reticulum (ER) stress are key contributors to insulin resistance and metabolic disease, and interleukin (IL)‑1β is involved in insulin resistance. The present study aimed to investigated the role of autophagy in LPS‑induced ER stress and inflammation, which may provide evidence for controlling metabolic disease associated with inflammation. Lipopolysaccharide (LPS) induced the activation of ER stress and the nod‑like receptor 3‑dependent expression of IL‑1β and caspase‑1, as shown by western blotting, which contributed to HepG2 cell death. This also involved the generation of mitochondrial reactive oxygen species and the autophagy signaling response, which are derived from the ER stress pathway. The percentage of apoptotic cells was measured by flow cytometry with fluorescein isothiocyanate/propidium iodide staining. Reactive oxygen species formation was detected by flow cytometry using the peroxide sensitive fluorescent probe 2',7'‑dichlorofluorescin diacetate. Autophagy activation was measured by western blotting and confirmed using transmission electron microscopy. Furthermore, inhibiting autophagy promoted ER stress and the proinflammatory response in addition to cell death. These findings provide insights into the protective role of autophagy in LPS‑induced cell death and ER stress, and further identified the association of autophagy, ER stress and inflammation in HepG2 cells.


The Fate and Transport of Chlorinated Polyfluorinated Ether Sulfonates and Other PFAS through Industrial Wastewater Treatment Facilities in China.
Wastewater from certain industrial processes can be primary emission sources of per- and polyfluoroalkyl substances (PFAS) and fluorinated alternatives like chlorinated polyfluorinated ether sulfonates (Cl-PFESA). Two such industrial processes are electroplating and textile printing and dyeing (PD). This study focused on the fate of Cl-PFESA in wastewater from these two industrial processes, in comparison to other PFAS, as they went through different wastewater treatment plants located in southeast China. The total target PFAS concentrations were 520 ± 30 and 4200 ± 270 ng/L at the effluents of the PD WWTP and electroplating WWTP, respectively. Specifically, 6:2 Cl-PFESA (18%) and 8:2 Cl-PFESA (0.7%) were abundant in electroplating-wastewater. Cl-PFESA were also detected in PD wastewater but at trace concentrations and were likely present due to diffuse emissions. The dissolved-phase Cl-PFESA and PFAS mass flows through the WWTPs were fairly constant throughout both facilities. The majority of Cl-PFESA was captured by sludge sedimentation. However, there were individual treatment processes that could cause the wastewater concentrations to fluctuate, and also could lead to relative enrichment of specific Cl-PFESAs as indicated by the 6:2/8:2 Cl-PFESA ratios. Cl-PFESA and perfluoroalkyl sulfonic acids were more influenced by the investigated treatment processes than perfluorocarboxylic acids.


The role of IRAK1 in breast cancer patients treated with neoadjuvant chemotherapy.
IRAK1 has been shown to be abnormally expressed in a set of tumors leading to tumorigenesis and progression. IRAK1 is a therapeutic target that drives breast cancer metastasis and resistance to paclitaxel. However, the exact role of IRAK1 in neoadjuvant chemotherapy (NCT) for breast cancer remains unclear. The aim of this study was to investigate the relationship between the expression of IRAK1 and the clinicopathological parameters and survival prognosis of breast cancer patients treated with NCT. Based on the clinical data and mRNA microarray data from 1,085 breast cancer patients in The Cancer Genome Atlas, the correlation between IRAK1 expression and clinicopathological parameters of breast cancer was analyzed. Immunohistochemistry was performed to evaluate the expression of IRAK1. The Human Protein Atlas and the String database were used to analyze the expression of IRAK1 protein and its interaction with altered neighboring proteins in breast cancer. IRAK1 alteration was analyzed in cBioPortal database. GEO enrichment of IRAK1 was performed using WEB-based Gene SeT AnaLysis Toolkit. The expression of IRAK1 was significantly downregulated following NCT. The decreased expression of IRAK1 following NCT was positively correlated with reduced tumor size. Finally, survival analysis confirmed that a shorter survival period was correlated to higher expression of IRAK1 both before and after NCT. These findings advanced our understanding about the expression pattern of IRAK1 in breast cancer, especially in those patients who were treated with NCT, suggesting that IRAK1 could be used as a prognostic indicator, as well as a potential indicator for evaluating NCT efficacy for breast cancer patients.


[Genetic base of heart diseases].
Progress in understanding of human genome enables the researches to reveal genetic basis of many disorders, including genetic heart diseases--defects developed by genetic disorders. The most frequent causes of genetic diseases are defects of many genes (e.g., a correlation has been observed between arterial hypertension and mutations in ACE and ADD1 genes). Moreover, a defect of single gene can be connected with several disorders (e.g., mutations in preseniline genes observed in Alzheimer disease and dilated cardiomyopathy). On the other hand, mutations in genes coding elements of particular signaling pathway can cause similar disorders (mutations in different components of RAS-MAPK pathway cause such disorders as Noonan syndrome, LEOPARD syndrome, Costello syndrome and CFC). The ability to identify genetic markers connected with heart diseases may contribute to the improvement of diagnostic and treatment of such disorders.


CD18 antibody treatment limits early myocardial reperfusion injury after initial leukocyte deposition.
Following myocardial ischemia, initial reperfusion with whole blood impairs the recovery of ventricular function. The exact mechanisms underlying early myocardial reperfusion injury are not clear, but leukocytes play an important role. In this study, we tested if treating the initial blood reperfusate with a monoclonal antibody (CL26) against the leukocyte adhesion protein (CD18 would reduce the leukocyte contribution to early reperfusion injury. We reasoned that blocking CD18 would reduce the initial retention of leukocytes in the heart and thereby limit the inflammatory response. Rat hearts were isolated and perfused at constant flow with a red cell-rich solution (K2RBC). The perfusate was not recirculated. Baseline measures were made of coronary flow, perfusion pressure, and ventricular pump function. No-flow, normothermic ischemia was induced for 30 min, followed immediately by reperfusion, at the preischemic flowrate, with diluted whole blood (DWB, treated with either vehicle or CL26). Reperfusion was continued with K2RBC for 40 min more, during which postischemic measures were made. We found that the cardiac retention of leukocytes was not significantly different for the two groups, nor were the recoveries of ventricular function. Later in reperfusion (R35), the coronary blood flowrate and the coronary vascular resistances were not different; however, the recoveries of ventricular pump function were significantly different (+dP/dt @ R35 (%Pre-I): Vehicle: 27 +/- 9% (n = 8); CL26: 51 +/- 6% (n = 7); P < 0.05). Also, at R35, the voltage required to capture and pace the vehicle-treated hearts was significantly greater than the voltage required to pace the CL26 hearts (P < 0.05). Because the coronary flowrate and leukocyte retention were similar for both groups, the improved recovery observed in the CL26-treated group was not due to either improved flow or to reduced leukocyte retention. Rather, the findings suggest that the beneficial effect of antibody treatment was to attenuate step(s) in the acute inflammatory response that occurred after the initial deposition of leukocytes in the heart.