Media attention and public perceptions of cancer and eastern equine encephalitis.
Previous research has found that members of the public have a skewed sense of health risk. The purpose of this research was to investigate how mass media use influences perceptions of threat from cancer and eastern equine encephalitis (EEE). Investigators performed a media content analysis of 253 health-related articles from 11 Massachusetts newspapers, then used logistic regression to analyze responses to a health communication survey of 613 Massachusetts adults. A greater proportion of cancer articles compared to those about EEE mentioned progress in combating the disease (61.0% vs. 16.2%, P < 0.0001), while a greater proportion of EEE articles mentioned new incidents of illness (35.4%, vs. 4.6% P < 0.0001). Over half of all respondents perceived EEE as an equal or greater threat than cancer. Paying a lot of attention to health media was related to higher odds of perceiving EEE as a threat (OR 2.14; 95% CI 1.03-4.45), and of perceiving EEE as a threat compared to cancer (OR 2.18; 95% CI 1.24-3.84). Media treatment of health stories that emphasize the novelty and unpredictability of EEE compared to cancer may lead to distorted perceptions of threat among news consumers.


Zinc deficiency and methylbenzylnitrosamine-induced esophageal cancer in rats.
Dietary zinc deficiency increases the incidence of and shortens the lag time for induction of esophageal tumors in rats by methylbenzylnitrosamine (MBN). Groups of control and zinc-deficient outbred Charles River CD rats were given 24, 17, 8, or 4 doses of MBN, administered twice weekly by intragastric intubation at doses of 2 mg/kg body weight. Between 58 and 93 days after the beginning of treatment, all rats were killed and examined. The frequency of esophageal tumors in the zinc-deficient groups was significantly higher than in the corresponding control groups. Following ip injection of [methyl-14C]MBN, DNA and RNA of esophagus and liver were more noticeably labeled than kidney, lung, and small intestine, which exhibited only modest labeling. In vitro incubation with [14C]MBN of tissue slices from esophagus, liver, kidney, and small intestine produced similar results. This pattern correlates well with the results of our studies of MBN-induced esophageal tumorigenesis.


Anticardiolipin and antineutrophil antibodies in giant cell arteritis.
IgG anticardiolipin antibodies (aCL) were found in a patient with Takayasu's arteritis and then in 11 of 22 patients with temporal arteritis (TA) studied prospectively. In comparison IgG aCL were found in only one of 18 elderly controls with rheumatoid arthritis and one of 47 healthy elderly controls. In TA IgG aCL were more frequent in those with acute disease (8/12), in those with an accompanying history of polymyalgia rheumatica (9/13), p less than 0.05); and levels normalized with corticosteroid treatment. Antineutrophil cytoplasmic antibodies (c-ANCA) were present in one patient with TA who had no systemic disease.


Human pregnancy-specific beta 1-glycoproteins are coded within chromosome 19.
We have isolated and characterized cDNAs that code for apoproteins having amino acid sequences highly similar to pregnancy-specific beta 1-glycoproteins (PS beta G). cDNAs coding for PS beta Gs, as well as the cDNA clone reported here, are members of the carcinoembryonic antigen (CEA) gene family. The previous localization of CEA-related genes to human chromosome 19, and the high level of DNA sequence conservation in the CEA family, suggested that the PS beta G genes are also located on this chromosome. We demonstrate here that chromosome 19 is indeed the site of PS beta G sequences. Our finding is in contrast to the recently reported indication that pregnancy-specific glycoproteins are encoded in chromosomes X and 6.


Lack of Effectiveness of Neutropenic Diet and Social Restrictions as Anti-Infective Measures in Children With Acute Myeloid Leukemia: An Analysis of the AML-BFM 2004 Trial.
Although nonpharmacologic anti-infective measures are widely used in children treated for acute myeloid leukemia (AML), there is little evidence of their effectiveness. We analyzed infectious complications in children during intensive treatment of AML according to the AML-BFM 2004 trial and surveyed sites on institutional standards regarding recommended restrictions of social contacts (six items), pets (five items), and food (eight items). A scoring system was developed with a restriction score for each item. Multivariable Poisson regression adjusted for sex, age, weight group, risk stratification, and prophylactic antibiotics was used to estimate the impact of the restrictions on the incidence ratios of fever of unknown origin, bacteremia, pneumonia, and gastroenteritis. Data on recommendations of nonpharmacologic anti-infective measures and infectious complications were available in 339 patients treated in 37 institutions. Analyses did not demonstrate a significant benefit of any of the restrictions regarding food, social contacts, and pets on the risk of fever, bacteremia, pneumonia, and gastroenteritis. In contrast, age, weight group, risk stratification, and nonabsorbable antibiotics had some influence on infections complications. The lack of effectiveness of dietary restrictions and restrictions regarding social contacts and pets should result in reconsideration of anti-infective policies.


Extraction and characterization of mango peel pectin as pharmaceutical excipient.
Present study includes extraction and characterization the mango peel derived pectin as a pharmaceutical excipients. Pectin was obtained using acidified water based extraction in soxhlet apparatus. To characterize the extracted pectin phytochemical screening was done and micromeritic properties, flow behavior, surface tension, viscosity and swelling index were calculated. Using water based extraction method 25.26% yield of pectin was obtained. The result revealed the fact that extracted mango peel pectin exhibited good flow properties (angle of repose 28.01), 41.90 +/- 2.62 dynes/cm2 surface tension, 0.46% w/w total ash, 0.76% loss on drying and pH was found 4.15, showed that this can be used in dosage form, without any irritation. Extracted pectin was soluble in warm water while insoluble in organic solvents. Results of evaluated parameters showed that mango peel derived pectin can be used as pharmaceutical excipient to prepare solid oral dosage form.


Long-term effect of HCV eradication in patients with mixed cryoglobulinemia: a prospective, controlled, open-label, cohort study.
Limited data are available about the efficacy of antiviral treatment in hepatitis C virus (HCV)-associated mixed cryoglobulinemia (MC), especially concerning the long-term effects of HCV eradication. The aim of this study was to evaluate the influence of MC on the virological response and the long-term effects of viral eradication on MC. We prospectively enrolled 424 HCV(+) patients belonging to the following groups: MC syndrome (MCS)-HCV (121 patients with symptomatic MC), MC-HCV (132 patients with asymptomatic MC), and HCV (158 patients without MC). Pegylated interferon plus ribavirin treatment was administered according to standard protocols. Posttreatment follow-up ranged from 35 to 124 months (mean 92.5 months). A significant difference was observed in the rate of sustained virological response between the HCV group and both the MC-HCV (P = 0.009) and MC-HCV+MCS-HCV (P = 0.014) groups. Multivariate logistic regression analysis identified cryoglobulinemia as an independent prognostic factor of nonresponse. The clinical-immunological response in MCS-HCV correlated with the virological one. All patients with sustained virological response also experienced a sustained clinical response, either complete or partial. In the majority of sustained virological response patients all MCS symptoms persistently disappeared (36 patients, 57%); in only two (3%) did definite MCS persist. All virological nonresponders were also clinical nonresponders, in spite of a transient improvement in some cases. No evolution to lymphoma was observed. For the first time we have evaluated both the effects of interferon-based therapy on HCV patients with and without MC and with and without symptoms, as well as the long-term effects of viral eradication on MC. MC is a negative prognostic factor of virological response. Clearance of HCV led to persistent resolution or improvement of MCS, strongly suggesting the need for a next generation of highly effective antiviral drugs.


Association Between P2RX7 Gene and Hepatocellular Carcinoma Susceptibility: A Case-Control Study in a Chinese Han Population.
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common types of liver cancer. It is hypothesized that P2RX7 genetic polymorphisms have strong association with HCC susceptibility. Therefore, a case-control study was designed and performed to verify the association between P2RX7 gene polymorphisms and HCC susceptibility. MATERIAL AND METHODS A total of 646 subjects were recruited in our study, including 323 HCC patients and 323 healthy controls. Five gene polymorphisms, -762C>T (rs2393799), 946G>A (rs28360457), 1513A>C (rs3751143), 1068G>A (rs1718119), and 1096C>G (rs2230911), were selected. Odds ratio (ORs) and 95% confidence interval (CI) were used to quantify the association between P2RX7 gene polymorphisms and the susceptibility to HCC. All tests were performed using SPSS 20 and a 2-sided P value of less than 0.05 was considered to be statistically significant. RESULTS Our results suggest that allelic frequencies of these 5 SNPs all conformed to Hardy-Weinberg equilibrium (HWE). There was no significant difference in genotype and allele distributions of -762C>T and 1096C>G between the case group and the control group. However, an increased risk of HCC was associated with 946G>A (A vs. G: OR=1.48, 95%CI=1.09-2.01, P=0.013; GA+AA vs. GG: OR=1.46, 95%CI=1.03-2.07, P=0.033). A similar increased risk was associated with 1513A>C polymorphism (C vs. A: OR=1.37, 95%CI=1.05-1.79, P=0.021; AC+CC vs. AA: OR=1.40, 95%CI=1.01-1.93, P=0.041). On the other hand, a decreased risk of HCC was associated with gene polymorphism of 1068G>A (A vs. G: OR=0.68, 95%CI=0.51-0.91, P=0.010; GA+AA vs. GG: OR=0.68, 95%CI=0.49-0.96, P=0.027; AA vs. GG: OR=0.42, 95%CI=0.18-0.99, P=0.048). CONCLUSIONS Our results suggest that 3 of the 5 polymorphisms of P2RX7 described above (1513A>C, 946G>A, and 1068G>A) are significantly associated with HCC susceptibility in a Chinese Han population. Studies with larger sample sizes are recommended to confirm whether our results will be applicable to different ethnic populations in China.


Proteomic profiling of animal models mimicking skeletal muscle disorders.
Over the last few decades of biomedical research, animal models of neuromuscular diseases have been widely used for determining pathological mechanisms and for testing new therapeutic strategies. With the emergence of high-throughput proteomics technology, the identification of novel protein factors involved in disease processes has been decisively improved. This review outlines the usefulness of the proteomic profiling of animal disease models for the discovery of new reliable biomarkers, for the optimization of diagnostic procedures and the development of new treatment options for skeletal muscle disorders. Since inbred animal strains show genetically much less interindividual differences as compared to human patients, considerably lower experimental repeats are capable of producing meaningful proteomic data. Thus, animal model proteomics can be conveniently employed for both studying basic mechanisms of molecular pathogenesis and the effects of drugs, genetic modifications or cell-based therapies on disease progression. Based on the results from comparative animal proteomics, a more informed decision on the design of clinical proteomics studies could be reached. Since no one animal model represents a perfect pathobiochemical replica of all of the symptoms seen in complex human disorders, the proteomic screening of novel animal models can also be employed for swift and enhanced protein biochemical phenotyping.


Traumatic Mandibular Cyst Defect Grafted with Autologous Dentin and Platelet-Rich Fibrin Composite: A Case Report.
Some cases of asymptomatic traumatic cyst can be sizable; therefore, they require complete curettage and grafting with bone substitution materials. This case report presents a sizeable traumatic mandibular cyst in a young man treated by surgical exploration and filled with autologous dentin graft (ADG) prepared from an extracted impacted tooth 48 (FDI tooth-numbering system) and advanced platelet-rich fibrin (A-PRF). Initially, an A-PRF membrane was used to cover the apices of teeth 42 and 43, which were protruding into the defect to protect their periapical structures. Then, a grafting strategy was introduced to achieve two fronts of bone formation: one by stimulation of bone outgrowth from the periphery due to A-PRF cellular activity, and a second by bone deposition directly on dentin particles in the center of the defect. On CBCT scans performed 7 months postoperatively, arrays of trabeculae that were extending from bone boundaries of the cyst defect were merged with more condensed bone deposited on ADG residuals in the center, thus filling the defect. It was found that autologous dentin combined with cellular A-PRF activity is a powerful tool to restore even sizable bone defects in a relatively short time frame with adequate bone remodeling.


Modelling galaxy clustering: halo occupation distribution versus subhalo matching.
We model the luminosity-dependent projected and redshift-space two-point correlation functions (2PCFs) of the Sloan Digital Sky Survey (SDSS) Data Release 7 Main galaxy sample, using the halo occupation distribution (HOD) model and the subhalo abundance matching (SHAM) model and its extension. All the models are built on the same high-resolution N-body simulations. We find that the HOD model generally provides the best performance in reproducing the clustering measurements in both projected and redshift spaces. The SHAM model with the same halo-galaxy relation for central and satellite galaxies (or distinct haloes and subhaloes), when including scatters, has a best-fitting χ2/dof around 2-3. We therefore extend the SHAM model to the subhalo clustering and abundance matching (SCAM) by allowing the central and satellite galaxies to have different galaxy-halo relations. We infer the corresponding halo/subhalo parameters by jointly fitting the galaxy 2PCFs and abundances and consider subhaloes selected based on three properties, the mass Macc at the time of accretion, the maximum circular velocity Vacc at the time of accretion, and the peak maximum circular velocity Vpeak over the history of the subhaloes. The three subhalo models work well for luminous galaxy samples (with luminosity above L*). For low-luminosity samples, the Vacc model stands out in reproducing the data, with the Vpeak model slightly worse, while the Macc model fails to fit the data. We discuss the implications of the modelling results.


Characterization of a salmon insulin-like growth factor I promoter.
We have identified four transcription initiation sites in the salmon insulin-like growth factor I (IGF-I) gene. Use of the most upstream transcription start site generates a minor mRNA species with a 5' untranslated region (UTR) of approximately 450-550 nucleotides, whereas transcription starting at the downstream initiation sites results in more abundant IGF-I mRNAs with 5'-UTRs approximately 250, 245, and 165 nucleotides in length. No consensus TATA box-like elements are present immediately upstream of the most upstream start site identified, nor is this region particularly GC-rich. Transient expression assays, however, demonstrated orientation-dependent promoter activity in a 386-nucleotide-long fragment containing the major downstream transcription start sites. Additionally, reverse transcriptase polymerase chain reaction (RT-PCR) analyses demonstrated tissue and developmental stage-specific use of the various transcription start sites identified.


Dynamic monitoring of cell adhesion and spreading on microelectronic sensor arrays.
Cellular interaction with and adhesion on different biological surfaces is a dynamic and integrated process requiring the participation of specialized cell surface receptors, structural proteins, signaling proteins, and the cellular cytoskeleton. In this report, the authors describe a label-free and real-time method for measuring and monitoring cell adhesion on special microplates integrated with electronic cell sensor arrays. These plates were used in conjunction with the real-time cell electronic sensing (RT-CES) system to dynamically and quantitatively monitor the specific interaction of fibroblasts with extracellular matrix (ECM) proteins and compared with standard adhesion techniques. Cell adhesion on ECM-coated cell sensor arrays is dependent on the concentration of ECM proteins coated and is inhibited by agents that disrupt the interaction of ECM with cell surface receptors. Furthermore, the authors demonstrate that the integrity of the actin cytoskeleton is required for productive cell adhesion and spreading on ECM-coated microelectronic sensors. Confirming earlier results, it is shown that interfering with Src expression or activity, via siRNA or small molecule, results in the disruption of adhesion and spreading of Bx PC3 cells. The results indicate that the RT-CES system offers a convenient and quantitative means of assessing the kinetics of cell adhesion in a high-throughput manner.


Relationship between prenatal growth, postnatal growth and childhood obesity: a review.
Evidence is accumulating that obesity risks become established early in life. The goal of this systematic review is to assess whether there is evidence that rapid postnatal growth holds different implications for childhood obesity risks for children who experienced different patterns of prenatal growth. We conducted systematic database searches in PubMed and Embase in October 2014 for studies assessing the implications of prenatal and postnatal growth for childhood obesity. The 18 studies meeting inclusion criteria indicated that risks of obesity increased with birthweight; risks of obesity also increased with rapid postnatal growth for children across the birthweight distribution. Fifteen studies indicated that rapid postnatal growth is linearly associated with obesity for children and adolescents of all sizes at birth, with no interaction effect. Three studies reported interaction effects with postnatal growth, conferring additional increased risk of obesity among children and adolescents who were small at birth. Both prenatal and postnatal growth are important risk factors for obesity, and their combined effects should be analyzed further to understand how obesity risks develop early in life.


Embryonal sarcoma of the liver in an adult patient.
Undifferentiated embryonal sarcomas (UESs) are uncommon tumours that are seen predominantly in late childhood. Cases in adults are rare and generally present once a large mass develops and may be mistaken for other tumours. A case of an UES of the liver with an isolated peritoneal metastasis is described. The patient presented with a palpable mass with imaging findings suggestive of a cystic tumour. She had complete surgical resection of the liver mass and isolated peritoneal metastasis. She was tumour-free on imaging at 6 months without adjuvant chemotherapy. An UES should be considered in the differential of large cystic hepatic lesions, with aggressive surgical resection considered when possible.


Frutalose®, a mixture of fructans obtained from enzymatic hydrolysis of chicory inulin, and normal defecation: evaluation of a health claim pursuant to Article 13(5) of Regulation (EC) No 1924/2006.
Following an application from Sensus B.V. (Royal Cosun), submitted for authorisation of a health claim pursuant to Article 13(5) of Regulation (EC) No 1924/2006 via the Competent Authority of the Netherlands, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver an opinion on the scientific substantiation of a health claim related to Frutalose® and maintenance of normal defecation. The scope of the application was proposed to fall under a health claim based on newly developed scientific evidence. The Panel considers that Frutalose®, a mixture of fructans obtained from enzymatic hydrolysis of chicory inulin, is sufficiently characterised. The claimed effect proposed by the applicant is 'contributes to regular bowel function by increasing stool frequency'. The proposed target population is 'the general healthy adult population'. Maintenance of normal defecation is a beneficial physiological effect provided that it does not result in diarrhoea. One human intervention study showed an effect of Frutalose® on the maintenance of normal defecation by increasing stool frequency and improving stool consistency (softer stools) when consumed daily at a dose of 15 g for 8 weeks. The results have not been replicated in other studies. There is a plausible mechanism by which Frutalose® could exert the claimed effect. The Panel concludes that the evidence provided is insufficient to establish a cause and effect relationship between the consumption of Frutalose® and maintenance of normal defecation under the proposed conditions of use.


Interaction effects at crossings of spin-polarized one-dimensional subbands.
We report conductance measurements of ballistic one-dimensional (1D) wires defined in GaAs/AlGaAs heterostructures in an in-plane magnetic field, B. When the Zeeman energy is equal to the 1D subband energy spacing, the spin-split subband N upward arrow intersects (N+1) downward arrow, where N is the index of the spin-degenerate 1D subband. At the crossing of N=1 upward arrow and N=2 downward arrow subbands, there is a spontaneous splitting giving rise to an additional conductance structure evolving from the 1.5(2e(2)/h) plateau. With further increase in B, the structure develops into a plateau and lowers to 2e(2)/h. With increasing temperature and magnetic field the structure shows characteristics of the 0.7 structure. Our results suggest that at low densities a spontaneous spin splitting occurs whenever two 1D subbands of opposite spins cross.


Ethology and the biological correlates of mood.
The insights of ethology-the science of animal behavior from a biological and psychological point of view-were incorporated in the 1950s by the British developmental psychiatrist, John Bowlby, into his attachment theory, which argued that a secure affective base in infancy was critical to the normal development of perception, cognition, learning, and emotion, in addition to that of physical parameters. The theory was illustrated by Harlow's pioneering experiments with baby monkeys: those raised with a wire-frame "mother" failed to thrive, compared with the more normal development of those deriving comfort contact from a terry-cloth surrogate. Modern neuroscience techniques have confirmed that the absence of sensory stimulation during periods of maximal synaptic expansion provides the substrate for a subsequent mood disorder. Ethology offers a novel "nature plus nurture" approach to the development of abnormal mood, as well as a target for treatment.


NATIONAL DIAGNOSTIC REFERENCE LEVELS AND ACHIEVABLE DOSES FOR STANDARD CT EXAMINATIONS IN SUDAN.
Radiation doses were determined to propose national diagnostic reference levels (NDRLs) and achievable doses (ADs) for computed tomography (CT) examinations in Sudan. Doses were estimated from retrospectively collected scan parameters for 1336 CT examinations of adult patients from 14 Sudanese hospitals using CT Expo 2.5 software. ADs and NDRLs were set at the 50th and 75th percentile of the hospital median dose distribution, respectively. The proposed CTDIvol (mGy) ADs ranged from: 10 (chest) to 64 (head), and that of the dose-length product (DLP; mGy.cm) ranged from 366 (chest) to 1225 (head). The proposed CTDIvol (mGy) NDRLs ranged from 15 kidney-ureter-bladder (KUB) to 79 (head), whereas that of the DLP (mGy.cm) ranged from 690 (chest) to 1490 (head). Current doses fell within the upper range of the doses presented in the literature emphasizing the need for implementation of the current ADs and NDRLs for CT to enhance patient protection and dose optimization in Sudan.


Brief Report: DSM-5 Sensory Behaviours in Children With and Without an Autism Spectrum Disorder.
Atypical responses to sensory stimuli are a new criterion in DSM-5 for the diagnosis of an autism spectrum disorder (ASD) but are also reported in other developmental disorders. Using the Short Sensory profile (SSP) and Autism Diagnostic Interview-Revised we compared atypical sensory behaviour (hyper- or hypo-reactivity to sensory input or unusual sensory interests) in children aged 10-14 years with (N = 116) or without an ASD but with special educational needs (SEN; N = 72). Atypical sensory behaviour was reported in 92 % of ASD and 67 % of SEN children. Greater sensory dysfunction was associated with increased autism severity (specifically restricted and repetitive behaviours) and behaviour problems (specifically emotional subscore) on teacher and parent Strengths and Difficulties Questionnaires but not with IQ.


Male breast cancer: a case report and review of the literature.
Breast cancer in men is an uncommon disease. Because of its rarity little is known about its aetiology, clinical behaviour and treatment. Retrospective studies show that when age- and stage-matched breast cancer in men and women are compared, there is no difference in survival between the two groups. Nevertheless, because of the absence of screening protocols and the limited amount of mammary tissue in men, allowing rapid local infiltration, a late diagnosis is often made, with a poor survival rate. Most of our current knowledge about the biology, natural history, surgical therapeutic strategies, adjuvant radiotherapy and chemotherapy protocols of male breast carcinoma has been extrapolated from its female counterpart. The Authors report the case of a male patient with breast cancer and pagetoid diffusion in the nipple region, and, on the basis of a review of the literature, summarise what is currently known about this rare neoplasm in terms of prognostic factors, therapy and survival.


Cell lines of human germinal cancer.
Three new established human germ cell tumour lines, H 12.1, H 12.5 and H 12.7, are described. Cytogenetic and growth characteristics, morphology, histology, and tumour marker and steroid hormone production in vitro and/or in vivo revealed properties commonly found in other germ cell tumour lines and in patients with these tumours. In vitro oestrone and oestradiol were produced by the H 12 lines and four other lines (833 KE, 1156 Q, 1428 A and 2102 EP) under high and low density (differentiation inducing) conditions. AFP was produced by one line and beta-hCG by six of seven lines under low density conditions. The pattern of oestrogen production suggests that these hormones could be useful in AFP and beta-hCG negative patients. Differentiated elements of somatic and extraembryonic character, observed in tumours of H 12.1 and H 12.7, underline the value of these lines in the study of differentiation and other germ cell tumour related questions.


Antioxidative low molecular weight compounds in marinated herring (Clupea harengus) salt brine.
This study aimed at unravelling the antioxidative capacity of low molecular weight compounds (LMWC) (peptides, amino acids and phenolic acids) present in salt brines from the marinated herring production. Brines were fractionated into <10kDa fractions using dialysis and further into 94 fractions using size exclusion chromatography. All samples were analysed for protein, total phenolic content (TPC) and antioxidant activities. Protein-enriched samples were pooled (P1, P2 and P3) and analysed for phenolic acids, total amino acids and peptide/protein sequence using advanced mass spectrometry. All salt brines contain LMWC holding ABTS-radical scavenging activity, reducing power and iron chelating activity. Generally, a strong correlation between TPC and ABTS-radical scavenging was found. In contrast, reducing power and iron chelating activity seemed to be caused by peptides. Protein/peptide sequencing revealed 1kDa peptides with the presence of HDF-motif which could be responsible for some of the antioxidant capacity observed in marinated herring salt brine.


In the right words: addressing language and culture in providing health care.
As part of its continuing mission to serve trustees, executives, and staff of health foundations and corporate giving programs, Grantmakers In Health (GIH) convened a group of experts from philanthropy, research, health care practice, and policy on April 4, 2003, to discuss the roles of language and culture in providing effective health care. During this Issue Dialogue, In the Right Words: Addressing Language and Culture in Providing Health Care, health grantmakers and experts from policy and practice participated in an open exchange of ideas and perspectives on language access and heard from fellow grantmakers who are funding innovative programs in this area. Together they explored ways to effectively support comprehensive language services, including the use of interpreters and translation of written materials. This Issue Brief synthesizes key points from the day's discussion with a background paper previously prepared for Issue Dialogue participants. It focuses on the challenges and opportunities involved with ensuring language access for the growing number of people who require it. Sections include: recent immigration trends and demographic changes; the effect of language barriers on health outcomes and health care processes; laws and policies regarding the provision of language services to patients, including an overview of public financing mechanisms; strategies for improving language access, including enhancing access in delivery settings, promoting advocacy and policy change, improving interpreter training, and advancing research; and roles for foundations in supporting improved language access, including examples of current activities. The Issue Dialogue focused mainly on activities and programs that ensure linguistic access to health care for all patients. Although language and culture are clearly inseparable, a full exploration of the field of cultural competence and initiatives that promote its application to the health care setting are beyond the scope of this Issue Brief. The day's discussion did, however, raise provocative issues of culture that are reflected throughout this report.


A portrait of gestational diabetes mellitus in Brazil: A systematic review and meta-analysis.
The diagnostic criteria for gestational diabetes mellitus (GDM), a transient hyperglycemic state during pregnancy, has varied remarkably over time, resulting in a diversity of prevalence rates. The aim of this systematic literature review was to provide estimates of prevalence rates of GDM in Brazil according to different diagnostic criteria. We identified, reviewed, and extracted data from the scientific literature on studies estimating the prevalence of diabetes in pregnant women living in Brazil. The databases searched were PubMed, LILACS, SciELO, Embase, Web of Science, and Cochrane Library. We grouped studies by the source of information assessing GDM, patients' age, and criteria used to diagnose GDM. When three or more studies were available in a group, we calculated the pooled prevalence. The Joanna Briggs Institute (JBI) appraisal tool was used to assess the risk of bias. The data were reported according to the 2020 PRISMA recommendations. The study protocol was registered in PROSPERO. We identified 1,328 records and selected 21 studies involving 122,635 pregnant women. Studies in adults only, with primary data and laboratory measurements, and using the IADPSG criteria (n = 3) had a GDM prevalence of 18.0% (95% confidence interval [CI]: 16.0-20.1%) and included 6,243 participants. Estimates of self-reported GDM (n = 3; 10,136 participants of all ages) had a pooled GDM prevalence of 2.1% (95% CI: 1.5-5.2%), with high heterogeneity (I2 = 85.0%, p < 0.01). Studies including adolescents had consistently low prevalences. The prevalence of GDM in Brazil varied, was greater when the IADPSG criteria were applied, and depended on the methods used to obtain the GDM information and the age structure of the sample.


Molecular mechanisms of steroid hormone signaling in plants.
Brassinosteroids (BRs), the polyhydroxylated steroid hormones of plants, regulate the growth and differentiation of plants throughout their life cycle. Over the past several years, genetic and biochemical approaches have yielded great progress in understanding BR signaling. Unlike their animal counterparts, BRs are perceived at the plasma membrane by direct binding to the extracellular domain of the BRI1 receptor S/T kinase. BR perception initiates a signaling cascade, acting through a GSK3 kinase, BIN2, and the BSU1 phosphatase, which in turn modulates the phosphorylation state and stability of the nuclear transcription factors BES1 and BZR1. Microarray technology has been used extensively to provide a global view of BR genomic effects, as well as a specific set of target genes for BES1 and BZR1. These gene products thus provide a framework for how BRs regulate the growth of plants.


Peroxisome proliferators activate extracellular signal-regulated kinases in immortalized mouse liver cells.
Peroxisome proliferators (PPs) are a class of nongenotoxic carcinogens in the rodent liver. The induction of immediate-early gene expression in immortalized mouse liver cells by the PPs Wy-14, 643, monoethylhexyl phthalate, ciprofibrate ethyl ester, and clofibrate suggested that they may be activating growth-regulatory signal transduction pathways. We report that incubation of quiescent ML457 cells with Wy-14,643 resulted in the appearance of two tyrosine-phosphorylated bands of approximately 44 and 42 kDa with maximal phosphorylation at 20 min. These two proteins were identified as extracellular signal-regulated kinases (ERKs) ERK1 and ERK2 (also known as mitogen-activated protein kinases, or MAPKs). Stimulation of quiescent ML457 cells with monoethylhexyl phthalate, ciprofibrate ethyl ester, and clofibrate also resulted in tyrosine phosphorylation of ERK1 and ERK2; however, the steroid PP dehydroepiandrosterone sulfate, which does not induce immediate-early gene expression, did not induce phosphorylation of ERK1 and ERK2. Kinase activity of ERK1 and ERK2 was stimulated by the PPs, consistent with their phosphorylation. The PPs also induced phosphorylation of the upstream regulator MAPK/ERK kinase (MEK). Preincubation of quiescent cells with MEK inhibitor PD98059 blocked activation of ERK1 and ERK2 by the PPs, implicating MEK activation as a requirement for PP-induced ERK activation. In addition, pretreatment with PD98059 greatly reduced the PP-induced expression of immediate-early genes c-fos, egr-1, and to a lesser extent junB. Induction of ERK phosphorylation and junB expression by Wy-14,643 was also seen in rat hepatocytes. These results attribute many of the effects of PPs on immediate-early gene expression to the activation of the MEK/ERK signal transduction pathway and add the PPs to the growing number of tumor promoters that modulate signaling proteins.


Transcriptomic signatures for human male infertility.
Introduction: Male infertility is a common, complex disorder. A better understanding of pathogenesis and etiology is needed for timely diagnosis and treatment. The aim of this study, therefore, was to identify genes involved in the pathogenesis of idiopathic male infertility based on data from transcriptomic level supported with data from genomic level. Materials and methods: First, we performed whole gene expression analysis in 20 testis biopsy samples of patients with severely impaired (10) and normal spermatogenesis (10). Further, we have performed systematic review of comparable male infertility studies and overlapped the most significantly expressed genes identified in our study with the most differentially expressed genes from selected studies. Gene Ontology analysis and KEGG functional enrichment have been performed with Enrichr analysis tool. Additionally, we have overlapped these genes with the genes where rare variants have been identified previously. Results: In 10 patients with severely impaired spermatogenesis and 10 controls, we identified more than 1,800 differentially expressed genes (p < 0.001). With the systematic review of three previously performed microarray studies that have met inclusion criteria we identified 257 overlapped differentialy expressed genes (144 downregulated and 113 upregulated). Intersection of genes from transcriptomic studies with genes with identified rare variants revealed a total of 7 genes linked with male infertility phenotype (CYP11A1, CYP17A1, RSPH3, TSGA10, AKAP4, CCIN, NDNF). Conclusion: Our comprehensive study highlighted the role of four genes in pathogenesis of male infertility and provided supporting evidence for three promising candidate genes which dysfunction may result in a male infertility disorder.


Ultrasound in regional anaesthesia.
Ultrasound guidance is rapidly becoming the gold standard for regional anaesthesia. There is an ever growing weight of evidence, matched with improving technology, to show that the use of ultrasound has significant benefits over conventional techniques, such as nerve stimulation and loss of resistance. The improved safety and efficacy that ultrasound brings to regional anaesthesia will help promote its use and realise the benefits that regional anaesthesia has over general anaesthesia, such as decreased morbidity and mortality, superior postoperative analgesia, cost-effectiveness, decreased postoperative complications and an improved postoperative course. In this review we consider the evidence behind the improved safety and efficacy of ultrasound-guided regional anaesthesia, before discussing its use in pain medicine, paediatrics and in the facilitation of neuraxial blockade. The Achilles' heel of ultrasound-guided regional anaesthesia is that anaesthetists are far more familiar with providing general anaesthesia, which in most cases requires skills that are achieved faster and more reliably. To this ends we go on to provide practical advice on ultrasound-guided techniques and the introduction of ultrasound into a department.


U-shaped relationship between serum uric acid levels and intrarenal hemodynamic parameters in healthy subjects.
Hyperuricemia has been reported to affect renal hemodynamics. In a recent study, both low and high levels of serum uric acid (SUA) were found to be associated with loss of kidney function. The goal of this study was to evaluate the relationship between SUA levels and intrarenal hemodynamic parameters in healthy subjects, using plasma clearance of para-aminohippurate (CPAH) and inulin (Cin). Renal and glomerular hemodynamics were evaluated by simultaneous measurements of CPAH and Cin in 48 healthy subjects (54.6 ± 13.4 yr). Intrarenal hemodynamic parameters, including efferent and afferent (Ra) arteriolar resistance, were calculated using Gómez's formulas. Relationships of SUA levels with these intrarenal hemodynamic parameters were examined. In quadratic regression analysis, SUA levels had a significant inverse U-shaped relationship with Cin (P < 0.0001, R2 = 0.350) and CPAH (P = 0.0093, R2 = 0.188) and a U-shaped relationship with Ra (P = 0.0011, R2 = 0.262). In multiple regression analysis with normal (3.5-6.0 mg/dl) and mildly low or high (<3.5 or >6.0 mg/dl) SUA levels entered as dummy variables of zero and one, respectively, mildly low or high SUA levels were significantly and independently associated with Ra (β = 0.230, P = 0.0403) after adjustment for several factors (R2 = 0.597, P < 0.0001). Both mild hyperuricemia and mild hypouricemia are significantly associated with increased Ra, although weakly. The increase in Ra in subjects with mild hyperuricemia or hypouricemia may be related to renal hemodynamic abnormalities, possibly leading to a decline in renal function.


Cognitive-behavioral group therapy for youths with anxiety disorders in the community: effectiveness in low and middle income countries.
Although cognitive-behavioral therapy (CBT) is established as a first line treatment for anxiety disorders in children and adolescents, there is little evidence about the effectiveness of CBT protocols in cases identified in the community in low and middle income countries (LaMICs). To evaluate the effectiveness of group CBT protocol for youths with anxiety disorders identified in a community sample in LaMICs. A total of 14 sessions of group CBT for youths and 2 concurrent sessions for parents based on Kendall's Coping Cat program were offered. Participants were selected from a cross-sectional community study; 45 subjects fulfilled inclusion criteria and 28 agreed to participate in the open clinical trial. Treatment effectiveness was evaluated with standard clinical, self- and parent-rated measures of anxiety, depression, externalizing symptoms and quality of life (QoL). Twenty youths completed the protocol. All scales showed an improvement of anxiety and reduction in externalizing symptoms over time, with a moderate to large effect size (d = 0.59 to 2.06; p < .05), but not in depressive symptoms or QoL. Consistent with previous evidence, group CBT is effective in treating anxiety disorders in youths. Results encourage further randomized clinical trials using CBT protocols adapted and developed to be used in LaMICs.


A framework for assessing clinical trial site readiness.
Clinical trial processes are unnecessarily inefficient and costly, slowing the translation of medical discoveries into treatments for people living with disease. To reduce redundancies and inefficiencies, a group of clinical trial experts developed a framework for clinical trial site readiness based on existing trial site qualifications from sponsors. The site readiness practices are encompassed within six domains: research team, infrastructure, study management, data collection and management, quality oversight, and ethics and safety. Implementation of this framework for clinical trial sites would reduce inefficiencies in trial conduct and help prepare new sites to enter the clinical trials enterprise, with the potential to improve the reach of clinical trials to underserved communities. Moreover, the framework holds benefits for trial sponsors, contract research organizations, trade associations, trial participants, and the public. For novice sites considering future trials, we provide a framework for site preparation and the engagement of stakeholders. For experienced sites, the framework can be used to assess current practices and inform and engage sponsors, staff, and participants. Details in the supplementary materials provide easy access to key regulatory documents and resources. Invited perspective articles provide greater depth from a systems, DEIA (diversity, equity, inclusion, and accessibility) and decentralized trials perspective.


Speckle-Tracking Echocardiography Improves Pre-operative Risk Stratification Before the Total Cavopulmonary Connection.
Single-ventricle patients with elevated pulmonary vascular resistance (PVR) or end-diastolic pressure (EDP) are excluded from undergoing total cavopulmonary connection (TCPC). However, a subset of patients deemed to be at acceptable risk experience prolonged length of stay (LOS) after TCPC. Routine assessment of ventricular function has been inadequate in identifying these high-risk patients. Speckle-tracking echocardiography (STE) is a novel method for assessment of myocardial deformation that may be useful in single-ventricle patients. The aim of this study was to perform a contemporary preoperative risk assessment for prolonged LOS to determine whether STE improves risk stratification before TCPC. Our single institution's perioperative data were retrospectively collected. The primary outcome was postoperative LOS >14 days. Longitudinal and circumferential STE deformation measures were analyzed on echocardiograms obtained during preoperative catheterization. Patient-specific, echocardiographic, and catheterization data were included in multivariable logistic regression. Receiver operating characteristic area under the curves (AUC) were analyzed. From 2007 to 2014, 135 patients who underwent TCPC were included in the analysis. The median LOS was 11 (IQR 9-14) days. The PVR (P < .01) and circumferential strain rate (CSR) (P < .01) were the only variables independently associated with LOS >14 days. For every 0.1 s-1 CSR increased, there was a 20% increased odds of prolonged LOS. The AUC for CSR was 0.70. The AUC for PVR and EDP combined was 0.68. The AUC for PVR, EDP, and CSR combined was 0.73. Preoperative CSR is independently associated with LOS >14 days and improves preoperative risk stratification in patients undergoing TCPC.


Distribution and Translocation of 141Ce (III) in Horseradish.
Rare earth elements (REEs) are used in agriculture and a large amount of them contaminate the environment and enter foods. The distribution and translocation of (141)Ce (III) in horseradish was investigated in order to help understand the biochemical behaviour and toxic mechanism of REEs in plants. The distribution and translocation of (141)Ce (III) in horseradish were investigated using autoradiography, liquid scintillation counting (LSC) and electron microscopic autoradiography (EMARG) techniques. The contents of (141)Ce (III) and nutrient elements were analysed using an inductively coupled plasma-atomic emission spectrometer (ICP-AES). The results from autoradiography and LSC indicated that (141)Ce (III) could be absorbed by horseradish and transferred from the leaf to the leaf-stalk and then to the root. The content of (141)Ce (III) in different parts of horseradish was as follows: root > leaf-stalk > leaf. The uptake rates of (141)Ce (III) in horseradish changed with the different organs and time. The content of (141)Ce (III) in developing leaves was greater than that in mature leaves. The results from EMARG indicated that (141)Ce (III) could penetrate through the cell membrane and enter the mesophyll cells, being present in both extra- and intra-cellular deposits. The contents of macronutrients in horseradish were decreased by (141)Ce (III) treatment. (141)Ce (III) can be absorbed and transferred between organs of horseradish with time, and the distribution was found to be different at different growth stages. (141)Ce (III) can enter the mesophyll cells via apoplast and symplast channels or via plasmodesmata. (141)Ce (III) can disturb the metabolism of macronutrients in horseradish.


Validation of quantitative estimation of tissue oxygen extraction fraction and deoxygenated blood volume fraction in phantom and in vivo experiments by using MRI.
The blood oxygenation level dependent signal of cerebral tissue can be theoretically derived using a network model formed by randomly oriented infinitely long cylinders. The validation of this model by phantom and in vivo experiments is still an object of research. A network phantom was constructed of solid polypropylene strings immersed in silicone oil, which essentially eliminated the effect of spin diffusion. The volume fraction and magnetic property of the string network was predetermined by independent methods. Ten healthy volunteers were measured for in vivo demonstration. The gradient echo sampled spin echo signal was evaluated with the cylinder network model. We found a strong interdependency between the two network characterizing parameters deoxygenated blood volume and oxygen extraction fraction. Here, different sets of deoxygenated blood volume/oxygen extraction fraction values were able to describe the measured signal equally well. However, by setting one parameter constant to a predetermined value, reasonable estimates of the other parameter were obtained. The same behavior was found for the in vivo demonstration. The signal theory of the cylinder network was validated by a well-characterized phantom. However, the found interdependency that was found between deoxygenated blood volume and oxygen extraction fraction requires an independent estimation of one variable to determine reliable values of the other parameter.


An Arabidopsis berberine bridge enzyme-like protein specifically oxidizes cellulose oligomers and plays a role in immunity.
The plant cell wall is the barrier that pathogens must overcome to cause a disease, and to this end they secrete enzymes that degrade the various cell wall components. Due to the complexity of these components, several types of oligosaccharide fragments may be released during pathogenesis and some of these can act as damage-associated molecular patterns (DAMPs). Well-known DAMPs are the oligogalacturonides (OGs) released upon degradation of homogalacturonan and the products of cellulose breakdown, i.e. the cellodextrins (CDs). We have previously reported that four Arabidopsis berberine bridge enzyme-like (BBE-like) proteins (OGOX1-4) oxidize OGs and impair their elicitor activity. We show here that another Arabidopsis BBE-like protein, which is expressed coordinately with OGOX1 during immunity, specifically oxidizes CDs with a preference for cellotriose (CD3) and longer fragments (CD4-CD6). Oxidized CDs show a negligible elicitor activity and are less easily utilized as a carbon source by the fungus Botrytis cinerea. The enzyme, named CELLOX (cellodextrin oxidase), is encoded by the gene At4 g20860. Plants overexpressing CELLOX display an enhanced resistance to B. cinerea, probably because oxidized CDs are a less valuable carbon source. Thus, the capacity to oxidize and impair the biological activity of cell wall-derived oligosaccharides seems to be a general trait of the family of BBE-like proteins, which may serve to homeostatically control the level of DAMPs to prevent their hyperaccumulation.


Modeling actor and partner effects in dyadic data when outcomes are categorical.
When 2 people interact in a relationship, the outcome of each person can be affected by both his or her own inputs and his or her partner's inputs. For Gaussian dyadic outcomes, linear mixed models taking into account the correlation within dyads are frequently used to estimate actor's and partner's effects based on the actor-partner interdependence model. In this article, we explore the potential of generalized linear mixed models (GLMMs) for the analysis of non- Gaussian dyadic outcomes. Several approximation techniques that are available in standard software packages for these GLMMs are investigated. Despite the different modeling options related to these different techniques, none of these have an overall satisfactory performance in estimating actor and partner effects and the within-dyad correlation, especially when the latter is negative and/or the number of dyads is small. An approach based on generalized estimating equations for the analysis of non-Gaussian dyadic data turns out to be an interesting alternative.


Significance of sentinel node biopsy in the management of squamous cell carcinoma arising from recessive dystrophic epidermolysis bullosa.
The most life-threatening complication developing in patients with recessive dystrophic epidermolysis bullosa (RDEB) is squamous cell carcinoma (SCC). To improve patient prognosis, early detection of regional lymph node metastasis is required. Herein, we report a patient diagnosed with non-Hallopeau-Siemens RDEB who developed SCC on the left foot with inguinal lymph node swelling. Use of the sentinel node biopsy (SNB) technique favorably minimized defective damage to the inguinal region in this case. Genetic analysis identified one novel COL7A1 mutation, a maternal c.238G > C (p.A80P) and one previously reported mutation, a paternal c.3631C > T (p.Q1211X). A published work review demonstrated that no COL7A1 mutations specific for SCC development in RDEB have previously been identified. It remains unclear if SNB in combination with gene diagnosis is beneficial for the management of SCC in RDEB patients, however, because of the limited number of case reports. To address this issue, COL7A1 mutational analysis should be performed in as many cases of RDEB as possible.


[The Role of Supraclavicular lymph node dissection in Breast Cancer Patients with Synchronous Ipsilateral Supraclavicular Lymph Node Metastasis].
Objective: In this study, we evaluated the effect of supraclavicular lymph node dissection in breast cancer patients who presented with ipsilateral supraclavicular lymph node metastasis (ISLM) without distant metastasis. Methods: A total of 90 patients with synchronous ISLM without distant metastasis between 2000 and 2009 were retrospectively analyzed. Patients were retrospectively divided into two groups, namely supraclavicular lymph node dissection group(34 patients) and non-dissection group(56 patients), according to whether they underwentsupraclavicular lymph node dissection or not.The Kaplan-Meier method was applied to analyze the locoregional relapse free survival (LRFS) and overall survival(OS). Results: Median follow-upwas 85 months(range, 6 to 11 months). Local recurrence in 32 cases, 47 cases of distant metastasis, of which 25 patients were accompanied by both locoregional relapse and distant metastasis. Of the 32 patients with locoregional relapse, 11 patients were in the lymph node dissection group and 21 patients in the control group. Of the 47 patients with distant metastases, 17 were treated with lymph node dissection, 30 in the control group. Thirty-two patients died in the whole group and 16 patients underwentlymph node dissection and 16 patients didn't. There was no significant difference between the rate of 5-year LRFS and 5-year OS (P=0.359, P=0.246). For patients of ER negative, the 5-year loco-regional relapse free survival rates were 63.7% and 43.3% in supraclavicular lymph node dissection group and control group, respectively. The 5-year overall survival rates were 52.1% and 52.3%, respectively, and there were no statistically significant differences (P=0.118, P=0.951). For patients of PR negative, the 5-yearloco-regional relapse free rates were 59.8% and 46.2%, respectively, and the 5-year overall survival rates were 50.6% and 43.2%, respectively, and there was no significant difference between the two groups (P=0.317, P=0.973). The 5-year recurrence-free survival rates of human epidermal growth factor receptor 2 (HER2)-positive patients were 61.2% and 48.0%(P=0.634), respectively, and the 5-year overall survival rates were 37.2% and 65.4%(P=0.032). Forty-seven patients suffered distant metastases and the 5-year metastases free survival rates were 37.3% and 38.5% in supraclavicular lymph node dissection group and control group, respectively. Conclusion: Supraclavicular lymph node dissection maybe an effective approach to improve the loco-regional control for the patients with ISLM, especially for ER negative and PR negative subtypes, but it might has adverseeffects for the patients with negative HER2 status.


The presence of an active S-adenosylmethionine decarboxylase gene increases the growth defect observed in Saccharomyces cerevisiae mutants unable to synthesize putrescine, spermidine, and spermine.
Saccharomyces cerevisiae spe1 delta SPE2 mutants (lacking ornithine decarboxylase) and spe1 delta spe2 delta mutants (lacking both ornithine decarboxylase and S-adenosylmethionine decarboxylase) are equally unable to synthesize putrescine, spermidine, and spermine and require spermidine or spermine for growth in amine-free media. The cessation of growth, however, occurs more rapidly in spe1 delta SPE2 cells than in SPE1 spe2 delta or spe1 delta spe2 delta cells. Since spe1 delta SPE2 cells can synthesize decarboxylated adenosylmethionine (dcAdoMet), these data indicate that dcAdoMet may be toxic to amine-deficient cells.


Comparison of Electroencephalography (EEG) Coherence between Major Depressive Disorder (MDD) without Comorbidity and MDD Comorbid with Internet Gaming Disorder.
Internet gaming disorder (IGD) has many comorbid psychiatric problems including major depressive disorder (MDD). In the present study, we compared the neurobiological differences between MDD without comorbidity (MDD-only) and MDD comorbid with IGD (MDD+IGD) by analyzing the quantitative electroencephalogram (QEEG) findings. We recruited 14 male MDD+IGD (mean age, 20.0 ± 5.9 years) and 15 male MDD-only (mean age, 20.3 ± 5.5 years) patients. The electroencephalography (EEG) coherences were measured using a 21-channel digital EEG system and computed to assess synchrony in the frequency ranges of alpha (7.5-12.5 Hz) and beta (12.5-35.0 Hz) between the following 12 electrode site pairs: inter-hemispheric (Fp1-Fp2, F7-F8, T3-T4, and P3-P4) and intra-hemispheric (F7-T3, F8-T4, C3-P3, C4-P4, T5-O1, T6-O2, P3-O1, and P4-O2) pairs. Differences in inter- and intra-hemispheric coherence values for the frequency bands between groups were analyzed using the independent t-test. Inter-hemispheric coherence value for the alpha band between Fp1-Fp2 electrodes was significantly lower in MDD+IGD than MDD-only patients. Intra-hemispheric coherence value for the alpha band between P3-O1 electrodes was higher in MDD+IGD than MDD-only patients. Intra-hemispheric coherence values for the beta band between F8-T4, T6-O2, and P4-O2 electrodes were higher in MDD+IGD than MDD-only patients. There appears to be an association between decreased inter-hemispheric connectivity in the frontal region and vulnerability to attention problems in the MDD+IGD group. Increased intra-hemisphere connectivity in the fronto-temporo-parieto-occipital areas may result from excessive online gaming.


Focus on trial endpoints of clinical relevance and the use of almotriptan for the acute treatment of migraine.
Almotriptan is a 5-HT(1B/1D) receptor agonist, or triptan, indicated for the acute treatment of migraine. It has been shown to be effective and well tolerated for the treatment of acute migraine in approximately 5000 patients enrolled in short-term placebo- and active-controlled trials and long-term open-label trials. A recent meta-analysis reported that almotriptan has the highest sustained pain-free (SPF) rate and lowest adverse-event (AE) rate of all oral triptans. Sustained pain free is a composite endpoint of pain freedom at 2 h, no recurrence of moderate-to-severe headache and no use of rescue medication from 2 to 24 h after dosing. Patient surveys have indicated that migraine sufferers consider complete pain relief, no recurrence, rapid onset and no side-effects to be the most important attributes of their acute treatment. Composite endpoints such as SPF and SPF with no AEs (SNAE) contain the attributes that migraine sufferers express as being the most important elements of an acute migraine therapy, and their use in future clinical trials should aid in the selection of agents that can offer patients the highest likelihood of consistent treatment success.


Autorecoding A-to-I RNA editing sites in the Adar gene underwent compensatory gains and losses in major insect clades.
As one of the most prevalent RNA modifications in animals, adenosine-to-inosine (A-to-I) RNA editing facilitates the environmental adaptation of organisms by diversifying the proteome in a temporal-spatial manner. In flies and bees, the editing enzyme Adar has independently gained two different autorecoding sites that form an autofeedback loop, stabilizing the overall editing efficiency. This ensures cellular homeostasis by keeping the normal function of target genes. However, in a broader range of insects, the evolutionary dynamics and significance of this Adar autoregulatory mechanism are unclear. We retrieved the genomes of 377 arthropod species covering the five major insect orders (Hemiptera, Hymenoptera, Coleoptera, Diptera, and Lepidoptera) and aligned the Adar autorecoding sites across all genomes. We found that the two autorecoding sites underwent compensatory gains and losses during the evolution of two orders with the most sequenced species (Diptera and Hymenoptera), and that the two editing sites were mutually exclusive among them: One editable site is significantly linked to another uneditable site. This autorecoding mechanism of Adar could flexibly diversify the proteome and stabilize global editing activity. Many insects independently selected different autorecoding sites to achieve a feedback loop and regulate the global RNA editome, revealing an interesting phenomenon during evolution. Our study reveals the evolutionary force acting on accurate regulation of RNA editing activity in insects and thus deepens our understanding of the functional importance of RNA editing in environmental adaptation and evolution.


Environmental regulation of Salmonella pathogenicity island 2 gene expression.
The enteric pathogen Salmonella typhimurium co-ordinates the expression of virulence determinants in response to environmental cues from the host organism. S. typhimurium possesses Salmonella pathogenicity island 2 (SPI2), a large virulence locus encoding a type III secretion system for virulence determinants required for systemic infections and accumulation inside host cells. We have generated transcriptional fusions to SPI2 genes to analyse expression and used antibodies against recombinant SPI2 proteins to monitor levels of SPI2 proteins under various conditions. Here, we demonstrate that SPI2 gene expression is induced by Mg2+ deprivation and phosphate starvation. These conditions are likely to represent the environmental cues encountered by S. typhimurium inside the phagosome of infected host cells. The induction of SPI2 gene expression is modulated by the global regulatory system PhoPQ and is dependent on SsrAB, a two-component regulatory system encoded by SPI2.


Optimisation of the RT-PCR detection of immunomagnetically enriched carcinoma cells.
Immunomagnetic enrichment followed by RT-PCR (immunobead RT-PCR) is an efficient methodology to identify disseminated carcinoma cells in the blood and bone marrow. The RT-PCR assays must be both specific for the tumor cells and sufficiently sensitive to enable detection of single tumor cells. We have developed a method to test RT-PCR assays for any cancer. This has been investigated using a panel of RT-PCR markers suitable for the detection of breast cancer cells. In the assay, a single cell line-derived tumor cell is added to 100 peripheral blood mononuclear cells (PBMNCs) after which mRNA is isolated and reverse transcribed for RT-PCR analysis. PBMNCs without added tumor cells are used as specificity controls. The previously studied markers epidermal growth factor receptor (EGFR), mammaglobin 1 (MGB1), epithelial cell adhesion molecule (EpCAM/TACSTD1), mucin 1 (MUC1), carcinoembryonic antigen (CEA) were tested. Two new epithelial-specific markers ELF3 and EphB4 were also tested. MUC1 was unsuitable as strong amplification was detected in 100 cell PBMNC controls. Expression of ELF3, EphB4, EpCAM, EGFR, CEA and MGB1 was found to be both specific for the tumor cell, as demonstrated by the absence of a signal in most 100 cell PBMNC controls, and sensitive enough to detect a single tumor cell in 100 PBMNCs using a single round of RT-PCR. ELF3, EphB4, EpCAM, EGFR, CEA and MGB1 are appropriate RT-PCR markers for use in a marker panel to detect disseminated breast cancer cells after immunomagnetic enrichment.


In silico prediction and in vivo validation of Daphnia pulex microRNAs.
Daphnia pulex, the crustacean with the first sequenced genome, is an important organism that has been widely used in ecological and toxicological research. MicroRNAs (miRNAs) are 21-25 nucleotide small non-coding RNAs that are involved in a myriad of physiological processes. In this research, we predicted 75 D. pulex miRNAs by sequence homology and secondary structure identification from the full genome sequence. Fourteen predicted miRNAs were selected for quantitative real time polymerase chain reaction (RT-PCR) validation. Out of these, eight (mir-8, mir-9, mir-12, mir-92, mir-100, mir-133, mir-153 and mir-283) were successfully amplified and validated. Next, expression levels were quantified at three different life stages (days 4, 8 and 12 of age) using U6 spliceosomal RNA as a reference gene. The expression of mir-8, mir-9, mir-12, mir-92 and mir-100 significantly differed across time suggesting these microRNAs might play a critical role during D. pulex development. This is the first study to identify and validate miRNAs in D. pulex, which is an important first step in further studies that evaluate their roles in development and response to environmental and ecological stimuli.


The Fluid Dynamical Performance of the Carpentier-Edwards PERIMOUNT Magna Ease Prosthesis.
The aim of the present in vitro study was the evaluation of the fluid dynamical performance of the Carpentier-Edwards PERIMOUNT Magna Ease depending on the prosthetic size (21, 23, and 25 mm) and the cardiac output (3.6-6.4 L/min). A self-constructed flow channel in combination with particle image velocimetry (PIV) enabled precise results with high reproducibility, focus on maximal and local peek velocities, strain, and velocity gradients. These flow parameters allow insights into the generation of forces that act on blood cells and the aortic wall. The results showed that the 21 and 23 mm valves have a quite similar performance. Maximal velocities were 3.03 ± 0.1 and 2.87 ± 0.13 m/s; maximal strain Exx , 913.81 ± 173.25 and 896.15 ± 88.16 1/s; maximal velocity gradient Eyx , 1203.14 ± 221.84 1/s and 1200.81 ± 61.83 1/s. The 25 mm size revealed significantly lower values: maximal velocity, 2.47 ± 0.15 m/s; maximal strain Exx , 592.98 ± 155.80 1/s; maximal velocity gradient Eyx , 823.71 ± 38.64 1/s. In summary, the 25 mm Magna Ease was able to create a wider, more homogenous flow with lower peak velocities especially for higher flow rates. Despite the wider flow, the velocity values close to the aortic walls did not exceed the level of the smaller valves.


Diabetes mellitus in a girl with thyroid hormone resistance syndrome: a little recognized interaction between the two diseases.
The syndrome of resistance to thyroid hormone (RTH) is characterized by elevated serum free thyroid hormones (FT4 and FT3) in the presence of unsuppressed TSH levels, reflecting resistance to the normal negative feedback mechanisms in the hypothalamus and pituitary. The degree of resistance within peripheral tissues determines whether thyrotoxic clinical features are associated with this condition. Classic features include attention deficit hyperactivity disorder, growth delay, tachycardia, and goiter. However, other features, such as frequent ear, nose and throat infections, hearing deficit, and decreased bone mass have recently been recognized. The phenotype of RTH is variable, with most patients presenting with mild to moderate symptoms. In this report we describe a girl with familiar RTH and diabetes mellitus. This is, to our knowledge, the first report regarding this association. Nearly one year after long-term triiodothyroacetic acid (Triac) therapy, we observed a reduction of thyroid hormone levels with an amelioration of insulin resistance. The possible interactions between these disorders are discussed.


Quantitative PET/CT scanner performance characterization based upon the society of nuclear medicine and molecular imaging clinical trials network oncology clinical simulator phantom.
The Clinical Trials Network (CTN) of the Society of Nuclear Medicine and Molecular Imaging (SNMMI) operates a PET/CT phantom imaging program using the CTN's oncology clinical simulator phantom, designed to validate scanners at sites that wish to participate in oncology clinical trials. Since its inception in 2008, the CTN has collected 406 well-characterized phantom datasets from 237 scanners at 170 imaging sites covering the spectrum of commercially available PET/CT systems. The combined and collated phantom data describe a global profile of quantitative performance and variability of PET/CT data used in both clinical practice and clinical trials. Individual sites filled and imaged the CTN oncology PET phantom according to detailed instructions. Standard clinical reconstructions were requested and submitted. The phantom itself contains uniform regions suitable for scanner calibration assessment, lung fields, and 6 hot spheric lesions with diameters ranging from 7 to 20 mm at a 4:1 contrast ratio with primary background. The CTN Phantom Imaging Core evaluated the quality of the phantom fill and imaging and measured background standardized uptake values to assess scanner calibration and maximum standardized uptake values of all 6 lesions to review quantitative performance. Scanner make-and-model-specific measurements were pooled and then subdivided by reconstruction to create scanner-specific quantitative profiles. Different makes and models of scanners predictably demonstrated different quantitative performance profiles including, in some cases, small calibration bias. Differences in site-specific reconstruction parameters increased the quantitative variability among similar scanners, with postreconstruction smoothing filters being the most influential parameter. Quantitative assessment of this intrascanner variability over this large collection of phantom data gives, for the first time, estimates of reconstruction variance introduced into trials from allowing trial sites to use their preferred reconstruction methodologies. Predictably, time-of-flight-enabled scanners exhibited less size-based partial-volume bias than non-time-of-flight scanners. The CTN scanner validation experience over the past 5 y has generated a rich, well-curated phantom dataset from which PET/CT make-and-model and reconstruction-dependent quantitative behaviors were characterized for the purposes of understanding and estimating scanner-based variances in clinical trials. These results should make it possible to identify and recommend make-and-model-specific reconstruction strategies to minimize measurement variability in cancer clinical trials.


Use of Single-Frequency Impedance Spectroscopy to Characterize the Growth Dynamics of Biofilm Formation in Pseudomonas aeruginosa.
Impedance spectroscopy has been applied in prokaryotic and eukaryotic cytometry as a label-free method for the investigation of adherent cells. In this paper, its use for characterizing the growth dynamics of P. aeruginosa biofilms is described and compared to crystal violet staining and confocal microscopy. The method allows monitoring the growth of biofilm-forming P. aeruginosa in a continuous and label-free manner over a period of 72 h in a 96 well plate format. Impedance curves obtained for P. aeruginosa PA14 wild type and mutant strains with a transposon insertion in pqsA and pelA genes exhibited distinct phases. We propose that the slope of the declining curve following a maximum at ca. 35-40 h is a measure of biofilm formation. Transplant experiments with P. aeruginosa biofilms and paraffin suggest that the impedance also reflects pellicle formation at the liquid-air interface, a barely considered contributor to impedance. Finally, the impairment of biofilm formation upon treatment of cultures with L-arginine and with ciprofloxacin, tobramycin and meropenem was studied by single frequency impedance spectroscopy. We suggest that these findings qualify impedance spectroscopy as an additional technique to characterize biofilm formation and its modulation by small molecule drugs.


[Total parathyroidectomy and autotransplantation of parathyroid tissue. Functional assessment of the autograft 5-10 years after surgery with the help of local ischemic blockade].
The aim of the present study was to assess the long-term function of autotransplanted parathyroid tissue. From the medical records of a consecutive series of 21 patients we found that during the time of follow-up (79 months) one patient developed parathyroid graft dependent recurrent hyperparathyroidism (HPT) and one patient suffered from hypoparathyroidism. Nine of the patients were available for measurements of the plasma concentrations of intact parathyroid hormone (iPTH) at rest and during a shortlasting ischaemic blockade of the autotransplant. In eight patients, the ischaemic blockade reduced the concentration of iPTH with on average 62% as compared to baseline values. In one patient, the autotransplant had been resected and as expected, iPTH did not change during ischaemic blockade. Our results indicate that total parathyroidectomy with autotransplantation provides a rational alternative to the surgical treatment of secondary HPT and that the ischaemic blockade manoeuvre seems suitable for assessment of the function of parathyroid autotransplants.


[Biomorphosis of arteries].
The discrimination between normal aging and disease is very difficult, especially in the vascular system. The main factors, gene expression, physical forces, and environmental conditions are effective in normal and pathological circumstances. The changes in extracellular and cellular level are described. During aging, a fibrosis and a reduction of the cellular functions in the vascular wall are found. This deteriorates the blood streaming and favours pathological processes, e.g. atherosclerosis.


Suppression of colorectal cancer metastasis by nigericin through inhibition of epithelial-mesenchymal transition.
To evaluate the effect of nigericin on colorectal cancer and to explore its possible mechanism. The human colorectal cancer (CRC) cell lines HT29 and SW480 were treated with nigericin or oxaliplatin under the conditions specified. Cell viability assay and invasion and metastasis assay were performed to evaluate the effect of nigericin on CRC cells. Sphere-forming assay and soft agar colony-forming assay were implemented to assess the action of nigericin on the cancer stem cell properties of CRC cells undergone epithelial-mesenchymal transition (EMT). Compared with oxaliplatin, nigericin showed more toxicity for the HT29 cell line (IC50, 12.92 ± 0.25 μmol vs 37.68 ± 0.34 μmol). A similar result was also obtained with the SW116 cell line (IC50, 15.86 ± 0.18 μmol vs 41.02 ± 0.23 μmol). A Boyden chamber assay indicated that a significant decrease in the number of HT29 cells migrating through polyvinylidene fluoride membrane was observed in the nigericin-treated group, relative to the vehicle-treated group [11 ± 2 cells per high-power field (HPF) vs 19.33 ± 1.52 cells per HPF, P < 0.05]. Compared to the control group, the numbers of HT29 cells invading through the Matrigel-coated membrane also decreased in the nigericin-treated group (6.66 ± 1.52 cells per HPF vs 14.66 ± 1.52 cells per HPF, P < 0.05). Nigericin also reduced the proportion of CD133+ cells from 83.57% to 63.93%, relative to the control group (P < 0.05). Nigericin decreased the number of spheres relative to the control group (0.14 ± 0.01 vs 0.35 ± 0.01, P < 0.05), while oxaliplatin increased the number of spheres relative to the control group (0.75 ± 0.02 vs 0.35 ± 0.01; P < 0.05). Nigericin also showed a decreased ability to form colonies under anchorage-independent conditions in a standard soft agar assay after 14 d in culture, relative to the control group (1.66 ± 0.57 vs 7 ± 1.15, P < 0.05), whereas the colony numbers were higher in the oxaliplatin group relative to the vehicle-treated controls (14.33 ± 0.57 vs 7 ± 1.15, P < 0.05). We further detected the expression of E-cadherin and vimentin in cells treated with nigericin and oxaliplatin. The results showed that HT29 cells treated with nigericin induced an increase in E-cadherin expression and a decrease in the vimentin expression relative to vehicle controls. In contrast, oxaliplatin downregulated the expression of E-cadherin and upregulated the expression of vimentin in HT29 cells relative to vehicle controls. This study demonstrated that nigericin could partly reverse the EMT process during cell invasion and metastasis.


Induction of adipocyte differentiation by a thiazolidinedione in cultured, subepidermal, fibroblast-like cells of an infant with congenital generalized lipodystrophy.
Congenital generalized lipodystrophy (CGL) is characterized by the absence of adipose tissue from birth due to a hypothetical differentiation block. The genetic causes of CGL are still not completely understood. Subepidermal, fibroblast-like cells were prepared from the sc tissue of an infant with CGL. Preadipocytes from sc adipose tissue and foreskin fibroblasts from three healthy patients, respectively, were used as controls. Adipose differentiation was induced in cultured cells by exposure to 10 nM insulin, 200 pM T(3), 1 microM cortisol, and 2 microM rosiglitazone. Under these conditions 42% of the subepidermal, fibroblast-like CGL cells developed into mature adipocytes. Adipogenic differentiation was dependent on rosiglitazone. The differentiation rate was comparable in cultures of preadipocytes from control patients maintained under the same conditions (53%, 38%, and 20%). In contrast, foreskin fibroblasts did not differentiate into adipocytes. Morphological changes in CGL cells during differentiation were associated with the expression of fat cell-specific mRNAs (PPARgamma, leptin, and glut-4). In addition, these cells revealed characteristic features of mature adipocytes, such as lipogenesis or leptin secretion. Taken together, we show that adipocyte precursor cells were present in subepidermal tissue of a patient with CGL and were able to differentiate into adipocytes in the presence of a thiazolidinedione. These findings strongly support clinical trials with thiazolidinediones in patients with CGL.


Revision arthroplasty of femoral cortex defect using a noncemented stem, Mennen plate, and bone graft.
Twelve patients who underwent total hip replacement complicated by aseptic loosening with severe bone loss were included in this study. Two patients had aseptic loosening of the second revision, six of the third revision, and the remaining four patients of the fourth revision total hip replacement. In all patients, the radiographs revealed an extremely thin cortex around the stem of the prosthesis and almost complete disappearance of one cortex. All patients were treated by revision total hip replacement in conjunction with Mennen plate fixation and allograft bone support. The allograft bone support included three cortical struts and nine massive bone grafts that used cement as a strew. The results were satisfactory in 10 patients in respect to functional activity, pain and radiographic evaluation. In two patients who underwent their fifth revision, the results were unsatisfactory but better than before the operation. Mennen plate fixation provides a sufficient and easy technique for aseptic loosening of total hip replacement with severe bone loss. By preserving the periosteal blood supply, the time required for bone graft incorporation is shortened, resulting in an early final outcome.


Squamous cell apocrine hidradenoma.
Apocrine hidradenoma is a benign adnexal neoplasm with apocrine differentiation. The neoplasm is composed of four different types of epithelial cells, including pale or clear cells, polygonal cells, mucinous cells and squamous cells, with variable proportions of them from case to case. In most examples of this neoplasm, clear or the polygonal cells are predominant, whereas the other types of neoplastic cells are less abundant. We report two cases of apocrine hidradenoma mostly composed of squamous cells. Histopathologic examination showed that the neoplasms were composed of both solid and cystic areas. The solid aggregations of neoplastic cells were composed of a peripheral layer of basaloid polygonal cells, whereas squamous cells forming the bulk of the aggregations. These squamous cells showed large eosinophilic cytoplasm and vesicular nuclei with prominent nucleoli. In one case, small foci of mucinous cells could also be seen in some aggregations of neoplastic cells, mostly around ductal structures. In both the cases, some of the tubular structures lined by epithelial cells showed evidence of decapitation secretion in their luminal border. The neoplastic stroma consisted of sclerotic collagen bundles when compared with adjacent normal dermis, and artefactual clefts separated the neoplasms from the surrounding tissue. The rare cases described in this report are exceptional because most of the neoplastic cells showed squamous appearance and for that reason we think that squamous cell apocrine hidradenoma is the most appropriate name for these neoplasms.


[Individual autonomy and the principles of occupational health care].
The effect of work-related diseases on the health condition of the population at large has increased the interest in etiology and epidemiology of these diseases and intensified activities aimed at providing effective treatment of occupational diseases, but first of all at preventing their occurrence. That is why workers are now recognised as the largest population group subjected to active counselling. In order to meet the recommendations of the International Labour Organization, Polish labour law has been modified so that every worker is guaranteed an opportunity to benefit from medical prevention within the range required by his/her working conditions. This concern for workers' health contributed to the fact that health has now become a supreme value to which all other values and human needs are submitted. The author discusses the issues of compulsory prophylactic examinations and protection against employment at a workplace that is inadmissible because of health reasons, in the perspective of the human right to keep his/her own ailments in secret and the right to freedom of choice concerning his/her own health and living and conditions.


Whole Blood Gene Expression Profiles of Patients with a Past Aneurysmal Subarachnoid Hemorrhage.
The pathogenesis of development and rupture of intracranial aneurysms (IA) is largely unknown. Also, screening for IA to prevent aneurysmal subarachnoid hemorrhage (aSAH) is inefficient, as disease markers are lacking. We investigated gene expression profiles in blood of previous aSAH patients, who are still at risk for future IA, aiming to gain insight into the pathogenesis of IA and aSAH, and to make a first step towards improvement of aSAH risk prediction. We collected peripheral blood of 119 patients with aSAH at least two years prior, and 118 controls. We determined gene expression profiles using Illumina HumanHT-12v4 BeadChips. After quality control, we divided the dataset in a discovery (2/3) and replication set (1/3), identified differentially expressed genes, and applied (co-)differential co-expression to identify disease-related gene networks. No genes with a significant (false-discovery rate <5%) differential expression were observed. We detected one gene network with significant differential co-expression, but did not find biologically meaningful gene networks related to a history of aSAH. Next, we applied prediction analysis of microarrays to find a gene set that optimally predicts absence or presence of a history of aSAH. We found no gene sets with a correct disease state prediction higher than 40%. No gene expression differences were present in blood of previous aSAH patients compared to controls, besides one differentially co-expressed gene network without a clear relevant biological function. Our findings suggest that gene expression profiles, as detected in blood of previous aSAH patients, do not reveal the pathogenesis of IA and aSAH, and cannot be used for aSAH risk prediction.


Morphological and quantitative analyses of intraductal dysplasia of the prostate.
The aim of our study was to characterize quantitatively the cellular and architectural features of intraductal dysplasia (ID) (subdivided into two grades), in comparison with benign prostatic hyperplasia (BPH) and adenocarcinoma (AC). The research was carried out on histological sections where the mean nuclear and cellular area, the mean nuclear cytoplasmic (N/C) ratio and parameters related to nuclear crowding and stratification were evaluated. The mean nuclear area and the mean N/C ratio steadily increased from BPH to ID and to AC. As for the mean cellular area, the values decreased from BPH to ID grade 1: in the two grades of ID the values remained about the same; in the AC, the mean cellular area was intermediate between ID and PBH. The mean crowding index showed increase in ID grade I, in comparison with BPH, and then a decline from ID grade 2 to AC. The stratification related features (mean epithelial height, mean nuclear stratification height, stratification index) showed ID values greater than in BPH, while in AC smaller than in BPH; in ID grades 1 and 2 the values were similar. The results clearly indicate that mean nuclear area helps to discriminate BPH and AC. A partial separation between the two grades of ID is possible by combining the mean nuclear area and the mean nuclear crowding index in a bivariate analysis.


The Role of Depression and Anxiety in Frail Patients with Heart Failure.
An increased interest regarding the impact of frailty on the prognosis of cardiovascular disease (CVD) has been observed in the last decade. Frailty is a syndrome characterized by a reduced biological reserve that increases the vulnerability of an individual in relation to stressors. Among the patients with CVD, a higher incidence of frailty has been reported in those with heart failure (HF). Regardless of its conceptualizations, frailty is generally associated with negative outcomes in HF and an increased risk of mortality. Psychological factors, such as depression and anxiety, increase the risk of negative outcomes on the cardiac function and mortality. Depression and anxiety are found to be common factors impacting the heart disease and quality of life (QoL) in patients with HF. Depression is considered an independent risk factor of cardiac-related incidents and death, and a strong predictor of rehospitalization. Anxiety seems to be an adequate predictor only in conjunction with depression. The relationship between psychological factors (depression and anxiety) and frailty in HF has hardly been documented. The aim of this paper is to review the reported data from relevant studies regarding the impact of depression and anxiety, and their effects on clinical outcomes and prognosis in frail patients with HF.


The role of drug lipophilicity in release from intra-adipose and intramuscular injection sites.
Release rates from intramuscular and intra-adipose injection sites are dependent upon several including injection depth. Little is known about the relationship between drug lipophilicity and transport rate of drugs through adipose and muscle tissue. The principal objective of the present study was to investigate to what extend drug lipophilicity affects release and release rate from adipose tissue. Nine pigs were given intravenous (0.1 mg/kg), intramuscular (0.2 mg/kg) and intra-adipose (0.2 mg/kg) injections of propranolol, alprenolol, carazolol, metoprolol and atenolol. The fraction not-absorbed versus time plots after intramuscular and intra-adipose injection showed a biphasic decline for all model compound with the exception of atenolol being the most hydrophilic drug. This biphasic decline indicates that two different mechanisms may be involved in drug release. Initial release rates after intra-adipose injection were negatively correlated (Kendall's rankorder test) with fat-buffer distribution constants. The extent of release after 24 h could be considered as a characteristic parameter for the second release phase. The amounts released after 24 h were lower for propranolol, alprenolol, carazolol and metoprolol than for atenolol. Incomplete release at 24 h can be explained by the decrease of the solvent drag after absorption of the vehicle is complete.


Avascular necrosis of the femoral head in children.
Two types of AVN occur in childhood. The first is the idiopathic type best characterized by Legg-Calvé-Perthes' disease associated with repeated infarctions that slow the healing process. The second is the traumatic type caused by a direct insult to the blood supply of the developing femoral head. Both can result in profound growth disturbances of the proximal femur and early degenerative changes. They may have little effect on hip function or appearance. The variables affecting these outcomes are the age of the child, the degree of femoral head involvement, the presence of at-risk signs, the ability of the acetabulum to contain the healing head, and whether or not the growth plate closes as a result of the AVN. Bone scans and magnetic resonance imaging offer some potential for improved accuracy in diagnosis and prediction. The recommendation treatment for AVN in children is to treat the synovitis whenever it occurs or recurs. Abduction bracing should be used for the first six months in most young children with idiopathic AVN of the Legg-Calvé-Perthes' type. Protected weightbearing with crutches should suffice for the early phases of traumatic AVN. Within six months, one should be able to determine the classification and whether to continue the treatment being used or to change to another form of treatment. Petrie casts are used rarely but can be very useful in certain patients. Prolonged crutch use may help to prevent collapse while relieving symptoms in the older child.(ABSTRACT TRUNCATED AT 250 WORDS)


[Osteomyelitis and papillary renal adenoma in a red panda (Ailurus fulgens fulgens)].
A 13 year-old female Red Panda (Ailurus fulgens fulgens) kept in a zoological garden was euthanatized due to poor general condition. Pathological examination revealed a chronic bacterial ulcerative to necrotizing dermatitis and osteomyelitis at the lower jaw with subsequent pyogranulomatous pneumonia and diffuse hydropic degeneration of the liver. Additionally, in the kidney a papillary renal adenoma was found. Immunohistochemistry revealed an expression of cytokeratins 8 and/or 19 indicating an origin from the renal tubular epithelium.


Alkaloid extracts of Ficus species and palm oil-derived tocotrienols synergistically inhibit proliferation of human cancer cells.
Tocotrienols have been reported to possess anticancer effects other than anti-inflammatory and antioxidant activities. This study explored the potential synergism of antiproliferative effects induced by individual alkaloid extracts of Ficus fistulosa, Ficus hispida and Ficus schwarzii combined with δ- and γ-tocotrienols against human brain glioblastoma (U87MG), lung adenocarcinoma (A549) and colorectal adenocarcinoma (HT-29) cells. Cell viability and morphological results demonstrated that extracts containing a mixture of alkaloids from the leaves and bark of F. schwarzii inhibited the proliferation of HT-29 cells, whereas the alkaloid extracts of F. fistulosa inhibited the proliferation of both U87MG and HT-29 cells and showed synergism in combined treatments with either δ- or γ-tocotrienol resulting in 2.2-34.7 fold of reduction in IC50 values of tocotrienols. The observed apoptotic cell characteristics in conjunction with the synergistic antiproliferative effects of Ficus species-derived alkaloids and tocotrienols assuredly warrant future investigations towards the development of a value-added chemotherapeutic regimen against cancers.


Effect of Microplastics on the Activity of Digestive and Oxidative-Stress-Related Enzymes in Peled Whitefish (Coregonus peled Gmelin) Larvae.
Microplastics (MPs) are emergent pollutants in freshwater environments and may impact aquatic organisms, including those of nutritional value. The specific activities of digestive and antioxidant enzymes can be used as good bioindicators of the potential effects of MPs on fish in case of waterborne MP contamination. In this study, we used fluorescent polystyrene microplastics (PS-MPs) to analyze the alterations in enzyme activities in larvae of Coregonus peled Gmelin (peled or Northern whitefish), one of the most valuable commercial fish species of Siberia. Our results indicate that peled larvae can ingest 2 µm PS microspheres in a waterborne exposure model. A positive correlation (rs = 0.956; p < 0.01) was found between MP concentration in water and the number of PS microspheres in fish guts, with no significant differences between 24 h and 6-day exposure groups. The ingestion of MPs caused alterations in digestive enzyme activity and antioxidant responses at the whole-body level. The presence of PS-MPs significantly stimulated (p < 0.05) the specific activity of α-Amylase and non-specific esterases in peled larvae after 24 h. However, a pronounced positive effect (p < 0.05) of MPs on the activity of pancreatic trypsine and bile salt-activated lipase was only found after 6 days of exposure compared to after 24 h. Intestinal membrane enzyme aminopeptidase N was also stimulated in the presence of PS-MPs after 6-day exposure. We also observed a significant increase in the specific activity of catalase in peled larvae after 6 days of exposure, which indicates the MP-induced modulation of oxidative stress. Taken together, these results highlight the potential impact of environmental MPs on northern commercial fish, their importance for estimating fish stocks, and the sustainability of freshwater ecosystems.


Hesperetin glucuronide, a photoprotective agent arising from flavonoid metabolism in human skin fibroblasts.
There is considerable interest in the biological properties of flavonoids in terms of their antioxidant and cytoprotective actions. The interaction of the flavanone hesperetin with human skin fibroblasts (FEK4) has revealed the potential for metabolism to hesperetin glucuronide and its subsequent extrusion. As a consequence of this observation, the effectiveness of hesperetin glucuronides, in comparison with that of the aglycone form, in protecting against UV-A radiation has been investigated. The results indicate that hesperetin glucuronides, but not hesperetin, protect against UV-A-induced necrotic cell death.


[Mechanism of interleukin-1beta increasing growth hormone expression in rat pituitary GH3 cells].
To investigate the effect(s) of interleukin-1beta (IL-1beta) on the activity of human growth hormone (hGH) gene promoter in rat pituitary GH3 cells and the molecular mechanism. The method of luciferase reporter gene was used. We firstly established stable GH3 cell line which contains hGH gene promoter -484-30 bp and luciferase reporter gene. After treating these cells with IL-1beta or IL-1beta plus various signaling transduction inhibitors, the concentration of GH in the medium and lysate of GH3 cells and luciferase activities in GH3 cells were measured to reflect the effect of IL-1beta on secretion and synthesis of GH and the promoter activity of the hGH gene and the molecular mechanism. Results IL-1beta (10-10(4)U/ml) increased secretion and synthesis of GH. IL-1beta at levels of 10(2)-10(4) U/ml promoted the luciferase expression in stable GH3 cells, and the maximal action was 1.61 times of the control (P < 0.001). Among the inhibitors of intracellular signaling transduction pathways, mitogen-activated protein kinases (MAPK) inhibitor PD98059 (40 micromol/L) and p38 MAPK inhibitor SB203580 (5 micromol/L) completely blocked the stimulatory effect of IL-1beta, and phosphoinositide 3-kinase (PI3-K) inhibitor LY294002 (10 micromol/L) partly blocked the induction of IL-1beta. Neither overexpression of Pit-1 nor inhibiting Pit-1 expression affected IL-1beta induction of hGH promoter activity. The stimulatory effect of IL-1beta was abolished following deletion of the -196 to -132 bp fragment. IL-1beta increases the activity of hGH gene promoter in rat pituitary GH3 cells. This stimulatory effect of IL-1beta appears to require the intracellular MAPK, p38 MAPK, and PI3-K dependent signaling pathways. The effect of IL-1beta requires the promoter sequence that spans the -196 to -132 bp fragment of the gene, but it is unrelated to Pit-1 protein.


Combination therapy targeting both cancer stem-like cells and bulk tumor cells for improved efficacy of breast cancer treatment.
Many types of tumors are organized in a hierarchy of heterogeneous cell populations. The cancer stem-like cells (CSCs) hypothesis suggests that tumor development and metastasis are driven by a minority population of cells, which are responsible for tumor initiation, growth and recurrences. The inability to efficiently eliminate CSCs during chemotherapy, together with CSCs being highly tumorigenic and invasive, may result in treatment failure due to cancer relapse and metastases. CSCs are emerging as a promising target for the development of translational cancer therapies. Ideal panacea for cancer would kill all malignant cells, including CSCs and bulk tumor cells. Since both chemotherapy and CSCs-specific therapy are insufficient to cure cancer, we propose combination therapy with CSCs-targeted agents and chemotherapeutics for improved breast cancer treatment. We generated in vitro mammosphere of 2 breast cancer cell lines, and demonstrated ability of mammospheres to grow and enrich cancer cells with stem-like properties, including self-renewal, multilineage differentiation and enrichment of cells expressing breast cancer stem-like cell biomarkers CD44(+)/CD24(-/low). The formation of mammospheres was significantly inhibited by salinomycin, validating its pharmacological role against the cancer stem-like cells. In contrast, paclitaxel showed a minimal effect on the proliferation and growth of breast cancer stem-like cells. While combination therapies of salinomycin with conventional chemotherapy (paclitaxel or lipodox) showed a potential to improve tumor cell killing, different subtypes of breast cancer cells showed different patterns in response to the combination therapies. While optimization of combination therapy is warranted, the design of combination therapy should consider phenotypic attributes of breast cancer types.