Occurrence of anti-Toxoplasma gondii antibodies in meat and dairy goat herds in Rio Grande do Norte, Brazil.
Toxoplasmosis is caused by Toxoplasma gondii, which is the main causative agent of abortion in small ruminants. Goats are among the animals that are most susceptible to this protozoon, and the disease that it causes leads to significant economic losses and has implications for public health, since presence of the parasite in products of goat origin is one of the main sources of human infection. Because of the significant economic impact, there is an urgent need to study the prevalence of T. gondii infection among goats in Sertão do Cabugi, which is the largest goat-producing region in Rio Grande do Norte. In the present study, the ELISA assay was used to test 244 serum samples from nine farms, located in four different municipalities in the Sertão do Cabugi region, which is an important goat-rearing region. The results showed that the prevalence of anti-T. gondii antibodies was 47.1% and that there was a significant association between positivity and the variables of age (≥ 34 months), location (Lajes, Angicos and Afonso Bezerra) and farm (all the farms). The avidity test was applied to all the 115 ELISA-positive samples to distinguish between acute and chronic infection. One hundred and three samples (89.6%) displayed high-avidity antibodies, thus indicating that most of the animals presented chronic infection, with a consequent great impact on the development of the goat production system and a risk to human health.


Critical features for biosynthesis, stability, and functionality of a G protein-coupled receptor uncovered by all-versus-all mutations.
The structural features determining efficient biosynthesis, stability in the membrane and, after solubilization, in detergents are not well understood for integral membrane proteins such as G protein-coupled receptors (GPCRs). Starting from the rat neurotensin receptor 1, a class A GPCR, we generated a separate library comprising all 64 codons for each amino acid position. By combining a previously developed FACS-based selection system for functional expression [Sarkar C, et al. (2009) Proc Natl Acad Sci USA 105:14808-14813] with ultradeep 454 sequencing, we determined the amino acid preference in every position and identified several positions in the natural sequence that restrict functional expression. A strong accumulation of shifts, i.e., a residue preference different from wild type, is detected for helix 1, suggesting a key role in receptor biosynthesis. Furthermore, under selective pressure we observe a shift of the most conserved residues of the N-terminal helices. This unique data set allows us to compare the in vitro evolution of a GPCR to the natural evolution of the GPCR family and to observe how selective pressure shapes the sequence space covered by functional molecules. Under the applied selective pressure, several positions shift away from the wild-type sequence, and these improve the biophysical properties. We discuss possible structural reasons for conserved and shifted residues.


Sequencing analysis of HPV-other type on an HPV DNA chip.
To identify the specific human papillomavirus (HPV) genotypes from HPV-other type on an HPV DNA chip test by sequencing. Among 13,600 women undergoing a routine gynecology examination including Pap smear and/or HPV test by DNA chip test in the healthcare system at Gangnam Center from July 2012 to February 2013, we prospectively collected and performed sequencing for a total of 351 consecutive cervicovaginal samples consisting of 180 samples that tested positive for HPV-other type and 171 samples that tested positive for either high-risk HPV or low-risk HPV. Of a total of 351 samples, individual HPV genotypes were successfully sequenced in 215 cases: 119 HPV-other type, 82 HPV-high-risk, and 14 HPV-low-risk. Based on the sequencing for 119 HPV-other type samples, 91.6% were detected as HPV types that were not included on the DNA chip; however, 7.6% (9/119) were proven to be high-risk HPV types: HPV 18 (n=4), HPV 33 (n=3), HPV 35 (n=1), and HPV 59 (n=1). For correlation analysis of all high-risk and HPV 16/18, the correlation rate was 76.2% and 86.6% with kappa-value of 0.38 and 0.69, respectively. HPV-other type on DNA chip test may still have possibility of high-risk HPV, i.e., HPV 18 and thus the significance of HPV-other type in detecting cervical disease remains to be investigated.


Care of acute myocardial infarction in Oklahoma: an update from the Cooperative Cardiovascular Project.
Acute myocardial infarction remains a common cause of morbidity and mortality in Oklahoma. Nearly 6,000 Oklahoma Medicare beneficiaries are admitted to the hospital with an acute myocardial infarction each year. The death rate from coronary heart disease in Oklahoma is one of the highest in the nation. Utilizing structured medical record review, we have evaluated care given to 6,104 Medicare beneficiaries with acute myocardial infarction in 1994, 1996, and 1998. Since 1994, there have been significant improvements in the use of aspirin and beta-blockers at discharge, and avoidance of calcium channel blockers in those patients with poor left ventricular function. Documentation of smoking cessation counseling decreased significantly from 1994 to 1998. Other measures of quality of care did not change significantly. Despite better performance on many of the measures of quality, we should not be too complacent about the results, as there continues to be considerable room for improvement in care.


Cytological findings of appendiceal mixed adenoneuroendocrine carcinoma in pleural effusion: Morphological changes evident after metastasis.
Goblet cell carcinoid (GCC) of the appendix is now regarded as a malignant tumor, and mixed adenoneuroendocrine carcinoma (MANEC) is a carcinoma progressing from GCC. We describe a man initially diagnosed with GCC of the appendix who died 4 years after diagnosis. Pleural fluid due to metastasis was noted in the terminal phase. Histological findings of the initial tumor indicated that cells with signet-ring morphology were predominant, but the cytological morphology of the fluid was more atypical, making it difficult to diagnose as metastatic GCC by cellular morphology alone. The cells in the pleural fluid were immunopositive for synaptophysin, which was compatible with GCC, but p53 and ki67 staining indicated that the metastatic tumor was more aggressive. These findings suggested a final diagnosis of poorly differentiated adenocarcinoma-type MANEC, which we define as a tumor with typical GCC characteristics and foci that cannot be distinguished from a poorly differentiated adenocarcinoma. This case, which we believe is reported here for the first time, indicates the cytological features of GCC cells may change at metastatic sites to be more atypical and aggressive as the tumor progresses, and these changes should be considered in diagnosis.


High-Throughput Sparsity-Based Inversion Scheme for Optoacoustic Tomography.
The concept of sparsity is extensively exploited in the fields of data acquisition and image processing, contributing to better signal-to-noise and spatio-temporal performance of the various imaging methods. In the field of optoacoustic tomography, the image reconstruction problem is often characterized by computationally extensive inversion of very large datasets, for instance when acquiring volumetric multispectral data with high temporal resolution. In this article we seek to accelerate accurate model-based optoacoustic inversions by identifying various sources of sparsity in the forward and inverse models as well as in the single- and multi-frame representation of the projection data. These sources of sparsity are revealed through appropriate transformations in the signal, model and image domains and are subsequently exploited for expediting image reconstruction. The sparsity-based inversion scheme was tested with experimental data, offering reconstruction speed enhancement by a factor of 40 to 700 times as compared with the conventional iterative model-based inversions while preserving similar image quality. The demonstrated results pave the way for achieving real-time performance of model-based reconstruction in multi-dimensional optoacoustic imaging.


Daclatasvir: A NS5A Replication Complex Inhibitor for Hepatitis C Infection.
To review the pharmacology, efficacy, and safety of daclatasvir in the treatment of patients with chronic hepatitis C virus (HCV) infection. A literature search through EMBASE and PubMed was conducted (January 1966 to August 2015) using the terms BMS-790052, daclatasvir, and hepatitis C. References from retrieved articles were reviewed for any additional material. Additionally, the new drug application and prescribing information were retrieved. The literature search was limited to human studies published in English. Phase 1, 2, and 3 studies describing the pharmacology, pharmacokinetics, efficacy, and safety of daclatasvir for HCV were identified. Daclatasvir, a nonstructural 5A protein inhibitor, combined with sofosbuvir, is indicated for adult patients with chronic HCV genotype 3 regardless of treatment or cirrhosis status. The phase III ALLY-3 trial (n = 152) demonstrated that daclatasvir taken once daily with sofosbuvir for 12 weeks was effective at achieving sustained virological response (SVR) rates in treatment-naïve (97%) and treatment-experienced (94%) patients without cirrhosis. Patients with cirrhosis had significantly lower SVR rates (58 and 69%, respectively). The most common adverse drug events associated with daclatasvir and sofosbuvir in ALLY-3 were headache (20%), fatigue (19%), and nausea (12%). Daclatasvir, when combined with sofosbuvir, is an effective agent to treat HCV genotype 3, with SVR rates above 90% for patients without cirrhosis who are treatment naïve or experienced. SVR rates for treatment-naïve or -experienced patients with cirrhosis are not as robust (58%-69%).


Thermal stability of peroxidase from the african oil palm tree Elaeis guineensis.
The thermal stability of peroxidase from leaves of the African oil palm tree Elaeis guineensis (AOPTP) at pH 3.0 was studied by differential scanning calorimetry (DSC), intrinsic fluorescence, CD and enzymatic assays. The spectral parameters as monitored by ellipticity changes in the far-UV CD spectrum of the enzyme as well as the increase in tryptophan intensity emission upon heating, together with changes in enzymatic activity with temperature were seen to be good complements to the highly sensitive but integral method of DSC. The data obtained in this investigation show that thermal denaturation of palm peroxidase is an irreversible process, under kinetic control, that can be satisfactorily described by the two-state kinetic scheme, N -->(k) D, where k is a first-order kinetic constant that changes with temperature, as given by the Arrhenius equation; N is the native state, and D is the denatured state. On the basis of this model, the parameters of the Arrhenius equation were calculated.


A role for GLABRA1 in dark-induced senescence.
The GLABRA (GL1) gene, belonging to the transcription factor-encoding myb gene family, is responsible for trichome formation in Arabidopsis thaliana (L.) Heynh. The leaves and stems of glabra1 mutant plants are devoid of trichomes. Having an easily observable phenotype, the gl1 mutation was one of the first markers established for genetic mapping of Arabidopsis thaliana. Since then, the GL1 gene has been assigned roles in other processes, also related to leaf structure. In this study we present some previously undescribed effects of the gl1 mutation on dark-induced senescence. This process was induced by covering selected mature leaves of Columbia wild-type and gl1 Arabidopsis with black paper for 4 days, while the plants remained growing in a normal photoperiod. While no visible differences in the external symptoms of senescence could be observed in the darkened leaves, the expression of senescence-associated genes was significantly lower in gl1 plants as compared to the wild type. The darkening of leaves led to a decrease in photosynthetic activity and the expression of photosynthesis-associated genes, in comparison to the control leaves. This effect was much less pronounced in gl1 than in the wild type plants. Therefore, gl1 plants seem to be less susceptible to dark-induced aging, suggesting a possible role for the GL1 gene in controlling the onset and progress of senescence. This result is also of practical importance, since gl1 is the genetic background of many other mutants. It may therefore be advisable to revise some of the results obtained with such mutants in light of findings presented here.


LDL cholesterol affects clinical outcomes in incident hemodialysis patients during the early stages of dialysis.
Using a cohort of incident hemodialysis (HD) patients, this study investigated the impact of lipid profiles on clinical outcomes, especially in the early period of dialysis. A prospective cohort of 867 incident HD patients was selected. In order to determine the impact of cholesterol level on primary outcome, Cox regression analyses were performed for LDL and non-HDL (NHDL) variables. Univariate analysis revealed an increase in primary outcome risk with an LDL cholesterol level of 100 mg/dl or higher compared to an LDL cholesterol level lower than 100 mg/dl. High LDL cholesterol remained a significant independent predictor of the composite outcome, even after adjusting for age, gender, diabetes mellitus, preexisting CV disease, albumin, and hs-CRP. Serum LDL cholesterol at the time of HD commencement was a significant independent risk factor for the composite outcome of all-cause mortality and CV events in incident HD patients during the early stages of dialysis.


Prolactin variations during risperidone therapy in a sample of drug-naive children and adolescents.
The aim of this prospective observational study was to investigate the variations of serum prolactin hormone (PRL) in a sample of 34 drug-naive patients (mean age 13 years) who started risperidone therapy assuming that several factors may favor the increase in serum PRL. Serum PRL and hyperprolactinemia clinical signs were examined at baseline (T0) and after almost 3 months of treatment (T1). We considered sex, pubertal status, risperidone dosage, psychiatric diagnosis, and any personal/family history of autoimmune diseases. The mean serum PRL value increased between T0 and T1 (P=0.004). The mean serum PRL was higher in females in the pubertal/postpubertal stage and for risperidone dosage up 1 mg/day. Hyperprolactinemia was found in 20% of patients at T0 and in 38% of patients at T1 (P=0.03). The mean serum PRL increase was greater in early-onset schizophrenia spectrum psychosis patients compared with no-early-onset schizophrenia spectrum psychosis patients (P=0.04). The increase in PRL was higher in patients with a personal and a family history of autoimmune diseases. This study suggests that the increase in serum PRL in patients treated with risperidone may be linked not only to the drug and its dosage but also to several risk factors such as sex, pubertal stage, psychiatric disease, and autoimmune disorders.


[Juvenile dermatomyositis].
Juvenile dermatomyositis is part of the idiopathic inflammatory myositis group of diseases, presenting acute or chronic multisystemic inflammatory injury, that mainly affects muscles and skin. It s incidence is 4/1,000,000, prevailing in women and Caucasians, with symptoms starting between 5 14 years of age. The etiology is unknown, nevertheless is well recognized the role of vasculitis produced by autoantibodies, such is responsible for the damage on skin and muscular microvasculature. The acute or chronic complications and the neuropathic manifestations (cerebral vasculitis and peripheric neuropathy) are rare, and both are the result of the same autoimmune vasculitis injury.


Regulatory T Cells as a Novel Candidate for Cell-Based Therapy in Kidney Disease.
Kidney disease is a significant health concern worldwide. Ineffective treatment can lead to disastrous consequences, such as organ failure and death. Research has turned to cell-based therapy, but has yet to produce an effective and reliable treatment for kidney disease. To address this problem, we examined four datasets of gene expression profiles from diseased and healthy kidney tissue in humans, mice, and rats. Differentially expressed genes (DEGs) were screened and subjected to enrichment analyses. Up-regulated genes in diseased kidney tissue were significantly enriched in pathways associated with regulatory T cells (Tregs). Analysis with the xCell tool showed that Tregs were generally increased in diseased kidney tissue in all species. To validate these results in vivo, kidneys were removed from mice with Adriamycin-induced nephropathy, and histology confirmed increase of Tregs. Furthermore, Tregs were adoptively transferred from healthy mice into mice with kidney injury, restoring normal structure to the damaged kidneys. Treg cells that were co-cultured with M2c macrophages exhibited up-regulation of chemokine receptors CCR2, CCR5, CCR7, CD62L, and CX3CR1. This may be the mechanism by which M2c cells enhance the migration of Tregs to the site of inflammation. We propose that Tregs may be an effective, novel candidate for cell-based therapy in pre-clinical kidney injury models.


[Efficacy of AboundTM for hand-foot syndrome caused by capecitabine].
Hand-foot syndrome( HFS) has been reported to be the most common adverse effect of capecitabine, with an incidence of more than 50%. AboundTM, containing β-hydroxy-β-methyl butyric acid( HMB), L-glutamine, and L-arginine is effective in the treatment of decubitus ulcers and in wound healing; however, whether AboundTM is efficacious for HFS caused by capecitabine is not clear. This study aimed at evaluating the effectiveness of AboundTM in the recovery from HFS caused by capecitabine. Capecitabine administration was discontinued in 6 patients with more than grade 2 HFS, and AboundTM was administered. The time to recovery was examined. The median time to recovery to less than grade 1 HFS was 10 days( range, 4-14 days). The grade of HFS decreased following the administration of AboundTM. The findings of this study suggest that AboundTM is effective against HFS caused by capecitabine.


Patients have been let out of wards; why not nurses too?
Tradition retains the practice of attaching mental nurses to wards rather than to groups of patients, even though the wards are increasingly empty as patients come to lead more active lives in hospital. A system is described which enables nurses to relate more fully to the people in their care instead of having to confine their activities to the place in which only a part of the care is provided. This system involves all ward nurses in leaving their wards empty in 'working hours', being relieved of the care of their intercurrently ill patients and undertaking in exchange the complete day care of their fitter patients in both wards and workplaces. The consequences of these changes are attractive to many nurses and helpful to many patients.


Gastro-intestinal protein loss in late survivors of Fontan surgery and other congenital heart disease.
Protein losing enteropathy is a serious complication of Fontan surgery. The aim of this study was to investigate gastro-intestinal protein loss in adults with congenital heart disease, both with and without Fontan surgery, and to correlate findings with systemic venous pressure. Forty eight patients were studied. The first group included adult survivors of Fontan surgery. The second and third groups were control patients with congenital heart disease who had not had Fontan surgery and had either normal or chronically elevated systemic venous pressure. Gastro-intestinal protein loss was assessed by measurement of faecal alpha-1-antitrypsin. Faecal alpha-1-antitrypsin levels were significantly higher in the Fontan group (0.55 +/- 0.15 mg. g-1 faeces, P = 0.002) and the control group with chronically elevated venous pressure (0.60 +/- 0.30 mg. g-1 faeces, P < 0.001) compared to the controls with normal venous pressure (0.29 = 0.12 mg. g-1 faeces). Of the 15 subjects who were found to have increased gastro-intestinal protein loss, only four had clinical protein-losing enteropathy. The degree of gastro-intestinal protein loss correlated significantly with venous pressure (P = 0.01) and with serum aspartate transaminase (P = 0.04). Increased gastro-intestinal protein loss is common in this select group of late survivors of Fontan surgery and in other subjects with congenital heart disease and chronic elevation of systemic venous pressure, and was present in patients who did not have protein-losing enteropathy. Increased faecal alpha-1-antitrypsin is an important finding in these patients as intervention at this stage, before the onset of florid protein-losing enteropathy, might prevent the development of further complications.


MLL5 is involved in retinal photoreceptor maturation through facilitating CRX-mediated photoreceptor gene transactivation.
Histone methylation, particularly at the H3K4 position, is thought to contribute to the specification of photoreceptor cell fate; however, the mechanisms linking histone methylation with transcription factor transactivation and photoreceptor gene expression have not yet been determined. Here, we demonstrate that MLL5 is abundantly expressed in the mouse retina. Mll5 deficiency impaired electroretinogram responses, alongside attenuated expression of a number of retina genes. Mechanistic studies revealed that MLL5 interacts with the retina-specific transcription factor, CRX, contributing to its binding to photoreceptor-specific gene promoters. Moreover, depletion of MLL5 impairs H3K4 methylation and H3K79 methylation, which subsequently compromises CRX-CBP assembly and H3 acetylation on photoreceptor promoters. Our data support a scenario in which recognition of H3K4 methylation by MLL5 is required for photoreceptor-specific gene transcription through maintaining a permissive chromatin state and proper CRX-CBP recruitment at promoter sites.


UMG Lenti: novel lentiviral vectors for efficient transgene- and reporter gene expression in human early hematopoietic progenitors.
Lentiviral vectors are widely used to investigate the biological properties of regulatory proteins and/or of leukaemia-associated oncogenes by stably enforcing their expression in hematopoietic stem and progenitor cells. In these studies it is critical to be able to monitor and/or sort the infected cells, typically via fluorescent proteins encoded by the modified viral genome. The most popular strategy to ensure co-expression of transgene and reporter gene is to insert between these cDNAs an IRES element, thus generating bi-cistronic mRNAs whose transcription is driven by a single promoter. However, while the product of the gene located upstream of the IRES is generally abundantly expressed, the translation of the downstream cDNA (typically encoding the reporter protein) is often inconsistent, which hinders the detection and the isolation of transduced cells. To overcome these limitations, we developed novel lentiviral dual-promoter vectors (named UMG-LV5 and -LV6) where transgene expression is driven by the potent UBC promoter and that of the reporter protein, EGFP, by the minimal regulatory element of the WASP gene. These vectors, harboring two distinct transgenes, were tested in a variety of human haematopoietic cell lines as well as in primary human CD34+ cells in comparison with the FUIGW vector that contains the expression cassette UBC-transgene-IRES-EGFP. In these experiments both UMG-LV5 and UMG-LV6 yielded moderately lower transgene expression than FUIGW, but dramatically higher levels of EGFP, thereby allowing the easy distinction between transduced and non-transduced cells. An additional construct was produced, in which the cDNA encoding the reporter protein is upstream, and the transgene downstream of the IRES sequence. This vector, named UMG-LV11, proved able to promote abundant expression of both transgene product and EGFP in all cells tested. The UMG-LVs represent therefore useful vectors for gene transfer-based studies in hematopoietic stem and progenitor cells, as well as in non-hematopoietic cells.


TNF-α enhances the currents of voltage gated sodium channels in uninjured dorsal root ganglion neurons following motor nerve injury.
The ectopic discharges observed in uninjured dorsal root ganglion (DRG) neurons following various lesions of spinal nerves have been attributed to functional alterations of voltage-gated sodium channels (VGSCs). Such mechanisms may be important for the development of neuropathic pain. However, the pathophysiology underlying the functional modulation of VGSCs following nerve injury is largely unknown. Here, we studied this issue with use of a selective lumbar 5 ventral root transection (L5-VRT) model, in which dorsal root ganglion (DRG) neurons remain intact. We found that the L5-VRT increased the current densities of TTX-sensitive Na channels as well as currents in Nav1.8, but not Nav1.9 channels in uninjured DRG neurons. The thresholds of action potentials decreased and firing rates increased in DRG neurons following L5-VRT. As we found that levels of tumor necrosis factor-alpha (TNF-α) increased in cerebrospinal fluid (CSF) and in DRG tissue after L5-VRT, we tested whether the increased TNF-α might result in the changes in sodium channels. Indeed, recombinant rat TNF (rrTNF) enhanced the current densities of TTX-S and Nav1.8 in cultured DRG neurons dose-dependently. Furthermore, genetic deletion of TNF receptor 1 (TNFR-1) in mice attenuated the mechanical allodynia and prevented the increase in sodium currents in DRG neurons induced by L5-VRT. These data suggest that the increase in sodium currents in uninjured DRG neurons following nerve injury might be mediated by over-production of TNF-α.


Validity of low-cost measures for global surveillance of physical activity in pre-school children: The SUNRISE validation study.
To validate parent-reported child habitual total physical activity against accelerometry and three existing step-count thresholds for classifying 3 h/day of total physical activity in pre-schoolers from 13 culturally and geographically diverse countries. Cross-sectional validation study. We used data involving 3- and 4-year-olds from 13 middle- and high-income countries who participated in the SUNRISE study. We used Spearman's rank-order correlation, Bland-Altman plots, and Kappa statistics to validate parent-reported child habitual total physical activity against activPAL™-measured total physical activity over 3 days. Additionally, we used Receiver Operating Characteristic Area Under the Curve analysis to validate existing step-count thresholds (Gabel, Vale, and De Craemer) using step-counts derived from activPAL™. Of the 352 pre-schoolers, 49.1 % were girls. There was a very weak but significant positive correlation and slight agreement between parent-reported total physical activity and accelerometer-measured total physical activity (r: 0.140; p = 0.009; Kappa: 0.030). Parents overestimated their child's total physical activity compared to accelerometry (mean bias: 69 min/day; standard deviation: 126; 95 % limits of agreement: -179, 316). Of the three step-count thresholds tested, the De Craemer threshold of 11,500 steps/day provided excellent classification of meeting the total physical activity guideline as measured by accelerometry (area under the ROC curve: 0.945; 95 % confidence interval: 0.928, 0.961; sensitivity: 100.0 %; specificity: 88.9 %). Parent reports may have limited validity for assessing pre-schoolers' level of total physical activity. Step-counting is a promising alternative - low-cost global surveillance initiatives could potentially use pedometers for assessing compliance with the physical activity guideline in early childhood.


Rhabdomyosarcoma of the head and neck: impact of demographic and clinicopathologic factors on survival.
To determine the survival factors for patients diagnosed with rhabdomyosarcoma of the head and neck. Data on patients diagnosed with rhabdomyosarcoma of the head and neck between 1973 and 2012 were extracted from the Surveillance, Epidemiology, and End Results database. Kaplan-Meier and Cox proportional hazard regression models were used to determine the demographic characteristics, prognostic factors, and treatment modalities that determine overall survival (OS) and disease-specific survival (DSS). Data on 503 patients diagnosed with rhabdomyosarcoma of the head and neck were analyzed; 51.3% were male and 48.7% were female, with a median OS of 4.9 years. Kaplan-Meier analysis determined 5-year survival rates of 30% for OS and 50% for DSS. Multivariate analysis found that age at diagnosis, tumor extent of disease, surgical resection, and radiation therapy were independent predictors of OS and DSS. To our knowledge, this is the largest year-span study to date to determine the factors of survival for rhabdomyosarcoma of the head and neck. Older age at diagnosis, histologic subtype of alveolar rhabdomyosarcoma, and further extent of disease were associated with decreased survival. Surgical resection improves survival in patients with localized or regional disease, and radiation therapy confers survival benefits in patients with distant extent.


Antiangiogenic activity of the endocannabinoid anandamide: correlation to its tumor-suppressor efficacy.
Endocannabinoids are now emerging as suppressors of key cell-signaling pathways involved in cancer cell growth, invasion, and metastasis. We have previously observed that the metabolically stable anandamide analog, 2-methyl-2'-F-anandamide (Met-F-AEA) can inhibit the growth of thyroid cancer in vivo. Our hypothesis was that the anti-tumor effect observed could be at least in part ascribed to inhibition of neo-angiogenesis. Therefore, the aim of this study was to assess the anti-angiogenic activity of Met-F-AEA, to investigate the molecular mechanisms underlying this effect and whether Met-F-AEA could antagonize tumor-induced endothelial cell sprouting. We show that Met-F-AEA inhibited bFGF-stimulated endothelial cell proliferation, in a dose-dependent manner, and also induced apoptosis, both effects reliant on cannabinoid CB1 receptor stimulation. Analyzing the signaling pathways implicated in angiogenesis, we observed that the bFGF-induced ERK phosphorylation was antagonized by Met-F-AEA, and we found that p38 MAPK was involved in Met-F-AEA-induced apoptosis. Moreover, Met-F-AEA was able to inhibit bi-dimensional capillary-like tube formation and activity of matrix metalloprotease MMP-2, a major matrix degrading enzyme. Importantly, we demonstrated that Met-F-AEA is also functional in vivo since it inhibited angiogenesis in the chick chorioallantoic neovascularization model. Finally, Met-F-AEA inhibited tumor-induced angiogenesis in a three-dimensional model of endothelial and thyroid tumor cell (KiMol) spheroids co-cultures in different 3-D polymeric matrices that resemble tumor microenvironment and architecture. Thus, our results suggest that anandamide could be involved in the control of cancer growth targeting both tumor cell proliferation and the angiogenic stimulation of the vasculature.


Diagnostic approach to polyarticular joint pain.
Identifying the cause of polyarticular joint pain can be difficult because of the extensive differential diagnosis. A thorough history and a complete physical examination are essential. Six clinical factors are helpful in narrowing the possible causes: disease chronology, inflammation, distribution, extra-articular manifestations, disease course, and patient demographics. Patients with an inflammatory arthritis are more likely to have palpable synovitis and morning stiffness; if the condition is severe, they may have fever, weight loss, and fatigue. Viral infections, crystal-induced arthritis, and serum sickness reactions are common causes of acute, self-limited polyarthritis. Because chronic arthritides may present abruptly, they need to be considered in patients who present with acute polyarticular joint pain. Joint palpation can help to distinguish inflammatory synovitis from the bony hypertrophy and crepitus that typically occur with osteoarthritis. Extra-articular manifestations of rheumatologic disease may be helpful in arriving at a more specific diagnosis. Many classic rheumatologic laboratory tests are nonspecific. A complete blood count, urinalysis, and a metabolic panel may provide more useful diagnostic clues. Plain-film radiographs may demonstrate classic findings of specific rheumatologic diseases; however, radiographs can be normal or only show nonspecific changes early in the disease process.


The dysentery epidemic in Poland in 1920-1921
This article describes in general the issues related to the dysentery epidemic in 1920-1921. The current literature on the subject lacks publications presenting these issues fully. Based on historical sources from that period, including articles published in medical magazines, the incidence rate, the methods and results of the battle against that epidemic were depicted. The article represents an important contribution to a better insight in the struggle of Polish medical services with infectious diseases afflicting people in the first years following the end of World War I. It also sheds light on the development of Polish studies on infectious diseases in the Second Polish Republic, the scientists' belief in the successful treatment of epidemic diseases and understanding of the need to educate people about the rules of hygiene and taking medicines.


[A case of ulcerative colitis with preexisting idiopathic thrombocytopenic purpura].
A 53-year-old man was diagnosed as having idiopathic thrombocytopenic purpura (ITP). Hematochezia appeared under steroid therapy for ITP after the diagnosis of ITP 18 months. Colonoscopic study demonstrated inflamed rectal mucosa but there was no evidence of infectious colitis. The colonoscopic and pathological findings were compatible with ulcerative colitis (UC). There have been a few reports of patients with UC complicated by ITP, but in all except one report, UC preceded ITP. This is the third case in which ITP preceded UC and the first case in which the proctitis type of UC was complicated by ITP in Japan.


A new recombined porcine reproductive and respiratory syndrome virus virulent strain in China.
Porcine reproductive and respiratory syndrome (PRRS) is one of the most important swine diseases worldwide. In the present study, a new virulent strain of PRRS virus (PRRSV), GDsg, was isolated in Guangdong province, China, and caused high fever, high morbidity, and high mortality in sows and piglets. The genome of this new strain was 15,413 nucleotides (nt) long, and comparative analysis revealed that GDsg shared 82.4% to 94% identity with type 2 PRRSV strains, but only 61.5% identity with type 1 PRRSV Lelystad virus strain. Phylogenetic analysis indicated that type 2 PRRSV isolates include five subgenotypes (I, II, III, IV, and V), which are represented by NADC30, VR-2332, GM2, CH-1a, and HuN4, respectively. Moreover, GDsg belongs to a newly emerging type 2 PRRSV subgenotype III. More interestingly, the newly isolated GDsg strain has multiple discontinuous nt deletions, 131 (19 + 18 + 94) at position 1404-1540 and a 107 nt insertion in the NSP2 region. Most importantly, the GDsg strain was identified as a virus recombined between low pathogenic field strain QYYZ and vaccine strain JXA1-P80. In conclusion, a new independent subgenotype and recombinant PRRSV strain has emerged in China and could be a new threat to the swine industry of China.


Burnout and demographic characteristics of workers experiencing different types of work-home interaction.
The purpose of this study was to explore configurations of positive versus negative interactions between work and home (WHI) and their relation to burnout and demographic characteristics. Sample of 533 Polish workers were interviewed by means of self-administered questionnaires (SWING and MBI-GS). Demographic and work characteristics were also controlled. Cluster analysis distinguished 5 types of WHIs: positive WHI (18%), negative WHI (15.9%), no interaction (29.3%), mutual positive interactions (15.4%) and positive HWI (21.4%). The quality of WHI was associated with number of work hours and tenure at main place of employment. The effect of gender on the quality of work-home interaction was not significant. Configuration of WHIs affected the level of burnout. Again, there was no significant difference between men and women in terms of burnout and its sub-dimensions. The least burned-out were people from positive WHI, positive HWI and mutual positive interaction groups. The most burned-out were people who experienced negative WHI the most often. In this group, predominance of men working more than 10 h per day was observed. The majority of study group (71%) experienced rather integration than segmentation of both spheres. Our results suggest that segmentation is not an universal and effective strategy of coping with work and home demands - it may prevent the positive home-work spillover, which can be buffer or remedy against stress or burnout. We consider cluster analysis the appropriate method in research on relation to work-family balance issue, which may be useful in unraveling relationships between this phenomenon and attitudes and behaviors.


Anti-inflammatory effects of α-MSH through p-CREB expression in sarcoidosis like granuloma model.
Lung inflammation due to sarcoidosis is characterized by a complex cascade of immunopathologic events, including leukocyte recruitment and granuloma formation. α-melanocyte stimulating hormone (α-MSH) is a melanocortin signaling peptide with anti-inflammatory properties. We aimed to evaluate the effects of α-MSH in a novel in vitro sarcoidosis model. An in vitro sarcoidosis-like granuloma model was developed by challenging peripheral blood mononuclear cells (PBMCs) derived from patients with confirmed treatment-naïve sarcoidosis with microparticles generated from Mycobacterium abscessus cell walls. Unchallenged PBMCsand developed granulomas were treated daily with 10 μM α-MSH or saline as control. Cytokine concentrations in supernatants of culture and in cell extracts were measured using Illumina multiplex Elisa and western blot, respectively. Gene expression was analyzed using RNA-Seq and RT-PCR. Protein secretion and gene expression of IL-7, IL-7R, IFN-γ, MC1R, NF-κB, phosphorylated NF-κB (p-NF-κB), MARCO, and p-CREB were measured with western blot and RNAseq. A significant increase in IL-7, IL-7R, and IFN-γ protein expression was found in developed granulomas comparing to microparticle unchallenged PBMCs. IL-7, IL-7R, and IFN-γ protein expression was significantly reduced in developed granulomas after exposure to α-MSH compared with saline treated granulomas. Compared with microparticle unchallenged PBMCs, total NF-κB and p-NF-κB were significantly increased in developed granulomas, while expression of p-CREB was not changed. Treatment with α-MSH promoted a significantly higher concentration of p-CREB in granulomas. The anti-inflammatory effects of α-MSH were blocked by specific p-CREB inhibition. α-MSH has anti-inflammatory properties in this in vitro granuloma model, which is an effect mediated by induction of phosphorylation of CREB.


A Missense Mutation rs781536408 (c.2395G>A) of TYK2 Affects Splicing and Causes Skipping of Exon18 in vivo.
TYK2 variants can impact disease onset or progression. In our previous study, we identified abnormal splicing that happened near rs781536408 in the TYK2 gene. The purpose of this research was to examine the effect of the mutation on alternative splicing in vivo and in vitro. Whole exome sequencing was performed to identify the mutations followed by bidirectional Sanger sequencing. Then the minigene analysis was carried out based on HeLa and HEK293T cell lines. The results showed that rs781536408 (c.2395G>A, p.G799R) was homozygous in the patient, but heterozygous in parents. PCR amplification confirmed the abnormal splicing in the somatic cells of the patients, but not in the parents. Sanger sequencing results showed that there was a skipping of exon18 near the mutation. For minigene analysis, there was no difference between the wild-type and the mutant type in the two minigene construction strategies, indicating that mutation c.2395G>A had no effect on splicing in vitro. Combining the results of in vivo, we speculated that the effect of the mutation on splicing was not absolute, but rather in degree.


Cell partitioning during the directional solidification of trehalose solutions.
Previous studies have demonstrated that ice/cell interaction influences post thaw viability and specific cryoprotective agents can affect those interactions. Trehalose, a disaccharide, has been shown to have a protective benefit during conventional slow freezing. Existing theories have been put forth to explain the protective benefit of trehalose during desiccation and vitrification, but these theories do not explain the protective benefit observed during conventional freezing protocols. The overall objective of this investigation was to characterize cell/ice interactions in the presence of trehalose using non-planar freezing conditions. To that end, lymphoblasts suspended in phosphate buffered saline solution with various levels of trehalose (0, 10, 100, and 300 mM) were frozen on a directional solidification stage. The partitioning of cells into the interdendritic space or engulfment by an advancing dendrite was determined as a function of velocity and solution composition. For a given temperature gradient, the fraction of cells entrapped into the interdendritic region increased with increasing velocity. With small additions of trehalose (10 mM), the velocity at which cells were entrapped in the interdendritic region increased. At high trehalose concentrations (100, 300 mM), interface morphology was significantly different and cells were engulfed by the advancing interface. Dehydration of cells in the region shortly before and after the interface was significant and depended upon of the type of interaction experienced by the cell (entrapped vs. engulfed). These studies suggest that one potential mechanism for the action of trehalose involves changing the ice/cell interactions during conventional slow freezing.


HLA-DR epitope region definition by use of monoclonal antibody probes.
Definition of HLA-DR epitopes has been attempted by utilizing monoclonal antibody probes. Hybridoma antibodies L203 and L227, known to bind different epitopes on human Ia-like molecules, were tested for their ability to block cytotoxicity of monoclonal and allogeneic anti-DR antibodies. Monoclonal cytotoxic antibodies segregated into two groups: those more effectively blocked by L203, and those more effectively blocked by L227. Alloantisera also segregated into two groups, but according to their DR specificity. Anti-DR1, -2, and -3 alloantisera were effectively blocked by both L203 and L227, whereas anti-DR7, -w9, -w10, and MT1 alloantisera were not blocked by either. Blocking was not correlated with immunoglobulin class of the alloantibody and further definition of the mechanism of cytotoxicity blocking remains to be elucidated. Based on these data and prior binding and immunochemical studies with L203 and L227, a model is proposed in which the tertiary structure of each DR molecule, or complex of associated molecules on the cell surface, has two reference epitopes, one defined by L203, and another defined by L227. HLA-DR epitopes defined by the cytotoxic monoclonal or alloantibodies to the L203 or L227 epitope in order to begin epitope mapping or grouping.


An Ontario solution to medically underserviced areas: evaluation of an ongoing program.
In 1969 a program was established to place physicians in area of Ontario deemed to be medically underserviced. The main features of the program are area designation, physician subsidies, student bursaries, community participation and physician recruitment. From 1969 to March 1973, 162 communities were designated as underserviced and 196 physicians placed. As the program became active the rate of increase of numbers of physicians practising in northern rural areas (population, less than 15 000) increased sharply, exceeding that for the entire province. Fifty-three percent of bursaried students have honoured their commitment. Seventy-five communities have built modern medical centres that have been an important factor in attracting physicians. Still unanswered are whether the physicians will stay and whether the health of the population will be improved.


Posterior atlantoaxial fixation: the Magerl screw technique.
Atlantoaxial transarticular fixation is a proven stabilization technique used to augment conventional sublaminar fusion. Along with its superior biomechanical profile comes the inherent risk of neurovascular injury and potential compromised fixation during its application. This article presents a detailed systematic guide to this procedure including preoperative evaluation, positioning, and the more subtle aspects of the surgical technique. A new instrumentation design that has enhanced the ease and accuracy of screw placement with less operative frustration and potential morbidity of previous systems also is presented.


Mechanistic antimicrobial approach of extracellularly synthesized silver nanoparticles against gram positive and gram negative bacteria.
The development of eco-friendly and reliable processes for the synthesis of nanoparticles has attracted considerable interest in nanotechnology. In this study, an extracellular enzyme system of a newly isolated microorganism, Exiguobacterium sp. KNU1, was used for the reduction of AgNO₃ solutions to silver nanoparticles (AgNPs). The extracellularly biosynthesized AgNPs were characterized by UV-vis spectroscopy, Fourier transform infra-red spectroscopy and transmission electron microscopy. The AgNPs were approximately 30 nm (range 5-50 nm) in size, well-dispersed and spherical. The AgNPs were evaluated for their antimicrobial effects on different gram negative and gram positive bacteria using the minimum inhibitory concentration method. Reasonable antimicrobial activity against Salmonella typhimurium, Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus was observed. The morphological changes occurred in all the microorganisms tested. In particular, E. coli exhibited DNA fragmentation after being treated with the AgNPs. Finally, the mechanism for their bactericidal activity was proposed according to the results of scanning electron microscopy and single cell gel electrophoresis.


Iron(II)-Catalyzed Aerobic Biomimetic Oxidation of Amines using a Hybrid Hydroquinone/Cobalt Catalyst as Electron Transfer Mediator.
Herein we report the first FeII -catalyzed aerobic biomimetic oxidation of amines. This oxidation reaction involves several electron transfer steps and is inspired by biological oxidation in the respiratory chain. The electron transfer from the amine to molecular oxygen is aided by two coupled catalytic redox systems, which lower the energy barrier and improve the selectivity of the oxidation reaction. An iron hydrogen transfer complex was utilized as the substrate-selective dehydrogenation catalyst along with a bifunctional hydroquinone/cobalt Schiff base complex as a hybrid electron transfer mediator. Various primary and secondary amines were oxidized in air to their corresponding aldimines or ketimines in good to excellent yield.


Opioid Modulation of Value-Based Decision-Making in Healthy Humans.
Modifying behavior to maximize reward is integral to adaptive decision-making. In rodents, the μ-opioid receptor (MOR) system encodes motivation and preference for high-value rewards. Yet it remains unclear whether and how human MORs contribute to value-based decision-making. We reasoned that if the human MOR system modulates value-based choice, this would be reflected by opposite effects of agonist and antagonist drugs. In a double-blind pharmacological cross-over study, 30 healthy men received morphine (10 mg), placebo, and the opioid antagonist naltrexone (50 mg). They completed a two-alternative decision-making task known to induce a considerable bias towards the most frequently rewarded response option. To quantify MOR involvement in this bias, we fitted accuracy and reaction time data with the drift-diffusion model (DDM) of decision-making. The DDM analysis revealed the expected bidirectional drug effects for two decision subprocesses. MOR stimulation with morphine increased the preference for the stimulus with high-reward probability (shift in starting point). Compared to placebo, morphine also increased, and naltrexone reduced, the efficiency of evidence accumulation. Since neither drug affected motor-coordination, speed-accuracy trade-off, or subjective state (indeed participants were still blinded after the third session), we interpret the MOR effects on evidence accumulation efficiency as a consequence of changes in effort exerted in the task. Together, these findings support a role for the human MOR system in value-based choice by tuning decision-making towards high-value rewards across stimulus domains.


Gastric pathophysiological ins and outs of helicobacter pylori: a review.
Helicobacter pylori infection induces chronic gastritis, peptic ulcer disease, gastric cancer and a number of related extragastric morbidities. Hence, it is now recognised as a worldwide problem. Although clinical outcomes are dependent upon bacterial virulence factors, host genetic diversity and environment, but the major focus of this review is on recent findings relevant to bacterial factors and gastric pathophysiology of H. pylori infection. This article presents a review of the published literature mainly from year 2000 to 2012. The topics of main concerns were bacterial virulent factors and the inflammatory response to H. pylori infection. The authors used MeSH terms "Helicobacter" with "pathophysiology," "pathogenesis," or "gastric inflammation" to search the PubMed database. All relevant studies identified were included and are described according to the aforementioned subheadings.


Increased prevalence of the GCM2 polymorphism, Y282D, in primary hyperparathyroidism: analysis of three Italian cohorts.
Glial cells missing-2 (GCM2) is key for parathyroid gland organogenesis. Its persistent expression in the adult parathyroid raises the possibility that overactive forms play a role in the evolution of parathyroid hyperactivity or tumorigenesis. A GCM2 c.844T → G; p.Y282D missense variant has been described within a transactivation inhibitory domain (amino acids 263-352). The aims of the study were to 1) assess the frequency of Y282D in Italian primary hyperparathyroidism (PHPT) and control (C) populations, 2) test for association of 282D with PHPT and its phenotypic features, and 3) compare the transactivation potency of GCM2 282D relative to wild-type Y282. Subjects included a large southern Italian cohort (310 PHPT and 433 C) and 2 replication cohorts from northern Italy. Association of 282D with PHPT was tested in all cohorts and with phenotypic features in the larger PHPT cohort. An in vitro GCM promoter-luciferase reporter assay was conducted in HEK293 cells. 282D was significantly increased in the PHPT group, with a minor allele frequency of 0.066 compared with 0.029 in the C group (P = .0008), in the discovery cohort and was more prevalent in the replication cohorts. Combined analysis (510 PHPT and 665 C) yielded a likelihood ratio of 2.27 (95% confidence interval = 1.50-3.42; P < .0001). The 282D variant was not associated with serum calcium, phosphate, creatinine, or PTH levels or with bone mineral density, fractures, or renal stones in the PHPT group. The 282D variant had significantly greater transcriptional activity than the wild-type Y282 (17× basal vs 12× basal; P < 0.05). The higher frequency of GCM2 282D in PHPT and enhanced transcriptional activity of this variant supports the notion that it could contribute causally to parathyroid tumorigenesis.


Antimicrobial activities and cellular responses to natural silicate clays and derivatives modified by cationic alkylamine salts.
Nanometer-scale silicate platelet (NSP) materials were previously developed by increasing the interlayer space and exfoliation of layered silicate clays such as montmorillonite and synthetic fluorinated mica by the process of polyamine exfoliation. In this study, the antibacterial activity and cytotoxicity of these nanometer-scale silicate clays were evaluated. The derivatives of NSP (NSP-S) which were modified by C18-fatty amine salts via ionic exchange association exhibited the highest antibacterial activity in the aqueous state among all clays. The high antibacterial activity, however, was accompanied by elevated cytotoxicity. The variations of cell surface markers (CD29 and CD44) and type I collagen expression of fibroblasts treated with the clays were measured to clarify the mechanism of the silicate-induced cytotoxicity. The signal transduction pathway involved the downregulation of extracellular-signal-regulated kinase (ERK), which appeared to participate in silicate-induced cytotoxicity. This study helped to understand the antibacterial potential of NSP and the interaction of natural and modified clays with cellular activities.


[Guarantee of drug quality for animal health and consumer protection].
The creation of the single market and the intended free trade of goods, individuals, capital investments and services lead to the question if the quality standards of veterinary drugs are going to be changed in view of an improved animal health and consumer protection. However, the comparison between registration and surveillance criteria that result from the German Law for Medicinal Products and the criteria valid in the European Union as a consequence of Regulations and Directives shows that no changes leading to a reduced quality are to be expected. On the contrary, the application of EU Directives to the respective national law results in a number of improvements, like for example the environmental assessment of veterinary drugs.


Autoimmune hemolytic anemia: current concepts.
Autoimmune hemolytic anemia (AIHA) is one end of a spectrum of clinical and serological disorders resulting from an autoimmune attack against red cells. Although the etiology of this disorder is far from firmly established, the pathogenesis of red cell destruction by the effector mechanisms of the immune system is well characterised and correlates well with the clinical and serological features of this disorder. Direct antiglobulin test (DAGT) negative AIHA, production crises, AIHA in children and following alpha methyldopa therapy are subgroups of AIHA which have recently been described or more clearly defined and understood. The addition of high dose immunoglobulin and danazol as well as the potential use of more novel approaches to the traditional triad of corticosteroids, splenectomy and immunosuppressive agents has expanded and increased the flexibility of the therapeutic options in this disorder.


Choosing a mate in a high predation environment: Female preference in the fiddler crab Uca terpsichores.
The interplay between a receiver's sensory system and a sender's courtship signals is fundamental to the operation of sexual selection. Male courtship signals that match a female receiver's preexisting perceptual biases can be favored yet the message they communicate is not always clear. Do they simply beacon the male's location or also indicate his quality? We explored this question in a species of fiddler crab Uca terpsichores that courts under elevated predation risk and that mates and breeds underground in the safety of males' burrows. Sexually receptive females leave their own burrows and are thereby exposed to avian predators as they sequentially approach several courting males before they choose one. Males court by waving their single greatly enlarge claw and sometimes by building a sand hood next to their burrow entrance. Hoods are attractive because they elicit a risk-reducing orientation behavior in females, and it has been suggested that claw waving may also serve primarily to orient the female to the male. If the wave communicates male quality, then females should discriminate mates on the basis of variation in elements of the wave, as has been shown for other fiddler crabs. Alternatively, variation in elements of the claw waving display may have little effect on the display's utility as a beacon of the location of the male and his burrow. We filmed courting males and females under natural conditions as females responded to claw waving and chose mates. Analysis of the fine-scale courtship elements between the males that females rejected and those they chose revealed no differences. When predation risk during courtship is high, males' courtship displays may serve primarily to guide females to safe mating and breeding sites and not as indicators of male quality apart from their roles as beacons.


Effects of sub-lethal high-pressure homogenization treatment on the outermost cellular structures and the volatile-molecule profiles of two strains of probiotic lactobacilli.
Applying sub-lethal levels of high-pressure homogenization (HPH) to lactic acid bacteria has been proposed as a method of enhancing some of their functional properties. Because the principal targets of HPH are the cell-surface structures, the aim of this study was to examine the effect of sub-lethal HPH treatment on the outermost cellular structures and the proteomic profiles of two known probiotic bacterial strains. Moreover, the effect of HPH treatment on the metabolism of probiotic cells within a dairy product during its refrigerated storage was investigated using SPME-GC-MS. Transmission electron microscopy was used to examine the microstructural changes in the outermost cellular structures due to HPH treatment. These alterations may be involved in the changes in some of the technological and functional properties of the strains that were observed after pressure treatment. Moreover, the proteomic profiles of the probiotic strains treated with HPH and incubated at 37°C for various periods showed different peptide patterns compared with those of the untreated cells. In addition, there were differences in the peaks that were observed in the low-mass spectral region (2000-3000 Da) of the spectral profiles of the control and treated samples. Due to pressure treatment, the volatile-molecule profiles of buttermilk inoculated with treated or control cells and stored at 4°C for 30 days exhibited overall changes in the aroma profile and in the production of molecules that improved its sensory profile, although the two different species imparted specific fingerprints to the product. The results of this study will contribute to understanding the changes that occur in the outermost cellular structures and the metabolism of LAB in response to HPH treatment. The findings of this investigation may contribute to elucidating the relationships between these changes and the alterations of the technological and functional properties of LAB induced by pressure treatment.


Stable π-extended p-quinodimethanes: synthesis and tunable ground states.
p-Quinodimethane (p-QDM) is a highly reactive hydrocarbon showing large biradical character in the ground state. It has been demonstrated that incorporation of the p-QDM moiety into an aromatic hydrocarbon framework could lead to new π-conjugated systems with significant biradical character and unique optical, electronic and magnetic properties. On the other hand, the extension of p-QDM is expected to result in molecules with even larger biradical character and higher reactivity. Therefore, the synthesis of stable π-extended p-QDMs is very challenging. In this Personal Account we will briefly discuss different stabilizing strategies and synthetic methods towards stable π-extended p-QDMs with tunable ground states and physical properties, including two types of polycyclic hydrocarbons: (1) tetrabenzo-Tschitschibabin's hydrocarbons, and (2) tetracyano-rylenequinodimethanes. We will discuss how the aromaticity, substituents and steric hindrance play important roles in determining their ground states and properties.


The burden of cancer on primary and secondary health care services before and after cancer diagnosis in New South Wales, Australia.
Primary and secondary healthcare service usage is assessed in the year before and following a cancer diagnosis, in cancer cases versus matched non-cancer controls in New South Wales (NSW), Australia over 2006-2012, for all invasive cancers collectively and for selected common sites: breast, prostate, colorectal and lung, and melanoma. The 45 and Up cohort (n ≈267,000) was linked to NSW Cancer Register (NSWCR), Emergency Department Data Collection (EDDC) and Medical Benefits Schedule (MBS) data using probabilistic record linkage. First-ever malignant cancers diagnosed after enrolment in the 45 and Up study comprised the study cases. Where possible, five controls were randomly selected per case from the 45 and Up cohort, matched by sex and year of birth. Controls comprised those with no cancer recorded on the NSWCR. For each month in the year preceding and following the cancer diagnosis, general practitioner, specialist and specified hospital ED service use was compared between cases and controls using proportions, means, and odds ratios derived from conditional logistic regression. Compared to controls, cases of all cancers combined had a significantly higher likelihood of GP and specialist consultation in the year leading up to diagnosis. This was most pronounced in the 3-4 months leading up diagnosis for all cancers, similarly for lung cancer (GPs and specialists) and melanoma (GPs), and colorectal cancer (specialists). Likelihood of a GP consultation remained significantly higher in cases than controls in the 12 months following diagnosis. During most of the year preceding cancer diagnosis, the likelihood of specified ED presentations was also significantly higher in cases than controls for all cancers, and most pronounced in the 2-3 months before diagnosis. Excepting melanoma, the likelihood of specified ED presentations remained significantly elevated for most of the year following diagnosis for all cancers combined and for the selected cancers. People with cancer experience a higher use of primary and secondary healthcare services in the year preceding and following diagnosis, with GPs continuing to play a significant role post diagnosis. The higher likelihood of pre-diagnosis GP consultations among cancer cases requires further investigation, including whether signals might be derived to alert GPs to possibilities for earlier cancer detection.


DNA-Carbon Nanotube Complexation Affinity and Photoluminescence Modulation Are Independent.
Short single-stranded DNA (ssDNA) has emerged as the natural polymer of choice for noncovalently functionalizing photoluminescent single-walled carbon nanotubes. In addition, specific empirically identified DNA sequences can be used to separate single species (chiralities) of nanotubes, with an exceptionally high purity. Currently, only limited general principles exist for designing DNA-nanotube hybrids amenable to separation processes, due in part to an incomplete understanding of the fundamental interactions between a DNA sequence and a specific nanotube structure, whereas even less is known in the design of nanotube-based sensors with determined optical properties. We therefore developed a combined experimental and analysis platform on the basis of time-resolved near-infrared fluorescence spectroscopy to extract the complete set of photoluminescence parameters that characterizes DNA-nanotube hybrids. Here, we systematically investigated the affinity of the d(GT)n oligonucleotide family for structurally defined carbon nanotubes by measuring photoluminescence response of the nanotube upon oligonucleotide displacement. We found, surprisingly, that the rate of displacement of the oligonucleotides is independent of the coverage on the nanotube, as inferred through the intrinsic optical properties of the hybrid. The kinetics of intensity modulation is essentially a single-exponential, and the time constants, which quantify the stability of DNA binding, span an order of magnitude. Surprisingly, these time constants do not depend on the intrinsic optical parameters within the hybrids, suggesting that the DNA-nanotube stability is not due to increased nanotube surface coverage by DNA. Further, a principal component analysis of the excitation and emission shifts along with intensity enhancement at equilibrium accurately identified the (8,6) nanotube as the partner chirality to (GT)6 ssDNA. When combined, the chirality-resolved equilibrium and kinetics data can guide the development of the DNA-nanotube pairs, with tunable stability and optical modulation. Additionally, this high-throughput optical platform could function as a primary screen for mapping the DNA-chirality recognition phase space.


Unusual circulation patterns of the Rias Baixas induced by Minho freshwater intrusion (NW of the Iberian Peninsula).
The Minho River, situated 30 km south of the Rias Baixas, is the most important freshwater source flowing into the Western Galician coast (NW of the Iberian Peninsula). The buoyancy generated by the Minho estuarine plume can reverse the normal circulation pattern inside the Rias Baixas affecting the exchange between the Rias and the ocean, changing the input of nutrients. Nevertheless, this inversion of the circulation patterns is not a well-monitored phenomenon. The only published results based on in situ data related to the presence of the Minho River plume inside the Rias de Vigo and Pontevedra correspond to an event measured on spring 1998. In this case unexpectedly higher inflow surface current velocities were found at the Ria de Pontevedra, located further away from Minho River. Thus, the main aim of this study is to research the main factors inducing this unusual pattern on the circulation of the Rias de Vigo and Pontevedra. A numerical model implementation of MOHID previously developed, calibrated, and validated for this coastal area was used. Several scenarios were performed in order to explain the individual effect of the Minho River, rivers discharging into each Rias, and estuarine morphology changes. According to the model results, the Minho River discharge is a key factor in the establishment of the negative circulation, while small rivers inside the Rias slightly attenuate this circulation. The negative circulation was stronger in Ria de Pontevedra independently of the distance of this coastal system from the Minho River mouth, showing that morphologic estuarine features are the main factor justifying the different local circulation patterns.


[Thymus and bones].
Rat congenital osteopetrosis and cyclophosphamide (an immunosuppressive drug) induced osteocondensation are useful experimental models for the understanding of the relationships which seem to exist between thymus and bone. The high levels of seric alphafetoprotein found in the osteopetrotic tl rat raise the question of the persistance of embryonic characters in congenital osteopetrosis.


Reducing 30-Day Readmissions for Chronic Obstructive Pulmonary Disease.
A quality improvement project to reduce 30-day readmissions for chronic obstructive pulmonary disease (COPD) is described. A telephone assessment using the Medical Research Council Scale was completed within the first 5 days after discharge in patients with a diagnosis of COPD to evaluate dyspnea level.


The Development of a Web-Based Program to Reduce Dietary Salt Intake in Schoolchildren: Study Protocol.
Salt intake of schoolchildren in the Australian state of Victoria is high. To protect future cardiovascular health, interventions that seek to reduce the amount of salt in children's diets are required. We sought to develop and pilot test a Web-based program (Digital Education to Limit Salt Intake in the Home [DELISH]) that aims to reduce dietary salt intake among schoolchildren and to improve child and parent knowledge, attitudes, and behaviors related to salt intake. This paper presents the DELISH study protocol, along with pilot findings used to inform the development of the program. The DELISH program is a 5-week Web-based intervention that targets schoolchildren aged 7-10 years and their parents. This is a single-arm study with a pretest and posttest design. We will assess change in salt intake through analysis of 24-hour urinary sodium excretion. Children and parents will complete online surveys assessing knowledge, attitudes, and behaviors related to salt intake. We will assess feasibility of the program via process measures, which include metrics to describe intervention uptake (eg, number of children who complete Web-based sessions and of parents who view online newsletters) and evaluation surveys and interviews conducted with children, parents, and schoolteachers. The first 2 Web sessions developed for children were pilot tested in 19 children aged 8-12 years. Findings from pilot testing indicated that most children (session 1: 18/19, 95%; and session 2: 19/19, 100%) enjoyed completing each session and liked the inclusion of comic strips and interactive games. Commonly reported areas of improvement related to sessions being text and content heavy. Based on these findings, we simplified sessions and developed 3 additional sessions for use in the DELISH program. The DELISH program was implemented during June-December 2016. We expect to have results from this study at the end of 2017. To our knowledge, this is the first Australian study to examine the effectiveness of a Web-based program to reduce salt intake among children in primary school. If shown to be acceptable and effective in lowering salt intake, the DELISH program could be tested using a more rigorous randomized controlled trial design.


Surgeons overestimate the risk of malignancy in thyroid nodules, evaluation of subjective estimates using a bayesian analysis.
Thyroid nodules are the most common endocrine condition treated by surgeons. The main purpose of the evaluation of a thyroid nodule is to rule out a carcinoma. Medical decisions concerning thyroid nodules are highly influenced by subjective beliefs. To assess the subjective probabilities of malignancy that are assigned to the clinical characteristics of a patient with a thyroid nodule in order to determine the degree of influence that these probabilities have on the final clinical suspicion of malignancy compared with objective data. A bayesian analysis was designed to predict the risk of malignancy of a thyroid nodule based on the causal relationship between the demographic and clinical risk factors that are detected during the first consultation. A model with demographic and clinical variables using general surgeons as experts was developed. The highest probability of malignancy (94%) was assigned to the pooled case of a male who was older than 60 years, with dysphonia, dysphagia, accelerated growth rate of the nodule and previous neck radiotherapy and who had a relative with thyroid cancer as well as multiple nodules that were larger than 1 cm and with hard consistency and palpable neck lymph nodes. For low risk cases in which the nodule characteristics are not suggestive of malignancy, the probability of malignancy assigned by clinicians was 33.59%; for high risk cases this was 75.54%. Surgeons make diagnostic decisions based on subjective beliefs that do not necessarily correspond to the objective measures of the characteristics of the nodules.


Association of Mild-to-Moderate Reduction in Glomerular Filtration Rate with Subclinical Atherosclerosis in Postmenopausal Women.
Due to loss of hormonal protective effects, postmenopausal women have an increased cardiovascular (CV) risk. Chronic kidney disease (CKD) is a well-established risk factor for CV disease, but little is known whether mild-to-moderate kidney dysfunction is associated with atherosclerosis burden in the postmenopausal asymptomatic women. Subclinical atherosclerosis was evaluated in 125 postmenopausal women with no clinical form of atherosclerosis, by carotid and femoral ultrasonography, ankle-brachial index (ABI), and flow-mediated dilation (FMD). Carotid and femoral atherosclerosis were defined as increased intima-media thickness (IMT) and/or the presence of plaques. Endothelial function was assessed by endothelial dependent (flow-mediated dilation at 1 minute [FMD1]) and independent (flow-mediated dilation after nitroglycerin [FMDNTG]) vasodilation. Classical CV risk factors (age, smoking, obesity, diabetes, blood pressure, and lipids) were evaluated. Kidney function was evaluated in terms of estimated glomerular filtration rate (eGFR) calculated by the CKD-EPI formula. Univariate linear regression and multivariate logistic regressions were used to evaluate the independent associations between kidney function and markers of subclinical atherosclerosis. In the unadjusted linear analysis, eGFR showed a significant negative association with markers of subclinical atherosclerosis: carotid IMT (R2 = 0.305; p < 0.001), femoral IMT (R2 = 0.19, p < 0.001), carotid plaques (R2 = 0.22; p < 0.001), femoral plaques (R2 = 0.09; p = 0.0005), ABI (R2 = 0.05; p = 0.01), FMD1 (R2 = 0.45; p < 0.001), and FMDNTG (R2 = 0.205, p < 0.001). After adjustment for classical CV risk factors the association remained significant. Mild-to-moderate reduced eGFR is related to subclinical atherosclerosis, independent of traditional CV risk factors. It is important to detect renal function decline, even if it is mild, to improve risk stratification of subclinical atherosclerosis in postmenopausal women.


[Histopathological findings of human thyroid tumors and signal intensities of magnetic resonance imaging (MRI)].
We studied the correlation between postoperative thyroid histological findings and signal intensities of preoperative magnetic resonance (MR) imaging. The study subjects included 20 cases with thyroid diseases (7 with adenomatous goiter, 2 with follicular adenoma, 6 with papillary carcinoma, 5 with follicular carcinoma). Solid diseases excluding secondary changes (calcification, hemorrhage, necrosis and fibrosis) were investigated by T1 weighted imaging (T1WI) and T2 weighted imaging (T2WI). The results of this study showed that high signal intensities on T1 and T2 indicated preserved follicular structures with a full colloid and sparse atypical cells, in both benign and malignant diseases. Trabecular and microfollicular structures that showed destruction of follicular components and sparse colloid, had a tendency to show low approximately iso signal intensities on T1WI imaging. These results suggest that differentiated grades and the cell proliferative ability of thyroid tumors may be predictable with a combination of T1WI and T2WI.


Dr Samuel Matthias Curl alias Dr Alan Carroll.
Samuel Matthias Curl was the first medical practitioner in Tawa commencing practice there in 1855. He moved to the Rangitikei district in 1862 and practised there until 1887 when he eloped to Sydney with Annie Douglas. Besides practising medicine in New Zealand he farmed in both areas, was noted for his agricultural research and his work on several committees. In Sydney he assumed the name of Dr Alan Carroll and worked as an anthropologist and child health adviser. He died on the 17 April 1911 and left his estate in trust to establish two scientific bequests.


Hydroxylation of steroids with nonpolar side chains with 11 alpha-hydroxylase of Rhizopus nigricans.
Steroids with nonpolar side chains with 2, 4 and 8 C atoms were used as substrates for the 11 alpha-hydroxylase of Rhizopus nigricans. Their bioconversion was compared to that of progesterone, which was found to be far the best substrate giving the highest total bioconversion. 3-keto-4-ene steroids with nonpolar side chains were converted to their hydroxylated products in a small yield or not at all. The absence of an oxygen function in the side chain did not affect the regio-specificity of the hydroxylation, but resulted in a much lower total bioconversion. The strong effect of the oxygen function and of the length of the side chain on hydroxylation with the 11 alpha-hydroxylase of Rhizopus nigricans was demonstrated.


Enhanced expression of the secreted form of clusterin following neoadjuvant hormonal therapy as a prognostic predictor in patients undergoing radical prostatectomy for prostate cancer.
The objective of this study was to characterize changes in clusterin expression in prostate cancer before and after neoadjuvant hormonal therapy (NHT), and to assess the prognostic significance of clusterin expression following NHT in patients undergoing radical prostatectomy. Paired needle biopsy and corresponding radical prostatectomy (RP) specimens obtained from 76 patients were analyzed for expression of clusterin protein by immunohistochemical staining with an antibody recognizing all of the clusterin isoforms. RP specimens following NHT demonstrated stronger expression of clusterin than the corresponding needle biopsy specimens. Clusterin protein was present in the cytoplasm of both biopsy and RP specimens; however, there was no nuclear staining identified in any specimens. The expression level of clusterin in biopsy specimens was significantly associated with the biopsy Gleason score, but not with other parameters available before RP. Furthermore, clusterin expression in RP specimens was significantly associated with the preoperative prostate specific antigen value and pathological stage, but not with other pathological factors. Biochemical recurrence-free survival in patients with strong clusterin expression in RP specimens was significantly lower than that in those with weak clusterin expression; however, the level of clusterin expression could not be used as an independent predictor of biochemical recurrence. These findings suggest that despite the lack of independent significance, the expression level of the secreted form of clusterin in prostate cancer tissue after NHT, which may inversely reflect the therapeutic effect of NHT, could be a useful parameter predicting biochemical recurrence in patients undergoing RP.


Motor response to apomorphine in patients with Parkinson's disease with long-duration response to levodopa.
The authors studied the motor response to apomorphine before and 1 year after levodopa therapy in 12 patients with Parkinson's disease. At the 1-year evaluation, the basal tapping score, recorded after a 12-hour levodopa withdrawal, was higher compared with the test performed while patients were de novo, indicating the presence of a long-duration response to levodopa. The amplitude (net increase) of the motor response to apomorphine was similar before and during levodopa therapy. However, because of the better baseline, the maximal tapping score was higher during levodopa therapy. The duration and the latency of the motor response to apomorphine did not change. The presence of a short-duration response to apomorphine, in the presence of a long-duration response to levodopa, may imply that either different compartment (i.e., postsynaptic versus presynaptic) or transduction pathways are involved in such responses.


Salivary corticosterone reflects plasmatic levels in a wild seabird.
Wild animals have been increasingly exposed to a wide range of stressors, mainly due to the intensification of human activities and habitat modifications. Consequently, new tools in order to assess the physiological and health status of wild animals have been developed. In particular, glucocorticoids have received a special attention. Primarily metabolic hormones, they are also used to evaluate the stress level of organisms. While historically measured in blood samples, new less-invasive methods have been recently developed to measure glucocorticoids in matrices such as faeces, hairs/feathers, or saliva. To date, measurements in saliva are still in their infancy despite the numerous advantages of the matrix: non-invasive, reflects the biologically active portion of glucocorticoids, allows to measure both baseline and stress-induced levels. In addition, most studies using saliva have been performed on domestic and captive animals, and recent development in wild animals have focused on mammals. Here, we show, for the first time, that saliva could also be reliably used in free-ranging birds, as glucocorticoid levels in saliva strongly correlated with plasma levels. This promising result opens new avenues for a non-invasive sampling method to assess health status of wild birds in conservation biology and ecology.


Comparative actions of dihydropyridine slow channel calcium blocking agents in conscious dogs: alterations in baroreflex sensitivity.
The effects of five dihydropyridine slow channel calcium blocking agents, nifedipine, nitrendipine, FR 34235, niludipine and nisoldipine were compared to those of the peripheral vasodilator hydralazine on the reflex bradycardia and tachycardia after abrupt increases and decreases in arterial pressure in conscious dogs. On alternate days, the baroreflex was elicited during control conditions (drug vehicle) and/or after low (2.5 micrograms/kg/min) or high (5.0 micrograms/kg/min) equihypotensive doses of calcium antagonists or hydralazine (0.05 and 0.1 mg/kg/min). Baroreflexes were elicited by means of bolus injection of nitroprusside and phenylephrine. Certain of the dihydropyridine calcium channel blocking agents were found to interfere significantly with the reflex bradycardia after a rise in pressure, a phenomenon usually attributed to an increase in parasympathetic tone. Nisoldipine, niludipine and FR 34235 decreased baroreceptor sensitivity (defined as delta cardiac interval/delta systolic arterial pressure; milliseconds per millimeter of mercury) in a dose-related manner. On the other hand, nifedipine, nitrendipine and hydralazine had no significant effect. The dihydropyridines and hydralazine had little effect on baroreceptor-induced withdrawal of vagal tone or increases in sympathetic tone in response to sudden decreases in blood pressure. Calcium antagonists with isopropyl substitution as part of the ester function on the dihydropyridine nucleus, nisoldipine, niludipine and FR 34235, interfered to a greater extent with the vagally mediated reduction in cardiac rate. Changes in baroreflex gain may provide a basis for differential actions of dihydropyridine calcium channel blockers on the magnitude of change in heart rate in response to an abrupt increase in arterial pressure.


Upregulation of SOX-2, FZD9, Nestin, OCT-4 and FGF-4 expression in human chorion derived-stem cells after angiogenic induction.
Angiogenic induction was made to promote angiogenesis by differentiating stem cells towards endothelial cells. However, the stemness property of induced cells has not been revealed yet. Hence, we aim to evaluate the differential mRNA expression of stemness genes in human chorion-derived stem cells (CDSC) after being cultured in EDM50 comprised bFGF and VEGF. Results indicated that CDSC cultured in EMD50 expressed significantly higher mRNA level of Sox-2, FZD9, BST-1 and Nestin. In addition Oct-4, FGF-4 and ABCG-2 were also upregulated. Our finding suggested that CDSC after angiogenic induction enhanced its stem cell properties. This could be contributed for the mechanism of stem cell therapy in ischemic problem.


Examining the Temporal Development of Phonetic and Lexical Learning in Second Language.
The purpose of this study was to investigate how second-language (L2) learners lexically encode confusable phonemes. Given the inconsistency of previous studies on whether and if so how learners can establish separate lexical representations of confusable categories, we examined (1) how phonetic categorization and lexical encoding abilities were developed at the early stage of learning and (2) whether there are any differences in those abilities between the words with a sound pair from a corresponding native language (L1)-dominant category and those lacking such category. Native speakers of Korean learned Arabic words with these two types of sound pairs for four days and then their phonetic categorization and lexical processing abilities were evaluated in AXB discrimination and lexical decision tasks, respectively. The results showed that phonetic categorization of the words with a sound pair from an L1-dominant category developed very early. With success in their discrimination abilities, L2 learners began to overcome lexical competition from the words with such a sound pair. By contrast, learners showed poor sound discrimination and lexical encoding skills for words with a sound pair lacking an L1-dominant category. This suggests that (1) L2 learners' accurate phonetic categorization abilities are prerequisite to success in L2 lexical encoding and (2) lexical representations of the L2 words with confusable phonemes depend on the distinct types of sound category matchup between L1 and L2.


Lasting modulation of in vitro oscillatory activity with weak direct current stimulation.
Transcranial direct current stimulation (tDCS) is emerging as a versatile tool to affect brain function. While the acute neurophysiological effects of stimulation are well understood, little is know about the long-term effects. One hypothesis is that stimulation modulates ongoing neural activity, which then translates into lasting effects via physiological plasticity. Here we used carbachol-induced gamma oscillations in hippocampal rat slices to establish whether prolonged constant current stimulation has a lasting effect on endogenous neural activity. During 10 min of stimulation, the power and frequency of gamma oscillations, as well as multiunit activity, were modulated in a polarity specific manner. Remarkably, the effects on power and multiunit activity persisted for more than 10 min after stimulation terminated. Using a computational model we propose that altered synaptic efficacy in excitatory and inhibitory pathways could be the source of these lasting effects. Future experimental studies using this novel in vitro preparation may be able to confirm or refute the proposed hypothesis.


Structural determination of lipid A of the lipopolysaccharide from Pseudomonas reactans. A pathogen of cultivated mushrooms.
The chemical structure of lipid A from the lipopolysaccharide of the mushroom-associated bacterium Pseudomonas reactans, a pathogen of cultivated mushroom, was elucidated by compositional analysis and spectroscopic methods (MALDI-TOF and two-dimensional NMR). The sugar backbone was composed of the beta-(1'-->6)-linked d-glucosamine disaccharide 1-phosphate. The lipid A fraction showed remarkable heterogeneity with respect to the fatty acid and phosphate composition. The major species are hexacylated and pentacylated lipid A, bearing the (R)-3-hydroxydodecanoic acid [C12:0 (3OH)] in amide linkage and a (R)-3-hydroxydecanoic [C10:0 (3OH)] in ester linkage while the secondary fatty acids are present as C12:0 and/or C12:0 (2-OH). A nonstoichiometric phosphate substitution at position C-4' of the distal 2-deoxy-2-amino-glucose was detected. Interestingly, the pentacyl lipid A is lacking a primary fatty acid, namely the C10:0 (3-OH) at position C-3'. The potential biological meaning of this peculiar lipid A is also discussed.


The role of metformin on vitamin B12 deficiency: a meta-analysis review.
Metformin is the only biguanide oral hypoglycemic drug, that is used to treat patients with type-2 diabetes mellitus. There are some reports of metformin being associated with decreased serum levels of vitamin B12 (VB12). The objective of this study is to systematically analyze the impact of metformin on the frequency of VB12 deficiency and serum levels of VB12. A search of various databases provided 18 retrospective cohort studies and 11 randomized controlled trials. Pooled estimates of odds ratio with 95% confidence interval using random effect model were conducted. Studies were examined for heterogeneity, publication bias and sensitivity analysis. Separate analysis of randomized control trials (RCTs) including both low-risk and high-risk bias was also conducted. 29 studies were selected with a total of 8,089 patients. 19 studies were rated intermediate or high quality. Primary outcome suggested increased incidence of VB12 deficiency in metformin group (OR = 2.45, 95% CI 1.74-3.44, P < 0.0001.) Heterogeneity was relatively high (I(2) = 53%), with minor publication bias. Secondary outcome suggested lower serum VB12 concentrations in metformin group (Mean difference = -65.8, 95% CI -78.1 to -53.6 pmol/L, P < 0.00001) with high heterogeneity (I(2) = 98%,) and low publication bias. RCTs analysis of low-and high-risk group revealed similar trends. We conclude that metformin treatment is significantly associated with an increase in incidence of VB12 deficiency and reduced serum VB12 levels.


Burden of falls attributable to low bone mineral density among people aged 60 years and over in China from 1990 to 2019.
Falls in older people have become a major public health, economic and societal problem. Osteoporosis predisposes older adults to high risk of falls, which were the most common outcome attributable to low bone mineral density (LBMD). In this study, we analyze the long-term trends in falls burden attributable to LBMD among people aged 60 years and over from 1990 to 2019, using data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019). Data from GBD 2019 were used to assess the long-term trends in mortality and disability-adjusted life-year (DALY) rates by Joinpoint regression. The age-period-cohort (APC) model was used to evaluate the effects of age, period and cohort on mortality rate of falls attributable to LBMD. The mortality and DALYs rates of falls attributable to LBMD among people aged 60 years and over increased from 1990 to 2019, with average annual percentage changes (AAPCs) of 1.74% (95% CI: -1.47 to 2.01%) and 0.99% (95% CI: 0.80-1.19%), respectively. APC analysis revealed that the mortality rate due to LBMD significantly increased among the older people over the age of 75 years. The risk of falls mortality due to LBMD during the period of 1990-2019 initially declined but later elevated. An overall increasing risk for falls death attributable to LBMD was presented across birth cohorts, but in cohorts born after 1930, the upward trend has slowed down. The overall net drift per year attributable to LBMD was above 0. The corresponding results showed that the negative impact of period and cohort effects among males was more pronounced than those among females. Falls attributable to LBMD remain an ongoing health burden in the older people in China, and the mortality has been on the rise from 1990 to 2019, especially among the older people aged 80+ years group. The prevention and treatment of LBMD should be emphasized, especially among males and oldest-old people. Furthermore, there is an urgent need to strengthen the implementation of system-wide, integrated and effective public health policies and other health interventions in China.


Measurement of choroidal melanomas: a comparison of methods.
The prognosis for death from metastatic choroidal melanoma following enucleation has been shown to be strongly correlated with a number of risk factors of which the most important are age of onset, aggressive cell types and tumour volume. The advantages of enucleation for the treatment of choroidal melanomas are put into question by the singular lack of a parallel increase in life expectancy following this treatment, and evidence that it may promote the development of metastatic disease. Alternative forms of treatment have been introduced including observation of small and asymptomatic tumours. We are using a computer-aided system for serial measurement and statistical analysis of area and volume of choroidal melanomas. A comparison of results using our method and the conventional method of estimating volume by the product of basal area and height for 51 measurements on 15 eyes over a 6-month period showed an overestimation of volume by conventional methods which could be corrected by applying a "shape constant" determined by linear regression. Calculation of tumour growth rates is also shape-dependent, and a slowing in growth rate or even a reduction in melanoma size is possible.


Multi-Layer Application of Self-Etch and Universal Adhesives and the Effect on Dentin Bond Strength.
Contemporary self-etch and multi-mode adhesives were introduced to ensure a fast and reliable bonding procedure. Yet, in terms of bond strength and stability they failed to perform as well as two-bottle, etch-and-rinse adhesives, which remain the gold standard in terms of durability. The purpose of this study was to assess the shear bond strength (SBS) of dental adhesives to dentin with different application protocols. Two self-etch (Adper Easy One and Xeno V) and two multi-mode adhesives (Single Bond Universal and Prime&Bond One Select) were used in the study. The highest SBS was obtained for Single Bond Universal applied in three layers, while the lowest, for Xeno V applied in one layer. Other tested adhesives obtained the highest SBS when applied in three layers. For all tested adhesives, multi-layer application resulted in an increase in adhesive layer thickness, as observed in SEM. The increased thickness of the adhesive layer produced by triple application of unfilled adhesives corresponded with higher SBS values. The present study showed that using triple adhesive layers with simplified adhesive systems can be recommended to improve their performance. Due to differences in the composition of self-etch and universal adhesives, the exact application protocol is product dependent.


Efficacy of ear-point stimulation on experimentally induced seizure.
This study was to observe the effects of ear-point stimulation on electrocorticogram of sensorimotor cortex and behaviors of rats with penicillin-induced seizure. The model of epilepsy was by injecting penicillin into the hippocampus. One hour later, the lower 1/2 auricular lobules containing ear-points Pizhixia, Shenmen_Zeng and Nao, etc. as humans, or great auricular nerve of seizure rats, were treated twice with electrical stimulation (parameters of stimulation were as follows: electrical current intensity 0.14 approximately 0.2 mA, frequency about 80Hz, 30 min on and 30 min off). The outcome showed that rats appeared epileptic-like electrocorticogram and convulsion behaviors 5 min after injected penicillin. When they were subsequently given the ear-point or great auricular nerve electrical stimulation separately, these epileptic-like electrocorticogram and seizure behaviors were definitely improved. These anti-seizure effects could be enhanced with hour extension of electrical stimulation. If the great auricular nerve of seizure rat was severed before electrical stimulating ear-points, the effects of anti-seizure disappeared. Otherwise, the seizure rats given sham ear-point electrical stimulation (the experimental conditions were same as that of ear-point stimulation other than electric current being no applied) did not show any improvement for epileptic-like electrocorticogram and seizure behaviors. Based on the results above, it was suggested that ear-point electrical stimulation could cause certainly efficacy of anti-seizure, which may be relative with the great auricular nerve.


Albumin and GTP modulate the affinity of prostaglandin E2 receptors in rat epididymal adipocyte membranes.
Detailed studies of PGE2 binding to isolated rat adipocyte membranes revealed two different classes of binding sites, namely high affinity-low capacity binding sites and low affinity-high capacity binding sites. Addition of albumin or GTP to the incubation medium enhanced the specific binding of PGE2 by decreasing the dissociation constant of the low affinity-high capacity binding sites. Albumin also increased the affinity of PGE2 binding to native canine renal medullary membranes and enhanced the binding of PGE2 to prostaglandin receptors solubilized from these membranes. Pretreatment of the adipocyte membranes with the alkylating agent NEM completely abolished the enhancement of PGE2 binding by GTP, while the enhancement of PGE2 binding by albumin was only partially inhibited. The enhancement of PGE2 binding by GTP was shown to be dependent on the presence of Mg+2, while the albumin effect was independent of Mg+2. These results suggest that the affinity of the prostaglandin receptors is modulated by more than one mechanism.


[Coverage of the chikungunya epidemic on Reunion Island in 2006 by the French healthcare system].
The chikungunya epidemic that occurred on Reunion Island between 2005 and 2006 was covered by the French health insurance system. This coverage involved a major increase in the number of paid sick leave days and prescription drug refunds in the first quarter of 2006. Special governmental measures such as full reimbursement of certain medications and waiving of the waiting period for sick leave in case of relapse greatly reduced the impact of the epidemic. Five years after, the database of the health insurance systems indicates a low incidence of chronic forms. Only cases managed on an outpatient basis were included in this study.