relevant bacterial species have yet to be characterized. Beside estrogen, environmental factors, such as smoking, douching, and some sexual practices can decrease vaginal Lactobacilli levels. 26 Estrogen deficiency during meno- pause often leads to a depletion in Lactobacilli whereas estrogen substitution generally leads to a reestablishment of the same bacteria. 27,28 Throughout all our study groups, a large majority of women were nonsmokers. Only 30% (6 out of 20) of samples in the control group, 57.14% (8 out of 14) of samples in the exposure group, and 20% (1 out of 5) of samples in the contraction group demonstrated a dominance of Lactobacillus spp. This may be an indicator for the impairment by the mere presence of prosthetic material caused on the vaginal microbiome and a positive result of the consequent continuous estrogen treatment in patients with diagnosed mesh exposure. The latter could also explain the higher relative abundance of the phyla Firmicutes (including the genus Lactobacillus) in the exposure group. The higher abundance of Actinobacter in the contraction group compared with controls may represent a risk factor for the occurrence of this mesh related complication although these findings again lack statistical significance. Overall, we did not detect any statistically significant differences in the diversity or richness measures between cases and controls at the genera and species level, except for the species Enterobacter spp, Acinetobacter spp., and Veillo- nella spp., which were more abundant in patients after mesh contraction (P = .045, P = .032, and P = .025, respectively). Other studies have shown that Veillonella spp. are associatedwith bacterial vaginosis, we believe that they could represent a risk factor for mesh contraction group. 29,30 Moreover, we detected a trend of an association between higher bacterial diversity and mesh complications when compared with controls, although these findings were not statistically significant. According to the literature, the rate of mesh exposure when placed via the vaginal route varies from 5% to 30%. 31 Surgical treatment of mesh‐related complications accounted for 7% of TVM procedures in our center. 32 Risk factors reported to be associatedwith complications included:
Analysis of covariance revealed that MAP at baseline was not associatedwith the time course of OPP or FLOW, although these effects were borderline significant at P ¼ 0.07 and P ¼ 0.09, respectively. Mean arterial pressure did, however, have a statistically significant influence on the time course of RESIST (P ¼ 0.002). Intraocular pressure at baseline did not influence the time course of OPP, but determined isometric exercise– induced changes in FLOW (P ¼ 0.007) and RESIST (P ¼ 0.002). Results of pressure–flow relationship in dependence of MAP are presented in Figure 4. Grouping MAP values resulted in the following tertiles: group 1: 70.3 6 3.1 mm Hg; group 2: 80.3 6 2.4 mm Hg; group 3: 90.2 6 3.0 mm Hg. A significant
Experimental autoimmune encephalomyelitis (EAE) is an acute or chronic neuro-inflammatory disease of the brain and spinal cord, induced by sensitization of animals with tissue or specific antigens of the central nervous system. The value and limits of different EAE models for MS research has recently been reviewed in detail ( 99 ), and therefore only few points directly related to the current topic are mentioned here. EAE can be induced in most, if not all, mammalian species including humans and leads to an inflammatory disease, which, depending upon the model, is associatedwith focal plaques of demyelination and/or diffuse neurodegeneration. The respective experimental models provide excellent tools to elucidate basic mechanisms of brain inflammation and immune mediated tissue injury in the central nervous system, mediated by different T-cell populations and components of the innate immune system. Most importantly, many anti-inflammatory or immunomodulatory therapies, which have been proven effective in MS patients, have been developed with the help of EAE models. However, the value of these treatments in patients, who have reached the progressive stage of MS, is limited. In addition, effective anti-inflammatory treatments in MS so far target many different immune cells simultaneously, including different T-cell populations, B- lymphocytes and in part also macrophages, while treatments selectively directed against the MHC Class II restricted CD4 +
As the first discovery of somatic activating mutations of the Gs protein in somatotrophic-secreting adenomas (16), the role of alterations of the cAMP signaling pathway in endocrine tumorigenesis and hyperfunction has been ex- tensively investigated. PKA is a pivotal component of the cAMP signaling cascade (17) and is involved in the regu- lation of steroidogenesis in adrenocortical cells (18). The constitutive activation of components of the cAMP path- way and, in particular, of one of its major effectors, PKA, has been related to the development of hypercortisolism associatedwith bilateral hyperplasias, mainly in case of germline mutations, and with sporadic unilateral adreno- cortical adenomas, in case of somatic aberrations. Con- sidering that PKA assumes a pivotal role in the regulation of steroidogenesis, it is not surprising that adrenal tumors carrying alterations in one of the subunits of PKA are mostly cortisol secreting. The functional characterization of the altered catalytic subunit ␣ of PKA has been clearly highlighted in our recent article (14), which showed that somatic mutations of the C ␣ subunit occurred in more than one third of patients with unilateral adenomas asso- ciated with ACTH-independent Cushing’s syndrome, who presented a more severe phenotype than patients without the mutation. Our results are consistent with these findings and with the report published by Goh et al (12), given that somatic mutations in the PRKACA gene have been found in 34% of patients with Cushing’s syn- drome. In the series described by Cao et al (11) and Sato et al (13), the prevalence of PRKACA gene mutations in patients with Cushing’s syndrome was higher (65% and 52%, respectively). A feasible explanation could be that stricter diagnostic criteria could have been applied for the diagnosis of hypercortisolism. Nonetheless, the ethnic background must be considered in interpreting these re- sults, because it is possible that Asian patients could have a higher frequency of PRKACA gene mutation. In addi- tion, the data reported in this article confirm that the same patients had higher cortisol levels after the DST. The ab- sence of mutations in the peripheral DNA suggests that these alterations occur only at a somatic level. The most
In the present study, higher CTP score as well as more advanced CTP stages were associatedwith severity of PHG. Moreover, CTP score was an inde- pendent risk factor for severe PHG on multivariate analysis. Similarly, although some studies did not find a correlation of CTP stages and the presence or severity of PHG [ 6 , 39 ], the majority of studies showed a significant association of PHG with the degree of hepatic dysfunction [ 21 , 38 , 40 , 41 ]. Previous studies have also shown that duration of liver disease corre- lates with development of PHG [ 6 , 7 ]. For example, the proportion of patients with PHG increased by nearly 50% within 5 years of observation [ 6 ]. Thus, differing results with respect to PHG and CTP stage in various studies may be in part explained by di- vergence in duration of disease of included patients and may be additionally dependent on availability and success of etiological treatment such as antiviral therapy for chronic viral hepatitis, as these factors contribute to portal hypertension severity [ 42 , 43 ].
Dontchos et al. and of King et al., but rather are complementary to their observations. The cru- cial difference between our results and those of the aforementioned studies stems from the study populations considered. While the former investigated high-risk populations, we focused on non-high risk individuals. We specifically did not include patients deemed at high risk for breast cancer development due to an estimated life time risk of >20% based on individual (including prior breast or ovarian cancer and mantle field irradiation before the age of 30 years) and familial criteria or the presence of a genetic suscueptibility as detailed in [ 21 ]. As it were, breast tissue from high-risk patients is known to strongly differ from that of normal breast tissues. For instance, in BRCA1/2 carriers, BRCA1/2 mutations infer genetic instability, alter estrogen signaling, which ultimately causes significant histological remodeling; e.g. [ 25 – 27 ]. In patients whose tissue incurred genotoxic insults due to radiation or chemotherapy, other genetic mechanisms contribute to tissue vulnerability and may eventually lead to the for- mation of cancerous lesions upon cell growth stimuli or tissue activation. This can for example be observed following double-strand DNA damage commonly induced by radiation, which leads to genomic instability that can activate mechanisms of cellular escape from apoptosis and ensuing malignant growth; reviewed in [ 28 ]. Together, our data and the aforementioned stud- ies provide evidence, at the imaging level, that tissue activity in tissue at risk (i.e. that harbors defects in its repair mechanisms) upon activation incurs sufficient alterations to progress towards malignant growth with time ( Fig 3 ). As can be derived from the cross-tabulation of the correlation between menopausal status and BPE levels as well as the cross-tabulation correlat- ing menopausal status to diagnostic outcome, post-menopausal age is associatedwith signifi- cantly lower BPE levels and significantly higher malignancy rates than pre-menopausal age.
The study showed that the prevalence of eating undercooked hamburgers was 10.8%. About one quarter of the participants reported usually serving medium-rare hamburgers at home. The majority of the focus-group participants (nearly 60%) liked their beef well-done. These results can be attributed to a higher proportion of the population acknowledging the health risks related to the consumption of undercooked beef. Z HANG et al. (1999) found similar results in their survey about prevalence of selected unsafe food-consumption practices and their associated factors in Kansas. However, results might vary in other geographical locations. Because Kansas is a major beef-production state in the U.S., higher media coverage may exists about the incidents of foodborne illness associatedwith undercooked hamburgers. In addition, there are old rural traditions of cooking all food well. On the other hand, aggressive education efforts on food safety have been realized in the past and resulted in better consumer awareness (P ENNER et al., 1994).
that these changes are raising the risk stakes, pushing supplier management to a strategic level. Fernandez (1995) earlier described the characteristics of a strategic supplier relationship as commitment to partnership, early involvement in decision making, mutual trust and crisis management. In agreement with Fernandez, Ford (1998) describes strategic relationships as substantial and maintains that it is not easy to change them quickly without incurring significant costs both in terms of disruptions and developing new relationships. Ford therefore asserts that strategic relationships are important assets and without them organisations cannot operate or even exist. He adds that an organization’s performance does not only depend on its own actions and wishes, especially when interdependencies are present. Hutt, Stafford, Walker and Reingen (2000) supports this thinking, stating that both communication and the pro-active exchange of information strengthen relationships. In similar vein, Leonard (2000) argues that building and maintaining a sound relationship creates alignment between parties. Lacity (2002) adds yet another dimension to the line of reasoning by arguing that collaborative interactions occur when both sides share similar goals and comments. However, Lacity stresses the fact that the best relationships embrace mutual dynamics, with each party aiming for fairness, not domination or exploitation. Cooray and Ratnatunga (2002) also believes that through relationship management, successful long-term relationships can be developed despite substantial differences between firms. Melymuka (2003) concurs, and argues that even though not all suppliers have the same importance to an organization, supplier management (and the risks associatedwith it) is now becoming a core competency.
The loci on chromosome 6p21 associatedwith total WBC and lymphocyte counts appear to be independent of each other as the lymphocyte association persists after adjustment for total WBC. While the closest replicated SNP associations are roughly 200 kb from each other, and a shared functional connectivity between these regions was not elucidated in the GRAIL analysis. At this locus, rs2524079 associatedwith lymphocyte count is in moderate LD with a number of SNPs in the periphery of the total WBC count locus, including rs2844619, a SNP significant in the total WBC count discovery phase analysis (D9 = 0.762, r 2 = 0.305, from HapMap Phase II CEU samples). The finding of multiple independent effects at a single locus has occurred in prior studies and include examples such as the finding of two independent signals within the PLAG1 locus associatedwith human height, suggesting a locus specific effect, in the current example affecting leucopoiesis or leukocyte homeostasis . Our chromosome 6p21 WBC and lymphocyte loci, both harbor candidate genes that have been previously implicated as associatedwith phenotypes closely related to immunological function. The locus associatedwith total WBC count on chromosome 6p21 contains genes associatedwith follicular lymphoma (CHCG22), progression of HIV-1 infection (CDSN, PSORS1C1 and PSORS1C2) and psoriasis (CCHCR1, PSORS1C1 and PSORS1C2) [67,68,69]. This gene rich region includes HLA family genes, particularly HLA-B and HLA-C that are candidates within the lymphocyte associated locus, and actually overlap with the psoriasis candidate locus identified previously via linkage mapping studies and includes PSORS1C1 and PSORS1C2, showing the relatedness of these two loci on chromosome 6p21 , although conditional analyses adjusting for total white blood cell count validate these as primarily independent effects. The lymphocyte associated regions containing HLA-B and HLA-C, harbors two genes that have been implicated in multiple GWAS as modifiers of immunological responses, associatedwith IL-18 levels, HIV-1 control, vitiligo, multiple clerosis, and psoriasis [49,68,70,71,72,73,74,75,76].
To corroborate that Apelin expression is associatedwith outcome in human breast cancer, we performed an unbiased meta-analysis of multiple datasets using the Kmplot (Gyo¨rffy et al, 2010) and PrognoScan (Mizuno et al, 2009) databases. We confirmed that high levels of Apelin expression in tumors are significantly associatedwith poor prognosis in breast cancer patients (Fig EV1A). Next, we determined whether Apelin blockage is a suitable strategy to amelio- rate cancer progression by ablating its expression in mammary cancer. Apelin-deficient (Apln / ) mice (Kuba et al, 2007) were crossed with MMTV-NeuT transgenic mice (Lucchini et al, 1992) to generate MMTV-NeuT; Apln / and MMTV-NeuT; Apln +/+ control littermates (termed NeuT;Apln / and NeuT;Apln +/+ hereafter). Apelin has been previously shown to be upregulated in tumor cells (Seaman et al, 2007; Wang et al, 2007; Liu et al, 2015). We con- firmed that Apelin expression is enhanced in tumors of MMTV-NeuT mice compared to epithelial cells isolated from the mammary gland of healthy mice (Fig EV1B), recapitulating human breast cancer (Sorli et al, 2007) and validating our model. Importantly, NeuT; Apln / tumor-bearing mice displayed a delay in the onset of NeuT- driven mammary tumors and a significantly prolonged survival compared with NeuT;Apln +/+ littermates (Figs EV1C and 1A). In line with enhanced survival, Apelin-null mice displayed a decreased tumor burden in the mammary glands compared to age-matched controls (Fig EV1D).
Linear fractures associatedwith Vinalia Faculae: While much of the southern floor of Occator is covered by relatively flat, knobby to smooth material that could very well be impact melt , in NE Occator is a mor- phologically distinct floor material. This material has distinct lobate margins extending away from the center of the crater , and has been interpreted to be a cry- ovolcanic flow . The surface of the flow has a ropy, hummocky texture somewhat similar to what is ob- served on the floor of Class 4 Ceres FFCs [4, 9, 10], and is highstanding compared to the immediately sur- rounding floor. Linear fractures cross the lobate mate- rial at its highest points, suggesting that they formed due to bending stresses as the floor was uplifted.
A limitation of our study is that due to recruitment proce- dures we tend to have more early stage colorectal cancer cases (stage I-II) compared to advanced metastatic patients (stage IV). This may indicate that our ﬁndings are mostly associatedwith early metabolic changes in colorectal carcinogenesis rather than with metastatic formation. Furthermore, ﬁndings are derived from cross-sectional data. Therefore, it is not pos- sible to explore to which extent metabolites are causally related to cancer or cancer-related changes. Lastly, although our study was performed using a single stringent metabolo- mics approach across two independent populations, we acknowledge that metabolomics assays can be conducted using a variety of analytical platforms. As such, future studies should include multiple platforms to ensure the highest ana- lytical coverage of the metabolome. Technical progress and the development of more comprehensive metabolite databases will also be needed to improve annotation of unknown com- pounds, including the unknown metabolites in our study. Future targeted approaches, allowing the quantitative mea- surement of metabolites, would allow quantiﬁcation of their absolute concentrations. 46,47
This prospective observational longitudinal cohort study reveals two major findings from long ‐term geriatric care patients. Our first major finding indicates that increased CV risk markers including ADMA, NT pro ‐BNP, CRP and BMI are associatedwith mortality in this older population. Mean plasma concentrations of ADMA and SDMA were higher than those of patients with diabetes, COPD or cardiovascular disease using the same analytical method. Concentrations of L ‐arginin, which are influenced by protein intake, were lower in the elderly patients under study compared with our previous observation in other group of patients. 9–18
On account of its high specific energy, relatively low cost and long cycle life, the lithium-ion battery in its various forms has found many applications in the last two decades (Eisler, 2016; Goodenough and Park, 2013; Tarascon and Armand, 2001; Yoshino, 2012). These range from consumer electronics, computer notebooks, mobile phones and power tools to electric vehicles and even stationary grid storage. As has been recently pointed out (Blomgren, 2017; Hu et al., 2017; Kim et al., 2012), installed capacity is expected to grow rapidly in future due to performance improvements and sinking costs. Electric vehicles and grid storage are likely to be particularly strong growth areas(Hu et al., 2017). The reason is to be found in the efforts currently being made internationally to limit greenhouse gas (GHG) emissions. The main goal of the climate agreement concluded in 2015 in Paris (COP21) is to hold global warming to “well below 2°C above pre-industrial levels” and, moreover, “to pursue efforts to limit the increase to 1.5°C” (United Nations/Framework Convention on Climate Change, 2015). This can only be achieved if sometime in the second half of this century net GHG emissions are reduced to zero globally. Since road transport alone is currently responsible for about 20% of GHG emissions in, for example, the EU (Eurostat, 2016a), one obvious route is the electrification of this sector in combination with low carbon, or carbon-free, sources of electrical energy. In the second area mentioned, namely, stationary grid storage, Li-ion battery technology may be used increasingly to combat mainly short-term intermittency problems associatedwith renewable energy sources (Arbabzadeh et al., 2016). The present paper is largely motivated by the current discussion on the possible, foreseeable material requirements for electrification in the transport sector and grid storage as well as on the concomitant supply risks associatedwith these metals and minerals. The supply risks require early identification and may also need international action for their mitigation (Ali et al., 2017). Using a recently developed procedure the paper compares in a semi- quantitative way the supply risks associated not only with the key metals and minerals, but also with the technologies used in Li-ion batteries.
There are a some studies in the literature reporting inversed old-new effects. Cy- cowicz et al. (2001) found an inversed old-new effect in a somewhat later time win- dow (800-1200 ms) in a source memory paradigm. The effect had a parieto-occipital focus, so the authors suggested it may reflect sensory reinstatement of the study im- age in visual cortex. This late posterior negativity (LPN) has been associatedwith continued and extended integration processing (Johansson and Mecklinger, 2003). Yet, given the latency difference as compared to the current effect, we do not con- sider this a likely interpretation of present results. Perhaps more relevant, Nessler et al. (2004) reported an inversed LPC effect in a false memory paradigm. As in the present case, the effect was based on a positive shift of correct rejection waveforms and peaked around 700 ms. In their task, subjects studied a list of words taken from 10 categories. At test they were to accept studied words as old and to reject both new items from different, novel categories and lures (i.e., new words from the study phase categories). They argued that their subjects may have focused on novel se- mantic information in order to reject new items from novel categories. Similarly, Azimian-Faridani and Wilding (2006) reported a positive shift of correct rejection waveforms at posterior sites around 700 ms, when they manipulated response crite- rion. Both studies suggested that the positive shift may have been due to target-like processing of new items affecting target-P300 amplitude and thus reducing (Azimian- Faridani and Wilding) or inverting (Nessler et al.) the standard old-new LPC effect. Thus, some subjects in the present case could have used a similar strategy and the difference between groups could reflect a difference in processing strategy.
Understanding the risk factors for breast cancer allows identifying women seeking interventions to modify the risks both in isolated cases, as also in larger populations; in epidemiological studies. 8, Many factors are associatedwith breast cancer, such as age and gender, race, ethnicity, benign diseases, lifestyle and dietary factors, reproductive and hormonal factors, exposure to ionizing radiation, environmental factors and smoke. 8-9 However, in 10% of cases it is associatedwith family history. 9 The family history is common in patients with breast cancer, with a low percentage, but all are related to mutations in germinative strains. 9-10
The mortality rate for cases of severe mastitis associatedwith detection of E. coli was 35.0% [ 13 ].
Studies focusing exclusively on severe mastitis are rare. Typical sample size of severe mastitis studies varied between as many as 104 cases in Erskine et al. [ 14 ] and 69 cases in Krömker et al. [ 15 ]. Studies are limited because of the need for rapid treatment, as severe mastitis is associatedwith a high risk of death. Severe mastitis is of particular importance because, in addition to a negative effect on the general condition of dairy cows and local and systemic irreparable tissue damage, it also leads to bacteremia and even death [ 13 , 16 , 17 ]. Pathogens cause cell damage in the udder, whereupon inflammation sets in as a defensive reaction of the body (e.g., swelling, redness and heat). Increased blood circulation in the affected udder quarter leads to an accelerated transport of immune cells, antibodies and an accelerated removal of cell debris. The explanation for the spreading mastitis is a reduced function and impaired defense of the neutrophil granulocytes, which leads to a faster multiplication of the bacteria [ 18 ]. Toxins or pathogens flood the body via the bloodstream and cause damage in other organs, which can lead to blood poisoning [ 13 , 19 ].
Sweden has a long tradition of labour market policies explicitly targeting job seekers with disabilities, ranging from in-work aids to subsidized employments, aiming at strengthening their position at the labour market. To ascertain that these programs are limited to the needy they are constrained to those job seekers that are classified as occu- pationally disabled by the Public Employment Service. In this study we have investi- gated the determinants of being classified as occupationally disabled by the PES. Simi- lar to the studies on disability retirement and self-reported disability we find that men were more likely to be classified as disabled and also that higher age and various meas- ures of socio-economic disadvantages were associatedwith a higher likelihood. Rather naturally, also all measures indicating poor health were associatedwith an increased likelihood of being classified as occupationally disabled. A final point is that over the time period under study it became increasingly likely to be classified as occupationally disabled and especially to receive a code related to mental, socio-medical, and learning disabilities.
Epi-microbia communities have been found to be important in the larval settlement processes of most marine invertebrates (Wieczorek & Todd, 1998), such as sponges (Woollacott & Hadfield, 1996), cnidarians (Bosch, 2013), ascidians (Wahl et al., 1994; Schuett et al., 2005) and bryozoans (Pukall et al., 2001; Kittelmann & Harder, 2005) . Under aseptic conditions, no settlement of planulae of the jellyfish Aurelia aurita (Schmahl, 1985), Cassiopea andromeda (Hofmann & Brand, 1987) and the hydrozoan Hydractinia echinata (Leitz & Wagner, 1993) occurred. Interestingly, bacteria and/or their products induced the settlement and metamorphosis of each of these organisms (Müller & Leitz, 2002). Intensive studies of scyphomedusae focused upon the general life history strategies, including the detailed morphology description of planula, scyphistoma and young ephyra, process of strobilation, development of ephyra to young medusa (Svane & Dolmer, 1995; Holst et al., 2007; Lucas et al., 2012), reproductive behavior, different changing factors leading to strobilation, growth rate and impact of predation rate of ephyrae (Hofmann et al., 1978; Båmstedt, 1990; Olesen et al., 1996; Barz & Hirche, 2007; Holst et al., 2007; Holst, 2012 a and b). Whereas the presence and activity of bacteria associatedwith of different life stages of scyphomedusae have received less attention. A few studies characterizing the bacterial community associatedwith early life stages were carried out on fish larva (Bergh, 1995; Hansen & Olafsen, 1999; Romero & Navarrete, 2006), scallop (Torkildsen et al., 2005) focusing on the colonization by pathogenic bacteria during early stage of commercial fish. Fraune et al.(2010) described the bacterial colonization in the early development of embryo in
Regarding associations between pleurisy prevalence and disease related factors, the univariable study differentiated clinical signs by age group (< and > 30 kg) and year (2007 and 2008). Similar to previous studies where observable respiratory disease in late finishing was associatedwith the presence of pleurisy , the present study found dyspnoea and coughing in pigs > 30 kg were associatedwith pleurisy in 2007 and 2008. In 2007 dyspnoea in pigs <30 kg could also be related to increased pleurisy in slaughter pigs, but this effect was not observed in 2008. However, these clinical observations are not specific for pleurisy and may indicate other, co-existent, respiratory diseases. Previous research has indicated a link between pleurisy prevalence and prevalence of pneumonia , but more recent work suggests this relationship may not be straightforward since lesions of pneumonia were negatively associatedwith pleurisy lesions [5,10]. Much opportunity remains to understand how pleurisy relates to pneumonia in pigs and how it might be detected ante mortem. Increased mortality was consistently and strongly associatedwith the units being defined as cases in each of the 3 years for which data was requested. This basis of this association is worthy of further investigation because, on one hand, it is another indication that pleurisy is a disease of generally lower health status units and, on the other, an indication of the economic consequences of pleurisy on units where it is a consistent problem. As a proxy for the overall health of a unit, increased numbers of group level medication periods in the post-weaning period were associatedwith units with consistent pleurisy. While this observation would be consistent with a tendency for pleurisy to occur on units of generally lower health status and with higher consequent production costs, it is probable that some of these additional medications would have been a direct consequence of pleurisy.