Distinct enzymatic responses in mice exposed to a range of low doses of ozone.

Short-term exposure of mice to low O3 doses, as defined by the product of concentration and exposure time (ct), was observed to induce alterations in two enzyme systems: first, that leading to changes in hepatic reduced ascorbic acid (RAA) content, and second to changes in plasma creatine phosphokinase (CPK) activity. RAA alterations were noticed immediately, 30 min and 120 min after termination of the exposure period, whereas CPK showed alterations immediately and 15 min after termination of the exposure. Later determinations, i.e., 24 hr after O3 exposure for RAA and 30 min after 03 exposure for CPK, revealed no significant differences when compared to control animals. Although differences in sensitivity existed, the dose response curves for both systems were more or less similar, showing a short decrease for the initial very low O3 doses, followed by a profound rise and a gradual decrease to control levels for subsequent ct doses. Exceptions were the 30 min curve for RAA and the immediate curve for CPK in so far as that both showed an additional depression. Neither plasma histamine nor plasma lactic acid dehydrogenase (LDH3) were observed to be altered by the range of O3 doses employed. These findings were explained on the basis of adaptation of the organism to a potentially noxious O3 stimulus by enhanced metabolic processes: a weak stimulus leading to only a small adjustment, and stronger stimuli to elevated enzyme activity as well. With increasing doses of O3 this elevation in enzyme activity was found to be gradually diminished, possibly due to a steadily growing demand, leaving the overshoot becoming continually smaller until a balanced state is achieved

The Shadow Price of Irrigation Water in Major Groundwater‐Depleting Countries

In many semiarid regions with irrigation, the depletion rate of groundwater resources has increased substantially during the last decades. A possible reason for this is that the price that users pay for their water does not reflect its scarcity and value. An alternative way to assess the perceived value of water is calculating its shadow price, which is defined here as the marginal value produced, and relates to the efficiency gain from current reallocation. Here we determine the shadow price of water used for irrigation for the most important groundwater‐depleting countries and for four staple crops and one cash crop. To quantify the shadow price, the relation between the output and the water input is represented using production functions. We use globally available panel data on country‐specific crop yields and prices together with crop‐specific water consumption, calculated with the global hydrological model PCR‐GLOBWB, to parameterize the production function by country and crop with econometric analyses. Our results show that the variation of shadow prices for staple crops within several countries is high, indicating economically inefficient use of water resources, including nonrenewable groundwater. We also analyze the effects of reallocating irrigation water between crops, showing that changes in water allocation could lead to either an increase in the economic efficiency of water use or large reductions in irrigation water consumption. Our study thus provides a hydroeconomic basis to stimulate sustainable use of finite groundwater resources globally

Identification of Dutch children diagnosed with atopic diseases using prescription data:a validation study

The aim of this study is to validate medication proxies for the identification of children diagnosed with atopic disorders that can be applied in various types of epidemiological research. Records of 7439 children, aged between 0 and 10 years, in the period 2001 until 2010, were retrieved from the Registration Network Groningen database, a general practitioners database in the north-eastern part of the Netherlands. The sensitivity and positive predictive value (PPV) of 22 medication proxies for the identification of children diagnosed with atopic disorders (asthma, atopic dermatitis, and allergic rhinitis) were computed using the registered diagnoses as gold standards. In addition, different capture periods (1 year, half year, and length of study period) for the detection of prescriptions were tested for all the medication proxies. The highest PPV (0.84, 95 % CI 0.81-0.87) in combination with a sufficient sensitivity value (0.54, 95 % CI 0.50-0.57) for the identification of children diagnosed with asthma was yielded for the medication proxy, a parts per thousand yen2 prescriptions for anti-asthma medication within 1 year, including 1 inhaled steroid. PPV and sensitivity were even higher in the age group 6-10 years. The proxies designed for the identification of children diagnosed with atopic dermatitis and allergic rhinitis yielded only high PPVs (a parts per thousand yen0.75) in combination with low sensitivity values (a parts per thousand currency sign0.22). Altering the capture period for the detection of prescriptions to half a year or the length of the study period only affected sensitivity values. Children diagnosed with asthma can be identified reliably with a range of medication proxies. The use of prescription data for the identification of children diagnosed with atopic dermatitis and allergic rhinitis is questionable

Risks versus benefits of medication use during pregnancy:What do women perceive?

Background: Understanding perception of risks and benefits is essential for informed patient choices regarding medical care. The primary aim of this study was to evaluate the perception of risks and benefits of 9 drug classes during pregnancy and associations with women's characteristics. Methods: Questionnaires were distributed to pregnant women who attended a Dutch Obstetric Care facility (first-and second-line care). Mean perceived risk and benefit scores were computed for 9 different drug classes (paracetamol, antacids, antibiotics, antifungal medication, drugs against nausea and vomiting, histamine-2 receptor antagonists/proton pump inhibitors, antidepressants, nonsteroidal anti-inflammatory drugs, and sedatives/anxiolytics). For each participant, we computed weighted risk and benefit sum scores with principal component analysis. In addition, major concerns regarding medication use were evaluated. Results: The questionnaire was completed by 136 women (response rate 77%). Pregnant women were most concerned about having a child with a birth defect (35%), a miscarriage (35%), or their child developing an allergic disease (23%), respectively, as a result of drug use. The majority of studied drug classes were perceived relatively low in risk and high in benefit. Higher risk scores were reported if women were in their first trimesters of pregnancy (p=0.007). Lower benefit scores were reported if women were single (p=0.014), smoking (p=0.028), nulliparous (p=0.006), or did not have a family history of birth defects (p=0.005). Conclusion: Pregnant women's concerns regarding potential drug adverse effects were not only focused on congenital birth defects but also included a wider range of adverse outcomes. This study showed that most of the studied drug classes were perceived relatively low in risk and high in benefit

Sialic acid-modified antigens impose tolerance via inhibition of T-cell proliferation and de novo induction of regulatory T cells

Sialic acids are negatively charged nine-carbon carboxylated monosaccharides that often cap glycans on glycosylated proteins and lipids. Because of their strategic location at the cell surface, sialic acids contribute to interactions that are critical for immune homeostasis via interactions with sialic acid-binding Ig-type lectins (siglecs). In particular, these interactions may be of importance in cases where sialic acids may be overexpressed, such as on certain pathogens and tumors. We now demonstrate that modification of antigens with sialic acids (Sia-antigens) regulates the generation of antigen-specific regulatory T (Treg) cells via dendritic cells (DCs). Additionally, DCs that take up Sia-antigen prevent formation of effector CD4+ and CD8+ T cells. Importantly, the regulatory properties endowed on DCs upon Sia-antigen uptake are antigen-specific: only T cells responsive to the sialylated antigen become tolerized. In vivo, injection of Sia-antigen–loaded DCs increased de novo Treg-cell numbers and dampened effector T-cell expansion and IFN-γ production. The dual tolerogenic features that Sia-antigen imposed on DCs are Siglec-E–mediated and maintained under inflammatory conditions. Moreover, loading DCs with Sia-antigens not only inhibited the function of in vitro–established Th1 and Th17 effector T cells but also significantly dampened ex vivo myelin-reactive T cells, present in the circulation of mice with experimental autoimmune encephalomyelitis. These data indicate that sialic acid-modified antigens instruct DCs in an antigen-specific tolerogenic programming, enhancing Treg cells and reducing the generation and propagation of inflammatory T cells. Our data suggest that sialylation of antigens provides an attractive way to induce antigen-specific immune tolerance

A Novel Role for CD55 in Granulocyte Homeostasis and Anti-Bacterial Host Defense

Background: In addition to its complement-regulating activity, CD55 is a ligand of the adhesion class G protein-coupled receptor CD97; however, the relevance of this interaction has remained elusive. We previously showed that mice lacking a functional CD97 gene have increased numbers of granulocytes. Methodology/Results: Here,wedemonstratethatCD55-deficientmicedisplay a comparable phenotype with about two-fold more circulating granulocytes in the blood stream, the marginated pool, and the spleen. This granulocytosis was independent of increased complement activity. Augmented numbers of Gr-1-positive cells in cell cycle in the bone marrow indicated a higher granulopoietic activity in mice lacking either CD55 or CD97. Concomitant with the increase in blood granulocyte numbers, Cd55-/mice challenged with the respiratory pathogen Streptococcus pneumoniae developed less bacteremia and died later after infection. Conclusions: Collectively, these data suggest that complement-independent interaction of CD55 with CD97 is functionall

Overexpression of CD97 in Intestinal Epithelial Cells of Transgenic Mice Attenuates Colitis by Strengthening Adherens Junctions

The adhesion G-protein-coupled receptor CD97 is present in normal colonic enterocytes but overexpressed in colorectal carcinoma. To investigate the function of CD97 in colorectal carcinogenesis, transgenic Tg(villin-CD97) mice overexpressing CD97 in enterocytes were generated and subjected to azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated tumorigenesis. Unexpectedly, we found a CD97 cDNA copy number-dependent reduction of DSS-induced colitis in Tg compared to wild-type (WT) mice that was confirmed by applying a simple DSS protocol. Ultrastructural analysis revealed that overexpression of CD97 strengthened lateral cell-cell contacts between enterocytes, which, in contrast, were weakened in CD97 knockout (Ko) mice. Transepithelial resistance was not altered in Tg and Ko mice, indicating that tight junctions were not affected. In Tg murine and normal human colonic enterocytes as well as in colorectal cell lines CD97 was localized preferentially in E-cadherin-based adherens junctions. CD97 overexpression upregulated membrane-bound but not cytoplasmic or nuclear β-catenin and reduced phospho-β-catenin, labeled for degradation. This was associated with inactivation of glycogen synthase kinase-3β (GSK-3β) and activation of Akt. In summary, CD97 increases the structural integrity of enterocytic adherens junctions by increasing and stabilizing junctional β-catenin, thereby regulating intestinal epithelial strength and attenuating experimental colitis

Radiotherapeutic alternatives for previously irradiated recurrent gliomas

Re-irradiation for recurrent gliomas has been discussed controversially in the past. This was mainly due to only marginal palliation while being associated with a high risk for side effects using conventional radiotherapy

Cancer Genomics Identifies Regulatory Gene Networks Associated with the Transition from Dysplasia to Advanced Lung Adenocarcinomas Induced by c-Raf-1

Background: Lung cancer is a leading cause of cancer morbidity. To improve an understanding of molecular causes of disease a transgenic mouse model was investigated where targeted expression of the serine threonine kinase c-Raf to respiratory epithelium induced initialy dysplasia and subsequently adenocarcinomas. This enables dissection of genetic events associated with precancerous and cancerous lesions. Methodology/Principal Findings: By laser microdissection cancer cell populations were harvested and subjected to whole genome expression analyses. Overall 473 and 541 genes were significantly regulated, when cancer versus transgenic and non-transgenic cells were compared, giving rise to three distinct and one common regulatory gene network. At advanced stages of tumor growth predominately repression of gene expression was observed, but genes previously shown to be upregulated in dysplasia were also up-regulated in solid tumors. Regulation of developmental programs as well as epithelial mesenchymal and mesenchymal endothelial transition was a hall mark of adenocarcinomas. Additionaly, genes coding for cell adhesion, i.e. the integrins and the tight and gap junction proteins were repressed, whereas ligands for receptor tyrosine kinase such as epi- and amphiregulin were up-regulated. Notably, Vegfr- 2 and its ligand Vegfd, as well as Notch and Wnt signalling cascades were regulated as were glycosylases that influence cellular recognition. Other regulated signalling molecules included guanine exchange factors that play a role in an activation of the MAP kinases while several tumor suppressors i.e. Mcc, Hey1, Fat3, Armcx1 and Reck were significantly repressed. Finally, probable molecular switches forcing dysplastic cells into malignantly transformed cells could be identified. Conclusions/Significance: This study provides insight into molecular pertubations allowing dysplasia to progress further to adenocarcinoma induced by exaggerted c-Raf kinase activity