Associations of particulate matter with atopic dermatitis and chronic inflammatory skin diseases in South Korea.

BACKGROUND: Particulate matter (PM) is a mixture of solid and liquid particles suspended in air, which originates from industrial plants or vehicle emissions. Although the skin is the primary body area of contact with air pollutants, the associations between PM and chronic inflammatory skin diseases has not been well established. AIM: To investigate associations between PM and atopic dermatitis (AD) and between PM and other chronic inflammatory dermatoses, using data from the Korean Health Insurance Review and Assessment Service. METHODS: Monthly disease statistics from the seven largest cities in South Korea (Seoul, Busan, Daegu, Incheon, Gwangju, Daejeon, Ulsan) and from Jeju Island (in total, a population of 23 288 000 for all eight areas) were included. Based on daily air pollution level and weather forecast from 2015 to 2019, multivariate negative binomial regression analysis was conducted to estimate monthly visits of AD with respect to outdoor air pollutants: coarse PM with a diameter of ≤ 10 µm (PM10) and fine PM with a diameter of ≤ 2.5 µm (PM2.5) ozone (O3 ), nitrogen dioxide (NO2 ), sulphur dioxide (SO2 ) and carbon monoxide (CO). RESULTS: Increases in the levels of PM2.5, PM10, SO2 and CO were associated with significant increases in monthly patient visits for AD. Every 10 µg/m3 increase in PM2.5 and PM10 resulted in patient visit increases of 2.71% (95% CI 0.76-4.71; P < 0.01) and 2.01% (95% CI 0.92-3.11, P < 0.001), respectively, while every 1 part per billion (ppb) increase in SO2 and every 100 ppb increase in CO resulted in visit increases of 2.26% (95% CI 1.35-3.17; P < 0.001) and 2.86% (95% CI 1.35-4.40; P < 0.001), respectively. O3 and NO2 were not associated with increased patient visits for AD. Increases in PM2.5 and PM10 concentrations were also significantly associated with increases in patient visits for psoriasis, seborrhoeic dermatitis and rosacea. CONCLUSION: Our data suggest that PM is associated with AD and other chronic inflammatory skin diseases.

Increased protein oxidation and decreased expression of nuclear factor E2-related factor 2 protein in skin tissue of patients with diabetes.

BACKGROUND: Reactive oxygen species (ROS) contribute to the cell dysfunction and tissue damage that result from glucolipotoxicity in diabetes. ROS formation in cells causes oxidative stress, thereby activating oxidative damage-inducing genes. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been shown to play an essential role in the vital defence mechanisms that help cells cope with oxidative stress. AIM: To compare Nrf2 protein expression in nondiabetic skin tissue with that in diabetic skin tissue. METHODS: Nrf2 expression was evaluated by Western blotting, reverse transcription (RT)-PCR, and immunohistochemical staining in diabetic and nondiabetic skin tissues. Dinitrophenylhydrazone derivatives of protein carbonyls in the oxidized proteins were measured by oxyblotting analysis. Cytoplasmic and nuclear Nrf2 protein expression was determined to identify the activity and level of Nrf2. RESULTS: Protein oxidation, a marker of oxidative stress, was found to be increased in diabetic skin tissue. In subcellular fraction analysis, Nrf2 protein was detected in the nuclei and cytoplasm of nondiabetic skin tissues, and the Nrf2 protein band was identified from among the multiple bands detected, using small interfering RNA-mediated Nrf2 gene silencing. Compared with nondiabetic tissue, diabetic skin tissue showed simultaneous downregulation of Nrf2 at both the mRNA and protein levels. Nuclear condensation, loss of nuclei, and vacuolization were seen in some parts of the specimen by haematoxylin and eosin staining of diabetic skin tissue. Immunohistochemical staining of Nrf2 confirmed the RT-PCR and Western blotting results. CONCLUSIONS: Collectively, our data show that expression of Nrf2 is clearly downregulated in diabetic skin tissue, and suggest that Nrf2 may be necessary for protection against glucose-induced oxidative stress.

TLR2-dependent amelioration of allergic airway inflammation by parasitic nematode type II MIF in mice.

In our previous studies, the recombinant type II macrophage migration inhibitory factor homologue (rAs-MIF) secreted from Anisakis simplex suppressed experimental inflammation mouse model through IL-10 production and CD4(+)CD25(+)Foxp3(+) T-cell recruitment. Also, TLR2 gene expression was significantly increased following rAs-MIF treatment. To know the relation between TLR2 and amelioration mechanisms of rAs-MIF, we induced allergic airway inflammation by ovalbumin and alum with or without rAs-MIF under TLR2 blocking systems [anti-TLR2-specific antibody (α-mTLR2 Ab) treatment and using TLR2 knockout mice]. As a result, the amelioration effects of rAs-MIF in allergic airway inflammation model (diminished inflammation and Th2 response in the lung, increased IL-10 secretion, CD4(+)CD25(+)Foxp3(+) T-cell recruitment) were diminished under two of the TLR2 blocking model. The expression of TLR2 on the surface of lung epithelial cell was significantly elevated by rAs-MIF treatment or Pam3CSK (TLR2-specific agonist) treatment, but they might have some competition effect on the elevation of TLR2 expression. In addition, the elevation of IL-10 gene expression by rAs-MIF treatment was significantly inhibited by α-mTLR2 Ab or Pam3CSK pretreatment. In conclusion, anti-inflammatory effects of the rAs-MIF on OVA-induced allergic airway inflammation might be closely related to TLR2.

Attitudes towards non-invasive prenatal testing for aneuploidy among US adults of reproductive age.

OBJECTIVE: To determine how adults in the United States view non-invasive prenatal testing using cell-free fetal DNA (cffDNA testing) in order to help estimate uptake. STUDY DESIGN: A national sample of 1861 US-based adults was surveyed using a validated online survey instrument. The survey was administered by a commercial survey research company. Respondents were randomized to receive a survey about prenatal testing for trisomy 13 and 18 or trisomy 21. Participants were asked to select among testing modalities, including cffDNA testing, and rank the features of testing that they considered most important to decision making. RESULT: There was substantive interest in the use of cffDNA testing rather than traditional screening mechanisms, with a minority of respondents reporting that they would support the use of both methods in combination. The lower rates of false-negative and false-positive test results and the ability to use the test earlier in the pregnancy were the most highly rated benefits of cffDNA testing. Participants expressed strong support for diagnostic confirmation via invasive testing after a positive result from either screening or cffDNA testing. However, almost one-third of participants reported that they would not endorse the use of either invasive or non-invasive prenatal testing. CONCLUSION: There appears to be support for uptake of non-invasive prenatal tests. Clinical guidelines should therefore go forward in providing guidance on how to integrate non-invasive methods into the current standard of care. However, our findings indicate that even when accuracy, which is rated by patients as the most important aspect of prenatal testing, is significantly improved over existing screening methods and testing is offered non-invasively, the number of individuals who reported that they would decline any testing remained the same. Attention should therefore be directed at ensuring that the right of informed refusal of prenatal testing is not impacted by new, non-invasive methods.

The effect of a Foley catheter balloon on cervical ripening.

The Foley catheter balloon may affect cervical ripening through changes in biochemical mediators by immunoassay and immunohistochemistry, when it is used for pre-induction cervical ripening. The aim of the study was to evaluate the changes in the biochemical mediators from the extra-amniotic space and immunohistochemistry in ripened cervical tissue after the insertion of a Foley catheter balloon (FCB) for pre-induction cervical ripening. A total of 18 pregnant women with a Bishop's score < 6, who were undergoing labour induction, were evaluated in this prospective study. The FCB was irrigated with 10 ml of phosphate buffered saline and the irrigant was collected 0, 2, 4 and 8 h after placement of the FCB or until spontaneous expulsion of the FCB occurred. Irrigant specimens were also collected from 10 spontaneous labouring (SL) women in the active phase of labour. The levels of interleukin (IL)-6, IL-8, matrix metalloproteinase (MMP)-8 and NO were measured. Cervical specimens were obtained from 12 women, including four undergoing induction; four SL and four non-pregnant (NP) women. Immunohistochemical staining was performed to localise hyaluronic acid synthase (HAS)-1, IL-6, IL-8, MMP-8, endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS). Results showed that the levels of IL-6, IL-8, and MMP-8 significantly increased over time in FCB group (p < 0.01). In the immunohistochemical analysis of cervical tissues, immunoreactivity of HAS-1 in the after FCB group was stronger than any of the other groups. The protein expressions of IL-6, IL-8, MMP-8, eNOS and iNOS were more prominent in the after FCB and SL groups than in the NP and the before FCB groups. iNOS was only observed in the after FCB and SL groups. It was concluded that FCB may affect cervical ripening through changes in biochemical mediators by immunoassay and immunohistochemistry, when it is used for pre-induction cervical ripening.

Best ethical practices for clinicians and laboratories in the provision of noninvasive prenatal testing.

OBJECTIVE: The goal of this study is to provide an ethical framework for clinicians and companies providing noninvasive prenatal testing using cell-free fetal DNA or whole fetal cells. METHOD: In collaboration with a National Institutes of Health-supported research ethics consultation committee together with feedback from an interdisciplinary group of clinicians, members of industry, legal experts, and genetic counselors, we developed a set of best practices for the provision of noninvasive prenatal genetic testing. RESULTS: Principal recommendations include the amendment of current informed consent procedures to include attention to the noninvasive nature of new testing and the potential for a broader range of results earlier in the pregnancy. We strongly recommend that tests should only be provided through licensed medical providers and not directly to consumers. CONCLUSION: Prenatal tests, including new methods using cell-free fetal DNA, are not currently regulated by government agencies, and limited professional guidance is available. In the absence of regulation, companies and clinicians should cooperate to adopt responsible best ethical practices in the provision of these tests.

Comparison of the clinical and quality-of-life outcomes after the inside-out TVT-O procedure with or without concomitant transvaginal gynaecological surgery.

The study was undertaken to compare the clinical and quality-of-life (QoL) outcomes of the inside-out transobturator vaginal tape (TVT-O)-only procedures and TVT-O procedures with concomitant transvaginal gynaecological surgery for the treatment of stress urinary incontinence (SUI). A review of charts from January 2006 to March 2010 identified 305 patients with urodynamic stress incontinence for whom we performed the TVT-O. Of the initial 305 patients, 272 (89.2%) were re-examined for complications 1 month, 4 months, 1 year and 2-4 years postoperatively (122 TVT-O only; 150 TVT-O + other transvaginal gynaecological surgery). They were also evaluated with the Urogenital Distress Inventory Questionnaire (UDI-6) and the Incontinence Impact Questionnaire (IIQ-7) 1-4 years after the procedure. The median follow-up was 37.3 months. The success rate was 89.3% in the TVT-O-only group vs 93.3% in the TVT-O with concomitant gynaecological surgery group (p =0.729). The QoL score was quite good for 91.8% of the TVT-O-only patients and for 96.7% of the TVT-O with concomitant gynaecologic surgery patients (p =0.405). In conclusion, gynaecological operations performed concomitantly with the TVT-O procedure do not affect the clinical and QoL outcomes of the TVT-O procedure.

PP177. The usefulness of gestation-corrected hyperuricemia as a predictor of the development of preeclampsia on subsequent pregnancy.

INTRODUCTION: Hyperuricemia has been described commonly in preeclamptic pregnancies, often preceding the diagnosis of preeclampsia and historically was used as a diagnostic marker of preeclampsia. OBJECTIVES: The aim of this study was to determine the usefulness of uric acid to predict the preeclampsia on subsequent pregnancy. METHODS: The retrospective chart review was done. The pregnant women who had previous preeclampia or gestational hypertension and checked serum uric acid were enrolled in this study. Fifty-eight women were collected. Hyperuricemia was defined as being one standard deviation above the gestation-specific mean . And we used uric acid z-scores ([serum uric acid value - gestation specific mean]/standard deviation of the population) to account for gestation-specific alterations in uric acid and tested this as a continuous variable. Linear regression analysis was used to assess the relationship between gestation-corrected hyperuricemia and development of preeclampsia on subsequent pregnancy. RESULTS: Of 58 women, nineteen had the development of recurrent preeclampsia (37.5%). Linear regression analysis showed that the absence or presence of gestation-corrected hyperuricemia was not associated with the development of preeclampsia on subsequent pregnancy (p=0.353, 95% CI 0.418-11.520). And gestation-specific uric acid z-score as a continuous variable did not show any association with the prediction of preeclampsia on subsequent pregnancy (p=0.353, 95% CI 0.087-2.394). CONCLUSION: Gestation-corrected hyperuricemia does not predict the development of preeclampsia on subsequent pregnancy.

Sinus thrombosis in a patient with intracranial hypotension: a suggested hypothesis of venous stasis. a case report.

We describe the case of a 26-year-old man with orthostatic headache. Cerebral angiography revealed thrombosis in the sagittal sinus. Spine MRI showed cerebrospinal fluid collection at the C1-2 level. We performed blood patch and the symptoms disappeared. We report a rare case of intracranial hypotension caused by CSF leak and describe our hypothesis that SIH can change the velocity of cerebral blood flow and cause thrombosis.

Expression of RUNX3 in skin cancers.

BACKGROUND: Expression of Runt-related transcription factor 3 (RUNX3) is reduced in a large number of cancers. However, a few studies have reported higher expression of RUNX3 in several cancers, including basal cell carcinoma (BCC). In light of this, we explored the expression of RUNX3 in skin cancers generally, to determine whether it acts as an oncogene or a tumour-suppressor gene in skin tumours. AIM: To investigate the expression of RUNX3 in normal skin and malignant skin tumours. METHODS: RUNX3 expression was evaluated by western blotting in 24 specimens, comprising 6 malignant melanoma (MM), 6 squamous cell carcinoma (SCC), 6 BCC and 6 normal skin specimens. Immunohistochemical staining was carried out to analyse RUNX3 expression in 16 MM, 16 SCC and 16 BCC specimens. To identify where the protein was expressed, the cytoplasmic and nuclear protein expression of RUNX3 in skin cancer tissues was determined. A cell-proliferation study was performed on an MM line (G361) by small interfering (si)RNA transfection. RESULTS: The western blotting experiments showed that RUNX3 was not expressed in normal skin tissues, but it was overexpressed in all MM and SCC samples, and in five of the six BCC samples. Using immunochemistry, RUNX3 was found to be overexpressed in all cancer tissues analysed. Subcellular fraction analysis revealed that RUNX3 was expressed in the nuclei but not the cytoplasm of all the skin cancer tissues analysed, and RUNX3 silencing by siRNA in G361 cells resulted in a decrease in proliferation. CONCLUSIONS: Based on these results, we suggest that RUNX3 has an oncogenic potential and does not act as a tumour suppressor in skin cancers.

The Caenorhabditis elegans GARP complex contains the conserved Vps51 subunit and is required to maintain lysosomal morphology.

In yeast the Golgi-associated retrograde protein (GARP) complex is required for tethering of endosome-derived transport vesicles to the late Golgi. It consists of four subunits--Vps51p, Vps52p, Vps53p, and Vps54p--and shares similarities with other multimeric tethering complexes, such as the conserved oligomeric Golgi (COG) and the exocyst complex. Here we report the functional characterization of the GARP complex in the nematode Caenorhabditis elegans. Furthermore, we identified the C. elegans Vps51 subunit, which is conserved in all eukaryotes. GARP mutants are viable but show lysosomal defects. We show that GARP subunits bind specific sets of Golgi SNAREs within the yeast two-hybrid system. This suggests that the C. elegans GARP complex also facilitates tethering as well as SNARE complex assembly at the Golgi. The GARP and COG tethering complexes may have overlapping functions for retrograde endosome-to-Golgi retrieval, since loss of both complexes leads to a synthetic lethal phenotype.

Amelioration of intestinal colitis by macrophage migration inhibitory factor isolated from intestinal parasites through toll-like receptor 2.

In a previous study, we cloned type II MIFs (As-MIF) from Anisakis simplex 3rd stage larva and expressed a recombinant protein that suppressed allergic airway inflammation via regulatory T (CD4(+) CD25(+) Foxp3(+) T; T(reg) )-cell recruitment. In this study, in an effort to evaluate the function of rAs-MIF on another immune disease, we induced intestinal inflammation in mice using dextran sodium sulphate (DSS) with or without the application of rAs-MIF treatment to the mice. As a consequence, weight losses were recovered, and the value of disease activity index (DAI) was reduced by rAs-MIF treatment during the experimental period. The levels of TGF-ß and IL-10 in the spleens and mesenteric lymph nodes (MLN) from the rAs-MIF-treated mice were higher, but the levels of IFN-γ, IL-6 and IL-13 were lower than those of the mice treated with DSS but not with rAs-MIF. Additionally, the T(reg) cells observed were greatly increased in the MLNs of the rAs-MIF-treated mice than those of mice not treated with rAs-MIF. The results of our in vitro experiments showed that the elevated IL-10 production induced by rAs-MIF was generated via toll-like receptor 2. In conclusion, rAs-MIF appears to ameliorate DSS-induced colitis and may prove useful as a therapeutic agent for the treatment of intestinal inflammatory disease.

Parasite excretory-secretory proteins elicit TRIF dependent CXCL1 and IL-6 mediated allergic inflammation.

Currently, little information is available regarding innate immunity to helminthic parasite infection. In this study, we isolated the excretory-secretory (ES) proteins from Anisakis simplex (sea mammal intestinal parasite) third stage larva. We determined that the levels of IL-17 in the lung and lung draining lymph node of mice were increased sixfold as a result of intranasal treatment with ES proteins. The ES protein treatment elicited pro-inflammatory cytokine and chemokine secretion (especially IL-6 and CXCL1) from mouse lung epithelial cell line and primary lung epithelial cells. In addition, the expression of IL-6 and CXCL1 in mouse embryonic fibroblast (MEF) cells was significantly increased by the ES protein treatment, but we did not detect these effects in the TRIF(-/-) MEF cells. These elevations of IL-6 and CXCL1 expression were also not diminished by RNase treatment. In conclusion, the ES proteins of helminthic parasite larva may elicit TRIF dependent pro-inflammatory cytokines, and this is not double-stranded RNA.

The "how" and "whys" of research: life scientists' views of accountability.

OBJECTIVES: To investigate life scientists' views of accountability and the ethical and societal implications of research. DESIGN: Qualitative focus group and one-on-one interviews. PARTICIPANTS: 45 Stanford University life scientists, including graduate students, postdoctoral fellows and faculty. RESULTS: Two main themes were identified in participants' discussions of accountability: (1) the "how" of science and (2) the "why" of science. The "how" encompassed the internal conduct of research including attributes such as honesty and independence. The "why," or the motivation for conducting research, was two-tiered: first was the desire to positively impact the research community and science itself, and second was an interest in positively impacting the external community, broadly referred to as society. Participants noted that these motivations were influenced by the current systems of publications, grants and funding, thereby supporting a complex notion of boundary-setting between science and non-science. In addition, while all participants recognised the "how" of science and the two tiers of "why," scientists expressed the need to prioritise these domains of accountability. This prioritisation was related to a researcher's position in the academic career trajectory and to the researcher's subsequent "perceived proximity" to scientific or societal concerns. Our findings therefore suggest the need for institutional change to inculcate early-stage researchers with a broader awareness of the implications of their research. The peer review processes for funding and publication could be effective avenues for encouraging scientists to broaden their views of accountability to society.

The gep oncogenes, Galpha(12) and Galpha(13), upregulate the transforming growth factor-beta1 gene.

Transforming growth factor-beta1 (TGFbeta1) plays a role in neoplastic transformation and transdifferentiation. Galpha(12) and Galpha(13), referred to as the gep oncogenes, stimulate mitogenic pathways. Nonetheless, no information is available regarding their roles in the regulation of the TGFbeta1 gene and the molecules linking them to gene transcription. Knockdown or knockout experiments using murine embryonic fibroblasts and hepatic stellate cells indicated that a Galpha(12) and Galpha(13) deficiency reduced constitutive, auto-stimulatory or thrombin-inducible TGFbeta1 gene expression. In contrast, transfection of activated mutants of Galpha(12) and Galpha(13) enabled the knockout cells to promote TGFbeta1 induction. A promoter deletion analysis suggested that activating protein 1 (AP-1) plays a role in TGFbeta1 gene transactivation, which was corroborated by the observation that a deficiency of the G-proteins decreased the AP-1 activity, whereas their activation enhanced it. Moreover, mutation of the AP-1-binding site abrogated the ability of Galpha(12) and Galpha(13) to induce the TGFbeta1 gene. Transfection of a dominant-negative mutant of Rho or Rac, but not Cdc42, prevented gene transactivation and decreased AP-1 activity downstream of Galpha(12) and Galpha(13). In summary, Galpha(12) and Galpha(13) regulate the expression of the TGFbeta1 gene through an increase in Rho/Rac-dependent AP-1 activity, implying that the G-protein-coupled receptor (GPCR)-Galpha(12) pathway is involved in the TGFbeta1-mediated transdifferentiation process.

Hyperthermia with magnetic nanowires for inactivating living cells.

We describe a method to induce hyperthermia in cells, in-vitro, by remotely heating Ni nanowires (NWs) with radio frequency (RF) electromagnetic fields. Ni NWs were internalized by human embryonic kidney cells (HEK-293). Only cells proximal to NWs or with internalized NWs changed shape on exposure to RF fields indicative of cell death. The cell death occurs as a result of hyperthermia, since the RF field remotely heats the NWs as a result of magnetic hysteresis. This is the first demonstration of hyperthermia induced by NWs; since the NWs have anisotropic and strong magnetic moments, our experiments suggest the possibility of performing hyperthermia at lower field strengths in order to minimize damage to untargeted cells in applications such as the treatment of cancer.

Practical approaches to incidental findings in brain imaging research.

A decade of empirical work in brain imaging, genomics, and other areas of research has yielded new knowledge about the frequency of incidental findings, investigator responsibility, and risks and benefits of disclosure. Straightforward guidance for handling such findings of possible clinical significance, however, has been elusive. In early work focusing on imaging studies of the brain, we suggested that investigators and institutional review boards must anticipate and articulate plans for handling incidental findings. Here we provide a detailed analysis of different approaches to the problem and evaluate their merits in the context of the goals and setting of the research and the involvement of neurologists, radiologists, and other physicians. Protecting subject welfare and privacy, as well as ensuring scientific integrity, are the highest priorities in making choices about how to handle incidental findings. Forethought and clarity will enable these goals without overburdening research conducted within or outside the medical setting.

Hydrogen peroxide-producing Lactobacilli in the vaginal flora of pregnant women with preterm labor with intact membranes.

OBJECTIVES: To investigate the role of vaginal infection in preterm delivery, we studied characteristics of vaginal discharge related to hydrogen peroxide-producing Lactobacilli. METHODS: Vaginal specimens were obtained from 66 women with normal pregnancy and 30 women with preterm labor with intact membranes. pH, leukocyte counts on wet smear, and scores by Nugent criteria on Gram stain were measured. Lactobacilli were tested for their production of hydrogen peroxide. RESULTS: Leukocyte levels in wet smears and Nugent scores of Gram-stained smear of women with preterm labor with intact membranes were significantly higher than those of normal pregnant women (P<0.01, P<0.05). Hydrogen peroxide-producing Lactobacilli levels in the vaginal flora of women with preterm labor with intact membranes were significantly lower (P<0.01). CONCLUSION: Distribution of hydrogen peroxide-producing Lactobacilli in vaginal flora as defense factors for infection may have an important role in the pathophysiology of preterm labor.