Neutrophil extracellular trap increase the risk of sepsis: a two-sample, one-way Mendelian randomization study / 中华危重病急救医学

OBJECTIVE@#To investigate the causal relationship between neutrophil extracellular trap (NET) and sepsis based on Mendelian randomization analysis.@*METHODS@#The genome wide association study (GWAS) dataset for the NET biomarker myeloperoxidase (MPO)-DNA complex based on Donkel et al. 's Rotterdam study (RS) and GWAS dataset for identifying sepsis from the UK biobank were selected to screen single nucleotide polymorphisms (SNPS) associated with MPO-DNA complex as instrumental variable (IV) for genetic variation, using MPO-DNA complex as exposure factor. Potential causal associations between MPO-DNA complex and the risk of occurrence of sepsis, 28-day death from sepsis, need for intensive care due to sepsis, and 28-day death from sepsis requiring intensive care were analyzed using a two-sample, one-way Mendelian randomization analysis primary analysis method of inverse analysis of variance (IVW). Potential pleiotropy was assessed using the MR Egger regression intercept test. Sensitivity analysis was performed using the "leave one out" test.@*RESULTS@#The GWAS data were obtained from a European population of both sexes, and the screening criteria was based on the three main assumptions of Mendelian randomization, resulting in 22 SNP entering the Mendelian randomization analysis. The results of the Mendelian randomization causal association effect analysis using the IVW method showed that for every standard deviation increase in the level of the MPO-DNA complex, the risk of sepsis increased by approximately 18% [odds ratio (OR) = 1.18, 95% confidence interval (95%CI) was 1.07-1.29, P < 0.001], the risk of 28-day death from sepsis increased by approximately 51% (OR = 1.51, 95%CI was 1.27-1.81, P < 0.001), an increase of approximately 38% in the risk of occurrence of needing intensive care due to sepsis (OR = 1.38, 95%CI was 1.12-1.70, P = 0.002), and an increase of approximately 125% in the risk of 28-day death from sepsis requiring intensive care (OR = 2.25, 95%CI was 1.21-4.18, P = 0.01). MR Egger regression intercept test suggested that there was no horizontal pleiotropy in the included SNP, and the MR-PRESSO test did not find outliers. Sensitivity analysis suggested that the results of Mendelian randomization were robust.@*CONCLUSIONS@#Rising NET can increase the risk of sepsis onset, progression and death as derived from Mendelian randomization analysis.

The effects of nonyl phenoxypolyethoxyl ethanol on cell damage pathway gene expression in SK-NSH cells

BACKGROUND/AIMS: Most pesticide formulations contain both chief and additive ingredients. But, the additives may not have been tested as thoroughly as the chief ingredients. The surfactant, nonyl phenoxypolyethoxylethanol (NP40), is an additive frequently present in pesticide formulations. We investigated the effects of NP40 and other constituents of a validamycin pesticide formulation on cell viability and on the expression of genes involved in cell damage pathways. METHODS: The effects of validamycin pesticide ingredients on cell viability and of NP40 on the mRNA expression of 80 genes involved in nine key cellular pathways were examined in the human neuroblastoma SK-N-SH cell line. RESULTS: The chemicals present in the validamycin pesticide formulation were cytotoxic to SK-N-SH cells and NP40 showed the greatest cytotoxicity. A range of gene expression changes were identified, with both up- and down-regulation of genes within the same pathway. However, all genes tested in the necrosis signaling pathway were down-regulated and all genes tested in the cell cycle checkpoint/arrest pathway were up-regulated. The median fold-change in gene expression was significantly higher in the cell cycle checkpoint/arrest pathway than in the hypoxia pathway category (p = 0.0064). The 70 kDa heat shock protein 4 gene, within the heat shock protein/unfolded protein response category, showed the highest individual increase in expression (26.1-fold). CONCLUSIONS: NP40 appeared to be particularly harmful, inducing gene expression changes that indicated genotoxicity, activation of the cell death (necrosis signaling) pathway, and induction of the 70 kDa heat shock protein 4 gene.

Nonoxynol-9 berberine plural gel has little effect on expression of SLPI, SP-D and lactoferrin in mice's vagina

The most frequently used spermicide Nonoxynol-9 [N-9] in the clinic alters the vaginal flora, which will result in an increased risk of opportunistic infection. So development of a novel spermicidal and microbicidal drug appears to be inevitable. Vaginal local immune is an important part of vaginal flora. Secretory leukocyte protease inhibitor [SLPI], surfactant proteins D [SP-D], and lactoferrin [LF] are anti-microbial molecules with important roles in immune system of female vaginas. To observe effect of a vaginal spermicide nonoxynol-9 [N-9] berberine plural gel on the expression of SLPI SP-D and LF in mice's vaginas. Female BABL/C mice were randomly divided into following 5 groups: normal control group, blank gel group, berberine gel group, 12% N-9 gel group and N-9 berberine plural gel group. Estradiol benzoate at physiological dose was done by hypodermic injection to every group's mice. After 72h, drug gels were separately injected into the mice's vaginas, while immunohistochemistry and Western blot were taken to detect the expression of the 3 indexes in mice's vaginas respectively after 24h and 72h of gel injection. The differences in the three indexes between normal control group and blank gel group were not significant statistically [p>0.05]. The expression of the three indexes in 12% N-9 gel group was decreased compared to that in blank gel group [p<0.05]. The differences in the three indexes between N-9 berberine plural gel group and blank gel group were not significant statistically [p>0.05]. Also, the three index's level of 24h and 72h in sub observation groups after treatment were without statistical significance [p>0.05]. Application of N-9 berberine plural gel had little impact on antimicrobial peptides in normal mice's vaginas

In vitro susceptibility of Staphylococcus aureus strains isolated from cows with subclinical mastitis to different antimicrobial agents

Sensitivity to commercial teat dips (nonoxinol-9 iodine complex and chlorhexidine digluconate) of 56 Staphylococcus (S.) aureus strains isolated from quarter milk samples of various German dairy herds treated with different teat dipping schemes was investigated in this study. The minimum inhibitory concentration was determined using a broth macrodilution method according to the German Veterinary Association guidelines. The main objective of the current study was to induce in vitro resistance induction of S. aureus to chemical disinfectants. Ten different strains were repeatedly passed ten times in growth media with sub-lethal concentrations of disinfectants. Nine strains showed a significant reduction in susceptibility to the nonoxinol-9 iodine complex but only one strain developed resistance to chlorhexidine digluconate. Stability of the acquired resistance was observed in all S. aureus strains adapted to the nonoxinol-9 iodine complex and chlorhexidine digluconate. In contrast, simultaneous resistance to different antibiotics was not observed in any of the ten investigated S. aureus strains. However, the isolates exhibited a high degree of resistance to penicillin G. Based on these results, resistance of S. aureus to chemical disinfectants may be more likely to develop if the chemicals are used at concentrations lower than that required for an optimal biocidal effect.

Establishing a Th17 based mouse model for preclinical assessment of the toxicity of candidate microbicides / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>To effectively block the invasion of human immunodeficiency virus (HIV)-1 on mucosal surface, vaginal anti-HIV-1 microbicides should avoid inflammatory responses and disruption of mucosa integrity because these will facilitate transepithelial viral penetration and replication. However, existing models fail to predict and evaluate vaginal mucosal toxicity induced by microbicides, and most importantly, they are unable to identify subtle or subclinical inflammatory reactions. This study was designed to develop a cost-effective in vivo model to evaluate microbicide safety in a preclinical study which can recapitulate the mucosal topical reaction.</p><p><b>METHODS</b>A murine model was employed with nonoxynol-9 (N-9) as the topical stimulant within the vagina. Different concentrations of N-9 (1%, 3%, and 4%) were topically applied to the vagina for five consecutive days. A panel of inflammatory cytokines including interleukine-2 (IL-2), IL-4, IL-6, IL-17A, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and immuno-regulatory IL-10 were assayed in vaginal lavage. Cytokines were quantified by using cytometric bead array (CBA) and reverse transcript (RT) real-time PCR. Histopathological evaluation of vaginal tissues was conducted on hematoxylin-eosin stained slides and scored with a semi-quantitative system according to the severity of epithelial disruption, leucocyte infiltration, edema, and vascular injection. The association between the cytokines and histopathological scores was assessed by linear regression analysis.</p><p><b>RESULTS</b>All three concentrations of N-9 induced inflammatory cytokine production. The 4% N-9 application resulted in a consistent production of cytokines in a time-dependent manner. The cytokines reached peak expression on day three with the exception of IL-4 which reached its peak on day one. Histopathological examination of 4% N-9 treated cervicovaginal tissues on day three showed intensive damage in four mice (sores: 10 - 13) and moderate damage in one mouse (score: 8), which were significantly associated with both inflammatory cytokines IL-17A and IL-6 and anti-inflammatory cytokines IL-4 and IL-10. Interestingly, IL-17A showed significant positive association with inflammatory cytokine TNF-α (r = 0.739; P < 0.05), anti-inflammatory cytokines IL-10 (r = 0.804; P < 0.01) and IL-4 (r = 0.668; P < 0.05).</p><p><b>CONCLUSIONS</b>Our data demonstrate that a panel of cytokines (IL-17A, IL-6, IL-4 and IL-10) could be used as surrogate biomarkers to predict the histopathological damage. Th17 may play a central role in orchestrating inflammatory cytokine responses. This Th17 based mouse model is cost-effective and suitable to assess the toxicity of candidate microbicides in preclinical studies.</p>

Nonoxynol-9 vaginal pessary: a preliminary Indian experience.

BACKGROUND: Barrier methods of contraception do not have systemic effects and allow the user complete control over their use. For women, the ease of use of a contraceptive is often more important than its efficacy. Hence, barrier methods could be offered as a useful alternative method of contraception. Nonoxynol-9 (a spermicide) is a locally acting, non-hormonal method free from systemic side-efforts. It is a woman-controlled, reversible method which is to be used before intercourse. There are little data available on its efficacy, side-effects and acceptability among Indian women. METHODS: The vaginal pessary nonoxynol-9 was offered as a contraceptive option to 3200 women attending the Family Planning clinics at 31 Human Reproduction Research Centres (HRRCs) of the Indian Council of Medical Research. The other contraceptives offered included an intrauterine device, oral pills, condoms, Norplant, tubal sterilization and vasectomy using the cafeteria approach. Those who accepted nonoxynol-9 were followed up to assess the rates of continuation, failure and side-effects. RESULTS: The nonoxynol-9 pessary was accepted by 541 women who were followed up for 3470 woman-months of use. The reasons given for acceptance were that it was user-controlled and/or they did not wish to use other methods because of the side-effects or contraindications of these methods. The overall continuation rates were 41.2% and 33% at 9 and 12 months of use, respectively. Most women (31.3%) discontinued its use due to personal reasons such as husband dissatisfaction, desire for further pregnancy, irregular use of pessary and difficulty in insertion. Twenty-nine women became pregnant during the study period (15 due to method failure and 14 due to user failure) giving a use-effectiveness of 8.8% at 12 months. The method failure rate was 4.3% at 12 months of use. The failure rates were lower compared with the reported failure rates of barrier contraceptives (1%-30% at 1 year of use) and the side-effects were minimal. CONCLUSION: Nonoxynol-9 had low acceptability (16.9%) and overall continuation rates--41.2% and 33% at 9 and 12 months of use. It could be offered to women looking for a short term, user-controlled contraceptive.

Nonoxynol 9 as an additive therapy in metronidazole-resistant cases of vaginal trichomoniasis

The present study was conducted on 30 female patients with rnetronidazole resistant vaginal trichomoniasis to investigate the efficacy of nonoxynol 9 [N-9], a non hormonal contraceptive with spermicidal effect, as an additive therapy to metronidazole [MNZ]. Study population were randomly divided into 3 groups according to treatment regimen: G.I: patients received high dose MNZ [2g daily for 7 days] n = 10; G. II patients received [100mg N-9 vaginal suppository daily for 7 days] n = 10; G. III: patients receiving conventional MNZ dose [1g daily for 7 days] plus [a 100mg N-9 suppository for 7 days] n = 10. Clinical and parasitological evaluation of cure was performed at return visits 1, 2, 4 and 6 weeks post treatment. Negative T. vaginalis vaginal smears were ensured by direct microscopic visualization and In Pouch TV culture technique. Most of the patients were in the 30-39 years age group [60%] and burning was the most frequent symptom [96.67%]. The cure rates were 70%, 40% and 90% for Gs I, II and III respectively, while adverse effects of treatment were recorded most frequently by patients of G.I. So, MNZ resistant trichomoniasis incidence seems to be on the rise. Topical therapy alone has a low cure rate while combined oral conventional doses of MNZ and intravaginal nonoxynol 9 treatment appears to be a good clinical trial with fairly good cure rate thus, avoiding the adverse side effects of high doses MNZ therapy and T. vaginalis health hazards potentiality

Effect of compound nonoxinol on the inhibition of bacteria in vitro / 中华男科学杂志

<p><b>OBJECTIVE</b>To study the effect of compound nonoxinol on the inhibition of bacteria in vitro.</p><p><b>METHODS</b>The minimal bactericidal concentration (MBC) and minimal bactericidal time (MBT) of nonoxinol providine iodine and compound nonoxinol, composed of nonoxinol and providine iodine were determined by inhibiting C. albicans and N. gonorrhoeae.</p><p><b>RESULTS</b>Nonoxinol alone showed no inhibiting effects on bacteria. The MBT was 2 minutes for both compound nonoxinol and providine iodine, but the MBC of providine iodine was higher than that of compound nonoxinol.</p><p><b>CONCLUSION</b>Compound nonoxinol works better in inhibiting bacteria than either nonoxinoother or providine iodine used alone.</p>

Spermicidal effect of Jieze No. 1 in combination with nonoxynol-9 in vitro / 华中科技大学学报（医学）（英德文版）

Spermicidal effect of Jieze No. 1 (JZ1) in combination with nonoxynol-9 (N-9) was examined in vitro. The minimum spermicidal concentration of JZ1 decoction, N-9 and their mixture solution in 20 s and 3 min were examined by improved spermicidal test of Sander-cramer in vitro. The percentages of progressively moving spermatozoa, moving spermatozoa and viable spermatozoa were also observed 20 s, 3 min and 30 min after the addition of the liquid medicine. Our results showed that sperms did not recover their activities in a revival test when the minimum spermicidal concentration of either JZ1 decoction, or N-9, or the mixed solution of the two agents, was used. N-9 (JZ1 in the mixed group) showed significant differences in the percentages of progressively moving spermatozoa, moving spermatozoa, and visible spermatozoa in 20 s, 3 min, and 30 min, when compared with N-9 alone (P < 0.01). We are led to conclude that JZ1 decoction can improve N-9 spermicidal action in vitro, and when used in combination with N-9, it has synergic effect.

Experimental research on tea saponin ameliorating nonoxynol spermicidal action in vitro / 中华男科学杂志

<p><b>OBJECTIVE</b>To study the effect of tea saponin in ameliorating nonoxynol(N-9) spermicidal action in vitro.</p><p><b>METHODS</b>According to the improved spermicidal test method in vitro recommended by International Planned Parenthood Foundation (IPPF), we evaluated the minimum spermicidal concentration of N-9, tea saponin and their mixed solution in 20 s and 3 min.</p><p><b>RESULTS</b>The minimum spermicidal concentration of N-9 in the mixed solution was (0.13 +/- 0.05) g/L in 20 s and (0.05 +/- 0.004) g/L in 3 min, and that of the tea saponin in the mixed solution was (2.40 +/- 1.07) g/L in 20 s and (1.27 +/- 0.38) g/L in 3 min, compared with the single ingredient N-9 [(0.48 +/- 0.15) g/L in 20 s, (0.34 +/- 0.079 g/L in 3 min], and tea saponin [(5.78 +/- 1.40) g/L in 20 s, (1.71 +/- 0.176) g/L in 3 min], P < 0.01.</p><p><b>CONCLUSION</b>Tea saponin can improve N-9 spermicidal action in vitro, and tea saponin and nonoxynol have proved of synergic effect.</p>

Phase I safety & preliminary acceptability of nonoxynol-9 vaginal pessary as a vaginal microbicide in low risk women in Pune, India.

BACKGROUND & OBJECTIVES: Though nonoxynol-9 (N-9) is available in India as a spermicidal pessary, data on its safety as a potential microbicide among Indian women are not available. Nonoxynol-9 containing compounds have shown anti-HIV activity in in vitro studies and protection against cervical infections. Nonoxynol-9 is being extensively evaluated as a vaginal microbicide world-wide. We assessed the safety and preliminary acceptability of nonoxynol-9 pessary as a vaginal microbicide in women at low risk for human immunodeficiency virus (HIV) infection and sexually transmitted diseases (STDs). METHODS: Twenty three HIV seronegative women enrolled in the study were given Today pessarys containing 5 per cent of nonoxynol-9 for vaginal use at bedtime for 14 days. Colposcopy was done at enrollment and on day 14 and speculum examination on day 7 to assess the local toxicity. RESULTS: Most of the women (16/23, 69.6%) did not experience any symptoms of genital irritation. The remaining 7 (30.4%, 95% CI 11.6-49.2) women reported 11 episodes of mild irritative symptoms of short duration. On clinical examination, three adverse events were reported of which one could have been product related. Eight (34.8%) women showed willingness to use the product for protection against HIV transmission if it was approved. INTERPRETATION & CONCLUSION: Nonoxynol-9 vaginal pessary was found to be safe and acceptable in once daily dose in low risk women after consecutive use for 14 days. Willingness for future use, if found safe and effective for HIV prevention was shown by 8 (34.8%) women.

A Development of Intelligent Picture Archiving Communication System that Embedded Computer-Aided Diagnosis and Speech Recognition / 대한의료정보학회지

The rapid technological progress in the fields of computer and engineering has accelerated the medical society to introduce a new advanced paradigm in handling medical information. This paper describes a fully integrated Computer Aided Diagnosis, Speech Recognition/PACS system running on a single platform. We feel that the combination of Computer Aided Diagnosis, Speech Recognition and PACS in a fully integrated single platform has created a tremendous synergy, with process improvements that maximize the advantage s of three systems. The Computer Aided Diagnosis and the Speech Recognition included marked improvement in experiments turnaround time and cost saving for departments because of decreased transcription costs. Proposed system should help others complete the task of digitalizing a hospital information system and may be adaptable to other systems as well.