Motivations, psychosocial burdens, and decision-making modes of post-partum women with stress urinary incontinence engaging in pelvic floor physical therapy: a qualitative research.

INTRODUCTION AND HYPOTHESIS: This qualitative research explores the motivations, psychosocial burdens, and decision-making modes of post-partum women with stress urinary incontinence (SUI) engaging in pelvic floor physical therapy (PFPT). METHODS: This study was conducted face-to-face in a treatment room using qualitative semi-structured interviews with post-partum women who received PFPT for SUI between May and October 2022. Participant interviews were transcribed verbatim and thematically analyzed using NVivo software, which is most commonly used for qualitative data analysis. RESULTS: Themes that impacted participants' decisions to receive PFPT included avoiding deterioration of SUI symptoms, believing that the sooner it is treated the better, being unable to adhere to home exercise programs, and dissatisfaction with quality of life. Some participants experienced psychosocial burdens when receiving PFPT, including impact on daily activities, worries about the baby, financial burdens, and uncertainty about the effect. There were two modes of decision making, which brought different experiences. Some participants preferred participant-provider shared decision making and reported effective doctor-patient communication, and striving for autonomous decisions. Other participants preferred their clinicians to decide on PFPT protocols in view of their trust in their midwives, institutional reputation, and lacking knowledge of PFPT. CONCLUSIONS: We discovered that participants had both motivations and psychosocial burdens when receiving therapy. Some participants preferred participant-provider shared decision making, whereas others preferred their midwives to make decisions. Further more standardized studies with more robust samples are needed.

Combined assisted bone age assessment and adult height prediction methods in Chinese girls with early puberty: analysis of three artificial intelligence systems.

BACKGROUND: The applicability and accuracy of artificial intelligence (AI)-assisted bone age assessment and adult height prediction methods in girls with early puberty are unknown. OBJECTIVE: To analyze the performance of AI-assisted bone age assessment methods by comparing the corresponding methods for predicted adult height with actual adult height. MATERIALS AND METHODS: This retrospective review included 726 girls with early puberty, 87 of whom had reached adult height at last follow-up. Bone age was evaluated using the Greulich-Pyle (GP), Tanner-Whitehouse (TW3-RUS) and China 05 RUS-CHN (RUS-CHN) methods. Predicted adult height was calculated using the China 05 (CH05), TW3 and Bayley-Pinneau (BP) methods. RESULTS: We analyzed 1,663 left-hand radiographs, including 155 from girls who had reached adult height. In the 6-8- and 9-11-years age groups, bone age differences were smaller than those in the 12-14-years group; however, the differences between predicted adult height and actual adult height were larger than those in the 12-14-years group. TW3 overestimated adult height by 0.4±2.8 cm, while CH05 and BP significantly underestimated adult height by 2.9±3.6 cm and 1.3±3.8 cm, respectively. TW3 yielded the highest proportion of predicted adult height within ±5 cm of actual adult height (92.9%), with the highest correlation between predicted and actual adult heights. CONCLUSION: The differences in measured bone ages increased with increasing bone age. However, the corresponding method for predicting adult height was more accurate when the bone age was older. TW3 might be more suitable than CH05 and BP for predicting adult height in girls with early puberty. Methods for predicting adult height should be optimized for populations of the same ethnicity and disease.

Endotoxin May Not Be the Major Cause of Postprandial Inflammation in Adults Who Consume a Single High-Fat or Moderately High-Fat Meal.

BACKGROUND: Metabolic endotoxemia is considered a cause for high-fat diet (HFD)-induced inflammation. However, convincing experimental evidence in humans is scant. OBJECTIVE: We determined whether a HFD or moderately HFD increases LPS and LPS-mediated cytokine production in the postprandial blood (PPB). METHODS: Ninety-eight volunteers (age: 37.3 ± 1.5 y) from the cross-sectional phenotyping study (PS) and 62 volunteers (age: 26.8 ± 1.2 y) from the intervention study (IS) consumed a breakfast containing 60% kcal fat (HF) and 36% kcal fat (moderately HF), respectively. For the IS, only the results from the placebo group are presented. Blood samples were probed for LPS-mediated cytokine production by incubating them with LPS inhibitor polymyxin B (PMB) for 24 h at 37°C besides the Limulus amebocyte lysate (LAL) assay. Repeated-measures ANOVA was used to compare the temporal changes of metabolic profiles and treatment outcomes. RESULTS: At least 87.5% of the plasma LPS measurements in 32 PS volunteers from each time point were below the LAL assay sensitivity (0.002 EU/mL). PMB suppressed IL-1ß (P = 0.035) and IL-6 (P = 0.0487) production in the 3 h PPB of the PS after 24 h incubation at 37°C compared to the vehicle control, suggesting the presence of LPS. However, the amount of LPS did not increase the cytokine concentrations in the 3 h PPB above the fasting concentrations. Such suppression was not detected in the PPB of the IS. Treating whole blood with lipoprotein lipase (LPL) significantly (P < 0.05) increased FFA and cytokine (IL-1ß, IL-6, TNF-α) concentrations in both studies. CONCLUSION: LPS may not be the major cause of postprandial inflammation in healthy adults consuming a moderately HF meal (36% kcal fat, similar to the typical American diet) or a HF meal (60% kcal fat). Plasma FFAs may modulate postprandial inflammation. The prevailing concept of HFD-induced metabolic endotoxemia requires careful re-evaluation. The PS was registered at clinicaltrials.gov as NCT02367287 and the IS as NCT02472171.

Association between sexual intercourse frequency and pelvic floor muscle morphology in pregnant women.

INTRODUCTION AND HYPOTHESIS: No studies have been performed to examine the association of sexual activity and pelvic floor muscle (PFM) morphology or function during pregnancy. The aim of this study was to survey the frequency of sexual intercourse and examine the associations between the frequency of sexual intercourse and the PFM morphology in pregnant women of mainland China. The relationship between sexual intercourse frequency and stress urinary incontinence (SUI)-related symptoms was also evaluated. METHODS: Pregnant women in their first or second trimester were enrolled from January 2017 and November 2017. The morphology of the PFM was examined by transperineal ultrasound, and SUI-related symptoms were assessed by the International Consultation of Incontinence Questionnaire-Short Form (ICIQ-SF). Multivariable regression analyses were used to estimate coefficients [95% confidence intervals (CI)] with adjustment for the possible effects of cofounders. RESULTS: In total, 323 pregnant women (mean age, 29.66 ± 4.32 years) were included in the analysis. Almost 49% of the women had no sexual intercourse during pregnancy. Compared with pregnant women who had no sexual intercourse, those who had sexual intercourse more than once a month had stronger LA th at rest (ß = 0.59, P = 0.004 for two or three times per month; ß = 0.59, P = 0.044 for weekly or more). No significant relationship was found between the frequency of sexual intercourse and any ICIQ-SF-related items. CONCLUSIONS: Chinese women had inactive sexual intercourse during pregnancy. There is a slight association between increased sexual intercourse frequency and a thicker levator ani muscle in pregnant women. Future work may be directed at determining the causality of this association.

[Correlation between variants of CYP21A2 gene promoter region and nonclassical 21-hydroxylase deficiency].

OBJECTIVE: To summarize the clinical characteristics of two children with nonclassical 21 hydroxylase deficiency (NC-21OHD) due to variants of CYP21A2 gene promoter region. METHODS: Clinical characteristics and the results of genetic testing were reviewed. RESULTS: The main clinical manifestations of the two children included precocious puberty with poor bone age/progression control and menstrual disorder with hirsutism. Patient 1 had compound heterozygous variants for -126C>T, -113G>A, -110T>C and p.I173N; her mother was heterozygous for -126C>T, -113G>A and -110T>C, and her father was heterozygous for p.I173N. Patient 2 had compound heterozygous variants for -126C>T, -113G>A and p.I2G, whose mother was heterozygous for -126C>T and -113G>A, and father was heterozygous for p.I2G. CONCLUSION: Diagnosis of NC-21OHD should be considered for children with hirsutism, menstrual disorder and poor bone age/progression control. The promoter region of CYP21A2 gene should be analyzed when no variant is detected in its coding regions.

Resveratrol increases phagocytosis and lipopolysaccharide-induced interleukin-1ß production, but decreases surface expression of Toll-like receptor 2 in THP-1 monocytes.

THP-1 monocytes were used to evaluate the effects of physiological levels of resveratrol aglycone, resveratrol-3-O-glucuronide, resveratrol-4'-O-glucuronide, and resveratrol-3-O-sulfate on phagocytosis, IL-1ß, IL-1α, and IL-18 production, viability, and TLR2 and TLR4 expression. THP-1 cells were treated with 1, 5, 10, and 15µM resveratrol or metabolites. Resveratrol-3-O-glucuronide, resveratrol-4'-O-glucuronide, and resveratrol-3-O-sulfate had no effect on the functional parameters tested. Resveratrol aglycone increased phagocytosis at concentrations of 5, 10, and 15µM and LPS-induced IL-1ß production at concentrations of 10 and 15µM. Expression of TLR4 increased slightly after resveratrol treatment, but surface expression of TLR2 was reduced as resveratrol concentrations increased. Our data suggest that resveratrol may be effective in modulating monocyte function in an environment where there is direct exposure to the aglycone, such as at the gut epithelium.

(-)-4-O-(4-O-ß-D-glucopyranosylcaffeoyl) Quinic Acid Inhibits the Function of Myeloid-Derived Suppressor Cells to Enhance the Efficacy of Anti-PD1 against Colon Cancer.

PURPOSE: Immunotherapy in the clinic has demonstrated its potential to control cancer through disinhibiting the immune system, especially for immune checkpoint inhibitors such as anti-programmed cell death protein 1/anti-programmed death-ligand 1 (anti-PD1/anti-PD-L1). However, although these new immunotherapies have resulted in durable clinical responses in various cancers, multiple mechanisms of immune resistance and suppression exist in tumors. One significant barrier to efficacy of anti-PD1 against colon cancer may be the recruitment of myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment. Here we demonstrated functional inhibition of G-MDSC with (-)-4-O-(4-O-ß-D-glucopyranosylcaffeoyl) quinic acid (QA), an inhibitor of PI3Kδ/γ, reshaped the tumor immune microenvironment and promoted cytotoxic T cell-mediated tumor regression, resultantly enhancing responses to anti-PD1 treatment in colon tumor model. METHODS: A syngeneic colon tumor mouse model was used to study the effects of QA on tumor immune microenvironment and its potential synergistic effects with anti-PD1 blockade. RESULTS: QA treatment inhibited G-MDSC function in the tumor tissue. Additionally, combination treatment induced CD8+ T lymphocyte-dependent tumor growth delay and prolonged survival time in colon cancer. CONCLUSIONS: Our results offered opportunities for new combination strategies using a selective small molecule PI3Kδ/γ inhibitor, to suppress MDSCs to enhance responses to immune checkpoint blockade in colon cancer.

Postprandial Inflammatory Responses and Free Fatty Acids in Plasma of Adults Who Consumed a Moderately High-Fat Breakfast with and without Blueberry Powder in a Randomized Placebo-Controlled Trial.

BACKGROUND: Saturated fatty acids (FAs) released from triglyceride-rich lipoproteins (TGRLs) activate Toll-like receptor 2 (TLR-2) and induce the expression of proinflammatory cytokines in monocytes. Certain plant polyphenols inhibit TLR-mediated signaling pathways. OBJECTIVE: We determined whether plasma free FAs (FFAs) after a moderately high-fat (MHF, 40% kcal from fat) breakfast modulate the inflammatory status of postprandial blood, and whether blueberry intake suppresses FFA-induced inflammatory responses in healthy humans. METHODS: Twenty-three volunteers with a mean ± SEM age and body mass index (in kg/m(2)) of 30 ± 3 y and 21.9 ± 0.4, respectively, consumed an MHF breakfast with either a placebo powder or 2 or 4 servings of blueberry powder in a randomized crossover design. The placebo powder was provided on the first test day and the blueberry powder doses were randomized with a 2-wk washout period. Plasma concentrations of lipids, glucose, and cytokines were determined. To determine whether FFAs derived from TGRL stimulate monocyte activation, and whether this is inhibited by blueberry intake, whole blood was treated with lipoprotein lipase (LPL). RESULTS: The median concentrations of FFAs and cytokines [tumor necrosis factor-α, interleukin (IL)-6 and IL-8] in postprandial plasma (3.5 h) decreased compared with fasting plasma regardless of the blueberry intake (P < 0.001 for FFAs and P < 0.05 for cytokines). However, concentrations of FFAs and cytokines including IL-1ß increased in LPL-treated whole blood compared with untreated blood samples from participants who consumed the placebo powder. Blueberry intake suppressed IL-1ß and IL-6 production in LPL-treated postprandial blood compared with the placebo control when fasting changes were used as a covariate. CONCLUSIONS: The plasma FFA concentration may be an important determinant affecting inflammatory cytokine production in blood. Supplementation with blueberry powder did not affect plasma FFA and cytokine concentrations; however, it attenuated the cytokine production induced by ex vivo treatment of whole blood with LPL. This trial was registered at clinicaltrials.gov as NCT01594008.

Inflammasome-mediated secretion of IL-1ß in human monocytes through TLR2 activation; modulation by dietary fatty acids.

Many studies have shown that TLR4- and TLR2-deficient mice are protected from high-fat diet-induced inflammation and insulin resistance, suggesting that saturated fatty acids derived from the high-fat diet activate TLR-mediated proinflammatory signaling pathways and induce insulin resistance. However, evidence that palmitic acid, the major dietary saturated fatty acid, can directly activate TLR has not been demonstrated. In this article, we present multiple lines of evidence showing that palmitic acid directly activates TLR2, a major TLR expressed on human monocytes, by inducing heterodimerization with TLR1 in an NADPH oxidase-dependent manner. Dimerization of TLR2 with TLR1 was inhibited by the n-3 fatty acid docosahexaenoic acid. Activation of TLR2 by palmitic acid leads to expression of pro-IL-1ß that is cleaved by caspase-1, which is constitutively present in monocytes, to release mature IL-1ß. Our results reveal mechanistic insight about how palmitic acid activates TLR2, upregulates NALP3 expression, and induces inflammasome-mediated IL-1ß production in human monocytes, which can trigger enhanced inflammation in peripheral tissues, and suggest that these processes are dynamically modulated by the types of dietary fat we consume.

Acylcarnitines activate proinflammatory signaling pathways.

Incomplete ß-oxidation of fatty acids in mitochondria is a feature of insulin resistance and type 2 diabetes mellitus (T2DM). Previous studies revealed that plasma concentrations of medium- and long-chain acylcarnitines (by-products of incomplete ß-oxidation) are elevated in T2DM and insulin resistance. In a previous study, we reported that mixed D,L isomers of C12- or C14-carnitine induced an NF-κB-luciferase reporter gene in RAW 264.7 cells, suggesting potential activation of proinflammatory pathways. Here, we determined whether the physiologically relevant L-acylcarnitines activate classical proinflammatory signaling pathways and if these outcomes involve pattern recognition receptor (PRR)-associated pathways. Acylcarnitines induced the expression of cyclooxygenase-2 in a chain length-dependent manner in RAW 264.7 cells. L-C14 carnitine (5-25 µM), used as a representative acylcarnitine, stimulated the expression and secretion of proinflammatory cytokines in a dose-dependent manner. Furthermore, L-C14 carnitine induced phosphorylation of JNK and ERK, common downstream components of many proinflammatory signaling pathways including PRRs. Knockdown of MyD88, a key cofactor in PRR signaling and inflammation, blunted the proinflammatory effects of acylcarnitine. While these results point to potential involvement of PRRs, L-C14 carnitine promoted IL-8 secretion from human epithelial cells (HCT-116) lacking Toll-like receptors (TLR)2 and -4, and did not activate reporter constructs in TLR overexpression cell models. Thus, acylcarnitines have the potential to activate inflammation, but the specific molecular and tissue target(s) involved remain to be identified.

Secondary oxidized di-2-ethylhexyl phthalate metabolites may be associated with progression from isolated premature thelarche to central precocious or early puberty.

Phthalate esters (PAEs) may act as estrogen receptor agonists, and their relationship with precocious puberty is a global health concern. However, their role in isolated premature thelarche (IPT) progression remains unclear. We conducted a cohort study investigating the relationship between IPT progression and urinary PAE metabolites. Girls with IPT aged 6-8 years were regularly followed up every three months for one year. Clinical data and urine PAE metabolite levels were collected. Participants who progressed to central precocious puberty (CPP) or early puberty (EP) had significantly higher ovarian volume, breast Tanner stage, and levels of the creatinine-adjusted urinary secondary oxidized di-2-ethylhexyl phthalate (DEHP) metabolites (Σ4DEHP). Breast Tanner stage (odds ratio [OR] = 7.041, p = 0.010), ovarian volume (OR = 3.603, p = 0.019), and Σ4DEHP (OR = 1.020, p = 0.005) were independent risk factors for IPT progression. For each 10 µg/g/Cr increase in the urine level of Σ4DEHP, the risk of progression from IPT to CPP/EP within one year increased by 20%. This study demonstrated that the breast Tanner stage, ovarian volume, and Σ4DEHP in urine were independent risk factors for IPT progression, and Σ4DEHP may be associated with the progression of IPT to CPP or EP.

Saturated fatty acids activate TLR-mediated proinflammatory signaling pathways.

Toll-like receptor 4 (TLR4) and TLR2 were shown to be activated by saturated fatty acids (SFAs) but inhibited by docosahexaenoic acid (DHA). However, one report suggested that SFA-induced TLR activation in cell culture systems is due to contaminants in BSA used for solubilizing fatty acids. This report raised doubt about proinflammatory effects of SFAs. Our studies herein demonstrate that sodium palmitate (C16:0) or laurate (C12:0) without BSA solubilization induced phosphorylation of inhibitor of nuclear factor-κB α, c-Jun N-terminal kinase (JNK), p44/42 mitogen-activated-kinase (ERK), and nuclear factor-κB subunit p65, and TLR target gene expression in THP1 monocytes or RAW264.7 macrophages, respectively, when cultured in low FBS (0.25%) medium. C12:0 induced NFκB activation through TLR2 dimerized with TLR1 or TLR6, and through TLR4. Because BSA was not used in these experiments, contaminants in BSA have no relevance. Unlike in suspension cells (THP-1), BSA-solubilized C16:0 instead of sodium C16:0 is required to induce TLR target gene expression in adherent cells (RAW264.7). C16:0-BSA transactivated TLR2 dimerized with TLR1 or TLR6 and through TLR4 as seen with C12:0. These results and additional studies with the LPS sequester polymixin B and in MyD88(-/-) macrophages indicated that SFA-induced activation of TLR2 or TLR4 is a fatty acid-specific effect, but not due to contaminants in BSA or fatty acid preparations.

Effects of Acid Modulators on the Microwave-Assisted Synthesis of Cr/Sn Metal-Organic Frameworks.

Metal-organic frameworks (MOFs) have attracted remarkable attention for their distinguished structural designability. Precisely controlling the particle size and improving the structural stability of MOF nanoparticles influence their catalytic activity significantly. In this study, six acids (nitric, hydrochloric, formic, acetic, succinic, and citric acids) were used as modulators to prepare bimetallic MIL-101 (Cr, Sn) (MIL stands for Materials of Institut Lavoisier) via a microwave-assisted hydrothermal method. Changes in volumetric, structural, stability, and catalytic properties, size, and shape of MIL-101 (Cr, Sn) were examined using scanning electron microscopy, X-ray diffraction, thermogravimetric analysis, and N2 adsorption-desorption measurements. All modulators altered the MOF properties. Compared with other samples, acetic acid as a modulator mildly altered the MOF morphology by narrowing their particle size distribution, enhancing the specific surface area, and significantly improving their water and thermal stabilities. The addition of acetic acid was suitable for the catalytic conversion of glucose to 5-hydroxymethylfurfural (5-HMF), achieving a 43.1% 5-HMF yield with 91.4% glucose conversion in a mixed solution of γ-valerolactone and saturated salt water at 150 °C after 30 min.

Association between phthalate exposure and accelerated bone maturation in Chinese girls with early puberty onset: a propensity score-matched case-control analysis.

Estrogen can promote the acceleration of bone maturation and phthalate esters (PAEs) have estrogen-mimicking effects. We investigated whether PAEs are associated with the acceleration of bone age (BA) in girls with early onset of puberty (EOP). This case-control study enrolled 254 girls with EOP from the Endocrinology Department at Shenzhen Children's Hospital between December 2018 and August 2019. Ultra-performance liquid chromatography and tandem mass spectrometry were used to analyze the 10 metabolites of PAEs (mPAEs) in urine samples. BA was measured using an artificial intelligence system. BA exceeding the chronological age (CA) by > 2 years (BA-CA ≥ 2 years) was referred to as significant BA advancement. Participants were divided into groups A (BA-CA ≥ 2 years; case group) and B (BA-CA < 2 years; control group). Propensity score matching (PSM) was performed for both groups in a 1:2 ratio with a caliper of 0.25. To identify potential dose-response relationships between PAEs exposure and BA advancement, we grouped the participants after PSM according to the tertiles of the mPAE concentrations. After PSM, 31 and 62 girls in groups A and B were selected. The concentration of Mono-ethyl phthalate (MEP) in group A was significantly higher than in group B (11.83 µg/g vs. 7.11 µg/g, P < 0.05); there was no significant difference in the levels of other mPAEs between the groups. The degree of BA advancement and proportion of significantly advanced BA in the lowest, middle, and highest tertiles of the MEP sequentially increased, as well as in the lowest, middle, and highest tertiles of Mono-(2-ethyl-5-carboxypentyl) phthalate; however, these were only statistically different between the highest and lowest MEP tertiles (both P < 0.05). For the remaining mPAEs, differences in the degree of BA advancement among the lowest, middle, and highest tertiles, as well as differences in the proportion of significantly advanced BA among the lowest, middle, and highest tertiles, were not significant (all P > 0.05). Our findings suggested that MEP was positively associated with BA advancement in girls with EOP. Exposure to PAEs may promote accelerated bone maturation.

A Mobility Aware Binary Tree Algorithm to Resolve RFID Jam and Bottleneck Problems in a Next Generation Specimen Management System.

Hospitals are continuously working to reduce delayed analysis and specimen errors during transfers from testing stations to clinical laboratories. Radio-frequency identification (RFID) tags, which provide automated specimen labeling and tracking, have been proposed as a solution to specimen management that reduces human resource costs and analytic delays. Conventional RFID solutions, however, confront the problem of traffic jams and bottlenecks on the conveyor belts that connect testing stations with clinical laboratories. This mainly results from methods which assume that the arrival rate of specimens to laboratory RFID readers is fixed/stable, which is unsuitable and impractical in the real world. Previous RFID algorithms have attempted to minimize the time required for tag identification without taking the dynamic arrival rates of specimens into account. Therefore, we propose a novel RFID anti-collision algorithm called the Mobility Aware Binary Tree Algorithm (MABT), which can be used to improve the identification of dynamic tags within the reader's coverage area and limited dwell time.

Temporal changes in postprandial blood transcriptomes reveal subject-specific pattern of expression of innate immunity genes after a high-fat meal.

White blood cells are among the first responders to dietary components and their metabolites absorbed from the gut. The objective of this study was to determine the whole blood transcriptome response to high-fat challenge meals. A total of 45 fasting and postprandial (3-h and 6-h) whole blood transcriptomes from 5 subjects in a crossover intervention trial of a high-fat meal supplemented with placebo, blueberry powder or docosahexaenoic acid (DHA) were analyzed using RNA sequencing. Select target genes were validated by quantitative reverse-transcription polymerase chain reaction in 180 samples from 20 subjects. The largest contributor to variance was the subject (13,856 genes differentially expressed), followed by the subject on a specific day (2276 genes), followed by the subject's postprandial response (651 genes). After determining the nonsignificance of individual dietary treatments (blueberry, DHA, placebo), treatments were used as replicates to examine postprandial responses to a high-fat meal. The universal postprandial response (95 genes) was associated with lipid utilization, fatty acid beta-oxidation and circadian rhythms. Subject-specific postprandial responses were enriched for genes involved in the innate immune response, particularly those of pattern recognition receptors and their downstream signaling components. Genes involved in innate immune responses are differentially expressed in a subject-specific and time-dependent manner in response to the high-fat meals. These genes can serve as biomarkers to assess individual responsiveness to a high-fat diet in inducing postprandial inflammation. Furthermore, the dynamic temporal change in gene expression in postprandial blood suggests that monitoring these genes at multiple time points is necessary to reveal responders to dietary intervention.

Inhibition of Nod2 signaling and target gene expression by curcumin.

Nod2 is an intracellular pattern recognition receptor that detects a conserved moiety of bacterial peptidoglycan and subsequently activates proinflammatory signaling pathways. Mutations in Nod2 have been implicated to be linked to inflammatory granulomatous disorders, such as Crohn's disease and Blau syndrome. Many phytochemicals possess anti-inflammatory properties. However, it is not known whether any of these phytochemicals might modulate Nod2-mediated immune responses and thus might be of therapeutic value for the intervention of these inflammatory diseases. In this report, we demonstrate that curcumin, a polyphenol found in the plant Curcuma longa, and parthenolide, a sesquiterpene lactone, suppress both ligand-induced and lauric acid-induced Nod2 signaling, leading to the suppression of nuclear factor-kappaB activation and target gene interleukin-8 expression. We provide molecular and biochemical evidence that the suppression is mediated through the inhibition of Nod2 oligomerization and subsequent inhibition of downstream signaling. These results demonstrate for the first time that curcumin and parthenolide can directly inhibit Nod2-mediated signaling pathways at the receptor level and suggest that Nod2-mediated inflammatory responses can be modulated by these phytochemicals. It remains to be determined whether these phytochemicals possess protective or therapeutic efficacy against Nod2-mediated inflammatory disorders.

Collaboration of Werner syndrome protein and BRCA1 in cellular responses to DNA interstrand cross-links.

Cells deficient in the Werner syndrome protein (WRN) or BRCA1 are hypersensitive to DNA interstrand cross-links (ICLs), whose repair requires nucleotide excision repair (NER) and homologous recombination (HR). However, the roles of WRN and BRCA1 in the repair of DNA ICLs are not understood and the molecular mechanisms of ICL repair at the processing stage have not yet been established. This study demonstrates that WRN helicase activity, but not exonuclease activity, is required to process DNA ICLs in cells and that WRN cooperates with BRCA1 in the cellular response to DNA ICLs. BRCA1 interacts directly with WRN and stimulates WRN helicase and exonuclease activities in vitro. The interaction between WRN and BRCA1 increases in cells treated with DNA cross-linking agents. WRN binding to BRCA1 was mapped to BRCA1 452-1079 amino acids. The BRCA1/BARD1 complex also associates with WRN in vivo and stimulates WRN helicase activity on forked and Holliday junction substrates. These findings suggest that WRN and BRCA1 act in a coordinated manner to facilitate repair of DNA ICLs.

Transgenic mice with ectopic expression of constitutively active TLR4 in adipose tissues do not show impaired insulin sensitivity.

INTRODUCTION: Chronic low-grade inflammation is associated with obesity and diabetes. However, what causes and mediates chronic inflammation in metabolic disorders is not well understood. Toll-like receptor 4 (TLR4) mediates both infection-induced and sterile inflammation by recognizing pathogen-associated molecular patterns and endogenous molecules, respectively. Saturated fatty acids can activate TLR4, and TLR4-deficient mice were protected from high fat diet (HFD)-induced obesity and insulin resistance, suggesting that TLR4-mediated inflammation may cause metabolic dysfunction, such as obesity and insulin resistance. METHODS: We generated two transgenic (TG) mouse lines expressing a constitutively active TLR4 in adipose tissue and determined whether these TG mice would show increased insulin resistance. RESULTS: TG mice fed a high fat or a normal chow diet did not exhibit increased insulin resistance compared to their wild-type controls despite increased localized inflammation in white adipose tissue. Furthermore, females of one TG line fed a normal chow diet had improved insulin sensitivity with reduction in both adiposity and body weight when compared with wild-type littermates. There were significant differences between female and male mice in metabolic biomarkers and mRNA expression in proinflammatory genes and negative regulators of TLR4 signaling, regardless of genotype and diet. CONCLUSIONS: Together, these results suggest that constitutively active TLR4-induced inflammation in white adipose tissue is not sufficient to induce systemic insulin resistance, and that high fat diet-induced insulin resistance may require other signals in addition to TLR4-mediated inflammation.

A randomised controlled trial in comparing maternal and neonatal outcomes between hands-and-knees delivery position and supine position in China.

BACKGROUND: the supine position is the most frequently offered for birth delivery in China and many other countries, but the hands-and-knees position is now gaining prominence with doctors in China. This study aims to examine the differences in maternal and neonatal outcomes among low-risk women who gave birth either in the hands-and-knees position or the supine position. METHODS: a randomised controlled trial was conducted in 11 hospitals in China from May to December in 2012. In total, 1400 women were recruited and randomly allocated to either the experimental group (n=700, 446 completed the protocol) who delivered in hands-and-knees position and the control group (n=700, 440 completed the protocol) who delivered in supine position. Women who could not maintain the randomised position during the second stage of labour were allowed to withdraw from the study. The primary maternal outcome measured was rate of episiotomy. Secondary outcomes included degree of perineum laceration, rate of emergency caesarean section, rate of shoulder dystocia, and duration of labour, postpartum bleeding, neonatal Apgar score, and the rate of neonatal asphyxia. Because outcome data were only collected for women who gave birth in the randomised position, per-protocol analyses were used to compare groups. The primary outcome, episiotomy, was also compared between groups using logistic regression adjusting for maternal age，gestational age at birth, whether the woman was primiparous, the process of second stage of labour and birthweight. FINDINGS: as compared with the control group, the experimental group had lower rates of episiotomy and second-degree perineum laceration (including episiotomy), and higher rates of intact perineum and first-degree perineum laceration, with a longer duration of second stage of labour. No significant differences were found in the amount of postpartum bleeding, shoulder dystocia, neonatal asphyxia and neonatal Apgar scores at 1minute and 5minutes. Adjusted for maternal age, gestational age, parity, duration of second stage of labour and birth weight, the hands-and-knees position reduced the need for episiotomy (OR=0.024, p<0.001). CONCLUSIONS: this study provided evidence that women who could maintain the hands-and-knees position during the second stage of labour had lower rates of episiotomy and second-degree perineum laceration (including episiotomy). Both midwives and obstetricians are suggested to learn the skills to assist women with delivery in this position.