Cancer-Derived Succinate Promotes Macrophage Polarization and Cancer Metastasis via Succinate Receptor.

Macrophages form a major cell population in the tumor microenvironment. They can be activated and polarized into tumor-associated macrophages (TAM) by the tumor-derived soluble molecules to promote tumor progression and metastasis. Here, we used comparative metabolomics coupled with biochemical and animal studies to show that cancer cells release succinate into their microenvironment and activate succinate receptor (SUCNR1) signaling to polarize macrophages into TAM. Furthermore, the results from in vitro and in vivo studies revealed that succinate promotes not only cancer cell migration and invasion but also cancer metastasis. These effects are mediated by SUCNR1-triggered PI3K-hypoxia-inducible factor 1α (HIF-1α) axis. Compared with healthy subjects and tumor-free lung tissues, serum succinate levels and lung cancer SUCNR1 expression were elevated in lung cancer patients, suggesting an important clinical relevance. Collectively, our findings indicate that the secreted tumor-derived succinate belongs to a novel class of cancer progression factors, controlling TAM polarization and promoting tumorigenic signaling.

Analytical validation of an inductively coupled plasma mass spectrometry method for urinary iodine concentration measurements in Taiwan.

BACKGROUND: Urinary iodine concentration (UIC) measured by Sandell-Kolthoff spectrophotometric method has been used in the Nutrition and Health Surveys in Taiwan but this method is time consuming and produces toxic waste from arsenic trioxide. The aim of this study was to develop and validate an inductively coupled plasma mass spectrometry (ICP-MS) system to determine UIC in Taiwan. METHODS: Samples and iodine calibrators were diluted 100-fold into an aqueous solution containing Triton X-100, 0.5% ammonia solution, and tellurium (128Te) as an internal standard. Digestion prior to analysis was not necessary. Precision, accuracy, serial dilution, and recovery tests were performed. A total of 1243 urine samples covering a wide range of iodine concentrations were measured by both Sandell-Kolthoff method and ICP-MS. Passing-Bablok regression and Bland-Altman plots were used to compare values across methods. RESULTS: The limit for detection and quantification by ICP-MS was 0.95 µg/L and 2.85 µg/L, respectively. The intra-assay and inter-assay coefficients were <10%, with a recovery range of 95%-105%. The results obtained by ICP-MS and the Sandell-Kolthoff method were highly correlated (Pearson's correlation: r = 0.996, 95% confidence interval [CI]: 0.9950-0.9961, p < 0.001). For UIC between 20 and 1000 µg/L, the y-intercept for the Passing-Bablok regression was -1.9 (95% CI: -2.5599 to -1.3500) and the slope was 1.01 (95% CI: 1.0000-1.0206). CONCLUSION: This validated ICP-MS system can be used for measuring UIC.

Reversal of Pulmonary Fibrosis: Human Umbilical Mesenchymal Stem Cells from Wharton's Jelly versus Human-Adipose-Derived Mesenchymal Stem Cells.

Pulmonary fibrosis (PF) is a progressive, non-reversible illness with various etiologies. Currently, effective treatments for fibrotic lungs are still lacking. Here, we compared the effectiveness of transplantation of human mesenchymal stem cells from umbilical cord Wharton's jelly (HUMSCs) versus those from adipose tissue (ADMSCs) in reversing pulmonary fibrosis in rats. Bleomycin 5 mg was intratracheally injected to establish a severe, stable, single left lung animal model with PF. On Day 21 post-BLM administration, one single transplantation of 2.5 × 107 HUMSCs or ADMSCs was performed. Lung function examination of Injury and Injury+ADMSCs rats displayed significantly decreased blood oxygen saturation and increased respiratory rates, while Injury+HUMSCs rats showed statistical amelioration in blood oxygen saturation and significant alleviation in respiratory rates. Reduced cell number in the bronchoalveolar lavage and lower myofibroblast activation appeared in the rats transplanted with either ADMSCs or HUMSCS than that in the Injury group. However, ADMSC transplantation stimulated more adipogenesis. Furthermore, matrix-metallopeptidase-9 over-expression for collagen degradation, and the elevation of Toll-like receptor-4 expression for alveolar regeneration were observed only in the Injury+HUMSCs. In comparison with the transplantation of ADMSCs, transplantation of HUMSCs exhibited a much more effective therapeutic effect on PF, with significantly better results in alveolar volume and lung function.

Xenograft of Human Umbilical Mesenchymal Stem Cells Promotes Recovery from Chronic Ischemic Stroke in Rats.

Stroke is a leading cause of adult disability. In our previous study, transplantation of human umbilical mesenchymal stem cells (HUMSCs) in Wharton's jelly in the acute phase of ischemic stroke promotes recovery in rats. Unfortunately, there is no cure for chronic stroke. Patients with chronic stroke can only be treated with rehabilitation or supportive interventions. This study aimed to investigate the potential of xenograft of HUMSCs for treating chronic stroke in rats. Rats were subjected to 90 min middle cerebral artery occlusion and then reperfusion to mimic ischemic cerebral stroke. On day 14 following stroke, HUMSCs were transplanted into the damaged cerebral cortex. The motor function in rats of the Stroke + HUMSCs group exhibited significant improvement compared to that of the Stroke + Saline group, and the trend persisted until day 56 post stroke. The cerebral cortex changes were tracked using magnetic resonance imaging, showing that cerebral atrophy was found starting on day 7 and was reduced significantly in rats receiving HUMSCs compared to that in the Stroke + Saline group from day 21 to day 56. HUMSCs were found to be existed in the rats' cerebral cortex on day 56, with signs of migration. The grafted HUMSCs did not differentiate into neurons or astrocytes and may release cytokines to improve neuroprotection, decrease inflammation and increase angiogenesis. Our results demonstrate that xeno-transplantation of HUMSCs has therapeutic benefits for chronic ischemic stroke. Most importantly, patients do not need to use their own HUMSCs, which is a gospel thing for clinical patients.

TLR2 Promotes Vascular Smooth Muscle Cell Chondrogenic Differentiation and Consequent Calcification via the Concerted Actions of Osteoprotegerin Suppression and IL-6-Mediated RANKL Induction.

Objective- Vascular smooth muscle cell (VSMC) transformation to an osteochondrogenic phenotype is an initial step toward arterial calcification, which is highly correlated with cardiovascular disease-related morbidity and mortality. TLR2 (Toll-like receptor 2) plays a pathogenic role in the development of vascular diseases, but its regulation in calcification of arteries and VSMCs remains unclear. We postulate that TLR2-mediated inflammation participates in mediating atherosclerotic arterial calcification and VSMC calcification. Approach and Results- We found that ApoE-/- Tlr2-/- genotype in mice suppressed high-fat diet-induced atherosclerotic plaques formation during initiation but progressively lost its preventative capacity, compared with ApoE-/- mice. However, TLR2 deficiency prohibited high-fat diet-induced advanced atherosclerotic calcification, chondrogenic metaplasia, and OPG (osteoprotegerin) downregulation in the calcified lesions. Incubation of VSMCs in a calcifying medium revealed that TLR2 agonists significantly increased VSMC calcification and chondrogenic differentiation. Furthermore, TLR2 deficiency suppressed TLR2 agonist-mediated VSMC chondrogenic differentiation and consequent calcification, which were triggered via the concerted actions of IL (interleukin)-6-mediated RANKL (receptor activator of nuclear factor κB ligand) induction and OPG suppression. Inhibition experiments with pharmacological inhibitors demonstrated that IL-6-mediated RANKL induction is signaled by p38 and ERK1/2 (extracellular signal-regulated kinase 1/2) pathways, whereas the OPG is suppressed via NF-κB (nuclear factor κB) dependent signaling mediated by ERK1/2. Conclusions- We concluded that on ligand binding, TLR2 activates p38 and ERK1/2 signaling to selectively modulate the upregulation of IL-6-mediated RANKL and downregulation of OPG. These signaling pathways act in concert to induce chondrogenic transdifferentiation of VSMCs, which in turn leads to vascular calcification during the pathogenesis of atherosclerosis.

Vanadium Derivative Exposure Promotes Functional Alterations of VSMCs and Consequent Atherosclerosis via ROS/p38/NF-κB-Mediated IL-6 Production.

Vanadium is a transition metal widely distributed in the Earth's crust, and is a major contaminant in fossil fuels. Its pathological effect and regulation in atherosclerosis remain unclear. We found that intranasal administration of the vanadium derivative NaVO3 significantly increased plasma and urinary vanadium levels and induced arterial lipid accumulation and atherosclerotic lesions in apolipoprotein E-deficient knockout mice (ApoE-/-) murine aorta compared to those in vehicle-exposed mice. This was accompanied by an increase in plasma reactive oxygen species (ROS) and interleukin 6 (IL-6) levels and a decrease in the vascular smooth muscle cell (VSMC) differentiation marker protein SM22α in the atherosclerotic lesions. Furthermore, exposure to NaVO3 or VOSO4 induced cytosolic ROS generation and IL-6 production in VSMCs and promoted VSMC synthetic differentiation, migration, and proliferation. The anti-oxidant N-acetylcysteine (NAC) not only suppresses IL-6 production and VSMC pathological responses including migration and proliferation but also prevents atherosclerosis in ApoE-/- mice. Inhibition experiments with NAC and pharmacological inhibitors demonstrated that NaVO3-induced IL-6 production is signaled by ROS-triggered p38-mediated NF-κB-dependent pathways. Neutralizing anti-IL-6 antibodies impaired NaVO3-mediated VSMC migration and proliferation. We concluded that NaVO3 exposure activates the ROS-triggering p38 signaling to selectively induce NF-κB-mediated IL-6 production. These signaling pathways induce VSMC synthetic differentiation, migration, and proliferation, leading to lipid accumulation and atherosclerosis.

Modulation of Decidual Macrophage Polarization by Macrophage Colony-Stimulating Factor Derived from First-Trimester Decidual Cells: Implication in Preeclampsia.

During human pregnancy, immune tolerance of the fetal semiallograft occurs in the presence of abundant maternal leukocytes. At the implantation site, macrophages comprise approximately 20% of the leukocyte population and act as primary mediators of tissue remodeling. Decidual macrophages display a balance between anti-inflammatory and proinflammatory phenotypes. However, a shift to an M1 subtype is reported in preeclampsia. Granulocyte-macrophage colony-stimulating-factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) are major differentiating factors that mediate M1 and M2 polarization, respectively. Previously, we observed the following: i) the preeclamptic decidua contains an excess of both macrophages and GM-CSF, ii) the preeclampsia-associated proinflammatory cytokines, IL-1ß and tumor necrosis factor-α, markedly enhance GM-CSF and M-CSF expression in cultured leukocyte-free first-trimester decidual cells (FTDCs), iii) FTDC-secreted GM-CSF polarizes macrophages toward an M1 subtype. The microenvironment is a key determinant of macrophage phenotype. Thus, we examined proinflammatory stimulation of FTDC-secreted M-CSF and its role in macrophage development. Immunofluorescence staining demonstrated elevated M-CSF-positive decidual cell numbers in preeclamptic decidua. In FTDCs, IL-1ß and tumor necrosis factor-α signal through the NF-κB pathway to induce M-CSF production, which does the following: i) enhances differentiation of and elevates CD163 expression in macrophages, ii) increases macrophage phagocytic capacity, and iii) inhibits signal-regulatory protein α expression by macrophages. These findings suggest that FTDC-secreted M-CSF modulates the decidual immune balance by inducing M2 macrophage polarization and phagocytic capacity in response to proinflammatory stimuli.

Estrogen Effects on Wound Healing.

Wound healing is a physiological process, involving three successive and overlapping phases-hemostasis/inflammation, proliferation, and remodeling-to maintain the integrity of skin after trauma, either by accident or by procedure. Any disruption or unbalanced distribution of these processes might result in abnormal wound healing. Many molecular and clinical data support the effects of estrogen on normal skin homeostasis and wound healing. Estrogen deficiency, for example in postmenopausal women, is detrimental to wound healing processes, notably inflammation and re-granulation, while exogenous estrogen treatment may reverse these effects. Understanding the role of estrogen on skin might provide further opportunities to develop estrogen-related therapy for assistance in wound healing.

Dectin-1-Mediated Pathway Contributes to Fusarium proliferatum-Induced CXCL-8 Release from Human Respiratory Epithelial Cells.

Fusarium species are causative agents of human respiratory disorders and are distributed widely in our environment. Little is known of their interaction with human respiratory epithelial cells, which may contribute to allergic airway responses. In this study, we report on the release of C-X-C motif chemokine ligand 8 (CXCL-8) from human bronchial epithelial BEAS-2B cells upon stimulation with Fusarium proliferatum extracts. F. proliferatum-induced cytokine release from BEAS-2B cells was determined by cytokine array and CXCL-8 enzyme-linked immunosorbent assay (ELISA) kits. Blocking antibodies and signaling pathway inhibitors were employed to delineate cell surface receptors and signaling pathways participating in CXCL-8 release. F. proliferatum extracts induced the release of CXCL-8 in a time-dependent manner. The dectin-1 receptor ligands, curdlan and laminarin, reduced CXCL-8 release. Cells pre-treated with anti-Dectin-1 antibodies (2 µg/mL) decreased CXCL-8 release by 24%. Furthermore, F. proliferatum-stimulated CXCL-8 release was reduced by 32%, 53%-81%, 40% and 26% after BEAS-2B cells were pretreated with activation inhibitors of spleen tyrosine kinase (Syk)-piceatannol-, mitogen-activated protein kinases (MAPKs)-PD98059, U0126, SB202190, SP600125-, phosphatidylinositol-3-kinase (PI3K)-LY294002-and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB)-BAY117082-, respectively. These results suggest that Dectin-1-mediated activation of the Syk, MAPKs, PI3K and NF-κB signaling pathways contributes to F. proliferatum-stimulated CXCL-8 release from BEAS-2B cells and provides an important basis for developing novel therapeutic strategies in clinical allergy.

TLR4 induces CREB-mediated IL-6 production via upregulation of F-spondin to promote vascular smooth muscle cell migration.

Toll-like receptor 4 (TLR4) is important in promoting inflammation and vascular smooth muscle cell (VSMC) migration, both of which contribute to atherosclerosis development and progression. But the mechanism underlying the regulation of TLR4 in VSMC migration remains unclear. Stimulation of VSMCs with LPS increased the cellular level of F-spondin which is associated with the regulation of proinflammatory cytokine production. The LPS-induced F-spondin expression depended on TLR4-mediated PI3K/Akt pathway. Suppression of F-spondin level by siRNA inhibited not only F-spondin expression but also LPS-induced phosphorylation of cAMP response element binding protein (CREB) and IL-6 expression, VSMC migration and proliferation as well as MMP9 expression. Moreover, suppression of CREB level by siRNA inhibited TLR4-induced IL-6 production and VSMC migration. Inhibition of F-spondin siRNA on LPS-induced migration was restored by addition of exogenous recombinant mouse IL-6. We conclude that upon ligand binding, TLR4 activates PI3K/Akt signaling to induce F-spondin expression, subsequently control CREB-mediated IL-6 production to promote VSMC migration. These findings provide vital insights into the essential role of F-spondin in VSMC function and will be valuable for developing new therapeutic strategies against atherosclerosis.

Determination of the Elemental Iodine in Human Breast Milk by Inductively Coupled Plasma mass Spectrometry.

Adequate iodine status in lactating women is defined by a maternal median urinary iodine concentration (UIC) ≧ 100 µg/L. However, the above-mentioned criterion does not account for the secretion of iodine into breast milk and could not truly reflect the amount of iodine delivered to the infants. Measuring breast milk median iodine concentration (BMIC) is crucial, but the method to measure BMIC has not been developed and validated in Taiwan. We adopted the ammonia dilution method without prior sample digestion to measure BMIC by inductively coupled plasma mass spectrometry (ICP-MS). Samples and iodate calibrators were prepared into an aqueous solution containing Triton X-100, 0.5% ammonia solution, and tellurium (128Te) as the internal standard. Precision, accuracy, serial dilution, and recovery tests were performed for method validation. The range of intra-assay and inter-assay coefficient of variation for the four human breast milk samples with different iodine concentrations were 3.2-4.7% and 2.3-5.5%, respectively. The standard NIST 1549 milk powder was prepared into three different concentrations of 50 µg/L, 100 µg/L, and 200 µg/L to assess the accuracy; the bias was < 5%. A recovery of 95-105% was achieved for four human breast milk samples spiked with sodium iodide solution. The serial dilution test confirmed linearity up to 0.998. The limit for detection and quantification was 0.78 µg/L and 2.34 µg/L, respectively. The results of the current study confirmed that this ICP-MS method is accurate and reliable in measuring BMIC.

Assessment of iodine nutritional status and gestational thyroid function reference ranges during the first trimester of pregnancy in Taiwan.

BACKGROUND: Iodine nutrition is critical for fetal neurodevelopment in the first trimester of pregnancy, a period associated with dramatic changes in thyroid function. The aim of this study was to evaluate iodine nutritional status and thyroid function reference ranges in the first trimester in Taiwan. METHODS: Pregnant women aged 20 years and above in the first trimester were recruited in Taipei Veterans General Hospital, Taiwan from March 2019 to July 2022. Each participant provided a spot urine sample for measurement of urinary iodine concentration (UIC) and a blood sample for checkup of thyroid function and thyroid autoantibodies. A simple food frequency questionnaire was also completed. RESULTS: A total of 209 women with a mean age of 32.9 ± 4.4 years were enrolled. The median UIC was 160.9 µg/L (interquartile range [IQR]: 105.0-246.2 µg/L), indicating overall iodine sufficiency. The gestational thyroid function reference ranges were: thyroid stimulating hormone (TSH) (median: 0.93 [0.007-2.9] µIU/mL), free T4 (1.3 [0.93-2.2] ng/dL), free T3 (3.0 [2.3-5.0] ng/dL), total T4 (9.9 [6.4-16.9] ng/dL), and total T3 (135 [88-231] ng/dL). If the nonpregnant reference range of serum TSH was used, eight women (4.8%) would be misclassified as having subclinical hyperthyroidism, and two women (1.2%) with subclinical hypothyroidism would be missed. In multivariate analysis, nulliparous (adjusted odds ratio [OR] from model 1-3: 2.02, 2.05, 2.02; 95% CI, 1.08-3.77, 1.10-3.81, 1.11-3.66; p = 0.027, 0.023, 0.022, respectively) and multivitamin nonusers (adjusted OR from model 1-3: 1.86, 1.85, 1.78; 95% CI, 1.04-3.34, 1.03-3.32, 1.004-3.71; p = 0.038, 0.039, 0.049, respectively) had increased odds of having lower UIC levels <150 µg/L. CONCLUSION: The iodine nutritional status in the first trimester is adequate in Taiwan; however, certain subgroups such as nulliparous and multivitamin nonusers are still at risk for iodine deficiency. Gestational thyroid function reference ranges are needed for correct diagnosis of thyroid dysfunction in pregnancy.

RED, a spindle pole-associated protein, is required for kinetochore localization of MAD1, mitotic progression, and activation of the spindle assembly checkpoint.

The spindle assembly checkpoint (SAC) is essential for ensuring the proper attachment of kinetochores to the spindle and, thus, the precise separation of paired sister chromatids during mitosis. The SAC proteins are recruited to the unattached kinetochores for activation of the SAC in prometaphase. However, it has been less studied whether activation of the SAC also requires the proteins that do not localize to the kinetochores. Here, we show that the nuclear protein RED, also called IK, a down-regulator of human leukocyte antigen (HLA) II, interacts with the human SAC protein MAD1. Two RED-interacting regions identified in MAD1 are from amino acid residues 301-340 and 439-480, designated as MAD1(301-340) and MAD1(439-480), respectively. Our observations reveal that RED is a spindle pole-associated protein that colocalizes with MAD1 at the spindle poles in metaphase and anaphase. Depletion of RED can cause a shorter mitotic timing, a failure in the kinetochore localization of MAD1 in prometaphase, and a defect in the SAC. Furthermore, the RED-interacting peptides MAD1(301-340) and MAD1(439-480), fused to enhanced green fluorescence protein, can colocalize with RED at the spindle poles in prometaphase, and their expression can abrogate the SAC. Taken together, we conclude that RED is required for kinetochore localization of MAD1, mitotic progression, and activation of the SAC.

An innovative web-based decision-aid about birth after cesarean for shared decision making in Taiwan: study protocol for a randomized control trial.

BACKGROUND: Taiwan has a high national caesarean rate coupled with a low vaginal birth after caesarean (VBAC) rate. This study aims to develop and evaluate a web-based decision-aid with communication support tools, to increase shared decision making (SDM) about birth after caesarean. METHODS: A quantitative approach will be adopted using a randomized pre-test and post-test experimental design in a medical centre in northern Taiwan. The web-based decision aid consists of five sections. Section 1 provides a two-part video to introduce SDM and how to participate in SDM. Section 2 presents an overview of functions and features of the birth decision-aid. Section 3 presents relevant VBAC information, including definitions, benefits and risks, and an artificial intelligence (AI) calculator for rate and likelihood of VBAC success. Section 4 presents the information regarding elective repeat caesarean delivery (ERCD), involving definitions, benefits, and risks. Section 5 comprises four steps of decision making to meet women's values and preferences. Pregnant women who have had one previous caesarean and are eligible for VBAC, will be recruited at 14-16 weeks. Participants will complete a baseline survey prior to random allocation to either the control group (usual care) or intervention group (usual care plus an AI-decision aid). A follow up survey at 35-38 weeks will measure change in decisional conflict, knowledge, birth mode preference, and decision-aid acceptability. Actual birth outcomes and satisfaction will be assessed one month after birth. DISCUSSION: The innovative web-based decision-aid with support tools will help to promote pregnant women's decision-making engagement and communication with their providers and improve opportunities for supportive communication about VBAC SDM in Taiwan. Linking web-based AI data analysis into the medical record will also be assessed for feasibility during implementation in clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov identifier (NCT05091944), Registered on October 24, 2021.

Ultrasonographic cervical length screening at 20-24 weeks of gestation in twin pregnancies for prediction of spontaneous preterm birth: A 10-year Taiwanese cohort.

BACKGROUND: Shortened cervical length is one of the primary predictors for spontaneous preterm deliveries in twin pregnancies. However, there is lack of consensus regarding cut-off values. Recent evidence highlights that established cut-offs for cervical length screening might not always apply across different populations. This study aims to present the distribution of cervical length in Taiwanese twin pregnancies and to assess its predictive value for spontaneous preterm birth during mid-trimester screening. MATERIALS AND METHODS: This retrospective analysis of cervical length screening in Taiwan evaluated 469 twin pregnancies between 20-24 weeks of gestation. Outcome data were obtained directly from the medical records of the delivery hospital. The study explored the predictive value of cervical length screening for spontaneous preterm birth and the characteristics of cervical length distribution in Taiwanese twin pregnancies. RESULTS: The average gestational age at screening was 22.7 weeks. Cervical length values displayed a non-normal distribution (p-value <0.001). The median, 5th and 95th centiles were 37.5 mm 25.1 mm, and 47.9 mm, respectively. Various cut-off values were assessed using different methods, yielding positive [negative] likelihood ratios for spontaneous preterm births between 32-37 weeks of gestational age (GA) (1.3-30.1 and [0.51-0.92]) and for very preterm births between 28-32 weeks GA (5.6-51.1 and [0.45-0.64]). CONCLUSIONS: The findings from our analysis of Taiwanese twin pregnancies uphold the moderate predictive potential of cervical length screening, consistent with prior investigations. The presented likelihood ratios for predicting preterm birth at different gestational ages equip clinicians with valuable tools to enhance their diagnostic rationale and resource utilization. By fine-tuning screening parameters according to the spontaneous preterm birth prevalence and clinical priorities of the particular population, healthcare providers can enhance patient care. Our data implies that a cervical length below 20 mm might provide an optimal balance between minimizing false negatives and managing false positives when predicting spontaneous preterm birth.

Iodine Concentration in the Breast Milk and Urine as Biomarkers of Iodine Nutritional Status of Lactating Women and Breastfed Infants in Taiwan.

Breast milk iodine concentration (BMIC) can be different when median urinary iodine concentration (UIC) is similar. The BMIC, UIC/creatinine (Cr), estimated 24-h urinary iodine excretion (24-h UIE) of lactating women in Taiwan is unknown. This study enrolled lactating women from Taipei Veterans General Hospital (August 2021-February 2023). Each participant provided a random spot urine sample, two breast milk samples, a blood sample, and completed a food frequency questionnaire on the same day. Iodine measurement was performed by inductively coupled plasma mass spectrometry. The median UIC of the enrolled 71 women was 91.1 µg/L, indicating insufficient iodine status; however, the median BMIC was 166.6 µg/L and this suggested that the amount of iodine delivered through breast milk was adequate for the breastfed infants. BMIC was correlated with UIC/Cr and 24-h UIE (both rs = 0.49) but not with UIC (rs = 0.18) or thyroid stimulating hormone (rs = 0.07). Women who did not consume dairy products (adjusted odds ratio: 24.41, 95% confidence interval: 1.26-471.2) and multivitamins (adjusted odds ratio: 8.26, 95% confidence interval: 1.76-38.79) were at increased odds for having lower BMIC. The results suggest that measuring maternal UIC alone may not be sufficient, as BMIC, UIC/Cr, and 24-h UIE are all important biomarkers. Ingestion of dairy products and multivitamins were independently associated with BMIC.

Pathological granuloma fibrosis induced by agar-embedded Mycobacterium abscessus in C57BL/6JNarl mice.

Introduction: Pulmonary granuloma diseases caused by Mycobacterium abscessus (M. abscessus) have increased in past decades, and drug-resistance in this pathogen is a growing public health concern. Therefore, an animal model of chronic granuloma disease is urgently needed. Methods: In this study, M. abscessus embedded within agar beads (agar-AB) was used to develop such a model in C57BL/6JNarl mice. Results: Chronic infection was sustained for at least 3 months after agar-AB infection, visible granulomas spread in the lungs, and giant cells and foamy cells appeared in the granulomas. More importantly, pulmonary fibrosis progressed for 3 months, and collagen fibers were detected by Masson trichrome staining. Further, inducible nitric oxide synthase (iNOS) was highly expressed within the alveolar space, and the fibrosis-mediator transforming growth factor beta (TGF-ß) began to be expressed at 1 month. Hypoxia-inducible factor (HIF-1α) expression also increased, which aided in normalizing oxygen partial pressure. Discussion: Although the transient fibrosis persisted for only 3 months, and the pulmonary structure resolved when the pathogen was cleard, this pulmonary fibrosis model for M. abscessus infection will provide a novel test platform for development of new drugs, regimens, and therapies.

Association between maternal factors and fetal macrosomia in full-term singleton births.

BACKGROUND: Macrosomia, defined as a birth weight of ≥4000 g, is associated with a high risk of birth injury. Fetal growth is highly correlated with maternal conditions, and several maternal factors are associated with neonatal birth size. The current study aimed to assess maternal factors related to fetal macrosomia in a Taiwanese population. METHODS: The medical records of pregnant mothers and their newborns were retrospectively reviewed. All singleton pregnancies delivered at and after 37 weeks of gestation were included in the analysis. Maternal and neonatal conditions were evaluated according to different birth weights. RESULTS: A total of 4262 infants were enrolled in our study. The mean birth weight was 3156 ± 383 g, including 77 (1.8%) cases with birth weight ≥4000 g, and 154 (3.6%) infants with birth weight <2500 g. The mean maternal body weight before delivery was 67.6 ± 10.0 kg. The mean 6-month gestational weight gain (6mGWG) was 12.3 ± 4.2 kg, and the mean maternal body mass index (BMI) was 26.2 ± 3.6 kg/m 2 . The maternal weight, height, and 6mGWG, gestational age, and placental weight were significantly positively correlated with neonatal birth weight. The odds ratios of macrosomia were 3.1 in neonates born to mothers with a 6mGWG of ≥15 kg, 6.3 in those born to mothers with gestational diabetes mellitus, and 4.1 in those born to mothers with a BMI of ≥30 kg/m 2 . Newborn macrosomia was associated with adverse events in pregnant mothers and newborn infants. CONCLUSION: Gestational diabetes mellitus, 6mGWG, and maternal BMI are significantly correlated with neonatal macrosomia in full-term singleton births. Further, neonatal macrosomia is an important cause of maternal and neonatal morbidity. Hence, pregnant women should undergo maternal counseling for weight management before and during pregnancy, and the appropriate delivery method should be identified to prevent perinatal adverse events.

Recent hepatitis C virus infections in HIV-infected patients in Taiwan: incidence and risk factors.

Outbreaks of sexually transmitted hepatitis C virus (HCV) infections have been recently reported in HIV-infected men who have sex with men (MSM) in Europe, Australia, and North America. Little is known concerning whether this also occurs in other Asia-Pacific countries. Between 1994 and 2010, a prospective observational cohort study was performed to assess the incidence of recent HCV seroconversion in 892 HIV-infected patients (731 MSM and 161 heterosexuals) who were not injecting drug users. A nested case-control study was conducted to identify associated factors with recent HCV seroconversion, and phylogenetic analysis was performed using NS5B sequences amplified from seroconverters. During a total followup duration of 4,270 person-years (PY), 30 patients (3.36%) had HCV seroconversion, with an overall incidence rate of 7.03 per 1,000 PY. The rate increased from 0 in 1994 to 2000 and 2.29 in 2001 to 2005 to 10.13 per 1,000 PY in 2006 to 2010 (P < 0.05). After adjustment for age and HIV transmission route, recent syphilis remained an independent factor associated with HCV seroconversion (odds ratio, 7.731; 95% confidence interval, 3.131 to 19.086; P < 0.01). In a nested case-control study, seroconverters had higher aminotranferase levels and were more likely to have CD4 ≥ 200 cells/µl and recent syphilis than nonseroconverters (P < 0.05). Among the 21 patients with HCV viremia, phylogenetic analysis revealed 7 HCV transmission clusters or pairs (4 within genotype 1b, 2 within genotype 2a, and 1 within genotype 3a). The incidence of HCV seroconversion that is associated with recent syphilis is increasing among HIV-infected patients in Taiwan.

Human Umbilical Mesenchymal Stem Cell Xenografts Repair UV-Induced Photokeratitis in a Rat Model.

Most patients with a corneal injury are administered anti-inflammatory medications and antibiotics, but no other treatments are currently available. Thus, the corneal injury healing is unsatisfactory, affects the vision, and has a risk of blindness in severe cases. Human umbilical mesenchymal stem cells exhibit pluripotent and anti-inflammatory properties and do not cause immunological rejection in the host. Rats were irradiated with type B ultraviolet (UVB) light to generate a stable animal model of photokeratitis. After irradiation-induced photokeratitis, human umbilical mesenchymal stem cells were implanted into the subconjunctival space of the lateral sclera, and the changes in the corneal pathology were evaluated. Three weeks after implantation, many mesenchymal stem cells were visible in the subconjunctival space. These mesenchymal stem cells effectively reduced the extent of injury to the adjacent corneal tissue. They accelerated the epithelial layer repair, reduced the inflammatory response and neovascularization, and improved the disorganization of collagen and fibronectin in the corneal stroma caused by the injury. In conclusion, xenografted human umbilical mesenchymal stem cells can survive in rat eye tissues for a long time, effectively support the structural integrity of injured corneal tissues, restore corneal permeability, and reduce abnormal neovascularization. This study provides a new approach to the treatment of photokeratitis.