The HIF-1α/EGF/EGFR Signaling Pathway Facilitates the Proliferation of Yak Alveolar Type II Epithelial Cells in Hypoxic Conditions.

The yak is a unique creature that thrives in low-oxygen environments, showcasing its adaptability to high-altitude settings with limited oxygen availability due to its unique respiratory system. However, the impact of hypoxia on alveolar type II (AT2) epithelial cell proliferation in yaks remains unexplored. In this study, we investigated the effects of different altitudes on 6-month-old yaks and found an increase in alveolar septa thickness and AT2 cell count in a high-altitude environment characterized by hypoxia. This was accompanied by elevated levels of hypoxia-inducible factor-1α (HIF-1α) and epidermal growth factor receptor (EGFR) expression. Additionally, we observed a significant rise in Ki67-positive cells and apoptotic lung epithelial cells among yaks inhabiting higher altitudes. Our in vitro experiments demonstrated that exposure to hypoxia activated HIF-1α, EGF, and EGFR expression leading to increased proliferation rates among yak AT2 cells. Under normal oxygen conditions, activation of HIF-1α enhanced EGF/EGFR expressions which subsequently stimulated AT2 cell proliferation. Furthermore, activation of EGFR expression under normoxic conditions further promoted AT2 cell proliferation while simultaneously suppressing apoptosis. Conversely, inhibition of EGFR expression under hypoxic conditions had contrasting effects. In summary, hypoxia triggers the proliferation of yak AT2 cells via activation facilitated by the HIF-1α/EGF/EGFR signaling cascade.

Mixed valence Ce-doped TiO2 with multiple energy levels and efficient charge transfer for boosted SERS performance.

Considering the variable valence characteristics of rare earth elements, they can be in a variety of valence forms coexistence. Doping of rare earth element with different valence states may produce different energy levels to tune the semiconductor energy band structure. We utilize rare earth element Ce doping TiO2 for the development of high-performance semiconductor surface-enhanced Raman scattering (SERS) substrates based on an energy-level tuning strategy. Ce doping not only forms multiple energy levels including Ce3+ and Ce4+ metal doping energy levels in the bandgap of TiO2, but also enriches the surface state level of TiO2 itself, which together promote the separation of photogenerated carriers and improve charge transfer efficiency between substrates and absorbed molecules. This endows TiO2 semiconductor substrate with a higher SERS enhancement factor, which can reach 2.2 × 106. The detectable concentration of methylene blue can be as low as 10-10 mol/L. Moreover, the semiconductor substrate exhibits excellent uniformity and stability. This study not only provides a new strategy to develop excellent semiconductor SERS substrate with multiple energy levels, but also lays the foundation for promising practical application of semiconductor substrate.

Risk factors associated with breakdown of perineal laceration repair after vaginal birth.

Underlying infection, estimated blood loss >500 ml and operative delivery are independent risk factors for breakdown of perineal laceration repair after vaginal birth.

Low oxygen concentration improves yak oocyte maturation and inhibits apoptosis through HIF-1 and VEGF.

The gas-phase environment of in vitro culture system plays an important role in the development of oocytes, and oxygen concentration is one of the important factors. In the present study, we aimed to explore the effect of different oxygen concentrations (20%, 10%, 5% or 1% O2 ) in yak oocyte maturation and to detect the expression of hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF) and cell apoptosis in yak COCs. First, the maturation rate of oocytes, cleavage rate and blastocysts rate following parthenogenetic activation in the group with 5% oxygen concentration were significantly higher (p < .05) than the other groups. Then, TUNEL analysis showed that the 5% oxygen concentration group significantly inhibited apoptosis of cumulus-oocyte complexes (COCs) compared to the other group, and the transcription and protein levels of pro-apoptotic factor Bax, HIF-1α and VEGF in yak COCs significantly reduced, while anti-apoptotic factor Bcl-2 significantly increased. Furthermore, immunohistochemical staining results indicated that HIF-1α protein was mainly located in theca follicle interna, mural follicular stratum granulosum, corona radiata and ovarian stroma in the follicular ovarian tissue, while VEGF protein was mainly located in the granulosa and theca cell layers. In summary, our findings demonstrate that 5% oxygen concentration may promote maturation and inhibit apoptosis of oocytes through HIF-1α-mediated VEGF expression.

Interventions to reduce the cesarean delivery rate in a tertiary hospital in China.

INTRODUCTION: High cesarean delivery rate has been a global public health concern. This study assesses the effect of medical interventions and societal changes on cesarean delivery rates in a Chinese tertiary hospital. MATERIAL AND METHODS: A retrospective study including all live births ≥34-week gestation between 2008 and 2016 from Guangzhou Women and Children's Medical Center was divided into 5 stages: (1) no interventions; (2) patient-controlled epidural analgesia; (3) episiotomy restriction; (4) new labor management; (5) universal two-child policy. An interrupted time series design was used to measure the effect of interventions on overall cesarean rate, primary cesarean rate, maternal and neonatal outcomes. RESULTS: There were 126,609 deliveries including 49,092 cesarean deliveries and 77,517 vaginal deliveries in this period. Overall cesarean delivery rate declined after implementing patient-controlled epidural analgesia, episiotomy restriction and universal two-child policy. Primary cesarean rate decreased after implementing episiotomy restriction. Cesarean rate with previous cesarean dramatically increased, and maternal request cesarean rate decreased gradually. Low Apgar rate (score ≤7 at 5 min) increased after episiotomy restriction and maternal postpartum hemorrhage rate increased after new labor management. CONCLUSIONS: Patient-controlled epidural analgesia, episiotomy restriction and the universal two-child policy showed the most significant effects to reducing the cesarean rate.

METTL14 gene polymorphisms decrease Wilms tumor susceptibility in Chinese children.

BACKGROUND: Wilms tumor is a highly heritable malignancy. Aberrant METTL14, a critical component of N6-methyladenosine (m6A) methyltransferase, is involved in carcinogenesis. The association between genetic variants in the METTL14 gene and Wilms tumor susceptibility remains to be fully elucidated. We aimed to assess whether variants within this gene are implicated in Wilms tumor susceptibility. METHODS: A total of 403 patients and 1198 controls were analyzed. METTL14 genotypes were assessed by TaqMan genotyping assay. RESULT: Among the five SNPs analyzed, rs1064034 T > A and rs298982 G > A exhibited a significant association with decreased susceptibility to Wilms tumor. Moreover, the joint analysis revealed that the combination of five protective genotypes exerted significantly more protective effects against Wilms tumor than 0-4 protective genotypes with an OR of 0.69. The stratified analysis further identified the protective effect of rs1064034 T > A, rs298982 G > A, and combined five protective genotypes in specific subgroups. The above significant associations were further validated by haplotype analysis and false-positive report probability analysis. Preliminary mechanism exploration indicated that rs1064034 T > A and rs298982 G > A are correlated with the expression and splicing event of their surrounding genes. CONCLUSIONS: Collectively, our results suggest that METTL14 gene SNPs may be genetic modifiers for the development of Wilms tumor.

A comparison of maternal fear of childbirth, labor pain intensity and intrapartum analgesic consumption between primiparas and multiparas: A cross-sectional study.

OBJECTIVES: To describe and compare fear of childbirth and in-labor pain intensity between primiparas and multiparas and explore the association between the amount of actual pain relief and fear of childbirth. METHODS: A convenience sampling method was used. A total of 260 women undergoing spontaneous or induced labor, including 97 primiparas and 163 multiparas, were recruited in a large academic specialized hospital in Guangzhou, China, from February 2018 to August 2019. The clinical data of maternal and neonatal were extracted from a structured electronic medical record system. Other demographic information, such as employment and family monthly income, was collected by a questionnaire. The Numeric Rating Scale (NRS) and the Chinese version of the Childbirth Attitude Questionnaire (C-CAQ) were applied to assess maternal in-labor pain intensity and fear of childbirth. The analgesic consumption and the frequency of manual boluses as rescue analgesia were stored and collected from the analgesia pump. RESULTS: Eighty-two (84.5%) primiparas and ninety-nine (60.7%) multiparas received epidural analgesia (P < 0.001). In the epidural subgroup, the primiparous average fear of childbirth (36.46 ± 10.93) was higher than that of the multiparas (32.06 ± 10.23) (P = 0.007). However, multiparas reported more intense in-labor pain [8.0 (8.0, 9.0) vs. 8.0 (7.0, 8.0)], had more successful manual boluses per hour [2.68 (1.65, 3.85) vs. 1.77 (0.90, 2.47)], more hourly analgesic consumption [23.00 (16.00, 28.25) vs. 17.24 (11.52, 21.36) mL] and more average analgesic consumption [0.35 (0.24, 0.45) vs. 0.26 (0.19, 0.35) mL/(h·kg)] than the primiparas (P < 0.05). Spearman's correlation analysis showed that the maximum in-labor pain was weakly positively correlated with fear of childbirth (r = 0.09) (P < 0.05), hourly analgesic consumption (r = 0.16) (P < 0.01) and average analgesic consumption (r = 0.17) (P < 0.05). No statistically significant association was uncovered between analgesic consumption and maternal fear of childbirth. CONCLUSIONS: Fear of childbirth is a potential predictor of labor pain intensity. Further study is needed to explore its role and value in pain management during delivery. Parity is not a determinant of pain relief use and should not be a preconceived preference of obstetric care team members to determine the distribution of epidural analgesia, especially when analgesia resources are insufficient.

Regulatory effects of HIF-1α and HO-1 in hypoxia-induced proliferation of pulmonary arterial smooth muscle cells in yak.

Hypoxia-inducible factor-1α (HIF-1α) and heme oxygenase-1 (HO-1) are important transcription regulators in hypoxic cells and for maintaining cellular homeostasis, but it is unclear whether they participate in hypoxia-induced excessive proliferation of yak pulmonary artery smooth muscle cells (PASMCs). In this study, we identified distribution of HIF-1α and HO-1 in yak lungs. Immunohistochemistry and immunofluorescence results revealed that both HIF-1α and HO-1 were mainly concentrated in the medial layer of small pulmonary arteries. Furthermore, under induced-hypoxic conditions, we investigated HIF-1α and HO-1 protein expression and studied their potential involvement in yak PASMCs proliferation and apoptosis. Western blot results also showed that both factors significantly increased in age-dependent manner and upregulated in hypoxic PASMCs (which exhibited obvious proliferation and anti-apoptosis phenomena). HIF-1α up-regulation by DMOG increased the proliferation and anti-apoptosis of PASMCs, while HIF-1α down-regulation by LW6 decreased proliferation and promoted apoptosis. More so, treatment with ZnPP under hypoxic conditions down-regulated HO-1 expression, stimulated proliferation, and resisted apoptosis in yak PASMCs. Taken together, our study demonstrated that both HIF-1α and HO-1 participated in PASMCs proliferation and apoptosis, suggesting that HO-1 is important for inhibition of yak PASMCs proliferation while HIF-1α promoted hypoxia-induced yak PASMCs proliferation.

Histological Analysis, Bioinformatics Profile, and Expression of Methylenetetrahydrofolate Reductase (MTHFR) in Bovine Testes.

Methylenetetrahydrofolate reductase (MTHFR), an enzyme expressed in mammalian testes, exerts a direct effect on spermatogenesis; however, its protein characteristics in bovine testes remain unknown. Here, we analysed bovine testicular structure, MTHFR bioinformatics profile, mRNA, and protein expression characteristics in yellow-cattle (y-c) and yak testis using histological procedures, bioinformatics analysis, qRT-PCR, and western blot. Testes from 13 bovines, ≤2 years juvenile (y-c, n = 3; yak, n = 3) and ≥3 years adult (y-c, n = 3; yak, n = 4) were collected and analysed. Anatomical characteristics of testis in y-c and yak were similar except the weight or size for which that of y-c was significantly higher or greater than yak. In y-c, an open reading frame (ORF) for 2600 nucleotides sequence, encoding 655 amino acids showed high homology with zebu cattle (99.51%) and wild yak (98.68%). Secondary and 3D protein structures were similar to that of humans with differences in the number of nucleotides, amino acids, and some physico-chemical characteristics. MTHFR mRNA expression in y-c and yak were significantly higher in adult testes compared with juvenile ones. However, its protein expression was higher, but not statistically significant, in adult y-c and yak compared to the juvenile ones. The highlights and inferences of these and other findings are discussed.

Low oxygen concentrations improve yak oocyte maturation and enhance the developmental competence of preimplantation embryos.

Mammalian oocyte maturation and early embryo development are highly sensitive to the in vitro culture environment, and oxygen concentration is one of the important factors. In the present study, we aimed to explore the effects of different oxygen concentrations (20%, 10%, 5% or 1% O2) on yak oocyte maturation, in vitro fertilization (IVF), and embryo development competence, as well as its effects on the oxidative response, metabolism, and apoptosis in cumulus-oocyte complexes (COCs) and the embryo. The results revealed that the maturation rate of oocytes, blastocysts rate and hatched blastocysts rate in the group with 5% oxygen concentration were significantly higher (P < 0.05) than other groups, but the cleavage rate with 5% oxygen concentration was significantly lower (P < 0.05) than the 20% and 10% oxygen concentrations. The maturation rate of oocytes, the cleavage rate, blastocysts rate and hatched blastocysts rate with the 1% oxygen concentration were the lowest. The blastocyst cultured with 5% oxygen concentration had significantly greater (P < 0.05) numbers of total cells, inner cell mass (ICM) cells and trophectoderm (TE) cells compared to the other groups. Analysis of the apoptosis index of oocytes and blastocyst cells by transferase dUTP nick end labeling (TUNEL) showed that the number of apoptotic cells significantly reduced (P < 0.05) with 5% oxygen concentration, but increased significantly (P < 0.05) in the 1% oxygen concentration group. Also, the qRT-PCR and western immunoblotting analysis confirmed that the transcription levels of the metabolism genes, antioxidant response genes, apoptosis genes, oocyte competence genes and embryonic developmental markers showed significant differences (P < 0.05) in the COCs or blastocysts matured in 5% oxygen concentration group compared to the other groups. In summary, our findings demonstrate that 5% oxygen concentration improves oocyte maturation and blastocyst development in the yak, increases blastocyst cell numbers, reduces apoptosis rate in the oocyte and blastocyst as well as reduces embryo cleavage rate.

Adipose Tissue Macrophages in Rheumatoid Arthritis: Prevalence, Disease-Related Indicators, and Associations With Cardiometabolic Risk Factors.

OBJECTIVE: Adipose tissue macrophages (ATMs) are a potent source of inflammatory cytokines, with profound effects on adipose tissue function, yet their potential role in rheumatoid arthritis (RA) pathobiology is largely unstudied. METHODS: Periumbilical subcutaneous adipose tissue was obtained from 36 RA patients and 22 non-RA controls frequency matched on demographics and body mass index. Samples were stained for the macrophage marker CD68, and the average proportions of ATMs, crown-like structures (periadipocyte aggregates of 3 or more ATMs), and fibrosis were compared between groups. RESULTS: The adjusted proportion of ATMs among all nucleated cells was 76% higher in RA than in non-RA samples (37.7 versus 21.3%, respectively; P < 0.001), and the adjusted average number of crown-like structures was more than 1.5-fold higher in the RA group than in controls (0.58 versus 0.23 crown-like structure/high-power field, respectively; P = 0.001). ATMs were significantly more abundant in early RA and in those with anti-cyclic citrullinated peptide seropositivity. Users of methotrexate, leflunomide, and tumor necrosis factor inhibitors had a significantly lower proportion of ATMs compared with nonusers. Crown-like structures were significantly higher in patients with rheumatoid factor seropositivity and in those with C-reactive protein levels ≥10 mg/liter, and significantly lower among those treated with statins. Linear ATMs were significantly associated with whole-body insulin resistance, but not with serum lipids. CONCLUSIONS: ATMs and crown-like structures were more abundant in RA patients and were associated with systemic inflammation, autoimmunity, and whole-body insulin resistance, suggesting possible contributions to the RA disease process. Lower levels of ATMs and crown-like structures associated with specific RA treatments suggest that adipose tissue inflammation may be ameliorated by immunomodulation.

Down-regulation of cellular protein heme oxygenase-1 inhibits proliferation of avian influenza virus H9N2 in chicken oviduct epithelial cells.

The pathogenesis of H9N2 subtype avian influenza virus (AIV) infection in hens is often related to oviduct tissue damage. Our previous study suggested that H9N2 AIV induces cellular apoptosis by activating reactive oxygen species (ROS) accumulation and mitochondria-mediated apoptotic signalling in chicken oviduct epithelial cells (COECs). Heme oxygenase-1 (HO-1) is an inducible enzyme that exerts protective effects against oxidative stress and activated HO-1 was recently shown to have antiviral activity. To study the potential involvement of HO-1 in H9N2 AIV proliferation, the role of its expression in H9N2-infected COECs was further investigated. Our results revealed that H9N2 AIV infection significantly up-regulated the expression of HO-1 and that HO-1 down-regulation by ZnPP, a classical inhibitor of HO-1, could inhibit H9N2 AIV replication in COECs. Similarly, the small interfering RNA (siRNA)-mediated knockdown of HO-1 also markedly decreased the virus production in H9N2-infected COECs. In contrast, adenoviral-mediated over-expression of HO-1 concomitantly promoted H9N2 AIV replication. Taken together, our study demonstrated the involvement of HO-1 in AIV H9N2 proliferation, and these findings suggested that HO-1 is a potential target for inhibition of AIV H9N2 replication.

Modulation of the innate immune-related genes expression in H9N2 avian influenza virus-infected chicken macrophage-like cells (HD11) in response to Escherichia coli LPS stimulation.

Macrophages play important roles in mediating virus-induced innate immune responses and are thought to be involved in the pathogenesis of bacterial superinfections. The innate immune response initiated by both low pathogenicity AIV and bacterial superinfection in their avian host is not fully understood. We therefore determine the transcripts of innate immune-related genes following avian H9N2 AIV virus infection and E. coli LPS co-stimulation of avian macrophage-like cell line HD11 cells. More pronounced expression of pro-inflammatory cytokines (IL-6 and IL-1ß) as well as the inflammatory chemokines (CXCLi1 and CXCLi2) was observed in virus infected plus LPS treated HD11 cells compared to H9N2 virus solely infected control. For two superinfection groups, the levels of genes examined in a prior H9N2 virus infection before secondary LPS treatment group were significantly higher as compared with simultaneous virus infection plus LPS stimulation group. Interestingly, similar high levels of IL-6 gene were observed between LPS sole stimulation group and two superinfection groups. Moreover, IL-10 and TGF-ß3 mRNA levels in both superinfection groups were moderately upregulated compared to sole LPS stimulation group or virus alone infection group. Although TLR4 and MDA5 levels in virus alone infection group were significantly lower compared to that in both superinfection groups, TLR4 upregulation respond more rapid to virus sole infection compared to LPS plus virus superinfection. Collectively, innate immune-related genes respond more pronounced in LPS stimulation plus H9N2 virus infection HD11 cells compared to sole virus infection or LPS alone stimulation control cells.

The NS1 protein of avian influenza virus H9N2 induces oxidative-stress-mediated chicken oviduct epithelial cells apoptosis.

The pathogenesis of H9N2 subtype avian influenza virus infection (AIV) in hens is often related to oviduct tissue damage. The viral non-structural NS1 protein is thought to play a key role in regulating the pathogenicity of AIV, but its exact function in this process remains elusive. In this study, the pro-apoptosis effect of H9N2 NS1 protein was examined on chicken oviduct epithelial cells (COECs) and our data indicated that NS1-induced oxidative stress was a contributing factor in apoptosis. Our data indicate that NS1 protein level was correlated with reactive oxygen species (ROS) in COECs transfected with NS1 expression plasmids. Interestingly, decreased activities of antioxidant enzymes, superoxide dismutase and catalase, were observed in NS1-transfected COECs. Treatment of COECs with antioxidants, such as pyrrolidine dithiocarbamate (PDTC) or N-acetylcysteine (NAC), significantly inhibited NS1-induced apoptosis. Moreover, although antioxidant treatment has little effect on the activation of caspase-8 in NS1-transfected cells, the activation of caspase-3/9 and Bax/Bcl-2 were significantly downregulated. Taken together, the results of our study demonstrated that expression of H9N2 NS1 alone is sufficient to trigger oxidative stress in COECs. Additionally, NS1 protein can induce cellular apoptosis via activating ROS accumulation and mitochondria-mediated apoptotic signalling in COECs.

Association of Elevations of Specific T Cell and Monocyte Subpopulations in Rheumatoid Arthritis With Subclinical Coronary Artery Atherosclerosis.

OBJECTIVE: Coronary artery disease (CAD) is the leading cause of excess deaths in rheumatoid arthritis (RA). However, identification of features denoting patients with a risk of developing CAD is lacking. The composition of circulating peripheral blood mononuclear cell (PBMC) subsets in RA patients differs markedly from that in healthy controls with regard to the extent of T cell activation, with clonal expansion and differentiation to effector memory status, and presence of inflammatory monocytes. In this study, we sought to evaluate whether elevations in these PBMC subpopulations in RA patients could denote those with an increased risk of subclinical CAD, as determined by the presence of coronary artery calcification (CAC). METHODS: The study cohort comprised 72 patients with RA who underwent cardiac computed tomography to assess CAC. PBMC subsets were determined by multiparameter flow cytometry. Multivariable logistic regression was used to determine the associations between PBMC subpopulations and the presence of CAC. RESULTS: Among the 72 patients with RA, 33% had CAC and exhibited significant increases in the levels of circulating CD4 T cell subsets denoting activation and differentiation to the effector memory phenotypes. Analogous increases in the levels of CD8 T cell subsets, as well as in the CD14(high)CD16+ intermediate monocyte subset, were also present in these patients, as compared to those without CAC. The increases in the CD4 and CD8 T cell subsets were highly intercorrelated, whereas the increases in CD14(high)CD16+ monocytes were independent of elevations in the CD4 T cell subsets. After adjustments for relevant confounders, the levels of CD4+CD56+CD57+ T cells and CD14(high)CD16+ monocytes remained associated with the presence of CAC. CONCLUSION: These findings indicate that PBMC subsets are markers for the presence of CAC and suggest that mechanisms of atherogenesis in RA may operate in part through the elevations in these subsets, raising further questions about the mechanisms underlying the presence of such alterations in cell composition in patients with RA and the potential for shared etiologic pathways between RA and cardiovascular disease.

C1q and tumor necrosis factor-related protein 3 is present in human cord blood and is associated with fetal growth.

BACKGROUND: To determine the presence of C1q and tumor necrosis factor-related protein 3 (CTRP3) in cord blood and its relationship with fetal growth among Chinese newborns. METHODS: This pilot study recruited 126 infants (small for gestational age [SGA], n=34; appropriate for gestational age [AGA], n=60; large for gestational age [LGA], n=32); cord blood CTRP3 levels were measured, and fetal growth parameters were collected. RESULTS: Median (25-75th percentile) CTRP3 levels in the SGA, AGA, and LGA groups were 297.2 (236.4-360.2), 297.5 (261.0-369.9), and 368.6 (298.5-507.1) ng/ml, respectively (P=0.01). LGA infants had higher CTRP3 levels than AGA infants (multiple linear regression analysis; P=0.01). The CTRP3 levels were positively correlated with birth weight (r=0.25, P<0.01), Ponderal index (r=0.28, P<0.01), and placental weight (r=0.20, P=0.03) in the total study population. In the subgroup analysis, CTRP3 levels were negatively correlated with birth length z scores (r=-0.39, P=0.03) and were positively correlated with the Ponderal index (r=0.43, P=0.02) only in the SGA group; no other significant correlations were observed. The CTRP3 levels were similar between the sexes (P=NS). CONCLUSIONS: CTRP3 is present in cord blood and might be involved in fetal growth.

Relationship between human cord blood adropin levels and fetal growth.

Adropin is a recently identified peptide and participates in the regulation of energy homeostasis and vascular function. The aim of this study was to examine the relationships between human cord blood adropin levels and fetal growth. A total of 159 newborns [preterm delivery (PTD), n=72; term delivery, n=87] were recruited. Adropin levels in cord blood were determined using enzyme-linked immunosorbent assay kits. Clinical information on fetal growth was collected. Adropin levels in PTD babies (median, 2028; 25th-75th, 1413-2484pg/ml) were lower than those in term delivery babies (median, 2305; 25th-75th, 1960-2684pg/ml, P=0.01). Birth weight and length z score, Ponderal index, placental length, breadth, thickness, surface area, volume and density were not significantly correlated to adropin concentrations in term delivery group. However, we found adropin concentrations were significantly correlated to gestational age at birth (Spearman's correlation coefficient=0.35, P<0.01) and placental weight (Spearman's correlation coefficient=0.24, P=0.04) in PTD group. We also found that boys had lower adropin levels than girls in PTD group (P=0.01). When the analysis was extended to the whole group (PTD and term deliveries combined), the results were similar to those for PTD group alone. After adjusting for maternal age and newborn's sex, every 100pg/ml increase of adropin concentration was significantly associated with a decreased risk of PTD (odds ratio, 0.95; 95% confidence interval, 0.91-0.99). Our study showed that cord blood adropin levels were positively correlated with gestational age and placental weight but not with other fetal growth parameters.

Immunologic characteristics of intrarenal T cells: trafficking of expanded CD8+ T cell ß-chain clonotypes in progressive lupus nephritis.

OBJECTIVE: To better define the immunologic character of the T cell infiltrate in lupus nephritis. METHODS: We performed double immunohistochemical staining and clonotypic T cell receptor (TCR) ß-chain sequencing in multiple anatomic regions isolated by laser-capture microdissection from renal biopsy samples. RESULTS: Systemic lupus erythematosus (SLE) kidneys have a variably patterned and often extensive infiltrate of predominantly clonally expanded T cells of CD4 and CD8 lineages. CD4+ T cells were prominent in nearly two-thirds of SLE biopsy samples and were distributed as broad periglomerular aggregates or intermixed with CD8+ T cells forming periglomerular caps. Sequencing of the TCR from periglomerular regions showed a predominance of clonally expanded T cells. The CD8+ T cells, which were present in all biopsy samples, often adhered to Bowman's capsule and infiltrated the tubular epithelium. They exhibited features that suggest participation in an adaptive immune response: differentiation into CD28(null) memory-effector phenotype, trafficking of the same expanded clonotype to different regions of the kidney and to the peripheral blood, and clonal persistence for years in repeat biopsy samples. CD8+ T cell tubulitis was especially associated with progressive changes. CONCLUSION: The immunologic characteristics of the infiltrating CD4+ and CD8+ T cells in the lupus kidney indicate that they have the potential to mediate injury, which may be relevant to development of progressive renal failure. Whereas the oligoclonality of the CD4+ T cell infiltrate is consistent with the paradigm of SLE as a class II major histocompatibility complex-associated autoimmune disease, the finding of CD8+ T cell clonality and trafficking implies participation in a distinct systemic adaptive immune response.

Circulating activated and effector memory T cells are associated with calcification and clonal expansions in bicuspid and tricuspid valves of calcific aortic stenosis.

We sought to delineate further the immunological significance of T lymphocytes infiltrating the valve leaflets in calcific aortic stenosis (CAS) and determine whether there were associated alterations in circulating T cells. Using clonotypic TCR ß-chain length and sequence analysis we confirmed that the repertoire of tricuspid CAS valves contains numerous expanded T cell clones with varying degrees of additional polyclonality, which was greatest in cases with severe calcification. We now report a similar proportion of clonal expansions in the much younger bicuspid valve CAS cases. Peripheral blood flow cytometry revealed elevations in HLA-DR(+) activated CD8 cells and in the CD8(+)CD28(null)CD57(+) memory-effector subset that were significantly greater in both bicuspid and tricuspid CAS cases with more severe valve calcification. Lesser increases of CD4(+)CD28(null) T cells were identified, principally in cases with concurrent atherosclerotic disease. Upon immunostaining the CD8 T cells in all valves were mainly CD28(null), and CD8 T cell percentages were greatest in valves with oligoclonal repertoires. T cell clones identified by their clonotypic sequence as expanded in the valve were also found expanded in the circulating blood CD28(null)CD8(+) T cells and to a lesser degree in the CD8(+)CD28(+) subset, directly supporting the relationship between immunologic events in the blood and the valve. The results suggest that an ongoing systemic adaptive immune response is occurring in cases with bicuspid and tricuspid CAS, involving circulating CD8 T cell activation, clonal expansion, and differentiation to a memory-effector phenotype, with trafficking of T cells in expanded clones between blood and the valve.

Deoxycholic acid modified-carboxymethyl curdlan conjugate as a novel carrier of epirubicin: in vitro and in vivo studies.

Deoxycholic acid hydrophobically modified-carboxymethylated-curdlan (DCMC) conjugate was developed as a novel carrier for the anticancer drugs. Epirubicin (EPB), as a model drug, was physically loaded into DCMC self-assembled nanoparticles. EPB-loaded DCMC nanoparticles were almost spherical in shape and their size, in the range of 327.4-511.5 nm, increased with the EPB-loading content increasing. In vitro release of EPB from DCMC self-assembled nanoparticles showed sustained drug release pattern and the release rate was related to pH of release media and drug loading content. The cytotoxic activity of EPB-loaded DCMC nanoparticles was assayed by the MTT colorimetric assay. Compared with free drug, EPB-loaded DCMC nanoparticles showed the higher cytotoxicity, which may be attributed to the enhanced cellular uptake. In vivo toxicity study indicated that DCMC conjugate did not induce unexpected side effects. Tissue biodistribution study was performed in tumor-bearing mice. The result showed that DCMC increased the uptake of EPB in the tumor and decreased the uptake of EPB in kidney and heart, compared to free drug. Moreover, tumor volume reductions induced by DCMC conjugate, free EPB and EDNs were 24.3%, 58.9% and 70%, respectively, which suggested that EDNs could effectively retard the growth of the tumor.