Amino acids 89–96 of Salmonella typhimurium flagellin represent the major domain responsible for TLR5-independent adjuvanticity in the humoral immune response

Toll-like receptor 5 (TLR5) signaling in response to flagellin is dispensable for inducing humoral immunity, but alterations of aa 89–96, the TLR5 binding site, significantly reduced the adjuvanticity of flagellin. These observations indicate that the underlying mechanism remains incompletely understood. Here, we found that the native form of Salmonella typhimurium aa 89–96-mutant flagellin extracted from flagella retains some TLR5 recognition activity, indicating that aa 89–96 is the primary, but not the only site that imparts TLR5 activity. Additionally, this mutation impaired the production of IL-1β and IL-18. Using TLR5KO mice, we found that aa 89–96 is critical for the humoral adjuvant effect, but this effect was independent of TLR5 activation triggered by this region of flagellin. In summary, our findings suggest that aa 89–96 of flagellin is not only the crucial site responsible for TLR5 recognition, but is also important for humoral immune adjuvanticity through a TLR5-independent pathway.     

缺氧应激反应中活性氧与缺氧诱导因子-1的相互作用

在缺氧条件下,线粒体会产生大量的活性氧（ reactive oxygen species, ROS）,随即大量的活性氧将会诱导机体产生缺氧应激反应。缺氧诱导因子1（hypoxia inducible factor 1, HIF?1）是缺氧应激反应中的中枢调控因子。有研究表明, ROS主要通过抑制脯氨酸羟化酶家族（ prolyl hydroxylases, PHDs）的活性来抑制HIF?1α的泛素化降解,从而稳定HIF?1。而HIF?1蛋白水平的升高有助于机体应对缺氧微环境。最近研究还发现, REDD?1可以通过ROS对HIF?1产生负调控作用,从而抑制肿瘤的形成;秀丽线虫呼吸突变体的产生会导致ROS水平增加,从而增强HIF?1的活性,最终延长的线虫寿命;以及ROS、 HIF?1促进自噬的产生。因此,了解缺氧条件下ROS与HIF?1之间的相互作用关系,对于今后肿瘤、衰老和自噬的研究具有重要意义。     

Using ultrasound radio frequency technology to assess regression of the structure and function of the carotid artery by radioiodine therapy in hyperthyroidism patients

Introduction

The aim of the study was to investigate the structure and function of the carotid artery in patients with hyperthyroidism by ultrasound radio frequency data technology (RF data) and the effect of ¹³¹I on them.

Material and methods

Seventy patients with primary hyperthyroidism and 74 healthy volunteers were enrolled in this study. Structural and functional parameters of the common carotid artery were measured in every patient before and after ¹³¹I treatment through the RF data, such as intima media thickness (IMT), functional compliance coefficient (CC), stiffness index (β), and pulse wave velocity (PWV). We also analyzed the correlation between these parameters and patients’ age, body mass index, hemodynamic parameters (blood pressure, heart rate), thyroid hormone levels and other risk factors.

Results

There was a significant difference in IMT between hyperthyroid patients and the control group at baseline (483.6 vs. 443.3 µm, p < 0.01); after treatment, the IMT decreased significantly (428.7 vs. 483.6 µm, p < 0.001). Furthermore, the IMT was correlated with patients’ age and systolic blood pressure (r = 0.525, p < 0.01 and r = 0.289, p < 0.05, respectively). The β and PWV were also higher than the control group (7.26 vs.5.87, 6.27 vs. 5.57 m/s, respectively; all p < 0.001); CC was lower than the control group (0.98 vs. 1.19 mm²/KPa, p < 0.01); after treatment, PWV and β were lower than baseline (5.66 vs. 6.27, 5.81 vs. 7.26 m/s, respectively; all p < 0.01), and CC was higher than baseline. In addition, they were significantly correlated with age (r = 0.525, p < 0.01 and r = 0.289, p < 0.05, respectively). However, these parameters were not correlated with the level of thyroid hormones.

Conclusions

Six-month ¹³¹I treatment for patients with hyperthyroidism reverses the structural and functional damage in the carotid artery, which is sensitively evaluated by the RF data technique.     

Clinical and pathological characteristics of extramammary Paget’s disease: report of 246 Chinese male patients

Extramammary Paget’s disease (EMPD) is a rare cutaneous neoplasm. The aim of this study was to elaborate the clinical and pathological features of Chinese EMPD male patients. The study comprised 246 patients with EMPD at our institute from January 1993 to December 2012. Scrotum was the most common initial site. The average age of onset was 63.9 years but the mean delay in diagnosis was 3.6 years. EPMD spread exclusively to the inguinal lymph nodes and the right inguinal lymph nodes are more likely to suffered Paget cells infiltration. Accompanying malignancies were found in 20 patients. Pathological examination revealed 63 patients defined as invasive EMPD. Immunohistochemical detection showed various expression levels of EMA, CEA, CK7, HER2/neu, Ki67, P53, CK20 and S100 in tumor tissues, but negative expression of VIM, LCA and HMB45. HER2/neu protein exhibited a significant association with invasive EMPD. A novel histological type of EMPD with CK7-/S100+ was identified. Elevated serum PSA level was observed in only 16% patients. Invasive EMPD often had advanced age of onset. Metastatic EMPD showed significantly shorter in the delay in diagnosis and the greater length of skin lesion in contrast to others. This study demonstrates the clinical and pathological features of Chinese male EMPD patients, and may provide implications for the management of Chinese EMPD patients.     

High altitude increases the expression of hypoxia-inducible factor 1α and inducible nitric oxide synthase with intest-inal mucosal barrier failure in rats

Background: The failure of intestinal mucosal barrier may induce multiple organ dysfunction and systemic inflammatory response syndrome, but little work has been done on whether hypobaric hypoxia related to the failure of intestinal mucosal barrier. Aims: To study the expression of hypoxia-inducible factor 1α (HIF-1α), inducible nitric oxide synthase (iNOS) and morphological changes of intestinal mucosa in albino rats at different altitude. Methods: 30 male Wistar rats raised in plain for one month were randomly divided into 3 groups: Plain 500 m group (n=10), High-altitude (HA) 3842 m group (n=10) and HA4767 m group (n=10). Each group was delivered to different altitude area at the same shipping time and executed after 3 days’ exposure to different altitude. Intestinal segments with the same location of all rats were removed for morphological analyses. Morphologic parameters (villous height, crypt depth, mucosal wall thickness and villous surface area) were measured by optical and scanning electron microscope. The expression of iNOS and HIF-1α were detected by immunohistochemistry. Results: Morphological indexes in higher altitude groups were exacerbated obviously compared with those of lower altitude groups. While the expression of iNOS and HIF-1α in higher altitude groups were significantly increased than those of lower altitude groups. Linear correlation analysis showed that the expression of iNOS was positively correlated with that of HIF-1α. Conclusions: Hypobaric hypoxia increases the expression of HIF-1α and iNOS in intestinal mucosa, however exacerbates the mucous morphologic parameters with altitude increasing. HIF-1α may regulate the expression of iNOS and be involved in the damage of intestinal mucosa.     

Restricted dendritic cell and monocyte progenitors in human cord blood and bone marrow

In mice, two restricted dendritic cell (DC) progenitors, macrophage/dendritic progenitors (MDPs) and common dendritic progenitors (CDPs), demonstrate increasing commitment to the DC lineage, as they sequentially lose granulocyte and monocyte potential, respectively. Identifying these progenitors has enabled us to understand the role of DCs and monocytes in immunity and tolerance in mice. In humans, however, restricted monocyte and DC progenitors remain unknown. Progress in studying human DC development has been hampered by lack of an in vitro culture system that recapitulates in vivo DC hematopoiesis. Here we report a culture system that supports development of CD34⁺ hematopoietic stem cell progenitors into the three major human DC subsets, monocytes, granulocytes, and NK and B cells. Using this culture system, we defined the pathway for human DC development and revealed the sequential origin of human DCs from increasingly restricted progenitors: a human granulocyte-monocyte-DC progenitor (hGMDP) that develops into a human monocyte-dendritic progenitor (hMDP), which in turn develops into monocytes, and a human CDP (hCDP) that is restricted to produce the three major DC subsets. The phenotype of the DC progenitors partially overlaps with granulocyte-macrophage progenitors (GMPs). These progenitors reside in human cord blood and bone marrow but not in the blood or lymphoid tissues.DCs, monocytes, and macrophages are closely related cell types whose interrelationship were long debated and only recently elucidated in the mouse (Geissmann et al., 2010; Merad et al., 2013). In mice, DCs and monocytes arise from a macrophage/dendritic progenitor (MDP; Fogg et al., 2006), which produces monocytes, and a common dendritic progenitor (CDP) that is restricted to the DC fate (Shortman and Naik, 2007; Liu et al., 2009; Geissmann et al., 2010; Merad et al., 2013). The CDP produces pre–plasmacytoid DCs (pDCs) and pre–conventional DCs (cDCs), the latter of which leaves the BM and circulates in the blood before entering tissues and developing into the different DCs subsets (Naik et al., 2006, 2007; Onai et al., 2007b, 2013; Ginhoux et al., 2009; Liu et al., 2009; Onai et al., 2013).In the mouse, DC differentiation is dependent on a hematopoietin, Flt3L, whose receptor, Flt3 (CD135), is expressed throughout DC development (McKenna et al., 2000; Karsunky et al., 2003; Waskow et al., 2008). In contrast, other hematopoietin receptors such as monocyte colony-stimulating factor receptor (M-CSFR or CD115) and granulocyte macrophage colony-stimulating factor receptor (GM-CSFR or CD116) are restricted to hematopoietic progenitors of DCs but not expressed on all mature DCs (Kingston et al., 2009).DC development in the human is far less well understood than in the mouse. Human monocytes can be induced to differentiate into potent antigen-presenting cells with some phenotypic features of DCs after in vitro culture with cocktails of cytokines (Sallusto and Lanzavecchia, 1994). However, these monocyte-derived DCs are more closely related to activated monocytes than to cDCs (Naik et al., 2006; Xu et al., 2007; Cheong et al., 2010; Crozat et al., 2010). Progress in defining the human DC lineage has been hampered, in part, by a paucity of reliable markers to distinguish these cells from monocytes, limited access to human tissues, the relatively small number of circulating DCs in blood, and the lack of a robust tissue culture system for the in vitro development of all DC subsets (Poulin et al., 2010; Ziegler-Heitbrock et al., 2010; Proietto et al., 2012).Here we report a stromal cell culture system that supports the development of CD34⁺ hematopoietic stem cell (HSC) progenitors into the three major subsets of human DCs, monocytes, granulocytes, and NK and B cells. Using this culture system, we have been able to define the sequential origin of human DCs from a human granulocyte-monocyte-DC progenitor (hGMDP), which develops into a more restricted human monocyte-dendritic progenitor (hMDP), which produces monocytes, and a human CDP (hCDP), which is restricted to produce the three major subsets of DCs.     

The effects of trunk stabilization exercise on bone density after menopause

[Purpose] This study examined the effect of low intensity exercise on bone density by conducting trunk stabilization exercise on females after menopause for 24 weeks. [Subjects and Methods] Thirty three female subjects over 47 years old and under the age of 53 were selected and 16 for experimental group and 17 for control group were randomly selected. Experimental group had performed spinal and pelvic stabilization exercise 30 minutes a day, 5times a week, for 24 weeks. Except for the daily life, control group did not participate in any characteristic movement. Bone density of every member in experimental group was measured using average value of bone density of 1st–4th lumbar through quantitative computer tomography. [Results] There was a meaningful difference in only control group about measured value of bone density within each group, experimental and control group, but there was no meaningful difference in measured value of bone density between two groups, experimental group and control group. [Conclusion] Through this research, we could see the fact that although trunk stability exercise could not change bone density meaningfully, it could maintain bone density. In the future, it is randomly necessary to study things related this because results of researches can show different results according to exercise intensity, exercise period, age, weight, hormone status and mediation period. It is considered that it will help to prevent and treat patients with osteoporosis a lot.Key words: Bone mineral density, Computer tomography, Low intensity exercise     

Effect of constrained weight shift on the static balance and muscle activation of stroke patients

[Purpose] The purpose of this study was to evaluate the effects of constrained weight shift induced by shoe lift beneath the unaffected lower extremity, on balance functions and electromyography of the affected lower extremity of stroke patients. [Subjects and Methods] Twelve patients with unilateral stroke were recruited as volunteers for this study. The subjects were repeatedly measured in a randomized order under three conditions: no-shoe lift, and shoe lifts of 5 mm and 10 mm heights beneath the unaffected lower extremity. [Results] Standing with a 10 mm shoe lift for the unaffected lower extremity decreased the mean velocity of mediolateral sway compared to no-shoe lift. Regarding the velocity of anteroposterior sway, standing with 5 mm and 10 mm shoe lifts decreased the mean velocity of anteroposterior sway. The muscle activation of the affected lower extremity was not significantly different among the no-shoe lift, 5 mm shoe lift and 10 mm shoe lift conditions; however, the muscle activities of the rectus femoris, biceps femoris, tibialis anterior, and medial gastrocnemius of the affected lower extremity progressively improved with increasing height of the shoe lift. [Conclusion] A constrained weight shift to the affected side elicited by a shoe insole of 10 mm height on the unaffected side can improve the static standing balance of stroke patients, and it resulted in 14–24% increases in the muscle activities of the affected leg.Key words: Constrained weight shift, Stroke, Balance