Immunology of atopic eczema: overcoming the Th1/Th2 paradigm

Atopic eczema (AE) is a challenge for modern medicine, because it is prevalent, severely affects quality of life of patients and their families, and causes high socioeconomic costs. The pathogenesis of AE is complex. While initial studies suggested a Th2 deviation as primary reason for the disease, numerous studies addressed a genetically predetermined impaired epidermal barrier as leading cause in a subgroup of patients. Recently, immune changes beyond the initial Th2 concept were defined in AE, with a role for specialized dendritic cells as well as newly identified T helper cell subsets such as Th17 and Th22 cells. Furthermore, trigger factors are expanded beyond classical Th2 allergens such as pollen or house dust mites to microbial products as well as self‐antigens. This review pieces together our current understanding of immune as well as barrier abnormalities into the pathogenesis mosaic of AE.     

Augmentation of Natural Killer Cell and Antibody-Dependent Cellular Cytotoxicity in BALB/c Mice by Sulforaphane,a Naturally Occurring Isothiocyanate from Broccoli through Enhanced Production of Cytokines IL-2 and IFN-γ

Effect of sulforaphane on cell-mediated immune (CMI) response was studied in normal as well as Ehrlich ascites tumor-bearing BALB/c mice. Administration of sulforaphane significantly enhanced natural killer (NK) cell activity in both normal as well as tumor-bearing animals, and the activity was observed earlier than in tumor-bearing control animals. Antibody-dependent cellular cytotoxicity (ADCC) also was enhanced significantly in both normal as well as tumor-bearing animals after sulforaphane administration compared with untreated control tumor-bearing animals. An early antibody-dependent complement-mediated cytotoxicity (ACC) also was observed in sulforaphane-treated normal and tumor-bearing animals. Administration of sulforaphane significantly enhanced the production of Interleukin-2 and Interferon-γ in normal as well as tumor-bearing animals. In addition, sulforaphane significantly enhanced the proliferation of splenocytes, bone marrow cells, and thymocytes by stimulating the mitogenic potential of various mitogens such as concanavalin A, phytohaemagglutinin, poke weed mitogen, and lipopolysaccharide.     

Regulation of sodium pump endocytosis by cardiotonic steroids: Molecular mechanisms and physiological implications

We have previously shown that ouabain and other cardiotonic steroids interact with the plasmalemmal Na/K-ATPase and cause a time and dose dependent endocytosis of the Na/K-ATPase. This endocytosis is demonstrable using fluorescence imaging as well as conventional biochemical and biophysical cell separation methods. In proximal tubule cells, this process appears to regulate the density of basolateral Na/K-ATPase expression directly as well as indirectly modulate transepithelial sodium transport.

Work with genetic manipulations, as well as pharmacological agents with cell culture models, have demonstrated that the cardiotonic steroid stimulated endocytosis of the plasmalemmal Na/K-ATPase requires caveolin and clathrin as well as the activation of c-Src, transactivation of the EGFR and activation of PI3K. Interestingly c-Src, EGFR and ERK1/2 all appear to be endocytosed along with the plasmalemmal Na/K-ATPase. These observations suggest a close analogy between a subset of plasmalemmal Na/K-ATPase and signaling companions with conventional receptor tyrosine kinases. While further studies are necessary to delineate the role of this endocytosis in the generation as well as the limit of signal transduction through the Na/K-ATPase signal cascade, we propose that it has an important role in the regulation of renal sodium handling as well as other important processes.     

血清C反应蛋白、降钙素原及乳酸在重症急性胰腺炎中的变化及临床意义

目的 探讨血清C反应蛋白(C-reactive protein, CRP)、降钙素原(procalcitonin, PCT)和乳酸在重症急性胰腺炎(severe acute pancreatitis, SAP)中的变化及其临床意义.方法 选取重症监护病房(ICU)于2013年4月至2016年4月期间收治的SAP患者68例,在患者入院后的第1、4、7天及好转后转出或死亡前分别对患者血清CRP含量、PCT浓度和乳酸水平进行检测评估APACHE-II分值,并根据患者的预后情况分为存活组和死亡组.分别采用免疫比浊法、电化学发光法和化学分析法检测存活组和死亡组血清CRP、PCT和乳酸水平.结果 存活组中,与第1天相比,第4天和第7天及转出前患者的血清CRP水平、PCT浓度、乳酸含量以及APACHE-II评分均显著性降低(P<0.05).在死亡组中,与第1天相比,第4天和第7天及转出前患者的血清CRP水平、PCT浓度、乳酸含量以及APACHE-II评分均显著性增加(P<0.05).与同时期存活组比较,死亡组患者的血清CRP水平、PCT浓度、乳酸含量以及APACHE-II评分均显著性增加(P<0.05).此外,血清CRP浓度、PCT水平和乳酸含量均与APACHE-II评分呈正相关(r=0.813, r=0.726, r=0.652,P<0.05).结论 随着SAP患者的病情发展,血清CRP含量、PCT水平、乳酸浓度以及APACHE-II评分出现不同程度的增加.这表明动态监测SAP患者血清CRP含量、PCT水平、乳酸浓度以及APACHE-II评分的改变有利于判断患者的病情发展方向以及采取有效的治疗手段,最终减少AP患者的死亡率.     

Drug-associated anaphylaxis: 20 years of reporting in the Netherlands (1974–1994) and review of the literature

Background Since 1963, the Drug Safety Unit of the Dutch Inspectorate for Health Care (DSU) holds a voluntary reporting system. Objective To analyse all reports received in the years 1974 to 1994, registered as anaphylaxis or as a diagnosis that could contain cases of anaphylaxis. Methods All reports were classified as probable or possible anaphylaxis according to previously described criteria and the causal relationship between exposure and anaphylaxis was assessed. Results Nine hundred and ninety-two reports possibly concerning anaphylaxis were received between 1974 and 1994. Fifty-six were unclassifiable. The remaining 936 reports concerned 326 men and 610 women. Three hundred and forty-five reports were classified as anaphylaxis probable, 485 as anaphylaxis possible, and 106 as anaphylaxis unlikely by previously specified criteria. Drugs frequently associated with anaphylaxis (causal relationship certain or probable) were: glafenine (326 reports classified as anaphylaxis probable or possible), combination preparations with (propy)phenazone or propyphenazone/phenacetine (39), diclofenac (30), dextran (20), ibuprofen (14), floctafenine (12), allergen extracts (12), sulfamethoxazole with trimethoprim (12), and trimethoprim (11). There is probably substantial under-reporting as well as reporting bias in these data. Furthermore, many reports were classified as possible and not as probable anaphylaxis because the temporal relationship was unknown or not reported. Conclusion Drugs that caused anaphylaxis most frequently were glafenine, NSAID and certain antibiotics. Data from a voluntary reporting system such as the DSU are valuable as an early warning system for drugs that may induce anaphylactic reactions.     

超声对睾丸肿瘤及肿瘤样病变的诊断及鉴别诊断

目的 探讨超声对睾丸肿瘤及肿瘤样病变的诊断及鉴别诊断价值.方法 回顾分析33例睾丸肿块患者的超声声像图表现,并与其病理结果进行对照.结果 33例睾丸肿块患者中,精原细胞瘤12例,淋巴瘤6例,表皮样囊肿6例,混合性生殖细胞瘤2例,畸胎瘤2例,胚胎性癌、内胚窦瘤各1例,其他3例.结论 超声检查对睾丸肿瘤及肿瘤样病变的诊断及鉴别诊断具有重要价值,可为进一步治疗方案的制定提供依据,是睾丸肿瘤首选的影像学检查方法.     

The genetics of osteoporosis: 'complexities and difficulties'

Osteoporosis is characterized by a decrease in bone mass as well as a deterioration of the bone architecture resulting in an increased risk of fracture. Although the disease is multifactorial, twin studies have shown that genetic factors account for up to 80% of the variance in bone mineral density, the best known predictor of the risk of osteoporosis. Some loci, such as the vitamin D and estrogen receptor genes, as well as the collagen type Ialpha1 locus, are promising genetic determinants of bone mass, and possibly other bone phenotypes, but this is controversial and the molecular basis of osteoporosis remains largely undefined. Considering that the effect of each candidate gene is expected to be modest, discrepancies between allelic association studies may have arisen because different populations carry different genetic backgrounds and exposure to environmental factors. Also, we realize the importance of gene-gene as well as gene-environment interactions as significant determinants of bone density and risk of osteoporosis. The use of new tools such as small nucleotide polymorphism maps now allows the possibility to perform allelic association studies in the context of whole-genome search. However, specific study design strategies in large epidemiological studies as well as the best statistical approach will need to be established. We may expect the development of population-specific at-risk profiles for osteoporosis that would include genetic and environmental factors, as well as their interactions. This should eventually lead to better prevention strategies and more adapted therapies against osteoporosis.     

Augmentation of natural killer cell and antibody-dependent cellular cytotoxicity in BALB/c mice by sulforaphane, a naturally occurring isothiocyanate from broccoli through enhanced production of cytokines IL-2 and IFN-gamma

Effect of sulforaphane on cell-mediated immune (CMI) response was studied in normal as well as Ehrlich ascites tumor-bearing BALB/c mice. Administration of sulforaphane significantly enhanced natural killer (NK) cell activity in both normal as well as tumor-bearing animals, and the activity was observed earlier than in tumor-bearing control animals. Antibody-dependent cellular cytotoxicity (ADCC) also was enhanced significantly in both normal as well as tumor-bearing animals after sulforaphane administration compared with untreated control tumor-bearing animals. An early antibody-dependent complement-mediated cytotoxicity (ACC) also was observed in sulforaphane-treated normal and tumor-bearing animals. Administration of sulforaphane significantly enhanced the production of Interleukin-2 and Interferon-γ in normal as well as tumor-bearing animals. In addition, sulforaphane significantly enhanced the proliferation of splenocytes, bone marrow cells, and thymocytes by stimulating the mitogenic potential of various mitogens such as concanavalin A, phytohaemagglutinin, poke weed mitogen, and lipopolysaccharide.     

Contribution of survivin to the immune system,allergies and autoimmune diseases

In addition to malignancies, survivin (a member of the apoptosis inhibitor family) has been implicated in the pathogenesis of inflammatory disorders, including autoimmune and allergic diseases. Survivin is constantly expressed in the proliferating hematopoietic progenitor cells, and it is re-expressed in the mature cells of the innate and adaptive immunity, upon activation. Survivin enhances the expression of co-stimulatory molecules and MHC class II molecules in dendritic cells, and promotes the lifespan of macrophages, neutrophils, and eosinophils, while suppressing natural killer (NK) cell activity. Survivin has been implicated in T cell maturation, T cell expansion, effector CD4⁺ T cell differentiation, maintenance of memory CD4⁺ T and CD8⁺ T cells, as well as antibody production. Upregulated expression of survivin was indicated in the T cells as well as various samples collected from allergic patients. Survivin can contribute to the pathogenesis of allergic diseases via the promotion of the Th2 polarization, promoting IL-4 expression, compromising activation-induced cell death (AICD) in Th2 cells, and preventing apoptosis of eosinophils, as well as, amplification of eosinophilia. Moreover, survivin can interfere with clonal deletion of autoreactive T and B cells, as well as suppress Treg cell development and activity supporting the development of autoimmune diseases. This review discusses the role of survivin in immunity, allergy and autoimmunity as well as provides evidence that survivin may be considered as a novel therapeutic target for the treatment of allergic and autoimmune diseases.     

Conjugated Polymers: Where We Come From,Where We Stand,and Where We Might Go

Conjugated polymers (CPs) are electronic materials which always attract the joint attention of synthetic chemistry, physics, and engineering. The present article deals with “classical” CPs such as polyacetylenes and polyarylenes, and also with more sophisticated cases such as ladder polymers and graphene nanoribbons. CPs exhibit a wide variety of fascinating electrical and optical properties which qualify them as active components of devices. Their performance, however, is shown to sensitively depend upon structural perfection and purity as well as on the thin-film morphology, which is also influenced by processing procedures. Nowadays, the need for innovative energy technologies and sustainable materials and processes as well as the emerging new opportunities of quantum technologies, are adding further momentum to CP research.     

The light microscopic localization of substance P- and somatostatin-like immunoreactive cells in the larval tiger salamander retina

Summary Light microscopic immunocytochemistry was utilized to localize the populations of substance P (SP)- and somatostatin (SOM)-like immunoreactive cells in the larval tiger salamander retina. Of 104 SP-immunostained cells observed, 82% were Type 1 amacrine cells. Another 8% of the SP-cells were classified as Type 2 amacrine cells, while 10% of the SP-cells had their cell bodies located in the ganglion cell layer and were designated as displaced amacrine cells. Each type of SP-like immunoreactive cell was observed in the central and peripheral retina. SP-immunopositive processes were observed in the inner plexiform layer as a sparse plexus in sublamina 1 and as a denser network of fibers in sublamina 5. Seventy-eight percent of the 110 somatostatin-immunopositive cells observed were designated as Type 1 amacrine cells. Another 12% of SOM-cells were classified as displaced amacrine cells, while only two SOM-immunopositive Type 2 amacrine cells were observed. Nine percent of the SOM-cells were designated as interplexiform cells, based on their giving rise to processes distributing in the outer plexiform layer as well as processes ramifying in the inner plexiform layer. Each type of SOM-immunoreactive cell was observed in the central and peripheral retina, with the exception of the Type 2 amacrine cells, whose somas were only found in the central retina. Lastly, SOM-immunopositive processes in the inner plexiform layer appeared as a fine plexus in sublamina 1 and as a somewhat denser network of fibers in sublamina 5.     

Vertebrate intestinal endoderm development

The endoderm gives rise to the lining of the esophagus, stomach and intestines, as well as associated organs. To generate a functional intestine, a series of highly orchestrated developmental processes must occur. In this review, we attempt to cover major events during intestinal development from gastrulation to birth, including endoderm formation, gut tube growth and patterning, intestinal morphogenesis, epithelial reorganization, villus emergence, as well as proliferation and cytodifferentiation. Our discussion includes morphological and anatomical changes during intestinal development as well as molecular mechanisms regulating these processes. Developmental Dynamics 240:501–520, 2011. © 2011 Wiley‐Liss, Inc.     

Autoradiographic analysis of [3H]dopamine and [3H]dopa uptake in the turtle olfactory bulb

Uptake and retention of exogenous tritiated dopamine and L-dopa was observed within turtle olfactory bulb slices. In the more superficial layers, periglomerular and superficial tufted cells, as well as their processes, and intraglomerular dendrites were recognized as labeled. Within the deeper part of the bulb, some labeled cells between the tanycytes, as well as nerve fibers and terminals within the granule cell layer, are reported. The results confirm the presence of specific intrinsic dopaminergic cells within the reptilian olfactory bulb.     

The GM-CSF receptor family: Mechanism of activation and implications for disease

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pluripotent cytokine produced by many cells in the body, which regulates normal and malignant hemopoiesis as well as innate and adaptive immunity. GM-CSF assembles and activates its heterodimeric receptor complex on the surface of myeloid cells, initiating multiple signaling pathways that control key functions such as cell survival, cell proliferation, and functional activation. Understanding the molecular composition of these pathways, the interaction of the various components as well as the kinetics and dose-dependent mechanics of receptor activation provides valuable insights into the function of GM-CSF as well as the related cytokines, interleukin-3 and interleukin-5. This knowledge provides opportunities for the development of new therapies to block the action of these cytokines in hematological malignancy and chronic inflammation.     

Mindfulness‐based approaches: are they all the same?

Mindfulness-based approaches are increasingly employed as interventions for treating a variety of psychological, psychiatric and physical problems. Such approaches include ancient Buddhist mindfulness meditations such as Vipassana and Zen meditations, modern group-based standardized meditations, such as mindfulness-based stress reduction and mindfulness-based cognitive therapy, and further psychological interventions, such as dialectical behavioral therapy and acceptance and commitment therapy. We review commonalities and differences of these interventions regarding philosophical background, main techniques, aims, outcomes, neurobiology and psychological mechanisms. In sum, the currently applied mindfulness-based interventions show large differences in the way mindfulness is conceptualized and practiced. The decision to consider such practices as unitary or as distinct phenomena will probably influence the direction of future research.     

Much meat, much malady: changing perceptions of the epidemiology of hepatitis E

Hepatitis E, which is caused by hepatitis E virus (HEV), may now be considered a zoonosis as well as an anthroponosis. Pigs, boars and deer have been identified as reservoirs, and their flesh and entrails—as meat and offal—as vehicles of HEV transmission. Shellfish also act as vehicles. Dietary, gastronomic and culinary preferences influence how extensively HEV conveyed by these vehicles can be inactivated before their ingestion by the host. Another route of infection is paved by HEV that is enterically shed by humans and by live animals into the environment. Although anthroponotic transmission of HEV is primarily environmental, zoonotic transmission may proceed along both foodborne and environmental routes.     

Translational mini-review series on Toll-like receptors: Toll-like receptor ligands as novel pharmaceuticals for allergic disorders

Characterization of the Toll-like receptor (TLR) family and associated signalling pathways provides a key molecular basis for our understanding of the relationship between exposure to microbial products and susceptibility to immune-mediated disorders. Indeed, ligation of TLR controls innate and adaptive immune responses by inducing synthesis of pro- as well as anti-inflammatory cytokines and activation of effector as well as regulatory lymphocytes. TLRs are therefore considered as major targets for the development of vaccine adjuvants, but also of new immunotherapies. Herein, we review the potential of TLR ligands as a novel class of pharmaceuticals for the prevention or treatment of allergic disorders.     

Behavioral patterns proceeding from liver thermoreceptors

Subdiaphragmatic denervated, liver heated rats eat as much and as long as subdiaphragmatic denervated, non-heated rats. This points to vagus and/or splanchnic nerve afferentation from hepatic thermoreceptors. Left abdomen heated rats eat and drink as much as left abdomen non-heated rats. Since however they show some different behavior patterns, the intervention of other nerve fibers other than vagal and/or splanchnic fibers should be acknowledged in order to account for the different behavior pattern.     

葛根素对糖尿病大鼠白内障过程中晶状体诱导型一氧化氮合酶的影响

目的: 观察大鼠糖尿病性白内障(DC)晶状体诱导型一氧化氮合酶(iNOS)基因表达变化及葛根素对DC的治疗作用。方法: 经腹腔注射链脲佐菌素(STZ)复制大鼠DC模型。实验分为STZ组(STZ,45 mg/kg bw,ip)、葛根素组(STZ+葛根素,140 mg/kg bw ip)和对照组(等量生理盐水,ip),分别于实验第20、40、60 d摘取大鼠晶状体,用逆转录聚合酶链反应(RT-PCR)、蛋白印迹(Western blot)和生化方法检测晶状体iNOS mRNA和蛋白表达及一氧化氮(NO)含量、一氧化氮合酶(NOS)活性变化,观察晶状体损伤的宏观和微观病理变化。 结果:对照组大鼠晶状体透明,iNOS mRNA未见明显表达,蛋白呈微弱表达,NOS活性较低,NO含量较少。在DC形成过程中,晶状体出现混浊、晶状体上皮细胞(LEC)有明显病变,并随病程延长而加重;晶状体iNOS mRNA和蛋白表达明显上调,NOS活性增强、NO生成增加,并呈现时间依赖性。用药40-60 d时葛根素组前述晶状体病理变化轻于STZ组,iNOS mRNA和蛋白表达明显低于STZ组,NOS活性及NO 生成低于STZ组。结论: 在大鼠DC形成过程中晶状体iNOS 基因表达上调、NO含量增加;葛根素可减轻晶状体损伤,机制可能与抑制iNOS 基因表达、减少NO生成有关。     

Use of monoclonal antibodies to assess expression of anaphylatoxin receptors in rat and murine models of lung inflammation

The anaphylatoxins C3a and C5a are involved in the pathophysiology of microbial as well as allergic inflammation in the lungs. Besides their expression in leukocytes, receptors for C3a and C5a (C3aR and C5aR) have been noted in alveolar and bronchial epithelial cells, bronchial smooth muscle cells as well as in vascular endothelial and smooth muscle cells of normal and inflamed human and murine lungs. Recently, however, expression of anaphylatoxin receptors in parenchymal cells of the lung (and kidney) has been challenged. Using well-characterized monoclonal antibodies (mabs) against murine and rat anaphylatoxin receptors, we reexamined the pulmonary distribution of C3aR and C5aR. Immunohistochemistry was performed on frozen sections of lung tissues from normal mice and rats as well as from animals subjected to lipopolysaccharide (LPS)-induced inflammation or from MRL/lpr mice suffering from autoimmune disease. Furthermore, ovalbumin (OVA)-induced models of allergic asthma in the rat and mouse were investigated. Prominent expression of both anaphylatoxin receptors was detectable in resident as well as infiltrating leukocytes. No C3aR protein was observed in alveolar macrophages. Upon LPS- and OVA-challenge as well as in autoimmune inflammation, numbers of infiltrating leukocytes expressing prominent amounts of anaphylatoxin receptors increased. Even under these highly inflammatory conditions, however, expression of C3aR and C5aR was not inducible in parenchymal cells. Thus, our findings identify infiltrating leukocytes as a prominent source of anaphylatoxin receptors in inflamed lungs. A direct involvement of parenchymal cells in anaphylatoxin-mediated pulmonary inflammation is unlikely.