Aging and uremia: Is there cellular and molecular crossover?

Many observers have noted that the morphological changes that occur in chronic kidney disease(CKD) patients resemble those seen in the geriatric population, with strikingly similar morbidity and mortality profiles and rates of frailty in the two groups, and shared characteristics at a pathophysiological level especially in respect to the changes seen in their vascular andimmune systems. However, whilst much has been documented about the shared physical characteristics of aging and uremia, the molecular and cellular similarities between the two have received less attention. In order to bridge this perceived gap we have reviewed published research concerning the common molecular processes seen in aging subjects and CKD patients, with specific attention to altered proteostasis, mitochondrial dysfunction, post-translational protein modification, and senescence and telomere attrition. We have also sought to illustrate how the cell death and survival pathways apoptosis, necroptosis and autophagy are closely interrelated, and how an understanding of these overlapping pathways is helpful in order to appreciate the shared molecular basis behind the pathophysiology of aging and uremia. This analysis revealed many common molecular characteristics and showed similar patterns of cellular dysfunction. We conclude that the accelerated aging seen in patients with CKD is underpinned at the molecular level, and that a greater understanding of these molecular processes might eventually lead to new much needed therapeutic strategies of benefit to patients with renal disease.     

Mast cell-derived TNF-α and histamine modify IL-6 and IL-8 expression and release from cutaneous tumor cells

Abstract: The coincidence of skin tumors and elevated mast cell (MC) numbers has been known for many years. However, it has remained controversial whether, in this context, MCs promote or inhibit tumor growth. Addressing this problem, different melanoma and squamous cell carcinoma cell lines were co‐cultivated with primary, dermal MC for 24 h and gene or protein expression of cytokines tumor necrosis factor (TNF‐α), interleukin‐6 (IL‐6) and interleukin‐8 (IL‐8) estimated. Co‐culture with MCs led to an increase in IL‐8 gene expression and IL‐8 protein release from melanoma cells and IL‐6 and IL‐8 gene expression and protein release from squamous cell carcinoma cells, respectively. Moreover induction of IL‐6 and IL‐8 was primarily regulated by MC‐derived TNF‐α. Our data suggest an interplay between MCs and tumor cells, which results in altered cytokine release and may, thus, have an impact on tumor growth, invasion and neovascularisation.     

Differential itch- and pain-related behavioral responses and µ-opoid modulation in mice

Intradermal microinjection of the pruritogen histamine, or the algogen capsaicin, in the mouse cheek differentially elicits mainly hindlimb scratching or ipsilateral forelimb wiping, respectively. We investigated the dose-dependency of these responses elicited by various pruritogens and algogens, and μ-opioid modulation. Histamine, 5-hydro-xytryptamine (5-HT) and agonists of protease-activated receptors PAR-2 and PAR-4, all elicited dose-related hindlimb scratching bouts with little forelimb wiping. In contrast, capsaicin, allyl isothiocyanate and bradykinin elicited dose-related forelimb wiping with little scratching. Morphine reduced capsaicin-evoked wiping but not pruritogen-evoked scratching. The μ-antagonist naltrexone decreased pruritogen-evoked scratching but not capsaicin-evoked wiping. A cowhage spicule inserted intradermal elicited equivalent scratching and wiping, while inactivated cowhage spicules loaded with histamine or capsaicin elicited significantly more scratching or wiping, respectively. The mouse cheek injection model appears to be a useful behavioral test that distinguishes between itch and pain.     

Clinical,microbiological, immunological and imaging characteristics of tunnels and fistulas in hidradenitis suppurativa and Crohn’s disease

Hidradenitis suppurativa (HS) tunnels and Crohn's disease (CD) fistulas are a challenge to treat. Although pathogenic similarities have been described between HS and CD, recent studies indicate that clinical, microbiological, immunological and imaging characteristics differ between these diseases. This review highlights the differences between HS tunnels and CD fistulas. Next-generation sequencing studies demonstrate a microbiome in HS tunnels dominated by Porphyromonas spp., Prevotella spp. whereas no specific bacteria have been associated with cutaneous CD. Immunologically, TNF has been found upregulated in HS tunnels along with various interleukins (IL-8, IL-16, IL-1α and IL-1β). In CD fistulas, Th1, Th17, IL-17, IFN-ɤ, TNF and IL-23 are increased. US imaging is an important tool in HS. US of HS tunnels depict hypoechoic band-like structure across skin layers in the dermis and/or hypodermis connected to the base of a widened hair follicle. In CD, MR imaging of simple perianal fistulas illustrates a linear, non-branching inflammatory tract relating to an internal opening in the anus or low rectum and an external opening to the skin surface. An increased awareness of the immediate potential differences between HS tunnels and CD fistulas may optimize treatment regimens of these intractable skin manifestations.     

Breastfeeding and atopic dermatitis: protective or harmful? facts and controversies

Conventional wisdom posits that breastfeeding during the first 4 months of life generally reduces the incidence of atopic dermatitis in the child. Recent studies question this truism, especially in cases when the mother herself is allergic. Studies about maternal dietary allergens in breast milk and their influence on atopic dermatitis have been questioned as well. There is evidence that probiotic and essential fatty acid supplementation, along with an allergen-avoidance diet, may reduce the chance of maternal dietary allergens provoking atopic dermatitis in the infant. Evidence on both sides of the controversy is presented in an effort to produce meaningful guidelines for breastfeeding infants at risk for atopic dermatitis.     

评介《Color Atlas and Synopsis of Blistering and Pustular Diseases》

喜读人民卫生出版社出版发行的(水疱性与脓疱性皮肤病的彩色图谱与概要).该书是由中国医学科学院皮肤病医院靳培英教授主编.靳教授治学严谨,博览群书,医术高明,患者至上,是中国医学科学院的十大名医之一.靳教授从医五十余载,特别对大疱性及脓疱性皮肤病有很深的造诣,本书是她丰富临床经验的概括与总结.全书内容翔实、文字简洁,图文并茂、印刷精良,对自身免疫性大疱性皮肤病及遗传性大疱性皮肤病均有精辟的论述,此外,对各类临床上以水疱、大疱及脓疱为特点的皮肤病也都作了介绍,使本书具有很高的可读性及实用性.     

Psoriasis and psoriatic arthritis: separate or one and the same?

The presence and severity of skin and joint symptoms in patients with psoriasis and psoriatic arthritis frequently do not correspond, a discrepancy that has raised the question of whether they represent two related but different disease processes. The fact that some agents seem to work preferentially in one state over the other reinforces this idea. However, there are also several agents with combined efficacy against cutaneous and articular inflammation that appear to support the existence of a common aetiology. Here we review the clinical, epidemiological and genetic evidence for and against a common pathogenesis for the two diseases. We then discuss the cellular and molecular targets of their selected therapies and how they potentially implicate effector pathways as a common immunopathogenic mechanism. Finally, we examine a recently proposed model of psoriasis pathogenesis involving type 1 interferon-producing plasmacytoid dendritic cells and how it may provide further clues to the aetiological links between psoriasis and psoriatic arthritis.     

NAAT-identified and self-reported gonorrhea and chlamydial infections: different at-risk population subgroups?

BACKGROUND: Information on the characteristics and behaviors of persons at high risk for gonorrhea and chlamydial infection has typically been derived from studies of sexually transmitted disease (STD) clinic populations. The Baltimore STD and Behavior Survey (BSBS) used urine-based nucleic acid amplification testing (NAAT) to assess the prevalence and behavioral correlates of gonorrhea and chlamydial infection in a population-based cross-sectional survey of adults in Baltimore, Maryland. GOAL: The goal of this study was to examine the demographic characteristics and behavioral markers of gonorrhea and chlamydial infection as reported by adults with a self-reported history of gonorrhea and chlamydial infection and to compare these to the characteristics and behaviors of individuals with current NAAT-identified gonorrhea and/or chlamydial infection. STUDY DESIGN: A probability sample of adults aged 18 to 35 years residing in Baltimore was evaluated with collection of urine specimens and administration of a health and behavior survey. Data and specimens were collected between January 1997 and September 1998. RESULTS: Respondents with NAAT-detected gonorrhea and/or chlamydial infection (7.9%) did not report a history of high-risk behaviors or more recent occurrences of those behaviors, and the majority were asymptomatic. However, adults in our study who self-reported a history of infection (26.0%) were more likely than those with no history of infection to report multiple partners, paid sex, partners with prior STDs, and STD symptoms-a pattern consistent with findings described in previous clinic-based reports. CONCLUSION: The risk profile generated from studies of clinic populations, with a focus on symptomatic disease, may not characterize the broader population with current, untreated, largely asymptomatic infection.     

Expression of IFNγ, coexpression of TNFα and matrix metalloproteinases and apoptosis of T lymphocytes and macrophages in granuloma annulare

Abstract Granuloma annulare, a prototype noninfectious granulomatous dermatitis, is morphologically characterized by a necrobiotic core surrounded by a cellular infiltrate. Because of many morphological similarities to tuberculosis, granuloma annulare has been suggested to represent a delayed-type hypersensitivity (Th1) reaction in the course of which inflammatory cells elicit matrix degradation. In the present study we (1) investigated the expression of interferon-á as the most important Th1-associated cytokine, (2) sought in situ evidence for the coexpression of the proinflammatory cytokine tumor necrosis factor-· and cytokine-regulated matrix metalloproteinases 2 (gelatinase A) and 9 (gelatinase B), and (3) sought to determine whether shrunken cells seen within necrobiotic areas of granuloma annulare are apoptotic cells. In situ hybridization combined with immunofluorescence showed that large numbers of infiltrating CD3⁺ lymphocytes express interferon-á. Application of catalyzed signal amplification in immunodetection revealed that the vast majority of CD3⁺ lymphocytes and CD68⁺ macrophages contained tumor necrosis factor-·. Immunohistochemistry demonstrated that macrophages producing tumor necrosis factor-· coexpress matrix metalloproteinases 2 and 9. In situ end-labeling combined with immunofluorescence detected few apoptotic T cells in perivascular regions and numerous apoptotic macrophages within necrobiotic areas. These results suggest that in granuloma annulare interferon-á⁺ Th-1 lymphocytes may cause a delayed-type hypersensitivity reaction whereby macrophages are differentiated to aggressive effector cells expressing tumor necrosis factor-α and matrix metalloproteinases. In parallel, activation-induced apoptosis in lymphocytes and macrophages may serve to restrict the destructive potential of the inflammatory cells. Received: 23 November 1999 / Received after revision: 28 March 2000 / Accepted: 14 April 2000     

Clinical and pathological features of 31 cases of lipedematous scalp and lipedematous alopecia

Little is known about lipedematous scalp (LS) and lipedematous alopecia (LA). We investigated the clinical and histopathological features of LS and LA with a 7-year retrospective re-evaluation of 31 patients. 23 cases were LS and 8 LA, with 25 females and 6 males. The overweight and obese groups contained 15 patients with 16 within the normal weight range. Scalp thickness varied between 9-18 mm in our patients by magnetic resonance imaging. Thickening of the subcutaneous adipose tissue layer was present in all cases. Dermal edema was seen in 22 patients, lymphatic dilatation in 17 and elastic fiber fragmentation in 21. When the relationship between dermal edema and elastic fibers was investigated, elastic fiber fragmentation was found in 86.4% of cases with dermal edema. Collagen fragmentation and coarsening were seen in two cases, and collagen was normal in 24 cases. The number of follicles was decreased in 9 cases and normal in 17. The clinical and histopathological findings were not statistically different between LS and LA groups (p>0.05). The majority of the patients in our study were females, suggesting an underlying hormonal pathology. The association with obesity suggested that anatomical differences can be present in lipid distribution. Dermal edema and lymphatic dilatation suggested the primary pathology is lymphatic system.     

Mycosis fungoides and Sézary syndrome: Role of chemokines and chemokine receptors

Mycosis fungoides is the most common form of cutaneous T-cell lymphoma(CTCL), and is characterized by a clonal expansion of malignant CD4+ T lymphocytes with skinhoming properties. Clinically and pathologically, mycosis fungoides can be categorized into patch, plaque and tumor stages. The clinical course of mycosis fungoides is usually chronic and indolent, but a proportion of patients may develop progressive disease with peripheral blood, lymph node and visceral organ involvement. Sézarysyndrome is an aggressive leukemic form of CTCL characterized by a clonal population of malignant T cells in the peripheral blood. Various forms of skin-directed and systemic treatments are available for mycosis fungoides and Sézary syndrome. However, current treatments are generally not curative, and can only control the disease. Currently, the etiology and pathogenesis of mycosis fungoides and Sézary syndrome are not well defined. Proposed mechanisms include chronic antigenic stimulation by infectious agents, expression of specific adhesion molecules, altered cytokine production, mutations of oncogenes and tumor suppressor genes, and avoidance of apoptosis. In recent years, a number of chemokine receptors and their corresponding chemokine ligands have been found to contribute to the migration and survival of lymphoma cells in mycosis fungoides and Sézary syndrome, including CC chemokine receptor 4(CCR4), CCR10, C-X-C chemokine receptor type 4(CXCR4), CCR7, CCR3 and CXCR3. Since chemokines and chemokine receptors have been found to play important roles in the pathophysiology of mycosis fungoides and Sézary syndrome, they may be potentially useful targets for the development of new treatments for these diseases in the future.     

Immunohistological and immunoelectron microscopic identification of TNFα in normal human and murine epidermis

Summary The presence, distribution and cellular localization of tumour necrosis factor-alpha (TNF) were investigated in normal human and murine epidermis using immunohistological and immunoelectron microscopic methods with monoclonal and polyclonal antibodies. The immunostaining revealed an intercellular plasma membrane and cytoplasmic labelling of the epidermal keratinocytes, but no labelling of Langerhans cells, melanocytes and Merkel cells. Large amounts of TNF were regularly found in the sebaceous glands. These findings demonstrate that epidermal keratinocytes and especially sebocytes produce and release TNF and that this keratinocytederived cytokine may be important for the structural and functional homeostasis of normal epidermis.Presented in part at the 18th annual meeting of the Arbeitsge-meinschaft Dermatologische Forschung (ADF), Mannheim, 9–11 November 1990     

Levels of matrix metalloproteinase-2, −9 and −8 in the skin,serum and saliva of smokers and non-smokers

Smoking induces skin ageing, affects wound healing and inflammatory responses in skin and mucous membranes but the mechanisms behind these adverse effects of smoking are not clear. The objective was to elucidate the mechanisms of smoking-related tissue damage, by comparing the levels of matrix metalloproteinases (MMPs) −2, −9, and −8 in the skin, serum and saliva of smokers and non-smokers. The study population consisted of 47 current smokers and 51 non-smokers, all males of Finnish origin. Skin samples from the upper inner arm were frozen in liquid nitrogen. Levels of MMP-2 and MMP-9 protein in the skin were assessed by zymography and MMP-8 isoforms were determined by Western blotting. From the serum samples, MMP-2 and MMP-9 were assessed by zymography and MMP-8 levels by time-resolved immunofluorometric assay (IFMA). From the salivary samples, MMP-8 levels were analysed by IFMA and MMP-9 levels by capture activity assay. In skin tissue, lower levels of both the pro and active forms of MMP-9 and of the active forms of MMP-8 were found in the smokers compared to the non-smokers. In serum, higher levels of proMMP-2 and proMMP-9 were found in the smokers compared to the non-smokers (P=0.001 and P<0.001, respectively), whereas MMP-8 levels did not differ significantly between the groups. Active forms of MMP-9 and MMP-2 could not be found in serum. In saliva, the amount of total MMP-9 was significantly lower in the smokers (156.0 U/ml) compared to the non-smokers (223.9 U/ml, P=0.032), whereas the levels of MMP-8 or active MMP-9 did not differ significantly between the groups. We conclude that smoking alters the levels of matrix metalloproteinases in skin tissue, serum and saliva, which may affect the turnover of extracellular matrix of skin even though the clinical impact of our findings is not clear.     

Erythrocyte superoxide dismutase, catalase activities and plasma nitrite and nitrate levels in patients with Behçet disease and recurrent aphthous stomatitis

Behçet disease (BD) and recurrent aphthous stomatitis (RAS) are two distinct diseases of unknown aetiology which are both characterized by oral aphthae. The aim of this study was to determine the possible association of both diseases with antioxidant status and nitric oxide levels. Twenty‐six patients (17 female, nine male) with RAS, 28 patients (17 female, 11 male) with BD and 31 (22 female, nine male) healthy control subjects were included in the study. Blood samples were studied for erythrocyte superoxide dismutase (SOD) and catalase (CAT) activities and plasma nitric oxide (NO) levels. Erythrocyte SOD activity in BD patients was significantly higher than in RAS patients and controls. Although SOD activity in RAS patients was higher than in controls, the difference was not statistically significant. No significant differences in CAT activities or NO levels were found between the three groups. In conclusion, changes in SOD activity may be important in the inflammatory reactions observed in BD and RAS, but NO does not seem to play a primary role in the aetiopathogenesis.