Kupffer cell cytotoxicity to hepatocytes in coculture requires L-arginine

Activated macrophages convert L-arginine to citrulline and unstable nitrogen oxides that have cytotoxic properties. We recently have shown that the inhibition of protein synthesis in Kupffer cell (KC):hepatocyte (HC) coculture, following exposure to gram-negative bacterial endotoxin (lipopolysaccharide), is due to the metabolism of L-arginine by this cytotoxic pathway. Although this finding supports a role for activated KCs and the L-arginine-dependent mechanism in the HC dysfunction seen in sepsis, it and previous studies have failed to demonstrate direct damage to HCs by adjacent KCs. The current study was undertaken to determine if KCs exposed to lipopolysaccharide could directly damage HCs and, if so, whether the damage was dependent on the metabolism of L-arginine. By using the release of aspartate aminotransferase as a marker of HC damage, it was found that a significant aspartate aminotransferase release by KC:HC cocultures in response to lipopolysaccharide occurred only if L-arginine was present. In addition, requirements for significant aspartate aminotransferase release included KC:HC ratios of 7.5:1 or greater and L-arginine concentrations of 1 mmol or more. Although the KC-induced damage was mild, these results show that in vitro HC damage in KC:HC coculture does require the metabolism of L-arginine and supports a hypothesis that toxic L-arginine metabolites may contribute to liver cell damage in patients with sepsis.     

Reflectance confocal microscopy of facial lentigo maligna and lentigo maligna melanoma: a preliminary study

Background Facial lentigo maligna (LM) and lentigo maligna melanoma (LMM) may be difficult to diagnose clinically and dermoscopically. Reflectance confocal microscopy (RCM) enables the in vivo assessment of equivocal skin lesions at a cellular level. Objectives To assess cytomorphological and architectural RCM features of facial LM/LMM. Methods Four women and eight men aged 58–88 years presenting with facial skin lesions suspicious of LM/LMM were included. In total, 17 lesion areas were imaged by RCM before biopsy. The histopathological diagnosis of LM was made in 15 areas; the other two were diagnosed as early LMM. Results A focal increase of atypical melanocytes and nests surrounding adnexal openings, sheets of mainly dendritic melanocytes, cord‐like rete ridges at the dermoepidermal junction (DEJ) and an infiltration of adnexal structures by atypical melanocytes were found to be characteristic RCM features of facial LM/LMM. Areas with a focal increase of atypical melanocytes and nests surrounding adnexal openings were observed at the basal layer in three cases. The remaining cases displayed these changes at suprabasal layers above sheets of mainly dendritic melanocytes. Cord‐like rete ridges at the DEJ and an infiltration of adnexal structures by atypical melanocytes were observed in all cases. Previously described criteria for RCM diagnosis of melanoma, such as epidermal disarray, pleomorphism of melanocytes and pagetoid spreading of atypical melanocytes, were additionally observed. Conclusions We observed a reproducible set of RCM criteria in this case series of facial LM/LMM.     

Results of a survey of German dermatologists on the therapeutic approaches to pemphigus and bullous pemphigoid

Background: The lack of controlled trials on the treatment of pemphigus and pemphigoid diseases limits an evidence‐based therapy of these disorders.The aim of this survey was to assess the current treatment standards at German dermatological hospitals and the need for future therapeutic trials. Methods: A two‐page questionnaire was sent to 42 German academic and non‐academic dermatological hospitals and evaluated at the Department of Dermatology, University Medical Center, Freiburg. Results: The response rate was 76%. Topical clobetasol propionate treatment was regarded as first line therapy of bullous pemphigoid in 27% of the hospitals. More than 50% used systemic corticosteroids at an initial dose of ≤ 1 mg/kg prednisolone‐equivalent in pemphigus and pemphigoid. Azathioprine is used as first line adjuvant in pemphigoid and pemphigus treatment in 69% and 81% of the hospitals, respectively. Dapsone and mycophenolate mofetil represent alternative options, as well as cyclophosphamide‐dexamethasone‐pulse therapy in pemphigus. Immunosuppressive treatment of pemphigoid and pemphigus is terminated by 58% and 46% of the hospitals 1–3 months after clinical remission, respectively, but the given time points appeared to be variable. Conclusions: The high response rate to this survey demonstrates the interest in this topic. The variability of the answers regarding initial doses of corticosteroids and time points for termination of therapy indicates the need for the establishment of guidelines and for controlled therapeutic trials.     

Role of matrix-degrading enzymes in melanoma progression

Cutaneous melanoma is an invasive and early metastazising tumor. Melanoma cells detach from the primary tumor, penetrate the basement membrane, invade lymphatics and blood vessels, and form metastases. These processes all depend on coordinated expression and/or activation of proteolytic enzymes. In addition to aspartyl- and cysteineproteinases, serine proteinases including the plasminogen activator system (uPA, uPAR, tPA, PAI-1 and PAI-2) and matrix metalloproteinases (MMPs) with their tissue inhibitors (TIMPs) play an essential role in these processes. In addition, melanoma cells require specific adhesion molecules such as integrins and CD44 for interaction with other cells and components of the extracellular matrix (ECM); these are also involved in binding activated MMPs on the cell surface. In this review we discuss these functional aspects of melanoma progression.     

“骨玄府”理论初探

玄府狭义指汗孔,广义指孔、窍、道等一类具有运行气机、流通津液、渗灌血脉、运转神机功能的微细结构。完善\"骨玄府\"理论假说,认为骨骼中的孔、窍、道等空腔结构以及形态各异的血管、淋巴管是骨玄府的结构基础。骨膜、骨质、骨髓中的骨玄府具有运行气血、滋养骨骼、沟通内外、支撑运动的生理功能以及易于郁滞、易于折损、易于疏松、难于恢复的病理特点。试从骨膜、骨质、骨髓三方面对骨玄府理论进行初步探讨,以期为进一步认识骨与关节疾病的发病机理提供理论依据,为临床治疗提供新思路。     

α,ωn‐Heterotelechelic Hyperbranched Polyethers Solubilize Carbon Nanotubes

The synthesis of novel linear‐hyperbranched (linhb) polyether block copolymers based on poly(ethylene oxide) and branched poly(glycerol), bearing a single pyrene or myristyl moiety at the α‐position of the linear chain is described. The polymers exhibit low polydispersity ( < 1.3) and controlled molecular weights ( = 5 000 g · mol^?1). The mainly hydrophilic block copolymers with multiple hydroxyl end groups readily dissolve multiwalled carbon nanotubes (MWCNTs) in water by mixing and subsequent sonification, resulting in noncovalent attachment of the linhb hybrid structure to the carbon nanotubes (CNTs). Transmission electron microscopy (TEM) was employed to visualize the solubilized nanotubes; after sulfation of the multiple hydroxyl groups the polymer layer was detected in the TEM images.

     

How do visual,spectroscopic and biomechanical changes of cartilage correlate in osteoarthritic knee joints?

Background

Characteristic changes in cartilage of human knee joints with different degrees of osteoarthritis (OA) have been investigated by visual, biophotonical and biomechanical examination. Knowledge about the cartilage composition and changes during the development of OA is important for diagnostic decisions and understanding the pathogenesis of OA.

Methods

Thirty two patients with severe knee OA received endoprosthetic replacement. During surgical intervention cartilage specimen were harvested from defined surface areas of the joints. The degree of cartilage defects was classified visually (ICRS Grade: International Cartilage Repair Society), biophotonically (NIRS: near infrared spectroscopy) and biomechanically (Young’s Modulus). To characterise links between the investigated parameters the Spearman’s rank correlation coefficient was used.

Findings

Significant negative correlations were found between visual macroscopic degree of degeneration (ICRS Grade) and biophotonic characteristics (NIRS) (ρ = −0.467) or cartilage stiffness (Young’s Modulus) (ρ = −0.501). Between NIRS and Young’s Modulus significant positive correlation of ρ = 0.535 was detected.

Interpretation

Visual, biophotonic and biomechanical properties of cartilage reveal strong correlations in all degrees of cartilage defects in patients with severe OA. According to these results, we indicate that an objective, non-invasive and non-destructive measurement of cartilage properties during open and arthroscopic knee surgery is possible by NIRS and provide a novel tool to evaluate disease intervention and treatment.