Single and combined inhibition of tumor necrosis factor,interleukin‐1, and RANKL pathways in tumor necrosis factor–induced arthritis: Effects on synovial inflammation,bone erosion,and cartilage destruction

Objective

To investigate the efficacy of single and combined blockade of tumor necrosis factor (TNF), interleukin‐1 (IL‐1), and RANKL pathways on synovial inflammation, bone erosion, and cartilage destruction in a TNF‐driven arthritis model.

Methods

Human TNF–transgenic (hTNFtg) mice were treated with anti‐TNF (infliximab), IL‐1 receptor antagonist (IL‐1Ra; anakinra), or osteoprotegerin (OPG; an OPG‐Fc fusion protein), either alone or in combinations of 2 agents or all 3 agents. Synovial inflammation, bone erosion, and cartilage damage were evaluated histologically.

Results

Synovial inflammation was inhibited by anti‐TNF (−51%), but not by IL‐1Ra or OPG monotherapy. The combination of anti‐TNF with either IL‐1Ra (−91%) or OPG (−81%) was additive and almost completely blocked inflammation. Bone erosion was effectively blocked by anti‐TNF (−79%) and OPG (−60%), but not by IL‐1Ra monotherapy. The combination of anti‐TNF with IL‐1Ra, however, completely blocked bone erosion (−98%). Inhibition of bone erosion was accompanied by a reduction of osteoclast numbers in synovial tissue. Cartilage destruction was inhibited by anti‐TNF (−43%) and was weakly, but not significantly, inhibited by IL‐1Ra, but was not inhibited by OPG monotherapy. The combination of anti‐TNF with IL‐1Ra was the most effective double combination therapy in preventing cartilage destruction (−80%). In all analyses, the triple combination of anti‐TNF, IL‐1Ra, and OPG was not superior to the double combination of anti‐TNF and IL‐1Ra.

Conclusion

Articular changes caused by chronic overexpression of TNF are not completely blockable by monotherapies that target TNF, IL‐1, or RANKL. However, combined approaches, especially the combined blockade of TNF and IL‐1 and, to a lesser extent, TNF and RANKL, lead to almost complete remission of disease. Differences in abilities to block synovial inflammation, bone erosion, and cartilage destruction further strengthen the rationale for using combined blockade of more than one proinflammatory pathway.

     

Factor XIII deficiency as a potential cause of supratentorial haemorrhage after posterior fossa surgery

Background  

Postoperative intracranial haemorrhage can be a dramatic event, carrying significant morbidity and mortality. Bleeding at sites remote from the operation area represents a small percentage of haemorrhages whose aetiology remains unclear (Harders et al. Acta Neurochir (Wien) 74(1-2):57–60, 1985).     

Inactivation of the deubiquitinase CYLD in hepatocytes causes apoptosis, inflammation, fibrosis, and cancer

The tumor suppressor cylindromatosis (CYLD) inhibits the NFκB and mitogen-activated protein kinase (MAPK) activation pathways by deubiquitinating upstream regulatory factors. Here we show that liver-specific disruption of CYLD triggers hepatocyte cell death in the periportal area via spontaneous and chronic activation of TGF-β activated kinase 1 (TAK1) and c-Jun N-terminal kinase (JNK). This is followed by hepatic stellate cell and Kupffer cell activation, which promotes progressive fibrosis, inflammation, tumor necrosis factor (TNF) production, and expansion of hepatocyte apoptosis toward the central veins. At later stages, compensatory proliferation results in the development of cancer foci featuring re-expression of oncofetal hepatic and stem cell-specific genes. The results demonstrate that, in the liver, CYLD acts as an important regulator of hepatocyte homeostasis, protecting cells from spontaneous apoptosis by preventing uncontrolled TAK1 and JNK activation.     

Barrier function and water-holding and transport properties of infant stratum corneum are different from adult and continue to develop through the first year of life

Skin water barrier development begins in utero and is believed to be complete by week 34 of gestational age. The goal of this investigation was to assess the dynamic transport and distribution of water of the stratum corneum of infants and compare it to those of adults. The interaction of water with the stratum corneum was assessed by measuring capacitance, transepidermal water loss (TEWL), rates of absorption-desorption as well as Raman spectra as a function of depth (a total of 124 infants (3-12 months) and 104 adults (14-73 years)). The results show that capacitance, TEWL, and absorption-desorption rates had larger values consistently for infant stratum corneum throughout the first year of life and showed greater variation than those of adults. The Raman spectra analyzed for water and for the components of natural moisturizing factor (NMF) showed the distribution of water to be higher and have a steeper gradient in infants than in adults; the concentration of NMF was significantly lower in infants. The results suggest that although the stratum corneum of infants may appear intact shortly after birth (<1 month), the way it stores and transports water becomes adult-like only after the first year of life.     

Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies

We addressed the impact of deleting TNF AU-rich elements (ARE) from the mouse genome on the regulation of TNF biosynthesis and the physiology of the host. Absence of the ARE affected mechanisms responsible for TNF mRNA destabilization and translational repression in hemopoietic and stromal cells. In stimulated conditions, TNF ARE were required both for the alleviation and reinforcement of message destabilization and translational silencing. Moreover, the mutant mRNA was no longer responsive to translational modulation by the p38 and JNK kinases, demonstrating that TNF ARE are targets for these signals. Development of two specific pathologies in mutant mice, i.e., chronic inflammatory arthritis and Crohn's-like inflammatory bowel disease, suggests that defective function of ARE may be etiopathogenic for the development of analogous human pathologies.     

Development of a brain nucleus involved in song production in zebra finches (Taeniopygia guttata) is disrupted by Aroclor 1248

We studied whether polychlorinated biphenyls (PCBs) may alter the development of song control brain nuclei in zebra finch (Taeniopygia guttata) offspring of pulse-exposed hens. We orally administered 40 microg of Aroclor 1248 to adult female finches before egg laying. When the progeny were 50 d old, we measured the volumes of the song control nuclei robustus arcopallialis (RA) and higher vocal center (HVC) using light microscopy. Both male and female progeny of exposed birds had a significantly smaller RA than control birds (36 and 16%, respectively; p < or = 0.05). The HVC did not differ in either sex between exposed and control groups. Perhaps impaired development of RA was caused by PCB action on steroid receptors. We conclude that animals living in contaminated areas may be at risk of neurological damage in hormone-sensitive brain areas and that changes in brain nuclei related to song may be a sensitive indicator of low-level PCB exposure.     

Evaluation der zentralen Hornhautbrechkraft nach myoper LASIK

PURPOSE: Comparison of the central corneal refractive power before and after myopic LASIK using the Keratograph and the Pentacam. The Scheimpflug technique (Pentacam) enables the measurement of the corneal refractive power by examining the anterior and posterior corneal curvature. METHOD: The corneal refractive power of 59 eyes was examined before, 3 months and 6 months after myopic LASIK. The refractive power was measured at the corneal apex and at a distance of 2 and 4 mm. Statistical analysis was performed using the Wilcoxon signed rank test; a p value of 0.05 or less was considered statistically significant. RESULTS: At the corneal apex and at a distance of 2 mm the findings with the Keratograph showed a higher refractive power of up to 1.05 D. The differences were statistically significant at all times. At a distance of 4 mm from the corneal apex postoperatively there was no statistically significant difference. CONCLUSION: The results using the Pentacam system showed a lower corneal refractive power following myopic LASIK at all times. Its measuring principle compared to that of the Keratograph should be preferred when detecting changes of the refractive power of the central cornea after corneal refractive procedures.     

The tissue distribution of Evans blue dye in a sheep model of sentinel node biopsy

BACKGROUND: Tc-Evans blue is a 'single dose' agent for lymphatic mapping combining radioactivity and blue dye for sentinel node identification. The mechanism and distribution of blue dye retention in the lymph node is not clearly understood. OBJECTIVE: To demonstrate the cellular distribution of Tc-Evans blue in sheep sentinel lymph nodes by measuring the radioactivity of different tissue components and correlating this with pathological examination. METHODS: Tc-Evans blue was used to identify sheep lymph nodes. Part of each node was sent for pathological examination including imprint cytology, and frozen and permanent section examination. Sections were examined without stains, with only red stains and conventional haematoxylin & eosin staining. The remaining nodal tissue was homogenized and components separated by enzymatic digestion and density gradient centrifugation. Fractions representing each tissue component were counted in a gamma counter and the distribution of Tc-Evans blue calculated. RESULTS: A dispersed population of blue staining cells was found. Their distribution, number and size indicated that they were histiocytes such as macrophages or antigen presenting cells. Radioactivity was distributed throughout the lymph node. Over 70% remained in the plasma, 19% in the leukocyte layer, and 10% was associated with erythrocytes and undigested tissue. CONCLUSION: The accumulation of radioactivity and blue colour in the lymph nodes indicates the mechanism of retention is a result of the binding interaction between Tc-Evans blue-protein and lymph node histiocytes including macrophages and antigen presenting cells.