Lack of association between glucocorticoid use and presence of the metabolic syndrome in patients with rheumatoid arthritis: a cross-sectional study

Lupus nephritis is a major contributor to morbidity and mortality in systemic lupus erythematosus, but little is known about the pathogenic processes that underlie the progressive decay in renal function. A common finding in lupus nephritis is thickening of glomerular basement membranes associated with immune complex deposition. It has been speculated that alterations in the synthesis or degradation of membrane components might contribute to such changes, and thereby to initiation and progression of nephritis through facilitation of immune complex deposition. Matrix metalloproteinases (MMPs) are enzymes that are intimately involved in the turnover of major glomerular basement membrane constituents, including collagen IV and laminins. Alterations in the expression and activity of MMPs have been described in a number of renal diseases, suggesting their relevance to the pathogenesis of various glomerulopathies. The same is true for their natural inhibitors, the tissue inhibitor of metalloproteinase family. Recent data from our group have identified an increase in proteolytic activity within the glomerulus coinciding with the development of proteinuria in the mouse model of systemic lupus erythematosus. (NXB × NZW)F₁ Here we review current understanding of MMP/tissue inhibitor of metalloproteinase function within the kidney, and discuss their possible involvement in the development and progression of lupus nephritis.     

Altered stomatal dynamics in ascorbate oxidase over-expressing tobacco plants suggest a role for dehydroascorbate signalling

Control of stomatal aperture is of paramount importance forplant adaptation to the surrounding environment. Here, we reporton several parameters related to stomatal dynamics and performancein transgenic tobacco plants (Nicotiana tabacum L., cv. Xanthi)over-expressing cucumber ascorbate oxidase (AO), a cell wall-localizedenzyme of uncertain biological function that oxidizes ascorbicacid (AA) to monodehydroascorbic acid which dismutates yieldingAA and dehydroascorbic acid (DHA). In comparison to WT plants,leaves of AO over-expressing plants exhibited reduced stomatalconductance (due to partial stomatal closure), higher watercontent, and reduced rates of water loss on detachment. Transgenicplants also exhibited elevated levels of hydrogen peroxide anda decline in hydrogen peroxide-scavenging enzyme activity. LeafABA content was also higher in AO over-expressing plants. Treatmentof epidermal strips with either 1 mM DHA or 100 µM hydrogenperoxide resulted in rapid stomatal closure in WT plants, butnot in AO-over-expressing plants. This suggests that signalperception and/or transduction associated with stomatal closureis altered by AO over-expression. These data support a specificrole for cell wall-localized AA in the perception of environmentalcues, and suggest that DHA acts as a regulator of stomatal dynamics. Key words: ABA, apoplast, ascorbic acid, ascorbate oxidase, dehydroascorbic acid (DHA), hydrogen peroxide, Nicotiana tabacum L., cv. Xanthi, stomata, transgenic plants, water stress Received 26 September 2007; Revised 11 December 2007 Accepted 12 December 2007     

Critical synergy of CD30 and OX40 signals in CD4 T cell homeostasis and Th1 immunity to Salmonella

CD30 and OX40 (CD134) are members of the TNFR superfamily expressed on activated CD4 T cells, and mice deficient in both these molecules harbor a striking defect in the capacity to mount CD4 T cell-dependent memory Ab responses. This article shows that these mice also fail to control Salmonella infection because both CD30 and OX40 signals are required for the survival but not commitment of CD4 Th1 cells. These signals are also needed for the survival of CD4 T cells activated in a lymphopenic environment. Finally, Salmonella and lymphopenia are shown to act synergistically in selectively depleting CD4 T cells deficient in OX40 and CD30. Collectively these findings identify a novel mechanism by which Th1 responses are sustained.     

Ly49H+ NK cells migrate to and protect splenic white pulp stroma from murine cytomegalovirus infection

In this study, we show that in the absence of a protective NK cell response, murine CMV causes destruction of splenic white and red pulp pulp areas in the first few days of infection. Destruction of T zone stroma is associated with almost complete loss of dendritic cells and T cells. We provide evidence that the virus replicates in red and white pulp stroma in vivo and in vitro. Control of white pulp viral replication is associated with migration of murine CMV-specific activated NK cells to white pulp areas, where they associate directly with podoplanin-expressing T zone stromal cells. Our data explain how NK cells protect the lymphoid-rich white pulp areas from CMV, allowing protective adaptive T cell-dependent immune responses to develop, and how this mechanism might break down in immunocompromised patients.     

Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium

Tumor progression alters the composition and physical properties of the extracellular matrix. Particularly, increased matrix stiffness has profound effects on tumor growth and metastasis. While endothelial cells are key players in cancer progression, the influence of tumor stiffness on the endothelium and the impact on metastasis is unknown. Through quantitative mass spectrometry, we find that the matricellular protein CCN1/CYR61 is highly regulated by stiffness in endothelial cells. We show that stiffness‐induced CCN1 activates β‐catenin nuclear translocation and signaling and that this contributes to upregulate N‐cadherin levels on the surface of the endothelium, in vitro. This facilitates N‐cadherin‐dependent cancer cell–endothelium interaction. Using intravital imaging, we show that knockout of Ccn1 in endothelial cells inhibits melanoma cancer cell binding to the blood vessels, a critical step in cancer cell transit through the vasculature to metastasize. Targeting stiffness‐induced changes in the vasculature, such as CCN1, is therefore a potential yet unappreciated mechanism to impair metastasis.     

The surgical treatment of brachial plexus injuries in adults

LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Evaluate clinically a patient with brachial plexus paralysis and define the appropriate electrophysiologic and radiographic studies. 2. Differentiate between preganglionic (root) avulsion and postganglionic lesions and identify appropriate motor donors and nerve grafts. 3. Describe various nerve reconstructive strategies and make appropriate selection of secondary procedures for shoulder stability, elbow flexion, and hand reanimation. 4. Anticipate the possible functional outcome.     

Side‐chain interactions in the regulatory domain of human glutamate dehydrogenase determine basal activity and regulation

Glutamate Dehydrogenase (GDH) is central to the metabolism of glutamate, a major excitatory transmitter in mammalian central nervous system (CNS). hGDH1 is activated by ADP and L‐leucine and powerfully inhibited by GTP. Besides this housekeeping hGDH1, duplication led to an hGDH2 isoform that is expressed in the human brain dissociating its function from GTP control. The novel enzyme has reduced basal activity (4–6% of capacity) while remaining remarkably responsive to ADP/L‐leucine activation. While the molecular basis of this evolutionary adaptation remains unclear, substitution of Ser for Arg443 in hGDH1 is shown to diminish basal activity (< 2% of capacity) and abrogate L‐leucine activation. To explore whether the Arg443Ser mutation disrupts hydrogen bonding between Arg443 and Ser409 of adjacent monomers in the regulatory domain (‘antenna’), we replaced Ser409 by Arg or Asp in hGDH1. The Ser409Arg‐1 change essentially replicated the Arg443Ser‐1 mutation effects. Molecular dynamics simulation predicted that Ser409 and Arg443 of neighboring monomers come in close proximity in the open conformation and that introduction of Ser443‐1 or Arg409‐1 causes them to separate with the swap mutation (Arg409/Ser443) reinstating their proximity. A swapped Ser409Arg/Arg443Ser‐1 mutant protein, obtained in recombinant form, regained most of the wild‐type hGDH1 properties. Also, when Ser443 was replaced by Arg443 in hGDH2 (as occurs in hGDH1), the Ser443Arg‐2 mutant acquired most of the hGDH1 properties. Hence, side‐chain interactions between 409 and 443 positions in the ‘antenna’ region of hGDHs are crucial for basal catalytic activity, allosteric regulation, and relative resistance to thermal inactivation.