Azathioprine and allopurinol: a potentially dangerous combination

We report the association of leucopenia and anaemia in five patients given a combination of azathioprine and allopurinol. Three subjects were renal transplant recipients with mild to moderate impairment of graft function. The complication appeared between 4 and 6 weeks following initiation of the combination therapy. Discontinuation of one of the two drugs resulted in full recovery within 4-8 weeks.     

Modified epinucleus pre-chop for the dense posterior polar cataract.

A novel technique for the surgical management of dense posterior polar cataracts is described. In instances where hydrodelineation may be difficult to achieve due to the density of the nucleus, the anterior epinucleus is first pre-chopped in a piecemeal in situ maneuver before mobilizing, segmenting, and emulsifying the dense endonucleus. This is followed by the removal of the posterior epinucleus and the posterior polar plaque. Because the chopper is repositioned at different meridians in the mid-periphery of the anterior epinucleus, it stops short of the central posterior epinucleus, thus avoiding extension of the crack toward the posterior polar plaque and the posterior capsule.     

Synergy between a plasminogen cascade and MMP-9 in autoimmune disease

Extracellular proteolysis by the plasminogen/plasmin (Plg/plasmin) system and MMPs is required for tissue injury in autoimmune and inflammatory diseases. We demonstrate that a Plg cascade synergizes with MMP-9/gelatinase B in vivo during dermal-epidermal separation in an experimental model of bullous pemphigoid (BP), an autoimmune disease. BP was induced in mice by antibodies to the hemidesmosomal antigen BP180. Mice deficient in MMP-9 were resistant to experimental BP, while mice deficient in Plg and both tissue Plg activator (tPA) and urokinase Plg activator (uPA) showed delayed and less intense blister formation induced by antibodies to BP180. Plg-deficient mice reconstituted locally with Plg or the active form of MMP-9 (actMMP-9), but not the proenzyme form of MMP-9 (proMMP-9), developed BP. In contrast, proMMP-9 or actMMP-9, but not Plg, reconstituted susceptibility of MMP-9-deficient mice to the skin disease. In addition, MMP-3-deficient mice injected with pathogenic IgG developed the same degree of BP and expressed levels of actMMP-9 in the skin similar to those of WT controls. Thus, the Plg/plasmin system is epistatic to MMP-9 activation and subsequent dermal-epidermal separation in BP.     

Identification of national trends in nursing education through the use of an online survey

Increased access and familiarity with computer technology has enhanced research data collection and analysis processes. Use of the Internet in these processes is rapidly becoming an alternative to traditional paper and pencil methods and can be a useful tool in conducting nursing education research. The purpose of this article is to discuss the use of online survey methodologies to identify nursing education trends and disseminate information nationwide. Advantages, disadvantages and pitfalls of using e-mail in conducting a Web-based survey are presented. The authors describe relevant aspects of developing and implementing an online survey; relate their experience in using this survey method with regard to its strengths and limitations; and, comment regarding efficacy of electronic collection and analysis of research data. The authors' experience in conducting a previously published national study of the integration of holistic nursing practices and complementary and alternative modalities in curricula of baccalaureate and higher degree schools of nursing is used as an exemplar. The authors conclude that, regardless of the current status of technology and lack of computer support in some schools of nursing, an online national survey is a valuable tool in conducting research in nursing education and increasingly will be the method of choice for gathering survey data.     

Basement Membrane and Repair of Injury to Peripheral Nerve: Defining a Potential Role for Macrophages, Matrix Metalloproteinases, and Tissue Inhibitor of Metalloproteinases-1

Injury to a peripheral nerve is followed by a remodeling process consisting of axonal degeneration and regeneration. It is not known how Schwann cell–derived basement membrane is preserved after injury or what role matrix metalloproteinases (MMPs) and their inhibitors play in axonal degeneration and regeneration. We showed that the MMPs gelatinase B (MMP-9), stromelysin-1 (MMP-3), and the tissue inhibitor of MMPs (TIMP)-1 were induced in crush and distal segments of mouse sciatic nerve after injury. TIMP-1 inhibitor activity was present in excess of proteinase activity in extracts of injured nerve. TIMP-1 protected basement membrane type IV collagen from degradation by exogenous gelatinase B in cryostat sections of nerve in vitro. In vivo, during the early phase (1 d after crush) and later phase (4 d after crush) after injury, induction of TNF-α and TGF-β1 mRNAs, known modulators of TIMP-1 expression, were paralleled by an upregulation of TIMP-1 and gelatinase B mRNAs. At 4 days after injury, TIMP-1, gelatinase B, and TNF-α mRNAs were localized to infiltrating macrophages and Schwann cells in the regions of nerve infiltrated by elicited macrophages. TIMP-1 and cytokine mRNA expression was upregulated in undamaged nerve explants incubated with medium conditioned by macrophages or containing the cytokines TGF-β1, TNF-α, and IL-1α. These results show that TIMP-1 may protect basement membrane from uncontrolled degradation after injury and that cytokines produced by macrophages may participate in the regulation of TIMP-1 levels during nerve repair.     

INAUGURAL ARTICLE by a Recently Elected Academy Member:B-cell signaling networks reveal a negative prognostic human lymphoma cell subset that emerges during tumor progression

Human tumors contain populations of both cancerous and host immune cells whose malignant signaling interactions may define each patient''s disease trajectory. We used multiplexed phospho-flow cytometry to profile single cells within human follicular lymphoma tumors and discovered a subpopulation of lymphoma cells with impaired B cell antigen receptor (BCR) signaling. The abundance of BCR-insensitive cells in each tumor negatively correlated with overall patient survival. These lymphoma negative prognostic (LNP) cells increased as tumors relapsed following chemotherapy. Loss of antigen receptor expression did not explain the absence of BCR signaling in LNP tumor cells, and other signaling responses were intact in these cells. Furthermore, BCR signaling responses could be reactivated in LNP cells, indicating that BCR signaling is not missing but rather specifically suppressed. LNP cells were also associated with changes to signaling interactions in the tumor microenvironment. Lower IL-7 signaling in tumor infiltrating T cells was observed in tumors with high LNP cell counts. The strength of signaling through T cell mediator of B cell function CD40 also stratified patient survival, particularly for those whose tumors contained few LNP cells. Thus, analysis of cell–cell interactions in heterogeneous primary tumors using signaling network profiles can identify and mechanistically define new populations of rare and clinically significant cells. Both the existence of these LNP cells and their aberrant signaling profiles provide targets for new therapies for follicular lymphoma.     

Adding the Female Condom to the Public Health Agenda on Prevention of HIV and Other Sexually Transmitted Infections Among Men and Women During Anal Intercourse

Legal barriers to conducting public health research on methods of protection for anal intercourse were lifted in the United States in 2003 when the US Supreme Court invalidated all state antisodomy laws. Although research funding has been available for the development of rectal microbicides, the female condom, which has already been approved for vaginal use, has not been evaluated for anal use.Although there is no evidence that the female condom is safe for anal intercourse, it has already been taken up for off-label use by some men who have sex with men. This demonstrates the urgent need for more protection options for anal intercourse and, more immediately, the need to evaluate the safety and efficacy of the female condom for anal intercourse.In the United States, anal intercourse is a common practice. Among men aged 25 to 44 years in the United States, 3.9% report having had anal intercourse with another man, and 40% report having had anal intercourse with a woman. Among women aged 25 to 44 years in the United States, 35% report having had heterosexual anal intercourse.¹ Hence, discussions about anal intercourse should not assume that the practitioners are all men who have sex with men (MSM). In fact, there are an estimated 4 times more women than there are MSM practicing receptive anal intercourse in the United States.² Unprotected anal intercourse is the sexual activity associated with the highest risk of HIV infection.³