Systemic necrotizing vasculitis

The revival of interest in systemic necrotizing vasculitis was initiated by the discovery of its association with anti-neutrophil cytoplasmic antibodies (ANCA). The close association of certain ANCA subspecificities, for example, proteinase 3 (Pr3) and myeloperxoidase ANCA, with Wegener's granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome has led to their designation as 'ANCA-associated vasculitides'. This article describes the common and divergent clinical and immunological features of the members of this 'new' family of systemic necrotizing vasculitis, which continues to grow with the widespread use of ANCA testing. In addition, the 'standard' treatment for systemic necrotizing vasculitis (daily 'low dose' cyclophosphamide plus glucocorticosteroids or 'Fauci's scheme') is compared with new stage and activity adapted therapeutic regimens.     

Microinjected cDNA encoding JAK2 protein-tyrosine kinase induces DNA synthesis in NIH 3T3 cells

Glut-2 is a low-affinity transporter present in the plasma membrane of pancreatic beta-cells, hepatocytes and intestine and kidney absorptive epithelial cells of mice. In beta-cells, Glut-2 has been proposed to be active in the control of glucose-stimulated insulin secretion (GSIS; ref. 2), and its expression is strongly reduced in glucose-unresponsive islets from different animal models of diabetes. However, recent investigations have yielded conflicting data on the possible role of Glut-2 in GSIS. Whereas some reports have supported a specific role for Glut-2 (refs 5,6), others have suggested that GSIS could proceed normally even in the presence of low or almost undetectable levels of this transporter. Here we show that homozygous, but not heterozygous, mice deficient in Glut-2 are hyperglycaemic and relatively hypo-insulinaemic and have elevated plasma levels of glucagon, free fatty acids and beta-hydroxybutyrate. In vivo, their glucose tolerance is abnormal. In vitro, beta-cells display loss of control of insulin gene expression by glucose and impaired GSIS with a loss of first phase but preserved second phase of secretion, while the secretory response to non-glucidic nutrients or to D-glyceraldehyde is normal. This is accompanied by alterations in the postnatal development of pancreatic islets, evidenced by an inversion of the alpha- to beta-cell ratio. Glut-2 is thus required to maintain normal glucose homeostasis and normal function and development of the endocrine pancreas. Its absence leads to symptoms characteristic of non-insulin-dependent diabetes mellitus.     

Axonal cytoskeletal changes after non-disruptive axonal injury

In animal models of human diffuse axonal injury, axonal swellings leading to secondary axotomy occur between 2 and 6 h after injury. But, analysis of cytoskeletal changes associated with secondary axotomy has not been undertaken. We have carried out a quantitative analysis of cytoskeletal changes in a model of diffuse axonal injury 4 h after stretch-injury to adult guinea-pig optic nerves. The major site of axonal damage was the middle portion of the nerve. There was a statistically significant increase in the proportion of small axons with a diameter of 0.5 micron and smaller in which there was compaction of neurofilaments. Axons with a diameter greater than 2.0 microns demonstrated an increased spacing between cytoskeletal elements throughout the length of the nerve. However, in the middle segment of the nerve these larger axons demonstrated two different types of response. Either, where periaxonal spaces occurred, there was a reduction in axonal calibre, compaction of neurofilaments but no change in their number, and a loss of microtubules. Or, where intramyelinic spaces occurred there was an increased spacing between neurofilaments and microtubules with a significant loss in the number of both. Longitudinal sections showed foci of compaction of neurofilaments interspersed between regions where axonal structure was apparently normal. Neurofilament compaction was correlated with disruption of the axolemma at these foci present some hours after injury. We suggest that the time course of these axonal cytoskeletal changes after stretch-injury to central axons is shorter than those changes documented to occur during Wallerian degeneration.     

Management of abdominal vascular injuries

Genomic DNAs were compared between males and females of the domesticated silkworm, Bombyx mori, strains C108, C137, J137, p50, and WILD-W (constructed by crossing a wild silkworm, B. mandarina, female with a male of strain C108) by polymerase chain reaction (PCR) with 700 arbitrary 10-mer primers. Four female-specific RAPDs (W-Kabuki, W-Samurai, W-Kamikaze, and W-Yamato) were found. The sex chromosome formulas of B. mori and B. mandarina are ZW (XY) for the female and ZZ (XX) for the male. The four female-specific RAPDs are assumed to be derived from the W chromosome because the other chromosomes are shared by both sexes. A computer search for deduced amino acid sequences of these four RAPDs revealed that all of them showed homology to previously reported amino acid sequences encoded in known retrotransposable elements from various organisms.     

Mechanisms of anterior cruciate ligament neovascularization and ligamentization

Columbia-Rambouillet cross-bred sheep were used to study the revascularization and ligamentization process of anterior cruciate ligament (ACL) reconstruction over a 6-month period using basic histology, immunohistochemistry, and electron microscopy. The reconstruction technique studied was a quadruple-hamstring, interference screw fixation technique. Further, these specimens, after retrieval at 6, 12, and 26 weeks, were compared with human arthroscopic 'second looks' and with 10 en bloc specimens obtained when a cruciate-sacrificing total knee replacement was performed. The study showed that, with this reconstruction technique, Sharpey's fibers were seen at 6 weeks in both sheep and human specimens. The intratunnel specimens showed proliferative chondrification, then ossification of the matrix. Intra-articular neovascularization, ligamentization, and junction ossification occurred. Myoblasts or smooth muscle cells appear to mediate the ligamentization as evidenced in electron microscopy by proliferate collagen manufacture. These myoblasts were seen in both the healing sheep and human second looks, but not seen in mature ACL grafts or in normal ACLs. At 6 months postoperatively, the sheep ACL reconstruction appeared clinically, histologically, and immunohistochemically indistinguishable from the normal sheep ACL. A correlation of this work with published animal studies in which biomechanical testing was performed and with human 'second looks' would imply that an ACL reconstruction may be vulnerable during this period of neovascularization and ligamentization.     

Dying dogma: the pathological diagnosis of epidermotropic metastatic malignant melanoma

Distinguishing primary cancer from a metastasis is a fundamental task in surgical pathology that has crucial therapeutic and prognostic implications. When metastatic melanoma involves the skin and extends into the epidermis (epidermotropic), differentiating it from primary cutaneous melanoma may be particularly difficult. Early investigators dismissed this issue as a nonproblem and dogmatically declared that junctional change was requisite for the diagnosis of primary cutaneous melanoma. Epidermotropic metastases of malignant melanoma (EMMM) are now recognized to have many features in common with primary melanoma, which can include involvement of the dermal-epidermal junction, extension of the intraepidermal component beyond the dermal component, and even an epidermal-only pattern. This article traces the evolution in criteria used to diagnose EMMM and highlights why much of the original thinking is no longer accepted. Current concepts in EMMM morphology are elaborated and illustrated. The role of immunomicroscopy and molecular pathology in the detection of EMMM is also discussed.