In this work we describe a forward genetic approach to identify mutations that affect blood vessel development in the zebrafish. By applying a haploid screening strategy in a transgenic background that allows direct visualization of blood vessels, it was possible to identify several classes of mutant vascular phenotypes. Subsequent characterization of mutant lines revealed that defects in Vascular endothelial growth factor (Vegf) signaling specifically affected artery development. Comparison of phenotypes associated with different mutations within a functional zebrafish Vegf receptor-2 ortholog (referred to as kdr-like, kdrl) revealed surprisingly varied effects on vascular development. In parallel, we identified an allelic series of mutations in phospholipase c gamma 1 (plcg1). Together with in vivo structure–function analysis, our results suggest a requirement for Plcg1 catalytic activity downstream of receptor tyrosine kinases. We further find that embryos lacking both maternal and zygotic plcg1 display more severe defects in artery differentiation but are otherwise similar to zygotic mutants. Finally, we demonstrate through mosaic analysis that plcg1 functions autonomously in endothelial cells. Together our genetic analyses suggest that Vegf/Plcg1 signaling acts at multiple time points and in different signaling contexts to mediate distinct aspects of artery development.

RATIONALE: Although cutaneous lesions are frequently seen in patients with hematological malignancies, cutaneous vasculitis is rarely seen in chronic lymphocytic leukemia (CLL). Here we report a case of CLL presenting as urticarial vasculitis. METHODS: Case report. RESULTS: An 83 year old male with long-standing thrombocytopenia presented to our clinic with a four month history of rash and intermittent lip edema. The rash was described as generalized, pruritic, raised, erythematous, persistent lesions with residual hyperpigmentation. Previous treatment with oral corticosteroids and antihistamines was not effective, nor did the rash resolve after stopping aspirin and hydrochlorothiazide. Skin biopsy showed superficial perivascular mixed inflammation, consistent with urticarial vasculitis. Laboratory tests revealed a normal white blood cell count (WBC = 5.5 × 109/l, lymphocytes = 3.1 × 109/l), a normal hemoglobin, and thrombocytopenia (platelet count = 114 × 109/μl). Complement studies were normal. Serum immunofixation showed an IgG-kappa monoclonal gammopathy. Flow cytometry on peripheral blood demonstrated a monoclonal B-lymphoid population, kappa immunophenotype, with CD20/CD5 co-expression, bright CD23 and 35% CD38 expression, consistent with CLL. CONCLUSIONS: We report a rare cutaneous manifestation of CLL, urticarial vasculitis. In this case, cutaneous lesions resulted in medical referral and evaluation, leading to the diagnosis of CLL. This case highlights the importance of prompt diagnosis of cutaneous vasculitis and the need for additional evaluation to exclude associated systemic conditions such as malignancy.

Embryos of the inland silverside Menidia beryllina were exposed to the organophosphorus pesticide terbufos at 9 combinations of temperature (20, 25 and 30°C) and salinity (5, 12.5 and 20%.). Nominal exposure concentrations were 12.5, 25, 50 and 100 pg terbufos 1-' with an acetone and seawater control for each temperature/salinity combination. Test durations were temperature dependent and ranged from 5 to 14 d. Endpoints were embryo survival, hatching and percentage of larvae with normal vertebrae. Embryo survival was significantly ( a = 0.05) lower in tests conducted at 20°C for all salinities. Salinity affected survival only at combinations of 20%0 and 100 ~g terbufos I ' Both temperature and salinity affected the percentage hatch, wlth the lowest hatching occurring in tests at 20 "C and in tests conducted at 20 L. The percentage of larvae with normal vertebrae was significantly (a = 0.05) reduced from controls at terbufos concentrations of 25 (7 to 32 %), 50 (44 to 62 %) and 100 pg 1-' (58 to 73 %) for the 3 temperatures tested, whereas salinity showed no significant effect. Anomalies in the development of vertebrae occurred across all temperature and salinity combinations, and were observed at concentrations as low as 12.5 pg terbufos 1-'

The selection of materials for components exposed to wear situations involves a diversity of factors; a systematic approach to selection is out-lined to ensure that no significant factors are overlooked. The relation between materials properties and wear is examined and materials to avoid wear are considered; ancillary factors that influence selection are reviewed.