Amyloidoma: A Case Report of Remote Insulin-Derived Amyloidosis in the Setting of Insulin-Dependent Diabetes.

The incidence of insulin-induced amyloidosis distant from an injection site is unknown. Due to its rare nature, only a few case reports have been reported, with even fewer describing amyloidoma as distant from the insulin injection site. We present a case of a 52-year-old male with a left arm mass that was determined to be cutaneous amyloidosis and successfully treated with total excision of the mass.

A Rapid Method for Directed Gene Knockout for Screening in G0 Zebrafish.

Zebrafish is a powerful model for forward genetics. Reverse genetic approaches are limited by the time required to generate stable mutant lines. We describe a system for gene knockout that consistently produces null phenotypes in G0 zebrafish.

Sphingosine 1-phosphate receptor-1 in cardiomyocytes is required for normal cardiac development.

Sphingosine 1-phosphate (S1P) is a bioactive lipid that acts via G protein-coupled receptors. The S1P receptor S1P1, encoded by S1pr1, is expressed in developing heart but its roles there remain largely unexplored. Analysis of S1pr1 LacZ knockin embryos revealed β-galactosidase staining in cardiomyocytes in the septum and in the trabecular layer of hearts collected at 12.

Redundancy and interaction of thrombin- and collagen-mediated platelet activation in tail bleeding and carotid thrombosis in mice.

Objective: Current antiplatelet strategies to prevent myocardial infarction and stroke are limited by bleeding risk. A better understanding of the roles of distinct platelet-activating pathways is needed. We determined whether platelet activation by 2 key primary activators, thrombin and collagen, plays distinct, redundant, or interacting roles in tail bleeding and carotid thrombosis in mice.

Local protease signaling contributes to neural tube closure in the mouse embryo.

We report an unexpected role for protease signaling in neural tube closure and the formation of the central nervous system. Mouse embryos lacking protease-activated receptors 1 and 2 showed defective hindbrain and posterior neuropore closure and developed exencephaly and spina bifida, important human congenital anomalies. Par1 and Par2 were expressed in surface ectoderm, and Par2 was expressed selectively along the line of closure.

Sphingosine-1-phosphate in the plasma compartment regulates basal and inflammation-induced vascular leak in mice.

Maintenance of vascular integrity is critical for homeostasis, and temporally and spatially regulated vascular leak is a central feature of inflammation. Sphingosine-1-phosphate (S1P) can regulate endothelial barrier function, but the sources of the S1P that provide this activity in vivo and its importance in modulating different inflammatory responses are unknown. We report here that mutant mice engineered to selectively lack S1P in plasma displayed increased vascular leak and impaired survival after anaphylaxis, administration of platelet-activating factor (PAF) or histamine, and exposure to related inflammatory challenges.

Roles of protease-activated receptors in a mouse model of endotoxemia.

Endotoxemia is often associated with extreme inflammatory responses and disseminated intravascular coagulation. Protease-activated receptors (PARs) mediate cellular responses to coagulation proteases, including platelet activation and endothelial cell reactions predicted to promote inflammation. These observations suggested that PAR activation by coagulation proteases generated in the setting of endotoxemia might promote platelet activation, leukocyte-mediated endothelial injury, tissue damage, and death.

Platelets, protease-activated receptors, and fibrinogen in hematogenous metastasis.

Procoagulant activity on tumor cells can enhance their ability to spread via the circulation to colonize distant organs. Toward defining the relative importance of the main host responses to coagulation for hematogenous metastasis, we examined lung metastases after intravenous injection of melanoma cells in Nf-E2(-/-) mice, which have virtually no circulating platelets; Par4(-/-) mice, which have platelets that fail to respond to thrombin; Par1 and Par2(-/-) mice, which have markedly attenuated endothelial responses to coagulation proteases; and Fib(-/-) mice, which lack fibrinogen. In a severe combined immunodeficiency (SCID) background, median lung tumor count in Nf-E2(-/-), Par4(-/-), and Fib(-/-) mice was 6%, 14%, and 24% of wild type, respectively; total tumor burden was only 4%, 9%, and 3% of wild type, respectively.

Combined deficiency of protease-activated receptor-4 and fibrinogen recapitulates the hemostatic defect but not the embryonic lethality of prothrombin deficiency.

The availability of the relevant mutant mouse lines provided an opportunity to test the doctrine that platelet activation and fibrin formation account for the importance of thrombin for hemostasis. Prothrombin-deficient mice that survive to birth exsanguinate in the perinatal period. By contrast, protease-activated receptor 4 (PAR4)-deficient mice, which have platelets that fail to respond to thrombin, survive to adulthood with only a mild bleeding diathesis, and fibrinogen-deficient mice show perinatal bleeding but those that survive this period can have a relatively normal life expectancy.