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Key Points Molecules that crosslink actin filaments into particular architectures are important components of cell structure and movement. Filamins are one of the first of such components recognized and are among the most important. Filamins are extended dimers composed of subunits that contain characteristic β-pleated sheet repeats. Vertebrate filamins have amino-terminal actin-binding domains and self-associate at the carboxyl termini of their subunits. The main human filamin (filamin A) is encoded on the X chromosome. A second filamin gene (filamin B) is encoded on chromosome 3 and a muscle-specific filamin gene (filamin C) is encoded on chromosome 7. So far two filamin genes have been recognized in Drosophila . Dictyostelium amoebae have only one filamin species which is truncated compared with vertebrate and Drosophila filamins. Filamins cause actin filaments to branch with high angles leading efficiently to the formation of actin gels in vitro . The filamins reside at branches between orthogonally intersecting filaments in the peripheral cytoplasm of cells. Filamins also bind over 20 diverse cellular proteins, including membrane receptors and intracellular signalling macromolecules. Cells missing the main filamins have defects in surface stability and locomotion and in some of the functions ascribed to the filamin binding partners. A mutation in the filamin A gene is lethal for males and the cause of periventricular heterotopia in females chimeric for the mutation. Filamins are large actin-binding proteins that stabilize delicate three-dimensional actin webs and link them to cellular membranes. They integrate cellular architectural and signalling functions and are essential for fetal development and cell locomotion. Here, we describe the history, structure and function of this group of proteins.

The seemingly magical transmutation of shed blood into a solid has fascinated inquisitive observers for millennia. Hippocrates, in De Carnibus, and Aristotle, in Meteorology, postulated that the phenomenon was due to cooling, and as late as the 1790s John Hunter suggested that exposure to air was the cause. In 1832, Johannes Müller identified the insoluble clot substance “fibrin,” and Rudolf Virchow named its hypothetical soluble plasma precursor “fibrinogen.” Fibrinogen was isolated by Prosper Sylvain Denis in 1856. Alexander Schmidt demonstrated that the transformation of fibrinogen into fibrin was a “fermentative” (enzymatic) process and named the fibrin ferment “thrombin”; he called . . .

The filamins are cytoplasmic proteins that regulate the structure and activity of the cytoskeleton by cross-linking actin into three-dimensional networks, linking the cell membrane to the cytoskeleton and serving as scaffolds on which intracellular signaling and protein trafficking pathways are organized (reviewed in refs. 1 , 2 ). We identified mutations in the gene encoding filamin B in four human skeletal disorders. We found homozygosity or compound heterozygosity with respect to stop-codon mutations in autosomal recessive spondylocarpotarsal syndrome (SCT, OMIM 272460) and missense mutations in individuals with autosomal dominant Larsen syndrome (OMIM 150250) and the perinatal lethal atelosteogenesis I and III phenotypes (AOI, OMIM 108720; AOIII, OMIM 108721). We found that filamin B is expressed in human growth plate chondrocytes and in the developing vertebral bodies in the mouse. These data indicate an unexpected role in vertebral segmentation, joint formation and endochondral ossification for this ubiquitously expressed cytoskeletal protein.

The therapeutic efficacy of prothrombin-complex concentrates in patients with hemophilia and inhibitors (antibodies) to factor VIII has been increasingly debated. We therefore entered 51 hemophiliacs with factor VIII inhibitors into a double-blind randomized crossover study to compare two commercial prothrombin-complex concentrates (Konȳne and Proplex) and an albumin placebo. Acute hemarthrosis of the elbow, knee, or ankle was treated with a single dose of a test preparation and assessed six hours later with objective and subjective criteria. In all measurements the concentrates were significantly more effective than the placebo. The data indicate that although prothrombin-complex concentrates, when used in a single dose, are only partially effective in the treatment of joint hemorrhage in hemophiliacs with inhibitors, their continued use for acute hemarthrosis is justified in the absence of any other effective and readily available therapy for this disorder. (N Engl J Med. 1980; 303:421–5.) THE development of an inhibitor (antibody to factor VIII) in a patient with hemophilia makes treatment of bleeding episodes extremely difficult. Therapeutic approaches such as those with steroids, exchange transfusion, bovine and porcine factor VIII, and immunosuppressive agents have usually met with disappointing results. 1 2 3 4 In 1969 Breen and Tullis reported that prothrombin-complex concentrates given to a patient with hemophilia A produced shortening of the silicone clotting time and cessation of hemorrhage. 5 The potential therapeutic implications of this observation were noted in 1972 by Fekete et al. 6 and by Roberts, 7 who reported beneficial clinical results with activated prothrombin-complex concentrates in patients . . .

Antiserums to human prothrombin contain antibodies directed against at least two different antigenic sites. During blood coagulation, prothrombin is cleaved into two major antigenically distinct fragments-thrombin and a \"pro\" fragment. The latter is present in normal serum, whereas thrombin loses its immunologic reactivity, presumably because of its combination with the natural thrombin inhibitors in blood.

Seven new cases of acquired inhibitors of Factor VIII have been typed immunologically as $\\gamma _{2}\\kappa _{2}$ antibodies. Electrophoretic mobility on starch block of a combined group of 13 such antibodies is considerably more rapid than that of the bulk of immunoglobulin G.

To the Editor: In their report (August 21 issue) describing the efficacy of nonactivated prothrombin-complex concentrates (PCCs) for the treatment of hemarthroses in patients with hemophilia with factor VIII inhibitors, Lusher et al. mention anecdotal knowledge of three patients who had myocardial infarction after repeated administration of large doses of nonactivated PCC. In each case the patient was young (less than 20 years), and one case was fatal (Lusher JM. Personal communications). Two of the episodes have been reported in the literature. 1 , 2 In hopes of preventing further similar occurrences, the following information should be recognized by all physicians responsible for . . .

Background. Four spotted fever group rickettsiae (SFGR) are known to infect humans in the United States. A member of the SFGR designated 364D and detected in Dermacentor occidentalis ticks has not previously been identified as a human pathogen. Methods. An 80-year-old man from a rural northern California community presented with an eschar on his forearm. A skin punch biopsy of the lesion was evaluated by immunohistochemistry and molecular analysis. Serum specimens obtained from the patient and 3 other area residents with similar illnesses were tested by immunofluorescence and Western immunoblot for antibodies to SFGR. Ticks were collected near the patient's residence and tested for SFGR. Results. Abundant intracellular rickettsiae and fragmented rickettsial antigens were observed in the mononuclear inflammatory infiltrates of the biopsy. Nucleotide sequences of DNA fragments amplified from the biopsy were identical to those of 364D. Convalescent sera from all four patients exhibited high immunoglobulin G titers to Rickettsia rickettsii, Rickettsia rhipicephali, and 364D antigens. Three adult D. occidentalis were positive for 364D, R. rhipicephali, and an unidentified Rickettsia species. Conclusions. This is the first confirmation of human disease associated with the SFGR 364D, which was likely transmitted by D. occidentalis. Although the patients described here presented with a single cutaneous eschar as the principal manifestation, the full spectrum of illness associated with 364D has yet to be determined. Possible infection with 364D or other SFGR should be confirmed through molecular techniques in patients who present with “spotless” Rocky Mountain spotted fever or have serum antibodies to R. rickettsii with group-specific assays.