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Emanuela Marchesini,1 Massimo Morfini,2 Leonard Valentino3,4 1Hemophilia Centre, SC Vascular and Emergency Department, University of Perugia, Perugia, Italy; 2Italian Association of Haemophilia Centres (AICE), Naples, Italy; 3National Hemophilia Foundation, New York, NY, USA; 4Rush University, Chicago, IL, USACorrespondence: Massimo Morfini via Dello Statuto N.1- I-50129, Firenze, ItalyTel +39 348 2306928Fax +39 055-4732 18Email drmassimomorfini@gmail.comAbstract: Progress in hemophilia therapy has been remarkable in the first 20 years of the third millennium, but the innovation began with the description the fractionation of plasma in 1946. The first concentrates followed the discovery of FVIII in the cryoprecipitate of frozen plasma and FIX in the supernatant in the early 1960s, which led to the initial attempts at replacement therapy. Unfortunately, the lack of screening methods for viral pathogens resulted in people with hemophilia (PWH) receiving concentrates contaminated by hepatitis A virus, hepatitis C virus, and human immunodeficiency virus, as these concentrates were made from large industrial pools of plasma derived from thousands of donors. Fortunately, by 1985, viral screening methods and proper virucidal techniques were developed that made concentrates safe. Increasingly pure products followed the introduction of chromatography steps with monoclonal antibodies in the production process. The problem of immunogenicity of exogenously administered concentrates has not yet had a complete solution. The development of alloantibodies against FVIII in about 25– 35% of PWH is the most serious adverse effect of replacement therapy. The next major advance followed the cloning of the F8 gene and later the F9 genes, which paved the way to produce concentrates of factors obtained by the recombinant DNA technology. The injected FVIII and FIX molecules had a relatively short circulating half-life in the plasma of people with hemophilia A and B, approximately 12 and 18 hours, respectively. The ability to prolong the plasma half-life and extend the interval between injections followed the application of methods to conjugate the factor molecule with the fragment crystallizable of IgG1 or albumin or by adding polyethylene glycol, which has led to an increase in the half-life of concentrates, especially for rFIX. The next frontier in hemophilia therapy is the application of durable and potentially curative therapies such as with gene addition therapy. Experiments in hemophilia B have demonstrated durable responses. Unfortunately, the results with gene therapy for hemophilia A have not been as remarkable and the durability must still be demonstrated. Nonetheless, the long-term safety, predictability, durability, and efficacy of gene therapy for hemophilia A and B remain an open question. At present, only healthy adult PWH have been enrolled in gene therapy clinical trials. The application of gene therapy to children and those with pre-existing antibodies against the delivery vector must also be studied before this therapy becomes widespread.Keywords: replacement therapy, adverse events, pharmacokinetics, extended half-life concentrates, non-replacement therapy, gene therapy

Drawing on a social identity framework of mathematical development, the authors present a model, Improving Girls' Math Identity (IGMI), designed to address two key "leaks" in the female STEM pipeline: undergraduate and middle school. IGMI involves a supportive professional development network for undergraduate women preparing to transition into mathematics-related careers, and a mentorship program connecting middle school girls with these undergraduates to develop metacognition, problem-solving, and spatial skills. Preliminary evidence demonstrates that the model successfully strengthens undergraduates' problem-solving abilities, improves resilience and persistence in pursuing STEM fields, and increases investment in supporting future cohorts of women in mathematics and science. [ABSTRACT FROM AUTHOR]

Introduction: Methylene blue dye has been used worldwide successfully with few complications in breast surgery. We present two different complications involving methylene blue: 1) skin and parenchymal necrosis when dye was injected in a subdermal fashion and 2) Mycoplasma infection caused by contaminated methylene blue in breast reduction surgery.Methods: We present two cases seen at the University of Arizona during 2008 and referred to a breast surgeon for management. We evaluated and managed complications of methylene blue dye injected by 2 referring surgeons for different indications. A review of the literature was performed.Results: The first case is a 67 year old female diagnosed with infiltrating ductal carcinoma of the left breast for which she was treated by her initial surgeon with left segmental mastectomy and sentinel node biopsy. The operating surgeon injected methylene blue in a subareolar subdermal fashion (distant from the primary tumor); unfortunately the patient suffered skin and breast necrosis requiring multiple surgical debridements and finally achieving delayed primary closure. The second case is a 45 year old female with infiltrating lobular carcinoma with a history of Mycoplasma infection secondary to methylene blue injected for breast reduction surgery. She required multiple debridements and had granulomas masquerading as cancer on MRI that confounded her extent of disease.Conclusions: The use of methylene blue dye in breast surgery is not without risk. In both cases methylene blue was responsible for complications requiring surgical debridement for local wound problems. In each case severe necrosis and infection were present. Methylene blue may cause not only significant morbidity, but may also produce cosmetically unsatisfactory results.