These observations have important implications for experiments involving genetic manipulation of the alpha1,3GT gene in transgenic animals in terms of promoter utilization, and particularly in genetically engineering cells for the animal cloning technology by nuclear transfer.
Islet cell autoantigen 69-kDa (ICA69), protein product of the human ICA1 gene, is one target of the immune processes defining the pathogenesis of Type 1 diabetes. We have characterized the genomic structure and functional promoters within the 5-regulatory region of ICA1. 5-RNA ligase-mediated rapid amplification of cDNA ends evaluation of ICA1 transcripts expressed in human islets, testis, heart, and cultured neuroblastoma cells reveals that three 5-untranslated region exons are variably expressed from the ICA1 gene in a tissue-specific manner. Surrounding the transcription initiation sites are motifs characteristic of non-TATA, non-CAAT, GC-rich promoters, including consensus Sp1/GC boxes, an initiator element, cAMP-responsive element-binding protein (CREB) sites, and clusters of other putative transcription factor sites within a genomic CpG island. Luciferase reporter constructs demonstrate that the first two ICA1 exon promoters reciprocally stimulate luciferase expression within islet-(RIN 1046-38 cells) and brain-derived (NMB7) cells in culture; the exon A promoter exhibits greater activity in islet cells, whereas the exon B promoter more efficiently activates transcription in neuronal cells. Mutation of a CREB site within the ICA1 exon B promoter significantly enhances transcriptional activity in both cell lines. Our basic understanding of expression from the functional core promoter elements of ICA1 is an important advance that will not only add to our knowledge of the ICA69 autoantigen but will also facilitate a rational approach to discover the function of ICA69 and to identify relevant ICA1 promoter polymorphisms and their potential associations with disease.
Wegener's granulomatosis (WG) is a complex autoimmune disorder that has been transformed from a uniformly lethal process to a chronic disease with a relapsing-remitting course. In the setting of frequent relapses, the need to manage cumulative disease damage and drug toxicities has spurred the identification and development of new potent and directed therapies. Biologic agents, which offer the potential for remission-induction and drug-sparing approaches to treat WG, have been studied in several small, open-label clinical series and one large, randomized, placebo-controlled clinical trial. This article discusses the results of these trials and the potential of these biologic agents to treat WG.
Hydroxychloroquine retinopathy (HCR) is a potentially blinding disease. Once HCR is detected, there is no treatment and the disease often continues to progress, even when the medication is stopped. Hence, primary prevention by appropriate dosing of hydroxychloroquine offers the best chance of minimizing the risk of HCR. This strategy remains challenging in practice as up to 56% of patients receive hydroxychloroquine at doses that place them at higher risk for HCR. 1 A key reason is disagreement in how to calculate dosages of hydroxychloroquine. 2,3 There are 2 methods: one uses ideal body weight (IBW); the other uses actual body weight (ABW). The IBW method assumes that hydroxychloroquine is stored mostly in lean tissue. 2 The daily dose must be normalized by lean body mass. This makes the calculation more complicated than the ABW method, which assumes that the drug is distributed evenly in muscle, skin, and fat. 3 We describe a free smartphone app-DoseCheckerthat can rapidly calculate the optimal weekly dose of hydroxychloroquine using elements of both methods.
The human leukocyte antigen (HLA)-DQA1*0102/DQB1*0602/DRB1*1501 (DR2) haplotype confers strong protection from type 1 diabetes. Growing evidence suggests that such protection may be mostly encoded by the DQB1*0602 allele, and we reported that even first degree relatives with islet cell antibodies (ICA) have an extremely low diabetes risk if they carry DQB1*0602. Recently, novel variants of the DQB1*0602 and *0603 alleles were reported in four patients with type 1 diabetes originally typed as DQB1*0602 with conventional techniques. One inference from this observation is that DQB1*0602 may confer absolute protection and may never occur in type 1 diabetes. By this hypothesis, all patients typed as DQB1*0602 positive with conventional techniques should carry one of the above diabetes-permissive variants instead of the protective DQB1*0602. Such variants could also occur in ICA/DQB1*0602-positive relatives, with the implication that their diabetes risk could be significantly higher than previously estimated. We therefore sequenced the DQB1*0602 and DQA1*0102 alleles in all ICA/DQB1*0602-positive relatives (n = 8) previously described and in six rare patients with type 1 diabetes and DQB1*0602. We found that all relatives and patients carry the known DQB1*0602 and DQA1*0102 sequences, and none of them has the mtDNA A3243G mutation associated with late-onset diabetes in ICA-positive individuals. These findings suggest that diabetes-permissive DQB1*0602/3 variants may be very rare. Thus, although the protective effect associated with DQB1*0602 is extremely powerful, it is not absolute. Nonetheless, the development of diabetes in individuals with DQB1*0602 remains extremely unlikely, even in the presence of ICA, as confirmed by our further evaluation of ICA/DQB1*0602-positive relatives, none of whom has yet developed diabetes.
Pr esentation of C a seDr. Naina Rastalsky (Medicine): A 68-year-old man with multiple myeloma was seen in the rheumatology clinic of this hospital because of increasing skin tightness, joint pain, and swelling of the hands and feet.The patient had been well until 2 years before this presentation, when anemia was noted on routine examination at another hospital. During the next 7 months, endoscopic and colonoscopic screening examinations were negative. Pathological examination of a bone marrow-biopsy specimen and aspirate revealed 30% plasma cells; flow-cytometric studies revealed an IgG lambda M component. A diagnosis of multiple myeloma was made. Skeletal radiographs reportedly revealed multiple lytic lesions. Lenalidomide, bortezomib, and dexamethasone were administered, followed by cyclophosphamide. Nine months before this presentation, the patient was admitted to this hospital; melphalan hydrochloride was administered, and autologous stem-cell transplantation was performed. Results of follow-up studies were consistent with complete remission.Three months before this presentation, the patient was seen by an orthopedist at this hospital for evaluation of low-back pain of 1 year's duration. Magnetic resonance imaging (MRI) of the lumbar spine, performed after the administration of intravenous gadolinium, revealed multilevel degenerative changes, multiple enhancing lesions in the lumbar spine and left iliac bone, and compression fractures of the first and second lumbar vertebrae, findings consistent with the history of multiple myeloma.Two months before this presentation, swelling and pain in the hands occurred, followed by pedal edema, tightening of the skin of the hands and feet, and diffuse hyperpigmentation on the trunk, arms, and legs. Maintenance therapy with lenalidomide was begun, but it was stopped during the first cycle because of worsening symptoms.Diffuse joint pain occurred and hyperpigmentation increased. One month before this presentation, on evaluation in the outpatient cancer center of this hospital,
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