Intercellular trafficking of the nuclear oncoprotein DEK.

DEK is a biochemically distinct, conserved nonhistone protein that is vital to global heterochromatin integrity. In addition, DEK can be secreted and function as a chemotactic, proinflammatory factor. Here we show that exogenous DEK can penetrate cells, translocate to the nucleus, and there carry out its endogenous nuclear functions. Strikingly, adjacent cells can take up DEK secreted from synovial macrophages. DEK internalization is a heparan sulfate-dependent process, and cellular uptake of DEK into DEK knockdown cells corrects global heterochromatin depletion and DNA repair deficits, the phenotypic aberrations characteristic of these cells. These findings thus unify the extracellular and intracellular activities of DEK, and suggest that this paracrine loop involving DEK plays a role in chromatin biology.

Attachment of Chlamydia trachomatis L2 to host cells requires sulfation.

Chlamydia trachomatis is a pathogen responsible for a prevalent sexually transmitted disease. It is also the most common cause of infectious blindness in the developing world. We performed a loss-of-function genetic screen in human haploid cells to identify host factors important in C. trachomatis L2 infection. We identified and confirmed B3GAT3, B4GALT7, and SLC35B2, which encode glucuronosyltransferase I, galactosyltransferase I, and the 3'-phosphoadenosine 5'-phosphosulfate transporter 1, respectively, as important in facilitating Chlamydia infection. Knockout of any of these three genes inhibits Chlamydia attachment. In complementation studies, we found that the introduction of functional copies of these three genes into the null clones restored full susceptibility to Chlamydia infection. The degree of attachment of Chlamydia strongly correlates with the level of sulfation of the host cell, not simply with the amount of heparan sulfate. Thus, other, as-yet unidentified sulfated macromolecules must contribute to infection. These results demonstrate the utility of screens in haploid cells to study interactions of human cells with bacteria. Furthermore, the human null clones generated can be used to investigate the role of heparan sulfate and sulfation in other settings not limited to infectious disease.

Repigmentation of hair following adalimumab therapy.

Repigmentation of canities, or age-related grey or white hair, is a rare occurrence. Generalized repigmentation of grey-white hair has been reported following inflammatory processes, and heterochromia (localized patches of hair repigmentation) is even more unusual, reported in association with medication use and malignancy. Tumor necrosis factor (TNF) inhibitors are increasingly utilized medications for inflammatory disorders, including psoriasis, rheumatoid arthritis, and inflammatory bowel disease. Hair loss, or alopecia, has been described among the side effects of these medications, but changes in hair pigmentation in association with this class of drugs have not previously been reported. We describe a patient with hair repigmentation associated with adalimumab therapy.

Cyclosporine and psoriasis: 2008 National Psoriasis Foundation Consensus Conference.

BACKGROUND: Cyclosporine is a valuable option for the treatment of psoriasis. This report summarizes studies regarding the use of cyclosporine since the last guidelines were published in 1998. OBJECTIVE: A task force of the National Psoriasis Foundation Medical Board was convened to evaluate treatment options. Our aim was to achieve a consensus on new updated guidelines for the use of cyclosporine in the treatment of psoriasis. METHODS: Reports in the literature were reviewed regarding cyclosporine therapy. LIMITATIONS: There are few evidence-based studies on the treatment of psoriasis with cyclosporine. RESULTS: A consensus was achieved on the use of cyclosporine in psoriasis including specific recommendations on dosing, monitoring, and use of cyclosporine in special situations. The consensus received approval from members of the National Psoriasis Foundation Medical Board. CONCLUSIONS: Cyclosporine is a safe and effective drug for the treatment of psoriasis. It has a particularly useful role in managing psoriatic crises, treating psoriasis unresponsive to other modalities, bridging to other therapies, and treating psoriasis within a rotational scheme of other medications. Appropriate patient selection and monitoring will significantly decrease the risks of side effects.

JAK-STAT signaling pathway inhibition: a role for treatment of discoid lupus erythematosus and dermatomyositis.

BACKGROUND: Discoid lupus erythematosus (DLE) and dermatomyositis (DM) are inflammatory autoimmune diseases that manifest primarily in the skin but can be linked to systemic complications. Although there is an in-depth understanding of the clinical presentation of these two diseases, much less is known regarding the pathophysiology. This has limited the effective treatment options for patients. OBJECTIVE: An understanding of the pathogenesis of each disease in greater detail will lead to newer targeted medications with less morbidity. This review article endeavors to substantiate the use of new treatments which target the JAK-STAT pathway while elaborating on the immunopathology as well. METHODS: PubMed was searched for relevant review articles, case reports, case series reports, randomized clinical trials (RCTs), basic science articles. Appropriate key terms and MeSH terms were utilized in the search. Clinicaltrials.gov was used to find relevant and current clinical trials being conducted in DLE and DM patients. RESULTS: A review of the literature supports the proposal that though there are likely many components and pathways involved in the destruction of keratinocytes, the Th1 cell immune response and specifically the JAK-STAT signaling pathway is common to both DLE and DM. CONCLUSION: Although further study is needed to determine the efficacy and benefits of JAK inhibitors over conventional therapy, these medications should be considered in refractory cases.

Toxic epidermal necrolysis.

UNLABELLED: Toxic epidermal necrolysis (TEN) is an unpredictable, life-threatening drug reaction associated with a 30% mortality. Massive keratinocyte apoptosis is the hallmark of TEN. Cytotoxic T lymphocytes appear to be the main effector cells and there is experimental evidence for involvement of both the Fas-Fas ligand and perforin/granzyme pathways. Optimal treatment for these patients remains to be clarified. Discontinuation of the offending drug and prompt referral to a burn unit are generally agreed upon steps. Beyond that, however, considerable controversy exists. Evidence both pro and con exists for the use of IVIG, systemic corticosteroid, and other measures. There is also evidence suggesting that combination therapies may be of value. All the clinical data, however, is anecdotal or based on observational or retrospective studies. Definitive answers are not yet available. Given the rarity of TEN and the large number of patients required for a study to be statistically meaningful, placebo controlled trials are logistically difficult to accomplish. The absence of an animal model further hampers research into this condition. This article reviews recent data concerning clinical presentation, pathogenesis and treatment of TEN. LEARNING OBJECTIVES: At the conclusion of this learning activity, participants should have acquired a more comprehensive knowledge of our current understanding of the classification, clinical presentation, etiology, pathophysiology, prognosis, and treatment of TEN.

Diversity of 23S rRNA genes within individual prokaryotic genomes.

BACKGROUND: The concept of ribosomal constraints on rRNA genes is deduced primarily based on the comparison of consensus rRNA sequences between closely related species, but recent advances in whole-genome sequencing allow evaluation of this concept within organisms with multiple rRNA operons. METHODOLOGY/PRINCIPAL FINDINGS: Using the 23S rRNA gene as an example, we analyzed the diversity among individual rRNA genes within a genome. Of 184 prokaryotic species containing multiple 23S rRNA genes, diversity was observed in 113 (61.4%) genomes (mean 0.40%, range 0.01%-4.04%). Significant (1.17%-4.04%) intragenomic variation was found in 8 species. In 5 of the 8 species, the diversity in the primary structure had only minimal effect on the secondary structure (stem versus loop transition). In the remaining 3 species, the diversity significantly altered local secondary structure, but the alteration appears minimized through complex rearrangement. Intervening sequences (IVS), ranging between 9 and 1471 nt in size, were found in 7 species. IVS in Deinococcus radiodurans and Nostoc sp. encode transposases. T. tengcongensis was the only species in which intragenomic diversity >3% was observed among 4 paralogous 23S rRNA genes. CONCLUSIONS/SIGNIFICANCE: These findings indicate tight ribosomal constraints on individual 23S rRNA genes within a genome. Although classification using primary 23S rRNA sequences could be erroneous, significant diversity among paralogous 23S rRNA genes was observed only once in the 184 species analyzed, indicating little overall impact on the mainstream of 23S rRNA gene-based prokaryotic taxonomy.