Michael Bigby

The ikaros gene is required for the development of all lymphoid lineages

The Ikaros gene encodes a family of early hematopoietic- and lymphocyte-restricted transcription factors. Mice homozygous for a germline mutation in the Ikaros DNA-binding domain lack not only T and B lymphocytes and natural killer cells but also their earliest defined progenitors. In contrast, the erythroid and myeloid lineages were intact in these mutant mice. We propose that Ikaros promotes differentiation of pluripotential hematopoietic stem cell(s) into the lymphocyte pathways. In the absence of a functional Ikaros gene, these stem cells are exclusively diverted into the erythroid and myeloid lineages.

Selective Defects in the Development of the Fetal and Adult Lymphoid System in Mice with an Ikaros Null Mutation

Mice homozygous for an Ikaros null mutation display distinct defects in the development of fetal and adult lymphocytes. Fetal T lymphocytes, and fetal and adult B lymphocytes and their earliest progenitors are absent. Postnatally, hematopoietic stem cells give rise to thymocyte precursors that undergo aberrant differentiation into the CD4 lineage and clonal expansion. The lack of NK cells and some gamma delta T cell subsets and a large reduction in thymic dendritic APCs suggest that Ikaros is essential for establishing early branch points in the postnatal T cell pathway. The lymphoid defects detected in Ikaros null mice reveal critical molecular differences between fetal and postnatal hematopoietic progenitors that dictate their ability to give rise to T cells. These studies also establish Ikaros as a tumor suppressor gene acting during thymocyte differentiation. Phenotypic comparison of this null mutation with a severe dominant-negative Ikaros mutation identifies molecular redundancy in the postnatal hemolymphoid system.

The pathogenesis of oral lichen planus

Both antigen-specific and non-specific mechanisms may be involved in the pathogenesis of oral lichen planus (OLP). Antigen-specific mechanisms in OLP include antigen presentation by basal keratinocytes and antigen-specific keratinocyte killing by CD8(+) cytotoxic T-cells. Non-specific mechanisms include mast cell degranulation and matrix metalloproteinase (MMP) activation in OLP lesions. These mechanisms may combine to cause T-cell accumulation in the superficial lamina propria, basement membrane disruption, intra-epithelial T-cell migration, and keratinocyte apoptosis in OLP. OLP chronicity may be due, in part, to deficient antigen-specific TGF-beta1-mediated immunosuppression. The normal oral mucosa may be an immune privileged site (similar to the eye, testis, and placenta), and breakdown of immune privilege could result in OLP and possibly other autoimmune oral mucosal diseases. Recent findings in mucocutaneous graft-versus-host disease, a clinical and histological correlate of lichen planus, suggest the involvement of TNF-alpha, CD40, Fas, MMPs, and mast cell degranulation in disease pathogenesis. Potential roles for oral Langerhans cells and the regional lymphatics in OLP lesion formation and chronicity are discussed. Carcinogenesis in OLP may be regulated by the integrated signal from various tumor inhibitors (TGF-beta 1, TNF-alpha, IFN-gamma, IL-12) and promoters (MIF, MMP-9). We present our recent data implicating antigen-specific and non-specific mechanisms in the pathogenesis of OLP and propose a unifying hypothesis suggesting that both may be involved in lesion development. The initial event in OLP lesion formation and the factors that determine OLP susceptibility are unknown.

AAD/ACMS/ASDSA/ASMS 2012 appropriate use criteria for Mohs micrographic surgery: A report of the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery

The appropriate use criteria process synthesizes evidence-based medicine, clinical practice experience, and expert judgment. The American Academy of Dermatology in collaboration with the American College of Mohs Surgery, the American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery has developed appropriate use criteria for 270 scenarios for which Mohs micrographic surgery (MMS) is frequently considered based on tumor and patient characteristics. This document reflects the rating of appropriateness of MMS for each of these clinical scenarios by a ratings panel in a process based on the appropriateness method developed by the RAND Corp (Santa Monica, CA)/University of California-Los Angeles (RAND/UCLA). At the conclusion of the rating process, consensus was reached for all 270 (100%) scenarios by the Ratings Panel, with 200 (74.07%) deemed as appropriate, 24 (8.89%) as uncertain, and 46 (17.04%) as inappropriate. For the 69 basal cell carcinoma scenarios, 53 were deemed appropriate, 6 uncertain, and 10 inappropriate. For the 143 squamous cell carcinoma scenarios, 102 were deemed appropriate, 7 uncertain, and 34 inappropriate. For the 12 lentigo maligna and melanoma in situ scenarios, 10 were deemed appropriate, 2 uncertain, and 0 inappropriate. For the 46 rare cutaneous malignancies scenarios, 35 were deemed appropriate, 9 uncertain, and 2 inappropriate. These appropriate use criteria have the potential to impact health care delivery, reimbursement policy, and physician decision making on patient selection for MMS, and aim to optimize the use of MMS for scenarios in which the expected clinical benefit is anticipated to be the greatest. In addition, recognition of those scenarios rated as uncertain facilitates an understanding of areas that would benefit from further research. Each clinical scenario identified in this document is crafted for the average patient and not the exception. Thus, the ultimate decision regarding the appropriateness of MMS should be determined by the expertise and clinical experience of the physician.

Adverse reactions to isotretinoin: a report from the adverse drug reaction reporting system

Between October 1982 and June 1985 the Adverse Drug Reaction Reporting System received reports of 104 suspected adverse reactions occurring in 93 patients who took isotretinoin. Adverse reactions involving the skin and mucous membranes (29 reports), central nervous system (23), musculoskeletal system (12), pregnancy (11), and eyes (8) were most commonly reported. Severe headache was the most frequently reported adverse reaction (15 reports). In four cases headaches were attributed to pseudotumor cerebri. Some of the reported reactions, for example, a disulfiram (Antabuse)-like reaction and oculogyric crisis, have not been described previously in the literature. Other reports, such as congenital malformations, serve to emphasize some of the serious reactions that are known to occur. These spontaneous reports of adverse reactions associated with isotretinoin use, together with the literature we review, may help alert physicians to the diverse spectrum of adverse reactions that may develop in patients taking isotretinoin.

Autocytotoxic T-cell clones in lichen planus

We examined the in vitro cytotoxic activity of cutaneous T‐cell lines and clones from lichen planus (LP) patients against autologous epidermal keratinocytes. T cells were cultured from LP lesions and adjacent clinically normal skin and cloned by limiting dilution. Keratinocytes were cultured from LP lesions and adjacent clinically normal skin and immortalized by transfection with the E6 and E7 genes from human papillomavirus 16 (HPV16). The lesional T‐cell line from one LP patient contained 27% γδ+ T cells and was significantly more cytotoxic against autologous lesional keratinocytes than the T‐cell line from clinically normal skin. Clones isolated from the lesional T‐cell line were significantly more cytotoxic against autologous lesional keratinocytes than clones isolated from the non‐lesional T‐cell line. Most cytotoxic clones from LP lesions were CD8+ and most non‐cytotoxic clones from LP lesions were CD4+. One cytotoxic clone was CD4– and CD8– and expressed the γδ T‐cell receptor. Two CD8+ LP lesional T‐cell clones showed dose‐dependent killing of HPV16 E6/E7‐immortalized autologous lesional and normal keratinocytes, but no cytotoxic activity against Epstein–Barr virus‐transformed autologous B‐cell blasts. The cytotoxic activity of CD8+ lesional T‐cell clones against autologous lesional keratinocytes was partially blocked with anti‐major histocompatibility complex (MHC) class I monoclonal antibodies. These data support the hypothesis that CD8+ lesional T cells recognize an antigen associated with MHC class I on lesional keratinocytes and that CD8+ cytotoxic T cells lyse keratinocytes in LP lesions.

Cutaneous reactions to nonsteroidal anti-inflammatory drugs: A review*

The nonsteroidal anti-inflammatory drugs are one of the most commonly prescribed classes of drugs used in medical practice. This review discusses the diverse cutaneous reactions associated with nonsteroidal anti-inflammatory drugs. Adverse cutaneous reactions occur most frequently with benoxaprofen, piroxicam, sulindac, meclofenamate sodium, zomepirac sodium, and phenylbutazone. The most serious adverse cutaneous reactions, Stevens-Johnson syndrome and toxic epidermal necrolysis, appear to be most often associated with sulindac and phenylbutazone. Tolmetin and zomepirac sodium, two structurally similar pyrrole derivatives, have been associated with a disproportionate number of cases of anaphylactoid reactions. Among the currently marketed nonsteroidal anti-inflammatory drugs, piroxicam appears to have the highest rate of phototoxic reactions. This phototoxic eruption is most often vesiculobullous.

Understanding and evaluating clinical trials

In this review, we attempt to provide the basic knowledge necessary to understand and evaluate clinical trials because properly conducted, randomized clinical trials are the best sources for determining the best available treatment. Other commonly used sources rarely provide sufficient detail necessary to determine the efficacy and safety of any treatment, and they often contain biases or pitfalls that make them unacceptable or unreliable. Our method for reviewing clinical trials allows a busy clinician to use his or her time most efficiently by deciding not to read the majority of poorly conceived, designed, executed, or reported trials and those trials with insignificant results. It provides a means to determine the quality of the trials that one does decide to read and to retain and retrieve the information when it is needed. The method involves recognizing and evaluating the features that strengthen clinical trials and help validate their conclusions. These features include proper selection and allocation of patients, inclusion of an appropriate control group, randomization, prior selection of clinically and biologically important outcome variables, blinding of assessment, consideration of patient compliance and drop out, and proper presentation and statistical analysis of results.

Pityriasis versicolor: a systematic review of interventions.

OBJECTIVE To determine the efficacy of topical or systemic agents in the treatment and prevention of pityriasis versicolor. DESIGN Systematic review and meta-analysis. DATA SOURCES The Cochrane Skin Group Specialized Register (to June 2008), Cochrane Central Register of Controlled Trials, MEDLINE (1950 to June 2008), EMBASE (1974 to June 2008), LILACS (to March 2009), the gray literature, and sources for registered trials to November 2008. Reference lists of all retrieved trials and review articles were checked for additional trials. STUDY SELECTION Controlled trials that examined therapies used in children or adults with a clinical or microscopic diagnosis of pityriasis versicolor. DATA EXTRACTION The primary outcome measure included a negative result from mycological evaluation of participants with direct microscopy using potassium hydroxide smear. The secondary outcome measures were findings from Woods light examination and a negative clinical evaluation result, with disappearance of visual signs (except pigmentary defects) and symptoms. DATA SYNTHESIS Results of treatment and prevention of pityriasis versicolor infection in 8327 participants in 93 controlled trials were examined. Overall, trials investigating the efficacy of therapeutic and prophylactic treatments for pityriasis versicolor are poorly reported and may be of low quality. Most trials did not adequately report the methods of randomization, concealment of allocation, and blinding, and many did not use intention-to-treat analysis. Most topical treatments used to treat pityriasis versicolor are effective compared with placebo, with numbers needed to treat of 1 to 3. Data suggest that longer durations of treatment and higher concentrations of active agents produce greater cure rates. CONCLUSIONS Most topical and systemic treatments used for pityriasis versicolor are effective compared with placebo. Randomized controlled clinical trials are needed to establish relative efficacy of topical and systemic agents used for treatment and prevention of pityriasis versicolor.

Urban legends series: lichen planus

Oral Diseases (2012) Lichen planus (LP) is a common disorder affecting the oral cavity (OLP) and skin. Despite intensive research, LP/OLP etiology and treatment remain controversial. We investigated four controversial topics: (i) Is hepatitis C virus (HCV) infection associated with LP and involved in its pathogenesis? (ii) Should all patients with LP be screened for HCV? (iii) Should patients with OLP have all their amalgam restorations removed? (iv) Are there any new treatments for OLP? Results from extensive literature searches suggested that: (i) Robust evidence from three meta-analyses indicate that HCV is associated with LP and might be involved in OLP pathogenesis (ii) It would be prudent to screen patients with LP/OLP at significant risk with an ELISA for HCV antibodies using country-specific screening strategies (iii) There is no evidence that either OLP or oral lichenoid lesions patients would routinely benefit from having all their amalgam restorations replaced. Weak evidence from potentially very biased, small, non-randomized, unblinded studies suggests that a small fraction of patients may benefit from targeted amalgam replacement. (iv) There is weak evidence that, among new OLP treatments, topical pimecrolimus, aloe vera, and oral curcuminoids may be useful. The development of specific formulations for oral delivery of topical medications is a promising field.