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Pseudoxanthoma elasticum (PXE) is a pleiotropic multisystem disorder affecting skin, eyes, and the cardiovascular system with progressive pathological mineralization. It is caused by mutations in the ABCC6 gene expressed primarily in the liver and kidneys, and at very low levels, if at all, in tissues affected by PXE. A question has arisen regarding the pathomechanism of PXE, particularly the “metabolic” versus the “PXE cell” hypotheses. We examined a murine PXE model (Abcc6−/−) by transplanting muzzle skin from knock-out (KO) and wild-type (WT) mice onto the back of WT and KO mice using mineralization of the connective tissue capsule surrounding the vibrissae as an early phenotypic biomarker. Grafting of WT mouse muzzle skin onto the back of KO mice resulted in mineralization of vibrissae, while grafting KO mouse muzzle skin onto the WT mice did not. Thus, these findings implicate circulatory factors as a critical component of the mineralization process. This mouse grafting model supports the notion that PXE is a systemic metabolic disorder with secondary mineralization of connective tissues and that the mineralization process can be countered or even reversed by changes in the homeostatic milieu.

Diabetic foot ulcers are among the most important complications of diabetes mellitus. In nearly 90% of persons who suffer limb loss from diabetes, ulcers precede amputation, and better and faster healing has been shown to reduce the frequency of amputations (Boulton et al., 2004). Ulcers are also associated with high mortality, and patients who have diabetes and foot ulcers have a 50% greater risk of dying than diabetic patients without a history of foot ulcers (Iversen et al., 2009). Poor healing is often observed in these patients. Therefore, a better understanding of which patients are likely to not heal with standard care and the reasons that these patients do not heal will help identify targets for intervention and indicate which patients may need advanced wound care modalities, such as engineered skin or hyperbaric oxygen. Baseline wound characteristics such as wound size, depth, stage, and duration, as well as 4-week healing rates, have been found to be predictive of the likelihood of complete healing (Margolis et al., 2002). Despite the fact that in vitro studies and animal models suggest that glycemia impairs healing, previous studies have not found hemoglobin A1c (HbA1c) levels to be correlated with healing; however, the study designs may have influenced these results. Using a novel study design, Christman and colleagues (2011, this issue) utilized electronic medical records from an active wound center to assess predictors of healing rates retrospectively. Delineation of wounded patients with diabetes into a “classic” neuropathic foot ulcer group and a complicated-wound group and multivariate analysis revealed that elevated HbA1c levels were associated with slower healing in patients with classic neuropathic diabetic foot ulcers and patients with peripheral vascular disease. Understanding at-risk populations has advantages in many areas, including focusing efforts and health-care dollars, improving treatment compliance, defining patients who need more advanced therapies, and identifying new therapeutic targets. Through the following questions, we examine this paper in greater detail. For brief answers, please refer to the supplementary information online .

QUESTIONS 1. Describe the features of the different types of xeroderma pigmentosum. 2. What is a founder effect? 3. What is the proposed hypothesis and rationale for this study? 4. What methods were employed in the study, and what were the results? 5. What were the conclusions and clinical implications? The occurrence of rare genetic diseases at higher than anticipated rates in selected populations may be the result of a common ancestor in such populations. This phenomenon is referred to as the founder effect. One such example is the occurrence of xeroderma pigmentosum (XP) in the population in the five-country region of North Africa called the Maghreb. In this population, XP occurs more commonly than in other parts of the world. XP is the prototypical nucleotide excision repair (NER) disorder. Via a multistep reaction, NER ordinarily eliminates DNA-distorting lesions caused by UV-induced photoproducts. The two branches of NER are global genome repair (GGR) and transcription-coupled repair. GGR searches nontranscribed regions of the genome for strand distortions, whereas transcription-coupled repair removes lesions that block RNA polymerase (Hoeijmakers, 2009). Eight subtypes of XP have been described. Specific mutations in one NER protein have been reported for each of the XPA-XPG subtypes, and these subtypes all have defective NER. The eighth type, the XP variant, has normal NER but aberrant translesional synthesis. All patients with XP display photosensitivity of varying degrees. Other cutaneous features of this disease include abnormal pigmentation and frequent skin cancers (Kraemer et al., 1987). Neurologic, growth, and ocular abnormalities vary among the eight subtypes, termed complementation groups. To better characterize this distinct population of patients with XP, Soufir et al. studied Maghrebi patients with XP. Through genetic and molecular analysis of a large cohort of 86 patients, a common XPC mutation was identified. Mathematical modeling was employed to determine the likelihood of a common ancestor. Assuming a 20to 30-year generation time, the original mutation was calculated to have occurred 1,250 years ago; on the basis of these results, a founder effect was proposed. Through the following questions, we examine this paper, as well as the mutations that underlie xeroderma pigmentosum, in greater detail. For brief answers, please refer to the supplementary information online

Advances in phototherapy have led to significant improvement in the care of patients with a variety of skin disorders, ranging from psoriasis to vitiligo. The use of narrow-band ultraviolet radiation B (NB-UVB), with peak fluence at 311 nm, has been one such advance. Superior in efficacy to broad-band UVB (BB-UVB), it combines added efficacy similar to that of photochemotherapy (PUVA), with less inconvenience (van Weelden et al., 1988; Coven et al., 1997; Gathers et al., 2002). However, experimental data suggest that the use of NB-UVB is not without cost. Several investigative studies have determined that NB-UVB possesses greater potential for skin carcinogenesis (Flindt-Hansen et al., 1991; Wulf et al., 1994; Gibbs et al., 1995) than BB-UVB, already a known carcinogen (Kraemer, 1997).

Many dermatology training programs in the United States include weekly exercises in which residents and faculty members review selected papers from the medical literature. Such exercises, commonly identified as “journal clubs,” are described in some detail in the program information that is periodically examined by the Residency Review Committee (RRC) for Dermatology. Having served for several years on the RRC for Dermatology, one of us (PRB) has had numerous opportunities to learn about the construction of the various journal clubs around the country. There is great diversity not only in their formats and attendance requirements but also in the types of papers and journals that are reviewed. Importantly, there has been a trend away from the Journal of Investigative Dermatology. And, in parallel, leaders of many training programs have reported increasing difficulty in integrating the basic science literature into this educational activity. That difficulty reflects the growing complexities of science and the expansion of the scientific base from which skin biology and skin pathology continue to emerge.

5. What were the conclusions and implications of the study? The results of well-performed randomized clinical trials (RCT) are considered the highest-quality evidence for altering or supporting clinical practice. Therapeutic options for the treatment of pemphigus vulgaris (PV) have evolved over the 50 years since the initial dramatic results with corticosteroids. Experts have no consensus for the optimal treatment for PV, which is a rare, potentially life-threatening disease (Mimouni and Nousari, 2003; Martin and Murrell, 2008). Indeed, a recent systematic review (Martin et al., 2009) discovered insufficient information for determining the safest and most effective treatment regimen. Therefore, an RCT is imperative to allow treatments to be thoroughly evaluated. In this issue, Beissert et al. (2010) report the results of a 1-year comparison of two doses of mycophenolate mofetil (MMF; 2 or 3 g/d) combined with corticosteroids and steroids alone in treating PV. The authors found no difference in the number of patients responding after 1 year between the treatment groups but found more side effects in the MMF-treated group, particularly in those treated with 3 g/d. Patients treated with MMF, however, were quicker to respond, had a shorter time to sustained response, and exhibited a longer time before relapse. MMF also resulted in steroid-sparing effects because the cumulative dose of prednisone was approximately 1 g less in MMF-treated patients. Unfortunately, this latter finding was not associated with decreased side effects or decreased morbidity during the study period. The implications of this study remain uncertain. Will dermatologists abandon (or at least use lower doses of) MMF, or will the reported secondary outcomes of faster response and steroid-sparing effects sustain its use? Through the following questions, we examine this paper, as well as the subject of PV treatment, in greater detail. For brief answers, please refer to the supplementary information online

Thyroid disease is common, and it often affects the skin. In fact, autoimmune thyroid diseases (AITDs) such as Graves disease and chronic lymphocytic thyroiditis affect 5% of the population; accordingly, they are the most common organ-specific autoimmune diseases (Stassi and De Maria, 2002; Weetman, 2003; Jacobson and Tomer, 2007). Although cutaneous manifestations of AITD are well described and thyroid hormone is known to regulate the development and function of skin (Leonhardt and Heymann, 2002; Burman and McKinley-Grant, 2006), a better understanding of these processes is needed. Therefore, Cianfarani et al. (2010, this issue) analyzed normal human skin, cultures of keratinocytes and dermal fibroblasts, and serum of patients with AITDs in hopes of elucidating the role of thyroid-specific molecules.