Safety of Antiandrogens for the Treatment of Female Androgenetic Alopecia with Respect to Gynecologic Malignancies.

The most common type of alopecia in women is female androgenetic alopecia (FAGA), characterized by progressive hair loss in a patterned distribution. Many oral therapies, including spironolactone (an aldosterone antagonist), androgen receptor blockers (e.g., flutamide/bicalutamide), 5-alpha-reductase inhibitors (e.g., finasteride/dutasteride), and oral contraceptives, target the mechanism of androgen conversion and binding to its respective receptor and therefore could be administered for the treatment of FAGA. Despite significant advances in the oral treatment of FAGA, its management in patients with a history of gynecological malignancies, the most common cancers in women worldwide, may still be a concern. In this review, we focus on the safety of antiandrogens for the treatment of FAGA patients. For this purpose, a targeted literature review was conducted on PubMed, utilizing the relevant search terms. To sum up, spironolactone seems to be safe for the systemic treatment of FAGA, even in high-risk populations. However, a general uncertainty remains regarding the safety of other medications in patients with a history of gynecologic malignancies, and further studies are needed to evaluate their long-term safety in patients with FAGA and risk factors to establish an optimal risk assessment and treatment selection protocol.

Efficacy of Methotrexate Alone vs Methotrexate Plus Low-Dose Prednisone in Patients With Alopecia Areata Totalis or Universalis: A 2-Step Double-Blind Randomized Clinical Trial.

Importance: Poor therapeutic results have been reported in patients with alopecia areata totalis (AT) or universalis (AU), the most severe and disabling types of alopecia areata (AA). Methotrexate, an inexpensive treatment, might be effective in AU and AT. Objective: To evaluate the efficacy and tolerance of methotrexate alone or combined with low-dose prednisone in patients with chronic and recalcitrant AT and AU. Design, Setting, and Participants: This academic, multicenter, double-blind, randomized clinical trial was conducted at 8 dermatology departments at university hospitals between March 2014 and December 2016 and included adult patients with AT or AU evolving for more than 6 months despite previous topical and systemic treatments. Data analysis was performed from October 2018 to June 2019. Interventions: Patients were randomized to receive methotrexate (25 mg/wk) or placebo for 6 months. Patients with greater than 25% hair regrowth (HR) at month 6 continued their treatment until month 12. Patients with less than 25% HR were rerandomized: methotrexate plus prednisone (20 mg/d for 3 months and 15 mg/d for 3 months) or methotrexate plus placebo of prednisone. Main Outcome and Measures: The primary end point assessed on photos by 4 international experts was complete or almost complete HR (Severity of Alopecia Tool [SALT] score <10) at month 12, while receiving methotrexate alone from the start of the study. Main secondary end points were the rate of major (greater than 50%) HR, quality of life, and treatment tolerance. Results: A total of 89 patients (50 female, 39 male; mean [SD] age, 38.6 [14.3] years) with AT (n = 1) or AU (n = 88) were randomized: methotrexate (n = 45) or placebo (n = 44). At month 12, complete or almost complete HR (SALT score <10) was observed in 1 patient and no patient who received methotrexate alone or placebo, respectively, in 7 of 35 (20.0%; 95% CI, 8.4%-37.0%) patients who received methotrexate (for 6 or 12 months) plus prednisone, including 5 of 16 (31.2%; 95% CI, 11.0%-58.7%) who received methotrexate for 12 months and prednisone for 6 months. A greater improvement in quality of life was observed in patients who achieved a complete response compared with nonresponder patients. Two patients in the methotrexate group discontinued the study because of fatigue and nausea, which were observed in 7 (6.9%) and 14 (13.7%) patients receiving methotrexate, respectively. No severe treatment adverse effect was observed. Conclusions and Relevance: In this randomized clinical trial, while methotrexate alone mainly allowed partial HR in patients with chronic AT or AU, its combination with low-dose prednisone allowed complete HR in up to 31% of patients. These results seem to be of the same order of magnitude as those recently reported with JAK inhibitors, with a much lower cost. Trial Registration: ClinicalTrials.gov Identifier: NCT02037191.

Targeted heat activation of HSP promoters in the skin of mammalian animals and humans.

The use of highly inducible HSP promoters for exerting spatial and/or temporal control over the expression of therapeutic transgenes has long been discussed. Localized and time-limited induction of the heat shock response may potentially also be of medical interest. However, such applications would require targeted delivery of heat doses capable of activating HSP promoters in tissues or organs of interest. Accessible areas, including the skin and tissues immediately underneath it, may be most readily targeted. A few applications for heat-directed or heat-controlled therapy in the skin might involve expression of proteins to restore or protect normal skin function, protein antigens for vaccination/immunotherapy, vaccine viruses or even systemically active proteins, e.g., cytokines and chemokines. A review of the literature relating to localized heat activation of HSP promoters and HSP genes in the skin revealed that a multitude of different technologies has been explored in small animal models. In contrast, we uncovered few publications that examine HSP promoter activation in human skin. None of these publications has a therapeutic focus. We present herein two, clinically relevant, developments of heating technologies that effectively activate HSP promoters in targeted regions of human skin. The first development advances a system that is capable of reliably activating HSP promoters in human scalp, in particular in hair follicles. The second development outlines a simple, robust, and inexpensive methodology for locally activating HSP promoters in small, defined skin areas.

Familial occurrence of an association of multiple intestinal atresia and choanal atresia: a new syndrome?

We report on two familial cases from a non-consanguineous marriage, presenting multiple intestinal and choanal atresia. Massive hydramnios and dilatation of the bowel were observed at 29 weeks of gestation during routine ultrasound scan of a healthy mother. The fetal karyotype was normal and cystic fibrosis screening was negative. Regular scans were performed throughout the pregnancy. The child was born at 34 weeks gestation. Choanal atresia was diagnosed at birth and abdominal investigations showed multiple atresia interesting both the small bowel and the colon. Further interventions were necessary because of recurrent obstructions. During the following pregnancy, a dilatation of the fetal intestinal tract was detected by ultrasonography at 27 weeks of gestation. Pregnancy was interrupted. Post-mortem examination of the fetus confirmed the stenosis of long segments of the small intestine associated with areas of colonic atresia. In both cases, histology and distribution were consistent with those reported in hereditary multiple intestinal atresia (HMIA). An association between multiple intestinal and choanal atresia has never been reported. We suggest it could correspond to a new autosomal recessive entity for which cytogenetic investigations and high-resolution array CGH revealed no visible anomalies.

Uncombable hair syndrome: a clinical report.

Uncombable hair syndrome, also named "pili trianguli et canaliculi" or "cheveux incoiffables", is a rare structural anomaly of the hair shaft first reported in 1973. Both inherited and sporadic forms have been described, characterized by dry and frizzy scalp hair that is impossible to comb. Diagnosis is suspected clinically and confirmed by scanning electron microscopy. The condition is usually isolated, however, several physical abnormalities can be associated. We report the case of a 2(1/2) year old-girl presenting isolated uncombable hair syndrome suspected clinically and confirmed by scanning electron microscopy.

SLURP1 is a late marker of epidermal differentiation and is absent in Mal de Meleda.

SLURP1 is a secreted member of the LY6/PLAUR protein family. Mutations in the SLURP1 gene are the cause of Mal de Meleda (MDM), a rare autosomal recessive genetic disease, characterized by inflammatory palmoplantar keratoderma. In this study, we have analyzed the expression of SLURP1 in normal and MDM skin. SLURP1 was found to be a marker of late differentiation, predominantly expressed in the granular layer of skin, notably the acrosyringium. Moreover, SLURP1 was also identified in several biological fluids such as sweat, saliva, tears, and urine from normal volunteers. In palmoplantar sections from MDM patients, as well as in their sweat, mutant SLURP1, including the new variant R71H-SLURP1, was either absent or barely detectable. Transfected human embryonic kidney 293T cells expressed the MDM mutant SLURP1 containing the single amino-acid substitution G86R but did not tolerate the MDM mutation W15R located in the signal peptide. Thus, most MDM mutations in SLURP1 affect either the expression, integrity, or stability of the protein, suggesting that a simple immunologic test could be used as a rapid screening procedure.

Quasi-normal cornified cell envelopes in loricrin knockout mice imply the existence of a loricrin backup system.

The cornified cell envelope, a lipoprotein layer that assembles at the surface of terminally differentiated keratinocytes, is a resilient structure on account of covalent crosslinking of its constituent proteins, principally loricrin, which accounts for up to 60%-80% of total protein. Despite the importance of the cell envelope as a protective barrier, knocking out the loricrin gene in mice results in only mild syndromes. We have investigated the epidermis and forestomach epithelium of these mice by electron microscopy. In both tissues, corneocytes have normal-looking cell envelopes, despite the absence of loricrin, which was confirmed by immunolabeling, and the absence of the distinctive loricrin-containing keratohyalin granules (L-granules). Isolated cell envelopes were normal in thickness (approximately 15 nm) and mass per unit area (approximately 7.3 kDa per nm2); however, metal shadowing revealed an altered substructure on their cytoplasmic surface. Their amino acid compositions indicate altered protein compositions. Analysis of these data implies that the epidermal cell envelopes have elevated levels of the small proline-rich proteins, and cell envelopes of both kinds contain other protein(s) that, like loricrin, are rich in glycine and serine. These observations imply that, in the absence of loricrin, the mechanisms that govern cell envelope assembly function normally but employ different building-blocks.