Hydroxyurea-induced genital ulcers and erosions: Two case reports.

Hydroxyurea is a chemotherapeutic agent used for myeloproliferative disorders and sickle cell anemia that is well known to cause painful mucocutaneous ulcers, typically involving the legs or mouth. However, genital ulcerations due to hydroxyurea therapy are a rare, and likely underrecognized, adverse effect with only a few cases reported in the literature to date. Ulcers of the lower legs caused by hydroxyurea are associated with a diagnostic delay, and this is likely exacerbated in cases of genital ulceration due to a lack of awareness. Herein we present two cases of painful genital ulceration in patients on hydroxyurea therapy. In the first Case, an 87 year-old male with polycythemia vera developed an ulcer on the scrotum, which was assessed initially through virtual visits during the COVID-19 pandemic, and was refractory to topical and oral antibiotic treatments. The second case was a 79 year-old male with essential thrombocythemia and a history of persistent leg ulcers who developed erosions of the glans penis. Both patients experienced complete resolution within weeks of discontinuing hydroxyurea therapy. In conclusion, genital ulcers and erosions induced by hydroxyrea may be underrecognized in clinical practice, but if identified, withdrawal of hydroxyurea leads to quick resolution of these lesions and the associated pain.

Efficacy of Systemic Dapsone Treatment for Pyoderma Gangrenosum: A Retrospective Review.

INTRODUCTION: Pyoderma gangrenosum (PG) is a neutrophilic dermatosis commonly treated with steroid immunosuppression. The utility of dapsone as a non-immunosuppressive treatment for PG has been reported in case reports and series. We sought to evaluate the response and tolerability of concurrent systemic dapsone therapy for treating PG. METHODS: We reviewed PG patients treated with systemic dapsone at Massachusetts General Hospital and Brigham and Women's Hospital from 2000-2015. A treatment episode was defined as a minimum of 4 weeks of dapsone therapy with a documented response of complete, partial, or no improvement in wound healing. RESULTS: 27 patients treated with systemic dapsone met inclusion criteria. 15.6% of treatment episodes demonstrated a response of complete healing, 81.3% of treatment episodes demonstrated a response of partial improvement, and 1 patient (3.1%) demonstrated no response. 9 patients (33.3%) had documented side effects of varying severity, with one (3.7%) requiring cessation of dapsone therapy. DISCUSSION: Systemic dapsone therapy may represent an effective and tolerable non-immunosuppressive adjuvant treatment for PG wound healing. J Drugs Dermatol. 2018;17(10):1058-1060.

Two Cases of Severe Erosive Pustular Dermatosis Mimicking Infection.

INTRODUCTION: Erosive pustular dermatosis of the scalp (EPDS) is a noninfectious inflammatory disorder characterized by pustules, erosions, ulcerations, and crusted erythematous plaques that is often associated with mechanical or chemical trauma. While its appearance may mimic infection, its etiology is thought to have an autoimmune component based on responsiveness to immunomodulators. CASE REPORT: Herein, the authors present 2 cases of EPDS that were initially treated as primary infections. In both cases, the wounds did not respond to antimicrobial treatment and led to severe ulceration, exposing cranial bone. Both wounds improved with topical corticosteroid therapy. CONCLUSIONS: These cases represent the importance of considering topical steroid treatment and a diagnosis of EPDS after debridement for purulent scalp ulcers.

The Association of Age With Clinical Presentation and Comorbidities of Pyoderma Gangrenosum.

Importance: Pyoderma gangrenosum is an inflammatory neutrophilic dermatosis. Current knowledge of this rare disease is limited owing to a lack of validated diagnostic criteria and large population studies. Objective: To evaluate the association of age with the clinical presentation and comorbidities of pyoderma gangrenosum. Design, Setting, and Participants: This was a multicenter retrospective cohort study performed at tertiary academic referral centers in urban settings. Adults (≥18 years) who were evaluated and diagnosed as having pyoderma gangrenosum at the Brigham and Women's and Massachusetts General Hospitals from 2000 to 2015 and the University of Pennsylvania Health System from 2006 to 2016 were included. Main Outcomes and Measures: Patient demographics, clinical features, medical comorbidities, and treatment. Results: Of the 356 validated cases of pyoderma gangrenosum included in the study, 267 (75%) were women and 284 (84.8%) were white. The mean (SD) age at presentation was 51.6 (17.7) years. Pathergy was recorded in 100 patients (28.1%). A total of 238 patients (66.9%) had associated medical comorbidities: inflammatory bowel disease in 146 patients (41.0%); inflammatory arthritis in 73 patients (20.5%); solid organ malignant neoplasms in 23 patients (6.5%); hematologic malignant neoplasms in 21 patients (5.9%); and hematologic disorders, specifically monoclonal gammopathy of undetermined significance, myelodysplastic syndrome, and polycythemia vera in 17 patients (4.8%). When stratified by age, pathergy was more common in patients 65 years or older (36.3% vs 24.3%; P = .02). Inflammatory bowel disease was the only medical comorbidity that was more common in patients younger than 65 years (47.7% vs 26.6%; P < .001), while a number of medical comorbidities were more common in those 65 years or older, including rheumatoid arthritis (13.3% vs 6.2%; P = .03), ankylosing spondylitis (1.8% vs 0%; P = .04), solid organ malignant neoplasms (13.3% vs 3.3%; P < .001), hematologic malignant neoplasms (9.7% vs 4.1%; P = .04), and the aforementioned hematologic disorders (10.6% vs 2.1%; P < .001). Conclusions and Relevance: Although clinical presentation in this large cohort was similar between different age groups, disease associations varied by age. The findings of this study may allow for a more focused, age-specific evaluation of patients with pyoderma gangrenosum.

Risk of developing pyoderma gangrenosum after procedures in patients with a known history of pyoderma gangrenosum-A retrospective analysis.

BACKGROUND: The risk of postoperative pyoderma gangrenosum (PG) in patients with a known history of PG is unknown. OBJECTIVE: To quantify risk and identify patient- and/or procedure-related risk factors for postsurgical recurrence or exacerbation of PG in patients with a known history of PG. METHODS: We retrospectively evaluated the likelihood of postsurgical recurrence or exacerbation of PG for all patients with a confirmed diagnosis of PG at Brigham and Women's Hospital and Massachusetts General Hospital from 2000 to 2015. RESULTS: In all, 5.5% of procedures (n = 33) led to recurrence of PG in 15.1% of patients (n = 25). Compared with skin biopsy, small open surgical procedures had an adjusted odds ratio (aOR) of 8.65 (95% confidence interval [CI], 1.55-48.33) for PG recurrence or exacerbation; large open surgical procedures had an aOR of 5.97 (95% CI, 1.70-21.00); and Mohs micrographic surgery/skin excision had an aOR of 6.47 (95% CI, 1.77-23.61). PG chronically present at the time of the procedure had an aOR of 4.58 (95% CI, 1.72-12.22). Immunosuppression, time elapsed since the original PG diagnosis, and procedure location did not significantly influence risk. LIMITATIONS: Our study is limited by its retrospective nature and relatively small sample size. CONCLUSION: There is a small but clinically meaningful risk for postsurgical recurrence or exacerbation of PG in patients with a known history of PG; higher risks occur with more invasive procedures and chronically present PG.

Factors influencing vitamin D status.

The steroid hormone vitamin D is required for normal calcium and phosphorus metabolism and is thus an important contributor to musculoskeletal health. Recent data have linked low vitamin D levels to a wide range of diseases, including cancer, cardiovascular disease, autoimmune disease and infection. Adequate levels of vitamin D are maintained through its cutaneous photosynthesis and oral ingestion. By some estimates, one billion people worldwide have vitamin D deficiency or insufficiency. A number of factors influence the photosynthesis and bioavailability of vitamin D and contribute to risk of impaired vitamin D status. These factors include variation in sun exposure due to latitude, season, time of day, atmospheric components, clothing, sunscreen use and skin pigmentation, as well as age, obesity and the incidence of several chronic illnesses. This review will focus on factors that influence vitamin D status and contribute to the prevalence of low vitamin D levels.

IGF-I activation of the AKT pathway is impaired in visceral but not subcutaneous preadipocytes from obese subjects.

Obesity morbidity is associated with excess visceral adiposity, whereas sc adipose tissue is much less metabolically hazardous. Human abdominal sc preadipocytes have greater capacity for proliferation, differentiation, and survival than omental preadipocytes. IGF-I is a critical mediator of preadipocyte proliferation, differentiation, and survival through multiple signaling pathways. We investigated IGF-I action in primary cultures of human preadipocytes isolated from sc and omental adipose tissue of obese subjects. IGF-I-stimulated DNA synthesis was significantly lower in omental compared with sc preadipocytes. IGF-I phosphorylation of the IGF-I receptor and the ERK pathway was comparable in sc and omental cells. However, omental preadipocytes had decreased insulin receptor substrate (IRS)-1 protein associated with increased IRS-1-serine(636/639) phosphorylation and degradation. IGF-I-stimulated phosphorylation of AKT on serine(473) but not threonine(308) was decreased in omental cells, and activation of downstream targets, including S6Kinase, glycogen synthase kinase-3, and Forkhead box O1 was also impaired. CyclinD1 abundance was decreased in omental cells due to increased degradation. Over-expression of IRS-1 by lentivirus in omental preadipocytes increased IGF-I-stimulated AKT-serine(473) phosphorylation. The mammalian target of rapamycin (mTOR)-Rictor complex regulates phosphorylation of AKT-serine(473) in 3T3-L1 adipocytes, but knockdown of Rictor by lentivirus-delivered short hairpin RNA in sc preadipocytes did not affect AKT-serine(473) phosphorylation by IGF-I. These data reveal an intrinsic defect in IGF-I activation of the AKT pathway in omental preadipocytes from obese subjects that involves IRS-1 but probably not mTOR-Rictor complex. We conclude that impaired cell cycle regulation by AKT contributes to the distinct growth phenotype of preadipocytes in visceral fat of obese subjects.

GIGYF2 gene disruption in mice results in neurodegeneration and altered insulin-like growth factor signaling.

Grb10-Interacting GYF Protein 2 (GIGYF2) was initially identified through its interaction with Grb10, an adapter protein that binds activated IGF-I and insulin receptors. The GIGYF2 gene maps to human chromosome 2q37 within a region linked to familial Parkinson's disease (PARK11 locus), and association of GIGYF2 mutations with Parkinson's disease has been described in some but not other recent publications. This study investigated the consequences of Gigyf2 gene disruption in mice. Gigyf2 null mice undergo apparently normal embryonic development, but fail to feed and die within the first 2 post-natal days. Heterozygous Gigyf2(+/-) mice survive to adulthood with no evident metabolic or growth defects. At 12-15 months of age, the Gigyf2(+/-) mice begin to exhibit motor dysfunction manifested as decreased balance time on a rotating horizontal rod. This is associated with histopathological evidence of neurodegeneration and rare intracytoplasmic Lewy body-like inclusions in spinal anterior horn motor neurons. There are alpha-synuclein positive neuritic plaques in the brainstem and cerebellum, but no abnormalities in the substantia nigra. Primary cultured embryo fibroblasts from Gigyf2 null mice exhibit decreased IGF-I-stimulated IGF-I receptor tyrosine phosphorylation and augmented ERK1/2 phosphorylation. These data provide further evidence for an important role of GIGYF2 in age-related neurodegeneration and IGF pathway signaling.

Mutations in the GIGYF2 (TNRC15) gene at the PARK11 locus in familial Parkinson disease.

The genetic basis for association of the PARK11 region of chromosome 2 with familial Parkinson disease (PD) is unknown. This study examined the GIGYF2 (Grb10-Interacting GYF Protein-2) (TNRC15) gene, which contains the PARK11 microsatellite marker with the highest linkage score (D2S206, LOD 5.14). The 27 coding exons of the GIGYF2 gene were sequenced in 123 Italian and 126 French patients with familial PD, plus 131 Italian and 96 French controls. A total of seven different GIGYF2 missense mutations resulting in single amino acid substitutions were present in 12 unrelated PD index patients (4.8%) and not in controls. Three amino acid insertions or deletions were found in four other index patients and absent in controls. Specific exon sequencing showed that these ten sequence changes were absent from a further 91 controls. In four families with amino acid substitutions in which at least one other PD case was available, the GIGYF2 mutations (Asn56Ser, Thr112Ala, and Asp606Glu) segregated with PD. There were, however, two unaffected carriers in one family, suggesting age-dependent or incomplete penetrance. One index case (PD onset age 33) inherited a GIGYF2 mutation (Ile278Val) from her affected father (PD onset age 66) and a previously described PD-linked mutation in the LRRK2 gene (Ile1371Val) from her affected mother (PD onset age 61). The earlier onset and severe clinical course in the index patient suggest additive effects of the GIGYF2 and LRRK2 mutations. These data strongly support GIGYF2 as a PARK11 gene with a causal role in familial PD.

Encapsulated cell-based delivery of CNTF reduces photoreceptor degeneration in animal models of retinitis pigmentosa.

PURPOSE: The objective of the present study was to evaluate the therapeutic efficacy of ciliary neurotrophic factor (CNTF) delivered through encapsulated cells directly into the vitreous of the eye in an rcd1 canine model of retinitis pigmentosa. The dose-range effect of the treatment was also investigated. METHODS: Polymer membrane capsules (1.0 cm in length and 1.0 mm in diameter) were loaded with mammalian cells that were genetically engineered to secrete CNTF. The cell-containing capsules were then surgically implanted into the vitreous of one eye of rcd1 dogs at 7 weeks of age, when retinal degeneration is in progress but not complete. The contralateral eyes were not treated. The capsules remained in the eyes for 7 weeks. At the end of the studies, the capsules were explanted, and CNTF output and cell viability were evaluated. The eyes were processed for histologic evaluation. RESULTS: In each animal, the number of rows of photoreceptor nuclei in the outer nuclear layer (ONL) was significantly higher in the eye that received a CNTF-secreting implant than in the untreated contralateral eye. No adverse effects were observed on the retina in the treated eyes. The explanted capsules produced a low level of CNTF. The cells in the capsules remained viable and densely distributed throughout. CONCLUSIONS: CNTF delivered through encapsulated cells directly into the vitreous of the eye protects photoreceptors in the PDE6B-deficient rcd1 canine model. Furthermore, sparing of photoreceptors appeared dose-dependent with minimum protection observed at CNTF doses of 0.2 to 1.0 ng/d. Incrementally greater protection was achieved at higher doses. The surgically implanted, cell-containing capsules were well tolerated, and the cells within the capsule remained viable for the 7-week implantation interval. These results suggest that encapsulated cell therapy may provide a safe and effective strategy for treating retinal disorders in humans.

Receptor-specific regulation of phosphatidylinositol 3'-kinase activation by the protein tyrosine phosphatase Shp2.

Receptor tyrosine kinases (RTKs) play distinct roles in multiple biological systems. Many RTKs transmit similar signals, raising questions about how specificity is achieved. One potential mechanism for RTK specificity is control of the magnitude and kinetics of activation of downstream pathways. We have found that the protein tyrosine phosphatase Shp2 regulates the strength and duration of phosphatidylinositol 3'-kinase (PI3K) activation in the epidermal growth factor (EGF) receptor signaling pathway. Shp2 mutant fibroblasts exhibit increased association of the p85 subunit of PI3K with the scaffolding adapter Gab1 compared to that for wild-type (WT) fibroblasts or Shp2 mutant cells reconstituted with WT Shp2. Far-Western analysis suggests increased phosphorylation of p85 binding sites on Gab1. Gab1-associated PI3K activity is increased and PI3K-dependent downstream signals are enhanced in Shp2 mutant cells following EGF stimulation. Analogous results are obtained in fibroblasts inducibly expressing dominant-negative Shp2. Our results suggest that, in addition to its role as a positive component of the Ras-Erk pathway, Shp2 negatively regulates EGF-dependent PI3K activation by dephosphorylating Gab1 p85 binding sites, thereby terminating a previously proposed Gab1-PI3K positive feedback loop. Activation of PI3K-dependent pathways following stimulation by other growth factors is unaffected or decreased in Shp2 mutant cells. Thus, Shp2 regulates the kinetics and magnitude of RTK signaling in a receptor-specific manner.