Vascular progenitors generated from tankyrase inhibitor-regulated naïve diabetic human iPSC potentiate efficient revascularization of ischemic retina.

Here, we report that the functionality of vascular progenitors (VP) generated from normal and disease-primed conventional human induced pluripotent stem cells (hiPSC) can be significantly improved by reversion to a tankyrase inhibitor-regulated human naïve epiblast-like pluripotent state. Naïve diabetic vascular progenitors (N-DVP) differentiated from patient-specific naïve diabetic hiPSC (N-DhiPSC) possessed higher vascular functionality, maintained greater genomic stability, harbored decreased lineage-primed gene expression, and were more efficient in migrating to and re-vascularizing the deep neural layers of the ischemic retina than isogenic diabetic vascular progenitors (DVP). These findings suggest that reprogramming to a stable naïve human pluripotent stem cell state may effectively erase dysfunctional epigenetic donor cell memory or disease-associated aberrations in patient-specific hiPSC. More broadly, tankyrase inhibitor-regulated naïve hiPSC (N-hiPSC) represent a class of human stem cells with high epigenetic plasticity, improved multi-lineage functionality, and potentially high impact for regenerative medicine.

Thalidomide for the treatment of chronic refractory prurigo nodularis.

Prurigo nodularis (PN) is a highly pruritic skin condition that is caused by chronic scratching. It occurs in patients with chronic itch and is characterized by multiple hyperkeratotic papules and nodules. The pathogenesis of PN is unclear, but involves a complex interplay of numerous pathways including neurogenic and inflammatory factors. As such, PN is very difficult to treat and patients are often refractory to multiple medications before finding a treatment that is effective. We present a woman with a 20-year history of exuberant prurigo nodularis who failed multiple therapies, including dapsone, azathioprine, mycophenolic acid, prednisone, topical steroids, and phototherapy. She only obtained significant relief of chronic pruritus and lesion flattening with thalidomide 100mg daily. Thalidomide is an antipruritic and anti-inflammatory agent that has shown to be very effective in treating a variety of dermatologic conditions. However, its use today is limited by concerns for its teratogenic and neuropathic side effects. With strict adherence to medication protocols, these adverse effects can be minimized. As such, thalidomide should be considered for patients with refractory dermatologic conditions.

Trends in Atopic Dermatitis Management: Comparison of 1990-1997 to 2003-2012.

BACKGROUND: Atopic dermatitis (AD) is primarily treated with topical therapies, systemic immunosuppressants, or adjunctive therapies. OBJECTIVE: As novel treatment approaches for AD emerge, we characterize AD treatment and examine trends in treatment over time. METHODS: Visits for AD were identified in the 2003-2012 National Ambulatory Medical Care Survey (NAMCS). We identified topical corticosteroids (TCS), antibiotics (Abx), antihistamines (AH), topical calcineurin inhibitors (TCI), and systemic immunosuppressants (SI) prescribed at AD visits. RESULTS: There were 990,000 annual visits for AD from 2003-2012 (3.2 visits/1000 people/year). TCS were the most frequently used medication (59% of visits). Topical calcineurin inhibitors (TCI) were the second most prescribed medication for AD among dermatologists (23% of visits), while antihistamines were second among all other physicians (16-44% of visits). Unlike other medications, use of TCIs decreased over time. LIMITATIONS: The NAMCS does not follow individual patients over time. CONCLUSIONS: TCI use has been decreasing. New topical AD treatments may provide an alternative to TCS, better treatment outcomes for moderate-to-severe atopic dermatitis, and an alternative to systemic antihistamines whose efficacy in AD is unproven and whose general use in AD management is discouraged by the American Academy of Dermatology. J Drugs Dermatol. 2018;17(2):135-140.

An assessment of the use of antihistamines in the management of atopic dermatitis.

BACKGROUND: Antihistamines are often used to treat pruritus associated with atopic dermatitis (AD) despite lack of evidence for their efficacy. The American Academy of Dermatology does not recommend the general use of antihistamines in the management of AD, although the value of short-term sedating antihistamine use for insomnia secondary to itch is recognized. OBJECTIVE: To assess the use of sedating and nonsedating antihistamines for AD in 2003-2012. METHODS: The National Ambulatory Medical Care Survey provided data on physician visits in 2003-2012. Sedating and nonsedating antihistamine use was identified at visits for AD. RESULTS: There were 990,000 annual visits for AD. Antihistamines were prescribed for AD in a significant proportion of visits across physician specialties (16%-44%). Dermatologists and pediatricians primarily used sedating antihistamines (58%-70%), whereas the majority of family/general practitioners, internists, and other specialists prescribed nonsedating antihistamines for AD (55%-100%) LIMITATIONS: We were limited by the accuracy of AD diagnosis and medication recording. CONCLUSIONS: Antihistamines are widely used for the treatment of AD. There is no high-level evidence to suggest that nonsedating antihistamines reduce itch in patients with AD or that sedating antihistamines provide benefit in controlling AD symptoms (except perhaps sleep and AD comorbidities, such as allergic rhinitis).

Aprepitant for the Treatment of Chronic Refractory Pruritus.

Chronic pruritus is a difficult condition to treat and is associated with several comorbidities, including insomnia, depression, and decreased quality of life. Treatment for chronic itch includes corticosteroids, antihistamines, and systemic therapies such as naltrexone, gabapentin, UV light therapy, and immunomodulatory treatments, including azathioprine, methotrexate, and cellcept. However, some patients still remain refractory to conventional therapy. Aprepitant is a neurokinin-1 receptor antagonist approved for the prevention of chemotherapy-induced and postoperative nausea and vomiting (CINV, PONV). Recently, aprepitant has demonstrated effectiveness in several case series and open label trials in relieving pruritus for patients refractory to other treatments. Patients with pruritus associated with Sézary syndrome, mycosis fungoides, lung adenocarcinoma, breast carcinoma, sarcomas, metastatic solid tumors, chronic kidney disease, hyperuricemia, iron deficiency, brachioradial pruritus, and Hodgkin's lymphoma have experienced considerable symptom relief with short-term use of aprepitant (up to two weeks). Due to differences in reporting and evaluation of drug effects, the mechanism of aprepitant's role is difficult to understand based on the current literature. Herein, we evaluate aprepitant's antipruritic effects and discuss its mechanism of action and adverse effects. We propose that aprepitant is an alternative for patients suffering from pruritus who do not obtain enough symptom relief from conventional therapy.

The Emerging Zika Virus Threat: A Guide for Dermatologists.

We provide a guide for dermatologists to follow if they encounter patients with a rash and clinical history suspicious of Zika virus infection, including diagnostic testing and management options. We also provide an illustrative case report of a patient from Brazil who was diagnosed with Zika virus infection after presenting with a generalized pruritic rash. One of the most prominent symptoms of Zika virus infection is a cutaneous eruption. As such, it is especially necessary for dermatologists to understand this virus so that they may appropriately recognize this entity as a diagnostic consideration in the clinic. The rash associated with Zika virus infection is most commonly an erythematous maculopapular eruption that presents after an initial 3-4 days of fever, headache, and arthralgia or myalgia. The rash typically lasts for an average of 6 days, and can spread to involve any part of the body, including the face, torso, extremities, palms, and soles.

Mandarin Tone Identification in Cochlear Implant Users Using Exaggerated Pitch Contours.

OBJECTIVE: To determine whether exaggerating the variations in fundamental frequency (F0) contours of Mandarin-based pitch fluctuations could improve tone identification by cochlear implant (CI) users. METHODS: Twelve normal-hearing (NH) listeners and 11 CI users were tested for their ability to recognize F0 contours modeled after Mandarin tones, in 4- or 5-alternatives forced-choice paradigms. Two types of stimuli were used: computer-generated complex tones and voice recordings. Four contours were tested with voice recordings: flat, rise, fall, and dip. A fifth contour, peak, was added for complex tones. The F0 range of each contour was varied in an adaptive manner. A maximum-likelihood technique was used to fit a psychometric function to the performance data and extract threshold at 70% accuracy. RESULTS: As F0 range increased, performance in tone identification improved but did not reach 100% for some CI users, suggesting that confusions between contours could always be made even with extremely exaggerated contours. Compared with NH participants, CI users required substantially larger F0 ranges to identify tones, on the order of 9.3 versus 0.4 semitones. CI users achieved better performance for complex tones than for voice recordings, whereas the reverse was true for NH participants. Confusion matrices showed that the "flat" tone was often a default option when the tone contour's F0 range presented was too narrow for participants to respond correctly. CONCLUSION: These results demonstrate markedly impaired ability for CI users to identify tonal contours, but suggest that the use of exaggerated pitch contours may be helpful for tonal language perception.

The PDL1-PD1 axis converts human TH1 cells into regulatory T cells.

Immune surveillance by T helper type 1 (T(H)1) cells is not only critical for the host response to tumors and infection, but also contributes to autoimmunity and graft-versus-host disease (GVHD) after transplantation. The inhibitory molecule programmed death ligand 1 (PDL1) has been shown to anergize human T(H)1 cells, but other mechanisms of PDL1-mediated T(H)1 inhibition such as the conversion of T(H)1 cells to a regulatory phenotype have not been well characterized. We hypothesized that PDL1 may cause T(H)1 cells to manifest differentiation plasticity. Conventional T cells or irradiated K562 myeloid tumor cells overexpressing PDL1 converted TBET(+) T(H)1 cells into FOXP3(+) regulatory T (T(reg)) cells in vivo, thereby preventing human-into-mouse xenogeneic GVHD (xGVHD). Either blocking PD1 expression on T(H)1 cells by small interfering RNA targeting or abrogation of PD1 signaling by SHP1/2 pharmacologic inhibition stabilized T(H)1 cell differentiation during PDL1 challenge and restored the capacity of T(H)1 cells to mediate lethal xGVHD. PD1 signaling therefore induces human T(H)1 cells to manifest in vivo plasticity, resulting in a T(reg) phenotype that severely impairs cell-mediated immunity. Converting human T(H)1 cells to a regulatory phenotype with PD1 signaling provides a potential way to block GVHD after transplantation. Moreover, because this conversion can be prevented by blocking PD1 expression or pharmacologically inhibiting SHP1/2, this pathway provides a new therapeutic direction for enhancing T cell immunity to cancer and infection.