The importance of the cellular stress response in the pathogenesis and treatment of type 2 diabetes

Organisms have evolved to survive rigorous environments and are not prepared to thrive in a world of caloric excess and sedentary behavior. A realization that physical exercise (or lack of it) plays a pivotal role in both the pathogenesis and therapy of type 2 diabetes mellitus (t2DM) has led to the provocative concept of therapeutic exercise mimetics. A decade ago, we attempted to simulate the beneficial effects of exercise by treating t2DM patients with 3 weeks of daily hyperthermia, induced by hot tub immersion. The short-term intervention had remarkable success, with a 1 % drop in HbA1, a trend toward weight loss, and improvement in diabetic neuropathic symptoms. An explanation for the beneficial effects of exercise and hyperthermia centers upon their ability to induce the cellular stress response (the heat shock response) and restore cellular homeostasis. Impaired stress response precedes major metabolic defects associated with t2DM and may be a near seminal event in the pathogenesis of the disease, tipping the balance from health into disease. Heat shock protein inducers share metabolic pathways associated with exercise with activation of AMPK, PGC1-a, and sirtuins. Diabetic therapies that induce the stress response, whether via heat, bioactive compounds, or genetic manipulation, improve or prevent all of the morbidities and comorbidities associated with the disease. The agents reduce insulin resistance, inflammatory cytokines, visceral adiposity, and body weight while increasing mitochondrial activity, normalizing membrane structure and lipid composition, and preserving organ function. Therapies restoring the stress response can re-tip the balance from disease into health and address the multifaceted defects associated with the disease

Multiple Measures of Adiposity Are Associated with Mean Leukocyte Telomere Length in the Northern Finland Birth Cohort 1966

Studies of leukocyte telomere length (LTL) and adiposity have produced conflicting results, and the relationship between body mass index (BMI) and telomere length throughout life remains unclear. We therefore tested association of adult LTL measured in 5,598 participants with: i) childhood growth measures (BMI and age at adiposity rebound (AR)); ii) change in BMI from childhood to adulthood and iii) adult BMI, waist-to-hip ratio (WHR), body adiposity index (BAI). Childhood BMI at AR was positively associated with LTL at 31 years in women (P = 0.041). Adult BMI and WHR in both men (P = 0.025 and P = 0.049, respectively) and women (P = 0.029 and P = 0.008, respectively), and BAI in women (P = 0.021) were inversely associated with LTL at 31 years. An increase in standardised BMI between early childhood and adulthood was associated with shorter adult LTL in women (P = 0.008). We show that LTL is inversely associated with multiple measures of adiposity in both men and women. Additionally, BMI increase in women from childhood to adulthood is associated with shorter telomeres at age 31, potentially indicating accelerated biological ageing

Long-term safety of adalimumab for patients with moderate-to-severe hidradenitis suppurativa

Introduction: Hidradenitis suppurativa (HS) is a chronic debilitating inflammatory skin disorder that affects regions rich in apocrine glands. Although the etiology of HS is not clear, inflammatory cytokines, like tumor necrosis factor (TNF)-α, participate in pathogenesis. Adalimumab (ADA), a human IgG1 monoclonal antibody that selectively targets TNFα, is the only EMA/FDA-approved biologic agent available for the therapy of moderate-to-severe HS. Areas covered: A comprehensive literature search was conducted to present existing studies with an emphasis on the safety profile of ADA for the treatment of moderate-to-severe HS. ADA is prescribed for more than 15 years for varied indications and has improved the therapeutic outcomes of many diseases. Clinical trials and real-life safety data from ADA administration in HS were presented, with particular attention to special populations, such as children, elderly, and pregnant women. Expert opinion: Existing data advise for limited safety concerns with long-term ADA treatment provided that patients are thoroughly screened for infections, latent tuberculosis, and history of malignancy before the start of treatment. © 2020, © 2020 Informa UK Limited, trading as Taylor & Francis Group

Methotrexate: An effective monotherapy for refractory generalized morphea

Introduction: Morphea is an inflammatory skin disorder characterized by excessive collagen deposition. Although treatment algorithms for morphea subtypes have been suggested, no consistent recommendations are available. This study attempts to evaluate the clinical efficacy of methotrexate (MTX) as monotherapy in refractory generalized morphea. Methods: It is a retrospective study, including 20 patients who had already been treated with various topical and systemic therapies with minimal clinical improvement. Patients received orally MTX at a of dosage 15 mg once weekly. Duration of the use, dosage of MTX, and adverse events were recorded. Clinical assessment of skin lesions was performed and documented. Results: The mean disease duration was 27 months before the initiation of MTX treatment. After 12 months of therapy, very good response was achieved in 6 patients (30%), good response in 10 patients (50%), and fair response in 2 patients (10%), while 2 patients (10%) had failed treatment. Patients were followed up for a mean time interval of 21 months. No serious adverse event was recorded. Conclusion: MTX has been already proved to be an effective and well-tolerated treatment in pediatric patients with morphea. The majority of the group of adult patients showed very good and good improvement when treated with MTX. Although this is an uncontrolled study, MTX monotherapy was considered a safe and effective treatment for the management of this specific clinical subset of morphea in adults. © 2017 Platsidaki et al

Childhood Vitiligo

Vitiligo is a common acquired depigmenting skin disease characterized by a progressive loss of functional melanocytes. It may appear from the first years of life to late adulthood. Childhood vitiligo (CV), defined as vitiligo that begins before the age of 12 years, is common and may differ from post-CV in terms of epidemiology, clinical presentation, comorbidities, and treatment options. Taking into consideration the potential significant psychosocial impact of the disease on both children and their parents, all available therapeutic options must be offered to patients who desire treatment. According to the most recent guidelines, topical corticosteroids, topical calcineurin inhibitors, and narrowband ultraviolet B phototherapy are the most commonly used treatment modalities for vitiligo in children. This review presents recent data regarding the whole spectrum of CV. Differences between CV and post-CV are also discussed. © 2019, Springer Nature Switzerland AG

Oral clindamycin and rifampicin combination therapy for hidradenitis suppurativa: a prospective study and 1-year follow-up

Background: Limited data exist on the use of systemic antibiotic treatment for hidradenitis supportive (HS). Aim: To investigate the effectiveness, safety and relapse rate of HS treated with a combination of daily oral clindamycin and rifampicin. Methods: This was a prospective, hospital-based study of oral clindamycin 600 mg and rifampicin 600 mg daily for 12 weeks for treatment of HS. Patients were followed up for 1 year to monitor for relapse. Results: In total, 26 patients with HS received oral clindamycin and rifampicin. Most were overweight or obese (73%), and most were smokers (88%). After 12 weeks, clinical response was noted in 19 patients (73%). Response was associated only with female sex (P = 0.02), and not with body mass index, Hurley stage or lesion location. Eight patients (31%) experienced adverse events. At the 1-year follow-up, there was sustained efficacy in 7 (41%) patients, while 10 (59%) had disease relapse after a mean time of 4.2 months. Conclusions: Oral clindamycin with oral rifampicin for 12 weeks is an effective and tolerable regimen for HS. © 2016 British Association of Dermatologist

A retrospective study of the characteristics of patients with early-onset compared to adult-onset hidradenitis suppurativa

Background: The mean age of onset of hidradenitis suppurativa (HS) is between 20 and 24 years. Very few data about patients with early-onset HS exist. Objective: To investigate the association of early-onset HS with the clinical characteristics: age, gender, body mass index (BMI), smoking, family history of HS, Hurley stage, and number of areas affected. Methods: This was a retrospective study of the reported early age at HS onset (≤17 years old) with clinical characteristics and with the severity of HS at first consultation visit. Results: In 166 patients, 42 patients (25.3%) reported early-onset HS. Compared to adult-onset HS, patients with early-onset HS were younger (mean age: 37 years vs. 27 years, P < 0.0001), had a significantly younger mean age of onset (28.2 years old vs. 14.5 years old, respectively, P < 0.0001), longer mean disease duration (8.8 years vs. 12.6 years, respectively, P = 0.011) and were less frequently smokers (P < 0.001), whereas there was no association with gender (P = 0.177) or BMI (0.086). Patients with a family history had increased risk for early-onset HS (OR: 2.45, 95% CI: 1.08–5.56). Early-onset HS was not associated with Hurley stage (OR: 1.12, 95% CI: 0.33–3.74) or with the number of body areas affected (OR: 1.54, 95% CI: 0.49–4.83). Conclusion: Early-onset HS was frequent and associated with a family history of HS. There was no difference in the severity of HS in adult life for patients with an onset of HS at ≤17 years, compared to patients with adult-onset, which may be reassuring information for these younger patients. © 2018 The International Society of Dermatolog

Imiquimod 3.75% for field-directed therapy of actinic keratosis: results of a prospective case-series study in Greece

Background: Imiquimod 3.75% is a field-directed treatment for actinic keratosis that can detect and treat clinical and subclinical lesions across an entire sun-exposed field. The detection of subclinical lesions is evidenced by an increase in lesions to the maximum lesion count during treatment (Lmax). We report clinical outcomes for the first 15 patients treated with imiquimod 3.75% in daily clinical practice in Greece. Methods: Fifteen patients with actinic keratosis lesions were treated with imiquimod 3.75% in an outpatient setting in two 2-week treatment cycles separated by a 2-week treatment-free interval. Actinic keratosis lesions were counted before treatment, at the end of the first treatment cycle (Week 2; Lmax), and 2 weeks after the second treatment cycle (Week 8). Local skin reactions (LSR) were also evaluated at Weeks 2 and 8. Results: The median baseline actinic keratosis lesion count was 25, which increased to a median Lmax of 29 at Week 2 and decreased to a median of 5 at Week 8. The median percentage and absolute reduction in actinic keratosis lesions from Lmax to Week 8 were 87% and 23%, respectively. Most of the LSR were mild-to-moderate in intensity at Week 2 and had resolved by Week 8. Conclusion: Imiquimod 3.75% effectively detected and cleared both the clinical and subclinical actinic keratosis lesions across the entire sun-exposed field in this cohort of Greek patients. Treatment was well tolerated. © 2019 The Authors. International Journal of Dermatology published by Wiley Periodicals, Inc. on behalf of International Society of Dermatolog