Genetic and cytometric analyses of subcutaneous adipose tissue in patients with hemophilia and HIV-associated lipodystrophy.

BACKGROUND: The authors recently performed plastic surgeries for a small number of patients with hemophilia, HIV infection, and morphologic evidence of lipodystrophy. Because the pathophysiological mechanism of HIV-associated lipodystrophy remains to be elucidated, we analyzed subcutaneous adipose tissues from the patients. METHODS: All six patients had previously been treated with older nucleoside analogue reverse-transcriptase inhibitors (NRTIs; stavudine, didanosine or zidovudine). Abdominal and inguinal subcutaneous fat samples were obtained from the HIV+ patients with hemophilia and HIV- healthy volunteers (n = 6 per group), and analyzed via DNA microarray, real-time PCR, flow cytometry and immunohistochemistry. RESULTS: The time from initial NRTI treatment to collecting samples were 21.7 years in average. Cytometric analysis revealed infiltration of inflammatory M1 macrophages into HIV-infected adipose tissue and depletion of adipose-derived stem cells, possibly due to exhaustion following sustained adipocyte death. Genetic analysis revealed that adipose tissue from HIV+ group had increased immune activation, mitochondrial toxicity, chronic inflammation, progressive fibrosis and adipocyte dysfunction (e.g. insulin resistance, inhibited adipocyte differentiation and accelerated apoptosis). Of note, both triglyceride synthesis and lipolysis were inhibited in adipose tissue from patients with HIV. CONCLUSIONS: Our findings provide important insights into the pathogenesis of HIV-associated lipodystrophy, suggesting that fat redistribution may critically depend on adipocytes' sensitivity to drug-induced mitochondrial toxicity, which may lead either to atrophy or metabolic complications.

Treatment of Human Immunodeficiency Virus-Associated Facial Lipoatrophy With Hyaluronic Acid Filler Mixed With Micronized Cross-Linked Acellular Dermal Matrix.

BACKGROUND: Human immunodeficiency virus (HIV)-associated facial lipoatrophy (FLA) is a stigmatizing side effect associated with the use of highly active antiretroviral therapy. We sought to evaluate the safety and efficacy of the hyaluronic acid filler mixed with micronized cross-linked acellular dermal matrix (HA/MADM) in HIV-associated FLA. METHODS: We conducted an open-label safety and efficacy study in patients with HIV-associated FLA. Fourteen patients received single injection of the HA/MADM, and 13 patients completed the 24-week follow-up evaluation. Treatment efficacy, safety, and patient and physician satisfaction were evaluated. Repeated measure analysis of variance with post-hoc analysis with the Wilcoxon signed rank test was performed to compare and incorporate parameters at each time point. RESULTS: All 13 patients maintained a significant improvement of the Carruthers Lipoatrophy Severity Scale grade throughout the study period, along with improvement of the depressed volume due to lipoatrophy measured using a three-dimensional camera system. More than 80% of patients and physicians were satisfied with the treatment, and no treatment-related adverse events were reported, except for one case of transient subcutaneous nodule formation. CONCLUSION: Our study findings suggest that injectable HA/MADM is a potentially effective and safe treatment option for treating HIV-positive patients with FLA.

A hundred years on: The role of human insulin.

There are multiple insulin preparations, and strengths, available in various delivery devices. Modern insulin analogues are characterised by better safety and tolerability, and are increasingly being used across much of the world. Does there still exist a role for human insulin? This brief communication explores the potential indications for human insulin, while discussing the concerns and caveats related to its use, and suggesting ways of safe and smart use of human insulin.

REVERSIBILITY OF LIPOATROPHY IN HIV-INFECTED PATIENTS TAKING ANTIRETROVIRAL THERAPY: A COHORT STUDY WITH ULTRASOUND ASSESSMENT.

The aim of this study was to characterize and compare changes in subcutaneous fat in the malar, brachial and crural region in a cohort of HIV-infected patients taking antiretroviral therapy. This prospective longitudinal study included 77 patients who were selected from the initial cohort evaluated in 2007 and 2008. We examined reversibility of lipoatrophy measured by ultrasound over at least five-year period and factors related to its reversibility. All 46 patients who used stavudine switched from stavudine to another combination. Of 58 patients on zidovudine, 16 (28%) were on a zidovudine based regimen at the second follow up. There was evidence for subcutaneous fat increase in the malar area (p<0.001) and no increase in the brachial and crural areas. Patients who were smokers and had poor adherence to the Mediterranean diet had a thinner malar area at the follow up measurement (p=0.030) and smaller increase in subcutaneous malar fat compared to others (p=0.040). Our study suggested that modest increase of subcutaneous fat in malar area coincided with stopping stavudine and fewer usage of zidovudine. Lifestyle with non-adherence to the Mediterranean diet and smoking were associated with a smaller increase in subcutaneous malar fat.

LIPODYSTROPHY FREQUENCY ACCORDING TO INSULIN TREATMENT REGIMEN IN TYPE 2 DIABETIC PATIENTS: IS INSULIN INJECTION FREQUENCY MATTERS IN ANALOG INSULIN ERA?

Objectives: We aimed to determine lipodystrophy frequency according to insulin treatment regimen and insulin injection frequency in type 2 diabetic patients. Methods: A total of 345 type 2 diabetic patients under insulin treatment for at least one year were included in this cross-sectional study. Patients were examined for presence of lipodystrophy, insulin injection frequency and dosage. Lipodystrophy was evaluated with visual inspection and palpation of all injection sites. Patients were evaluated into three categories according to daily insulin dose requirement: Group 1= Standard-dose insulin users 0.6 U/kg/day; Group 2= Medium-dose insulin users 0.61-1.9 U/kg/day, Group 3= High-dose insulin users ≥2 U/kg/day. Results: Lipodystrophy was seen in 28% of the patients. Lipodystrophy was significantly higher in group 3. There was no significant difference between the groups in terms of lipodystrophy size. Duration of insulin treatment, daily total insulin dose, daily insulin dose per weight and number of daily insulin injections were significantly higher in the group with lipodystrophy. Daily injection number of long-acting, rapidly-acting analog and total insulin injections were significantly higher in group 3 than group 1 and 2. Number of daily insulin injections and lipodystrophy frequency were significantly higher in basal-bolus insulin user group. Multivariate analysis showed that insulin injection frequency is the independent risk factor for lipodystrophy. Conclusion: Lipodystrophy is still a clinical problem in patients with high-dose insulin requirement and frequent insulin injections. Reducing daily insulin requirement and daily number of injections should be given priority in the management of patients to prevent the development of lipodystrophy.

Wiedemann-Rautenstrauch syndrome in an Indian patient with biallelic pathogenic variants in POLR3A.

Wiedemann-Rautenstrauch syndrome (WRS; MIM# 264090) is a rare neonatal progeroid disorder resulting from biallelic pathogenic variants in the POLR3A. It is an autosomal recessive condition characterized by growth retardation, lipoatrophy, a distinctive face, sparse scalp hair, and dental anomalies. Till date, 19 families are reported with WRS due to variants in POLR3A. Here, we describe an 18 months old male child with biallelic c.2005C>T p.(Arg669Ter) and c.1771-7C>G variant in heterozygous state identified by exome sequencing in POLR3A leading to WRS phenotype. The variant c.1771-7C>G was earlier found to be associated with hereditary spastic ataxia. We emphasize on the phenotype in an Indian patient with WRS.

Ultrasound in Sports and Occupational Dermatology.

Chronic exposure to trauma, friction, or extreme conditions can generate cutaneous or ungual lesions in sports and certain occupations. Although some of these dermatologic conditions are diagnosed with a naked-eye examination, there are cases in which the provision of the underlying anatomic alterations can be helpful for the diagnosis and management. In comparison with computed tomography or magnetic resonance imaging, ultrasound has the highest axial resolution, which is critical for the observation of anatomic changes in the skin and nail. We review the ultrasound characteristics of frequent cutaneous and ungual lesions related to sports and occupations with a clinical correlation. The ultrasound features in some particular conditions such as "biker's and surfer's panniculitis," "fiddler's neck," piezogenic papules, and lipoatrophy semicircularis, among others, are discussed.

Mitochondrial Unfolded Protein Responses in White Adipose Tissue: Lipoatrophy, Whole-Body Metabolism and Lifespan.

The mitochondrial unfolded protein response (UPRmt) is a stress response mediated by the expression of genes such as chaperones, proteases, and mitokines to maintain mitochondrial proteostasis. Certain genetically modified mice, which defect mitochondrial proteins specifically in adipocytes, developed atrophy of the white adipose tissue, resisted diet-induced obesity, and had altered whole-body metabolism. UPRmt, which has beneficial functions for living organisms, is termed "mitohormesis", but its specific characteristics and detailed regulatory mechanism have not been elucidated to date. In this review, we discuss the function of UPRmt in adipose atrophy (lipoatrophy), whole-body metabolism, and lifespan based on the concept of mitohormesis.

De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction.

Gorlin-Chaudhry-Moss syndrome (GCMS) is a dysmorphic syndrome characterized by coronal craniosynostosis and severe midface hypoplasia, body and facial hypertrichosis, microphthalmia, short stature, and short distal phalanges. Variable lipoatrophy and cutis laxa are the basis for a progeroid appearance. Using exome and genome sequencing, we identified the recurrent de novo mutations c.650G>A (p.Arg217His) and c.649C>T (p.Arg217Cys) in SLC25A24 in five unrelated girls diagnosed with GCMS. Two of the girls had pronounced neonatal progeroid features and were initially diagnosed with Wiedemann-Rautenstrauch syndrome. SLC25A24 encodes a mitochondrial inner membrane ATP-Mg/Pi carrier. In fibroblasts from affected individuals, the mutated SLC25A24 showed normal stability. In contrast to control cells, the probands' cells showed mitochondrial swelling, which was exacerbated upon treatment with hydrogen peroxide (H2O2). The same effect was observed after overexpression of the mutant cDNA. Under normal culture conditions, the mitochondrial membrane potential of the probands' fibroblasts was intact, whereas ATP content in the mitochondrial matrix was lower than that in control cells. However, upon H2O2 exposure, the membrane potential was significantly elevated in cells harboring the mutated SLC25A24. No reduction of mitochondrial DNA copy number was observed. These findings demonstrate that mitochondrial dysfunction with increased sensitivity to oxidative stress is due to the SLC25A24 mutations. Our results suggest that the SLC25A24 mutations induce a gain of pathological function and link mitochondrial ATP-Mg/Pi transport to the development of skeletal and connective tissue.

Reversal of steroid-induced lipoatrophy with serial injections of isotonic saline in a child.

The problem of side-effects of injectable corticosteroids has gradually become more acute with rampant and unlimited misuse of the drug, particularly by non-dermatologists. Serial saline injections at the site of steroid-induced lipoatrophy in a child served as a safe, relatively rapid, and cost-effective solution.

Use of dermal fat grafts for treating anetoderma with lipoatrophy following involution of hemangiomas.

Infantile hemangioma (IH) is a benign vascular tumor that gradually involutes over several years. Rapidly involuting congenital hemangioma (RICH) is the relatively rare congenital vascular tumor that is fully grown at birth and does not undergo postnatal growth and involutes during the first year. However, after involution of both IH and RICH, some have severe sequelae, such as redundant skin or conspicuous scarring, requiring additional treatment. We present the case of a 6-year-old girl with a concave deformity due to subcutaneous atrophy, skin darkening, and altered skin texture of her left zygomatic region following involution of a hemangioma. We successfully treated this patient by transferring a dermal fat graft. This technique can be beneficial for atrophic sequelae after regression of a hemangioma and is easy to perform and cosmetically effective.

Insulin Adverse Events.

The negative consequencies of diabetes treatment are traditionally regarded as caused by a disastrous treatment rather than adverse events of the insulin preparations. However, hypoglycemia, changes at the injection site (lipatrophy, lipoma), insulin allergy, obesity and increased risk of certain forms of cancer can easily be regarded as adverse events of the drug, and needle-phobia, psychological problems, increased risk of suicide are adverse events related to insulin and its administration. Also macroangiopathy and even microangiopathy to some extent can be regarded as adverse events as the most crucial part of the treatment of Type 1 diabetes is the insulin treatment. There is still room for improvments of insulin as a drug. We need insulins with more predictable absorption and kinetics, leading to more stable near-normal blood glucose, less risk of hypoglycemia, less effect in periphery and more effect on the liver, and less risk of vascular complications, obesity, cancer.

Adipocyte-specific disruption of ATPase copper transporting α in mice accelerates lipoatrophy.

AIMS/HYPOTHESIS: ATPase copper transporting α (ATP7A), also known as Menkes disease protein, is a P-type ATPase that transports copper across cell membranes. The critical role of ATP7A-mediated copper homeostasis has been well recognised in various organs, such as the intestine, macrophages and the nervous system. However, the importance of adipocyte ATP7A-mediated copper homeostasis on fat metabolism is not well understood. Here, we sought to reveal the contribution of adipose ATP7A to whole-body fat metabolism in mice. METHODS: We generated adipocyte-specific Atp7a-knockout (ASKO) mice using the Cre/loxP system, with Cre expression driven by the adiponectin promoter. ASKO mice and littermate control mice were aged on a chow diet or fed with a high-fat diet (HFD); body weight, fat mass, and glucose and insulin metabolism were analysed. Histological analysis, transmission electron microscopy and RNA-sequencing (RNA-Seq) analysis of white adipose tissue (WAT) were used to understand the physiological and molecular changes associated with loss of copper homeostasis in adipocytes. RESULTS: Significantly increased copper concentrations were observed in adipose tissues of ASKO mice compared with control mice. Aged or HFD-fed ASKO mice manifested a lipoatrophic phenotype characterised by a progressive generalised loss of WAT. Dysfunction of adipose tissues in these ASKO mice was confirmed by decreased levels of both serum leptin and adiponectin and increased levels of triacylglycerol and insulin. Systemic metabolism was also impaired in these mice, as evidenced by a pronounced glucose intolerance, insulin resistance and hepatic steatosis. Moreover, we demonstrate a significant induction of lipolysis and DNA-damage signalling pathways in gonadal WAT from aged and HFD-fed ASKO mice. In vitro studies suggest that copper overload is responsible for increased lipolysis and DNA damage. CONCLUSIONS/INTERPRETATION: Our results show a previously unappreciated role of adipocyte Atp7a in the regulation of ageing-related metabolic disease and identify new metallophysiologies in whole-body fat metabolism. DATA AVAILABILITY: The datasets generated during the current study are available in the Genome Sequence Archive in BIG Data Center, Beijing Institute of Genomics (BIG), Chinese Academy of Sciences, under accession number CRA001769 (http://bigd.big.ac.cn/gsa).

Diabetes mellitus coexisted with progeria: a case report of atypical Werner syndrome with novel LMNA mutations and literature review.

Werner syndrome (WS) is a rare, adult-onset progeroid syndrome. Classic WS is caused by WRN mutation and partial atypical WS (AWS) is caused by LMNA mutation. A 19-year-old female patient with irregular menstruation and hyperglycemia was admitted. Physical examination revealed characteristic faces of progeria, graying and thinning of the hair scalp, thinner and atrophic skin over the hands and feet, as well as lipoatrophy of the extremities, undeveloped breasts at Tanner stage 3, and short stature. The patient also suffered from severe insulin-resistant diabetes mellitus, hyperlipidemia, fatty liver, and polycystic ovarian morphology. Possible WS was considered and both WRN and LMNA genes were analyzed. A novel missense mutation p.L140Q (c.419T>A) in the LMNA gene was identified and confirmed the diagnosis of AWS. Her father was a carrier of the same mutation. We carried out therapy for lowering blood glucose and lipid and improving insulin resistance, et al. The fasting glucose, postprandial glucose and triglyceride level was improved after treatment for 9 days. Literature review of AWS was performed to identify characteristics of the disease. Diabetes mellitus is one of the clinical manifestations of WS and attention must give to the differential diagnosis. Gene analysis is critical in the diagnosis of WS. According to the literature, classic and atypical WS differ in incidence, pathogenic gene, and clinical manifestations. Characteristic dermatological pathology may be significantly more important for the initial identification of AWS. Early detection, appropriate treatments, and regular follow-up may improve prognosis and survival of WS patients.

Linear lipoatrophy following intra-articular triamcinolone acetonide injection mimicking linear scleroderma.

A 12-year-old female with oligoarticular juvenile inflammatory arthritis developed an atrophic linear plaque involving the left medial forearm and proximal arm 7 months after intra-articular triamcinolone injection for arthritis. The plaque spontaneously resolved without treatment over approximately one year. It is important to recognize this rare complication of intra-articular steroid injection in order to avoid potential misdiagnosis as linear scleroderma and subsequent immunosuppressive treatment.

Low prevalence of lipodystrophy in HIV-infected Senegalese children on long-term antiretroviral treatment: the ANRS 12279 MAGGSEN Pediatric Cohort Study.

BACKGROUND: The long-term benefits of antiretroviral treatment (ART) are associated with metabolic complications, especially lipodystrophy, which has been well described among HIV-infected adults and children on ART in developed settings. Specifically, stavudine, and to a lesser extent zidovudine and protease inhibitors (PI), have been consistently implicated in the development of lipodystrophy. In 2006, following advice from the WHO, Senegal began phasing out stavudine from first-line ART. The objectives of this cross-sectional analysis are to assess and identify risk factors affecting the prevalence of lipodystrophy in Senegalese children and adolescents on long-term ART participating in a cohort study. METHODS: Lipodystrophy was clinically assessed in two- to 18-year-old children on ART for at least six months and with no concurrent severe acute malnutrition. Risk factors for lipodystrophy were identified using stepwise multivariable logistic regression. Explanatory variables included clinical and personal data, immunovirologic status, and therapeutic history. RESULTS: Overall, 254 children were assessed for lipodystrophy. The median age was 10.9 years (IQR: 8.1-14.2) and the median duration on ART was 54 months (32-84). Only 18% had been previously treated with stavudine, with a median treatment duration of 8 months (5-25). Ongoing treatment included 76% of children receiving zidovudine (median duration of 48 months (26-74)) and 27% receiving PI (lopinavir/ritonavir; median duration of 49 months (23-59)). Mild signs of lipodystrophy were observed in 33 children (13%): 28 with lipoatrophy, 4 with lipohypertrophy and one with combined type. Boys were more likely to present with lipoatrophy than girls (aOR: 4.3, 95% CI: 1.6-11.7). Children previously treated with stavudine for ≥1 year had a greater risk for lipoatrophy than those never exposed (3.8, 1.0-14.0), although the association was weak. There was no association between lipodystrophy and age or current or cumulative treatment with lopinavir/ritonavir or zidovudine. CONCLUSIONS: We report low prevalence of mild lipodystrophy in children and adolescents on long-term ART receiving a stavudine-sparing regimen. These findings are reassuring for clinicians in low-income settings where zidovudine is massively prescribed and lopinavir/ritonavir is the only widely available PI. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01771562 (registration date: 01/18/2013).

Lipodystrophy diagnosis in people living with HIV/AIDS: prediction and validation of sex-specific anthropometric models.

BACKGROUND: Body composition alterations, or lipodystrophy, can lead to serious health problems in people living with HIV/AIDS (PLWHA). The objectives of this study are to predict and validate sex-specific anthropometric predictive models for the diagnosis of lipodystrophy in PLWHA. METHODS: A cross-sectional design was employed to recruit 106 PLWHA (men = 65 and women = 41) in Brazil during 2013-2014. They were evaluated using dual-energy X-ray absorptiometry, and 19 regions of body perimeters and 6 skinfold thicknesses were taken. Sex-specific predictive models for lipodystrophy diagnosis were developed through stepwise linear regression analysis. Cross-validations using predicted residual error sum of squares was performed to validate each predictive model. RESULTS: Results support the use of anthropometry for the diagnosis of lipodystrophy in men and women living with HIV/AIDS. A high power of determination with a small degree of error was observed for lipodystrophy diagnosis for men in model six (r2 = 0.77, SEE = 0.14, r2PRESS = 0.73, SEE PRESS = 0.15), that included ratio of skinfold thickness of subscapular to medial calf, skinfold thickness of thigh, body circumference of waist, formal education years, time of diagnosis to HIV months, and type of combined antiretroviral therapy (cART) (with protease inhibitor "WI/PI = 1" or without protease inhibitor "WO/PI = 0"); and model five for women (r2 = 0.78, SEE = 0.11, r2PRESS = 0.71, SEE PRESS = 0.12), that included skinfold thickness of thigh, skinfold thickness of subscapular, time of exposure to cART months, body circumference of chest, and race (Asian) ("Yes" for Asian race = 1; "No" = 0). CONCLUSIONS: The proposed anthropometric models advance the field of public health by facilitating early diagnosis and better management of lipodystrophy, a serious adverse health effect experienced by PLWHA.

Stem cell and skin rejuvenation.

Stem cell-based therapies have been widely used for their abilities to repair and regenerate different types of tissues and organs in cosmetic and plastic surgeries. It involves the clinical application of different types of stem cells. Different stem cells have been reported to be applicable in different areas of cosmetic surgeries like face lipoatrophy, skin rejuvenation, breast enhancement, and body contouring. However, adipose-derived stem cells remain the most widely used by cosmetic surgeons as they have the potential and capability to differentiate into mesenchymal, ectodermal, and endodermal lineages and are easily accessible to harvest. The purpose of this review is to summarize available applications of stem in cosmetic and plastic surgeries.