Multimodal Management of Atrophic Acne Scarring in the Aging Face

Atrophic facial acne scarring is a widely prevalent condition that can have a negative impact on a patient’s quality of life. The appearance of these scars is often worsened by the normal effects of aging. A number of options are available for the treatment of acne scarring, including chemical peeling, dermabrasion, ablative or nonablative laser resurfacing, dermal fillers, and surgical techniques such as subcision or punch excision. Depending on the type and extent of scarring, a multimodal approach is generally necessary to provide satisfactory results. Resurfacing techniques correct surface irregularities, long-lasting dermal fillers address the volume loss resulting from acne, and sub-superficial musculoaponeurotic system (SMAS) face-lift procedures counter the soft tissue laxity and ptosis associated with aging. This article briefly reviews the evolution of individual approaches to treating atrophic acne scarring, followed by case examples illustrating results that can be achieved using a multimodal approach. Representative cases from patients in their 30s, 40s, and 50s are presented. In the author’s clinical practice, multimodal approaches incorporating fractionated laser, injectable poly-l-lactic acid, and sub-SMAS face-lift procedures have achieved optimal aesthetic outcomes, high patient satisfaction, and durability of aesthetic effect over time

Lasers and ancillary treatments for scar management Part 2: Keloid, hypertrophic, pigmented and acne scars

The formation of a wide range of excessive scars following various skin injuries is a natural consequence of healing. Scars resulting from surgery or trauma affect approximately 100 million people per annum in the developed world and can have profound physical, aesthetic, psychological and social consequences. Thus, scar treatment is a priority for patient and physician alike. Laser treatment plays an important role in scar management with additional support from ancillary modalities. Subsequent to part 1: Burns scars, part 2 focuses on our strategies and literature review of treatment of keloid, hypertrophic, pigmented and acne scars where lasers are used in conjunction with other measures, and illustrated with case studies

Truncating mutations in the Wilson disease gene ATP7B are associated with very low serum ceruloplasmin oxidase activity and an early onset of Wilson disease

<p>Abstract</p> <p>Background</p> <p>Mutations in the gene ATP7B cause Wilson disease, a copper storage disorder with a high phenotypic and genetic heterogeneity. We aimed to evaluate whether 'severe' protein-truncating ATP7B mutations (SMs) are associated with low serum ceruloplasmin oxidase activities and an early age of onset when compared to missense mutations (MMs).</p> <p>Methods</p> <p>The clinical phenotype of 59 genetically confirmed WD patients was analyzed retrospectively. Serum ceruloplasmin was measured by its oxidase activity with <it>o</it>-dianisidine dihydrochloride as substrate and immunologically.</p> <p>Results</p> <p>Thirty-nine patients had two MMs, 15 had the genotype SM/MM, and 5 patients had two SMs on their ATP7B alleles. Enzymatic and immunologic serum ceruloplasmin levels differed significantly between the three groups (P < 0.001 and P < 0.01, respectively). The lowest levels were measured in patients with two SMs (0.0 U/L; IQR, 0.0-0.0 U/L and 0.02 g/L; IQR, 0.01-0.02 g/L, respectively) and the highest in patients with two MMs (17.8 U/L; IQR, 5.8-35.1 U/L and 0.11 g/L; IQR,0.10-0.17 g/L, respectively). The age of onset was also significantly different between the three patient groups (P < 0.05), with SM/SM patients showing the earliest onset (13 years; IQR, 9-13 years) and patients with two MMs showing the latest onset (22 years; IQR, 14-27 years). By ROC curve analysis a ceruloplasmin oxidase level ≤ 5 U/L can predict the presence of at least one SM with a sensitivity of 80% and a specificity of 79.5%.</p> <p>Conclusions</p> <p>In our German study cohort truncating ATP7B mutations were associated with lower ceruloplasmin serum oxidase levels and an earlier age of onset when compared to MMs. Measurement of serum ceruloplasmin oxidase might help to predict presence of truncating ATP7B mutations and might facilitate the mutation analysis.</p

Down syndrome is an oxidative phosphorylation disorder

Down syndrome is the most common genomic disorder of intellectual disability and is caused by trisomy of chromosome 21. Several genes in this chromosome repress mitochondrial biogenesis. The goal of this study was to evaluate whether early overexpression of these genes may cause a prenatal impairment of oxidative phosphorylation negatively affecting neurogenesis. Reduction in the mitochondrial energy production and a lower mitochondrial function have been reported in diverse tissues or cell types, and also at any age, including early fetuses, suggesting that a defect in oxidative phosphorylation is an early and general event in Down syndrome individuals. Moreover, many of the medical conditions associated with Down syndrome are also frequently found in patients with oxidative phosphorylation disease. Several drugs that enhance mitochondrial biogenesis are nowadays available and some of them have been already tested in mouse models of Down syndrome restoring neurogenesis and cognitive defects. Because neurogenesis relies on a correct mitochondrial function and critical periods of brain development occur mainly in the prenatal and early neonatal stages, therapeutic approaches intended to improve oxidative phosphorylation should be provided in these periods.Funding sources: This work was supported by grants from Instituto de Salud Carlos III [FIS-PI17/00021, FIS-PI17/00166]; Fundación Mutua Madrileña [MMA17/01]; Precipita-FECYT crowdfunding program [PR194]; Gobierno de Aragón [LMP135_18, Grupos Consolidados B33_17R] and FEDER 2014–2020 “Construyendo Europa desde Aragón”. CIBERER is an initiative of the ISCIII

Orexin-A is Associated with Increases in Cerebrospinal Fluid Phosphorylated-Tau in Cognitively Normal Elderly Subjects

Study Objectives: To evaluate the role of orexin-A with respect to cerebrospinal fluid (CSF) Alzheimer disease (AD) biomarkers, and explore its relationship to cognition and sleep characteristics in a group of cognitively normal elderly individuals. Methods: Subjects were recruited from multiple community sources for National Institutes of Health supported studies on normal aging, sleep and CSF biomarkers. Sixty-three participants underwent home monitoring for sleep-disordered breathing, clinical, sleep and cognitive evaluations, as well as a lumbar puncture to obtain CSF. Individuals with medical history or with magnetic resonance imaging evidence of disorders that may affect brain structure or function were excluded. Correlation and linear regression analyses were used to assess the relationship between orexin-A and CSF AD-biomarkers controlling for potential sociodemographic and sleep confounders. Results: Levels of orexin-A, amyloid beta 42 (Aβ42), phosphorylated-tau (P-Tau), total-tau (T-Tau), Apolipoprotein E4 status, age, years of education, reported total sleep time, number of awakenings, apnea-hypopnea indices (AHI), excessive daytime sleepiness, and a cognitive battery were analyzed. Subjects were 69.59 ± 8.55 years of age, 57.1% were female, and 30.2% were apolipoprotein E4+. Orexin-A was positively correlated with Aβ42, P-Tau, and T-Tau. The associations between orexin-A and the AD-biomarkers were driven mainly by the relationship between orexin-A and P-Tau and were not influenced by other clinical or sleep characteristics that were available. Conclusions: Orexin-A is associated with increased P-Tau in normal elderly individuals. Increases in orexin-A and P-Tau might be a consequence of the reduction in the proportion of the deeper, more restorative slow wave sleep and rapid eye movement sleep reported with aging. Clinical Trial Registration: Clinicaltrials.gov registration number NCT01962779. Significance Orexin is a key regulator of sleep-wake homeostasis. Deposition of abnormal phosphorylated tau (P-Tau) in neurons and glia is one of the major features of Alzheimer's disease (AD). Our results show a positive association between cerebrospinal fluid (CSF) levels of orexin-A and P-Tau in a group of cognitively normal elderly. Further, this correlation was not influenced by total sleep time, number of awakenings or sleep disordered breathing. Both findings could be explained by the decrease in the proportion of deeper restorative sleep stages that is part of normal aging or, alternatively, by AD pathology causing orexin dysfunction early in the disease process. Understanding the role of orexin dysfunction in older adults might help unfold new preventive therapies for AD

Macrophages in Alzheimer’s disease: the blood-borne identity

Alzheimer’s disease (AD) is a progressive and incurable neurodegenerative disorder clinically characterized by cognitive decline involving loss of memory, reasoning and linguistic ability. The amyloid cascade hypothesis holds that mismetabolism and aggregation of neurotoxic amyloid-β (Aβ) peptides, which are deposited as amyloid plaques, are the central etiological events in AD. Recent evidence from AD mouse models suggests that blood-borne mononuclear phagocytes are capable of infiltrating the brain and restricting β-amyloid plaques, thereby limiting disease progression. These observations raise at least three key questions: (1) what is the cell of origin for macrophages in the AD brain, (2) do blood-borne macrophages impact the pathophysiology of AD and (3) could these enigmatic cells be therapeutically targeted to curb cerebral amyloidosis and thereby slow disease progression? This review begins with a historical perspective of peripheral mononuclear phagocytes in AD, and moves on to critically consider the controversy surrounding their identity as distinct from brain-resident microglia and their potential impact on AD pathology

Improved Learning and Memory in Aged Mice Deficient in Amyloid β-Degrading Neutral Endopeptidase

BACKGROUND: Neutral endopeptidase, also known as neprilysin and abbreviated NEP, is considered to be one of the key enzymes in initial human amyloid-beta (Abeta) degradation. The aim of our study was to explore the impact of NEP deficiency on the initial development of dementia-like symptoms in mice. METHODOLOGY/PRINCIPAL FINDINGS: We found that while endogenous Abeta concentrations were elevated in the brains of NEP-knockout mice at all investigated age groups, immunohistochemical analysis using monoclonal antibodies did not detect any Abeta deposits even in old NEP knockout mice. Surprisingly, tests of learning and memory revealed that the ability to learn was not reduced in old NEP-deficient mice but instead had significantly improved, and sustained learning and memory in the aged mice was congruent with improved long-term potentiation (LTP) in brain slices of the hippocampus and lateral amygdala. Our data suggests a beneficial effect of pharmacological inhibition of cerebral NEP on learning and memory in mice due to the accumulation of peptides other than Abeta degradable by NEP. By conducting degradation studies and peptide measurements in the brain of both genotypes, we identified two neuropeptide candidates, glucagon-like peptide 1 and galanin, as first potential candidates to be involved in the improved learning in aged NEP-deficient mice. CONCLUSIONS/SIGNIFICANCE: Thus, the existence of peptides targeted by NEP that improve learning and memory in older individuals may represent a promising avenue for the treatment of neurodegenerative diseases

Reduced Slow-Wave Sleep Is Associated with High Cerebrospinal Fluid A beta 42 Levels in Cognitively Normal Elderly

Study Objectives: Emerging evidence suggests a role for sleep in contributing to the progression of Alzheimer disease (AD). Slow wave sleep (SWS) is the stage during which synaptic activity is minimal and clearance of neuronal metabolites is high, making it an ideal state to regulate levels of amyloid beta (Aβ). We thus aimed to examine relationships between concentrations of Aβ42 in the cerebrospinal fluid (CSF) and measures of SWS in cognitively normal elderly subjects. Methods: Thirty-six subjects underwent a clinical and cognitive assessment, a structural MRI, a morning to early afternoon lumbar puncture, and nocturnal polysomnography. Correlations and linear regression analyses were used to assess for associations between CSF Aβ42 levels and measures of SWS controlling for potential confounders. Resulting models were compared to each other using ordinary least squared linear regression analysis. Additionally, the participant sample was dichotomized into “high” and “low” Aβ42 groups to compare SWS bout length using survival analyses. Results: A significant inverse correlation was found between CSF Aβ42 levels, SWS duration and other SWS characteristics. Collectively, total SWA in the frontal lead was the best predictor of reduced CSF Aβ42 levels when controlling for age and ApoE status. Total sleep time, time spent in NREM1, NREM2, or REM sleep were not correlated with CSF Aβ42. Conclusions: In cognitively normal elderly, reduced and fragmented SWS is associated with increases in CSF Aβ42, suggesting that disturbed sleep might drive an increase in soluble brain Aβ levels prior to amyloid deposition