Exploring Potential Mechanisms Accounting for Iron Accumulation in the Central Nervous System of Patients with Alzheimer's Disease.

Elevated levels of iron occur in both cortical and subcortical regions of the CNS in patients with Alzheimer's disease. This accumulation is present early in the disease process as well as in more advanced stages. The factors potentially accounting for this increase are numerous, including: (1) Cells increase their uptake of iron and reduce their export of iron, as iron becomes sequestered (trapped within the lysosome, bound to amyloid ß or tau, etc.); (2) metabolic disturbances, such as insulin resistance and mitochondrial dysfunction, disrupt cellular iron homeostasis; (3) inflammation, glutamate excitotoxicity, or other pathological disturbances (loss of neuronal interconnections, soluble amyloid ß, etc.) trigger cells to acquire iron; and (4) following neurodegeneration, iron becomes trapped within microglia. Some of these mechanisms are also present in other neurological disorders and can also begin early in the disease course, indicating that iron accumulation is a relatively common event in neurological conditions. In response to pathogenic processes, the directed cellular efforts that contribute to iron buildup reflect the importance of correcting a functional iron deficiency to support essential biochemical processes. In other words, cells prioritize correcting an insufficiency of available iron while tolerating deposited iron. An analysis of the mechanisms accounting for iron accumulation in Alzheimer's disease, and in other relevant neurological conditions, is put forward.

Examining the Role of a Functional Deficiency of Iron in Lysosomal Storage Disorders with Translational Relevance to Alzheimer's Disease.

The recently presented Azalea Hypothesis for Alzheimer's disease asserts that iron becomes sequestered, leading to a functional iron deficiency that contributes to neurodegeneration. Iron sequestration can occur by iron being bound to protein aggregates, such as amyloid ß and tau, iron-rich structures not undergoing recycling (e.g., due to disrupted ferritinophagy and impaired mitophagy), and diminished delivery of iron from the lysosome to the cytosol. Reduced iron availability for biochemical reactions causes cells to respond to acquire additional iron, resulting in an elevation in the total iron level within affected brain regions. As the amount of unavailable iron increases, the level of available iron decreases until eventually it is unable to meet cellular demands, which leads to a functional iron deficiency. Normally, the lysosome plays an integral role in cellular iron homeostasis by facilitating both the delivery of iron to the cytosol (e.g., after endocytosis of the iron-transferrin-transferrin receptor complex) and the cellular recycling of iron. During a lysosomal storage disorder, an enzyme deficiency causes undigested substrates to accumulate, causing a sequelae of pathogenic events that may include cellular iron dyshomeostasis. Thus, a functional deficiency of iron may be a pathogenic mechanism occurring within several lysosomal storage diseases and Alzheimer's disease.

The Azalea Hypothesis of Alzheimer Disease: A Functional Iron Deficiency Promotes Neurodegeneration.

Chlorosis in azaleas is characterized by an interveinal yellowing of leaves that is typically caused by a deficiency of iron. This condition is usually due to the inability of cells to properly acquire iron as a consequence of unfavorable conditions, such as an elevated pH, rather than insufficient iron levels. The causes and effects of chlorosis were found to have similarities with those pertaining to a recently presented hypothesis that describes a pathogenic process in Alzheimer disease. This hypothesis states that iron becomes sequestered (e.g., by amyloid ß and tau), causing a functional deficiency of iron that disrupts biochemical processes leading to neurodegeneration. Additional mechanisms that contribute to iron becoming unavailable include iron-containing structures not undergoing proper recycling (e.g., disrupted mitophagy and altered ferritinophagy) and failure to successfully translocate iron from one compartment to another (e.g., due to impaired lysosomal acidification). Other contributors to a functional deficiency of iron in patients with Alzheimer disease include altered metabolism of heme or altered production of iron-containing proteins and their partners (e.g., subunits, upstream proteins). A review of the evidence supporting this hypothesis is presented. Also, parallels between the mechanisms underlying a functional iron-deficient state in Alzheimer disease and those occurring for chlorosis in plants are discussed. Finally, a model describing the generation of a functional iron deficiency in Alzheimer disease is put forward.

Exploring Whether Iron Sequestration within the CNS of Patients with Alzheimer's Disease Causes a Functional Iron Deficiency That Advances Neurodegeneration.

The involvement of iron in the pathogenesis of Alzheimer's disease (AD) may be multifaceted. Besides potentially inducing oxidative damage, the bioavailability of iron may be limited within the central nervous system, creating a functionally iron-deficient state. By comparing staining results from baseline and modified iron histochemical protocols, iron was found to be more tightly bound within cortical sections from patients with high levels of AD pathology compared to subjects with a diagnosis of something other than AD. To begin examining whether the bound iron could cause a functional iron deficiency, a protein-coding gene expression dataset of initial, middle, and advanced stages of AD from olfactory bulb tissue was analyzed for iron-related processes with an emphasis on anemia-related changes in initial AD to capture early pathogenic events. Indeed, anemia-related processes had statistically significant alterations, and the significance of these changes exceeded those for AD-related processes. Other changes in patients with initial AD included the expressions of transcripts with iron-responsive elements and for genes encoding proteins for iron transport and mitochondrial-related processes. In the latter category, there was a decreased expression for the gene encoding pitrilysin metallopeptidase 1 (PITRM1). Other studies have shown that PITRM1 has an altered activity in patients with AD and is associated with pathological changes in this disease. Analysis of a gene expression dataset from PITRM1-deficient or sufficient organoids also revealed statistically significant changes in anemia-like processes. These findings, together with supporting evidence from the literature, raise the possibility that a pathogenic mechanism of AD could be a functional deficiency of iron contributing to neurodegeneration.

A Simplified Method for the Histochemical Detection of Iron in Paraffin Sections: Intracellular Iron Deposits in Central Nervous System Tissue.

Although all cells contain iron, most histochemical methods fail to reveal the presence of iron within many cells of the central nervous system (CNS), particularly neurons. Previously, a sensitive method was developed that limited the extraction of iron in paraffin sections, and this method revealed staining within neurons. However, the staining was often too robust making it difficult to discern discrete intracellular structures. In 1970, a study incorporated acetone in an iron histochemical procedure to facilitate the demarcation of staining features. In the present study, both acetone and limits to iron extraction were included in a simplified staining procedure. This procedure was applied to paraffin sections of CNS tissue from CISD2 deficient and littermate control mice. Discrete nuclear and cytoplasmic staining features were detected in all mice. Although widely present in neurons, punctate cytoplasmic staining was particularly prominent in large neurons within the hindbrain. Evaluation of extended depth of focus images, from serial focal planes, revealed numerous stained cytoplasmic structures. Additionally, the simplified staining procedure was applied to paraffin sections from Alzheimer's disease and control cases. Despite suboptimal processing conditions compared to mouse tissue, discrete staining of cytoplasmic structures was revealed in some neurons, although many other neurons had nondescript staining features. In addition, initial findings revealed iron deposited within some vessels from patients with Alzheimer's disease. In summary, since paraffin sections are commonly used for histological preparations, this simplified histochemical procedure could facilitate the study of iron in various CNS conditions by revealing staining details often missed by other procedures.

Substrate Reduction Therapy for Krabbe Disease: Exploring the Repurposing of the Antibiotic D-Cycloserine.

Krabbe disease is a lysosomal storage disease that is caused by a deficiency in galactosylceramidase. Infantile onset disease is the most common presentation, which includes progressive neurological deterioration with corresponding demyelination, development of globoid cells, astrocyte gliosis, etc. Hemopoietic stem cell transplantation (HSCT) is a disease modifying therapy, but this intervention is insufficient with many patients still experiencing developmental delays and progressive deterioration. Preclinical studies have used animal models, e.g., twitcher mice, to test different experimental therapies resulting in developments that have led to progressive improvements in the therapeutic impact. Some recent advances have been in the areas of gene therapy and substrate reduction therapy (SRT), as well as using these in combination with HSCT. Unfortunately, new experimental approaches have encountered obstacles which have impeded the translation of novel therapies to human patients. In an effort to identify a safe adjunct therapy, D-cycloserine was tested in preliminary studies in twitcher mice. When administered as a standalone therapy, D-cycloserine was shown to lengthen the lifespan of twitcher mice in a small but significant manner. D-Cycloserine is an FDA approved antibiotic used for drug resistant tuberculosis. It also acts as a partial agonist of the NMDA receptor, which has led to numerous human studies for a range of neuropsychiatric and neurological conditions. In addition, D-cycloserine may inhibit serine palmitoyltransferase (SPT), which catalyzes the rate-limiting step in sphingolipid production. The enantiomer, L-cycloserine, is a much more potent inhibitor of SPT than D-cycloserine. Previously, L-cycloserine was found to act as an effective SRT agent in twitcher mice as both a standalone therapy and as part of combination therapies. L-Cycloserine is not approved for human use, and its potent inhibitory properties may limit its ability to maintain a level of partial inactivation of SPT that is also safe. In theory, D-cycloserine would encompass a much broader dosage range to achieve a safe degree of partial inhibition of SPT, which increases the likelihood it could advance to human studies in patients with Krabbe disease. Furthermore, additional properties of D-cycloserine raise the possibility of other therapeutic mechanisms that could be exploited for the treatment of this disease.

An Engineered Galactosylceramidase Construct Improves AAV Gene Therapy for Krabbe Disease in Twitcher Mice.

Krabbe disease is an inherited neurodegenerative disease caused by mutations in the galactosylceramidase gene. In the infantile form, patients die before 3 years of age. Systemic adeno-associated virus serotype 9 (AAV9) gene therapy was recently shown to reverse the disease course in human patients in another lethal infantile neurodegenerative disease. To explore AAV9 therapy for Krabbe disease, we engineered a codon-optimized AAV9 galactosylceramidase vector. We further incorporated features to allow AAV9-derived galactosylceramidase to more efficiently cross the blood-brain barrier and be secreted from transduced cells. We tested the optimized vector by a single systemic injection in the twitcher mouse, an authentic Krabbe disease model. Untreated twitcher mice showed characteristic neuropathology and motion defects. They died prematurely with a median life span of 41 days. Intravenous injection in 2-day-old twitcher mice reduced central and peripheral neuropathology and significantly improved the gait pattern and body weight. Noticeably, the median life span was extended to 150 days. Intraperitoneal injection in 6- to 12-day-old twitcher mice also significantly improved the motor function, body weight, and median life span (to 104 days). Our results far exceed the ≤70 days median life span seen in all reported stand-alone systemic AAV therapies. Our study highlights the importance of vector engineering for Krabbe disease gene therapy. The engineered vector warrants further development.

Lower Eyelid Blepharoplasty: Does the Literature Support the Longevity of this Procedure?

BACKGROUND: Lower eyelid blepharoplasty has continued to evolve with ongoing debate regarding optimal techniques. Despite large case series publishing excellent results and minimal complications, the true longevity of these procedures remains unclear. OBJECTIVES: The aim of this study was to determine how thoroughly the aesthetic surgery literature assesses the longevity of lower blepharoplasty. METHODS: A 20-year comprehensive literature review from 1997 to 2017 was conducted. The titles and abstracts of 180 articles were reviewed, yielding 86 potential publications; 49 studies met inclusion criteria and were analyzed. RESULTS: A total of 10,698 patients were included for analysis. Reported follow-up ranged between 1 week and 192 months. Mean follow-up was 14.8 months for the 29 studies (59.2%) that reported these data. Pooled analysis of complication rates demonstrated 0.77% (n = 82) reoperation, 0.37% (n = 39) scleral show, 0.25% (n = 27) lid malposition, and 0.24% (n = 25) ectropion rates, among others. Forty-four studies (89.8%) published postoperative photographs with a total of 141 unique postoperative time points that were supported with photographic evidence (mean: 15.3 months; range: 1 week-192 months). In this series, for only 10 patients (0.094%) were postoperative photographs available at time points beyond 24 months. CONCLUSIONS: Lower eyelid blepharoplasty is a powerful procedure with seemingly minimal morbidity despite its technical demands. The longevity of this procedure is poorly supported with photographic evidence in the literature. Studies do not adequately report or represent their follow-up to capture long-lasting results. Standardized reporting of results is needed to ensure that anyone seeking this treatment can be adequately counseled.

Safety and efficacy of anti-PD-L1 therapy in the woodchuck model of HBV infection.

Immune clearance of Hepatitis B virus (HBV) is characterized by broad and robust antiviral T cell responses, while virus-specific T cells in chronic hepatitis B (CHB) are rare and exhibit immune exhaustion that includes programmed-death-1 (PD-1) expression on virus-specific T cells. Thus, an immunotherapy able to expand and activate virus-specific T cells may have therapeutic benefit for CHB patients. Like HBV-infected patients, woodchucks infected with woodchuck hepatitis virus (WHV) can have increased hepatic expression of PD-1-ligand-1 (PD-L1), increased PD-1 on CD8+ T cells, and a limited number of virus-specific T cells with substantial individual variation in these parameters. We used woodchucks infected with WHV to assess the safety and efficacy of anti-PD-L1 monoclonal antibody therapy (αPD-L1) in a variety of WHV infection states. Experimentally-infected animals lacked PD-1 or PD-L1 upregulation compared to uninfected controls, and accordingly, αPD-L1 treatment in lab-infected animals had limited antiviral effects. In contrast, animals with naturally acquired WHV infections displayed elevated PD-1 and PD-L1. In these same animals, combination therapy with αPD-L1 and entecavir (ETV) improved control of viremia and antigenemia compared to ETV treatment alone, but with efficacy restricted to a minority of animals. Pre-treatment WHV surface antigen (sAg) level was identified as a statistically significant predictor of treatment response, while PD-1 expression on peripheral CD8+ T cells, T cell production of interferon gamma (IFN-γ) upon in vitro antigen stimulation (WHV ELISPOT), and circulating levels of liver enzymes were not. To further assess the safety of this strategy, αPD-L1 was tested in acute WHV infection to model the risk of liver damage when the extent of hepatic infection and antiviral immune responses were expected to be the greatest. No significant increase in serum markers of hepatic injury was observed over those in infected, untreated control animals. These data support a positive benefit/risk assessment for blockade of the PD-1:PD-L1 pathway in CHB patients and may help to identify patient groups most likely to benefit from treatment. Furthermore, the efficacy of αPD-L1 in only a minority of animals, as observed here, suggests that additional agents may be needed to achieve a more robust and consistent response leading to full sAg loss and durable responses through anti-sAg antibody seroconversion.

Public Interest in Breast Augmentation: Analysis and Implications of Google Trends Data.

INTRODUCTION: Breast augmentation is the most common aesthetic surgery performed in the United States (US) annually. Analysis of Google Trends (GT) data may give plastic surgeons useful information regarding worldwide, national, and regional interest for breast augmentation and other commonly performed aesthetic surgeries. METHODS: Data were collected using GT for breast augmentation and associated search terms from January 2004 to May 2017. Case volume was obtained from the American Society of Plastic Surgeons (ASPS) annual reports for the calendar year 2005-2016. RESULTS: Trend analysis showed that total search term volume for breast augmentation and breast implants gradually decreased worldwide and in the US over the study period while the search term boob job slowly increased. Univariate linear regression demonstrated a statistically significant positive correlation between average annual Google search volume of "breast augmentation" and the annual volume of breast augmentations performed in the US according to ASPS data (R 2 = 0.44, p = 0.018). There was no significant correlation between national volume of breast augmentations performed and search volume using the terms "breast implants" or "boob job" over time (p = 0.84 and p = 0.07, respectively). In addition, there appears to be country specific variation in interest based on time of year and peaks in interest following specific policies. CONCLUSIONS: To our knowledge, this is the first and only analysis of GT data in the plastic surgery literature to date. To that end, this study highlights this large and potentially powerful data set for plastic surgeons both in the US and around the world. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Metabolic pathways as possible therapeutic targets for progressive multiple sclerosis.

Unlike relapsing remitting multiple sclerosis, there are very few therapeutic options for patients with progressive forms of multiple sclerosis. While immune mechanisms are key participants in the pathogenesis of relapsing remitting multiple sclerosis, the mechanisms underlying the development of progressive multiple sclerosis are less well understood. Putative mechanisms behind progressive multiple sclerosis have been put forth: insufficient energy production via mitochondrial dysfunction, activated microglia, iron accumulation, oxidative stress, activated astrocytes, Wallerian degeneration, apoptosis, etc. Furthermore, repair processes such as remyelination are incomplete. Experimental therapies that strive to improve metabolism within neurons and glia, e.g., oligodendrocytes, could act to counter inadequate energy supplies and/or support remyelination. Most experimental approaches have been examined as standalone interventions; however, it is apparent that the biochemical steps being targeted are part of larger pathways, which are further intertwined with other metabolic pathways. Thus, the potential benefits of a tested intervention, or of an established therapy, e.g., ocrelizumab, could be undermined by constraints on upstream and/or downstream steps. If correct, then this argues for a more comprehensive, multifaceted approach to therapy. Here we review experimental approaches to support neuronal and glial metabolism, and/or promote remyelination, which may have potential to lessen or delay progressive multiple sclerosis.

Selective Serotonin Reuptake Inhibitor-Induced Hyponatremia and the Plastic Surgery Patient.

Cosmetic plastic surgery procedures continue to increase in frequency, and a greater number of them now occur outside of an acute-care hospital setting. In addition, antidepressant use is also rising, with a greater number of patients taking selective serotonin reuptake inhibitors to aid in a variety of mood and anxiety disorders. Americans spend more than $86 billion each year on antidepressants, as 34 million people in the United States are taking at least one of these medications. Many side effects of selective serotonin reuptake inhibitors are well known and not clinically relevant to practicing surgeons. Hyponatremia, however, is a well-documented side effect of these medications that has received relatively little attention in the surgical literature. Postoperative hyponatremia results because of a decrease of antidiuretic hormone suppression that occurs with selective serotonin reuptake inhibitor administration. Here, the authors first review the literature reporting hyponatremia with selective serotonin reuptake inhibitor use. The authors then present two cases of severe postoperative hyponatremia after plastic surgery operations. The authors propose that patients using selective serotonin reuptake inhibitors, especially elderly patients and those undergoing procedures with expected large fluid shifts, should be tested preoperatively and postoperatively for serum sodium levels so that a diagnosis of hyponatremia may be made early and treated before a catastrophic event. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Piloting electronic medical record-based early detection of inpatient deterioration in community hospitals.

Patients who deteriorate in the hospital outside the intensive care unit (ICU) have higher mortality and morbidity than those admitted directly to the ICU. As more hospitals deploy comprehensive inpatient electronic medical records (EMRs), attempts to support rapid response teams with automated early detection systems are becoming more frequent. We aimed to describe some of the technical and operational challenges involved in the deployment of an early detection system. This 2-hospital pilot, set within an integrated healthcare delivery system with 21 hospitals, had 2 objectives. First, it aimed to demonstrate that severity scores and probability estimates could be provided to hospitalists in real time. Second, it aimed to surface issues that would need to be addressed so that deployment of the early warning system could occur in all remaining hospitals. To achieve these objectives, we first established a rationale for the development of an early detection system through the analysis of risk-adjusted outcomes. We then demonstrated that EMR data could be employed to predict deteriorations. After addressing specific organizational mandates (eg, defining the clinical response to a probability estimate), we instantiated a set of equations into a Java application that transmits scores and probability estimates so that they are visible in a commercially available EMR every 6 hours. The pilot has been successful and deployment to the remaining hospitals has begun. Journal of Hospital Medicine 2016;11:S18-S24. © 2016 Society of Hospital Medicine.

Enhanced Histochemical Detection of Iron in Paraffin Sections of Mouse Central Nervous System Tissue: Application in the APP/PS1 Mouse Model of Alzheimer's Disease.

Histochemical methods of detecting iron in the rodent brain result mainly in the labeling of oligodendrocytes, but as all cells utilize iron, this observation suggests that much of the iron in the central nervous system goes undetected. Paraffin embedding of tissue is a standard procedure that is used to prepare sections for microscopic analysis. In the present study, we questioned whether we could modify the iron histochemical procedure to enable a greater detection of iron in paraffin sections. Indeed, various modifications led to the widespread labeling of iron in mouse brain tissue (for instance, labeling of neurons and neuropil). Sites of focal concentrations, such as cytoplasmic punctate or nucleolar staining, were also observed. The modified procedures were applied to paraffin sections of a mouse model (APP/PS1) of Alzheimer's disease. Iron was revealed in the plaque core and rim. The plaque rim had a fibrillary or granular appearance, and it frequently contained iron-labeled cells. Further analysis indicated that the iron was tightly associated with the core of the plaque, but less so with the rim. In conclusion, modifications to the histochemical staining revealed new insights into the deposition of iron in the central nervous system. In theory, the approach should be transferrable to organs besides the brain and to other species, and the underlying principles should be incorporable into a variety of staining methods.

Substrate reduction therapy for Krabbe's disease.

Krabbe's disease (KD) is a lysosomal storage disorder in which galactosylceramide, a major glycosphingolipid of myelin, and psychosine (galactose-sphingosine) cannot be adequately metabolized because of a deficiency in galactosylceramidase. Substrate reduction therapy (SRT) has been tested in preclinical studies. The premise of SRT is to reduce the synthesis of substrates that are not adequately digested so that the substrate burden is lowered, resulting in less accumulation of unmetabolized material. SRT is used for Gaucher's disease, in which inhibitors of the terminal biosynthetic step are used. Unfortunately, an inhibitor for the final step of galactosylceramide biosynthesis, i.e., UDP glycosyltransferase 8 (a.k.a. UDP-galactose ceramide galactosyltransferase), has not been found. Approaches that inhibit an earlier biosynthetic step or that lessen the substrate burden by other means, such as genetic manipulations, have been tested in the twitcher mouse model of KD. Either as a stand-alone therapy or in combination with other approaches, SRT slowed the disease course, indicating that this approach has potential therapeutic value. For instance, in individuals with adult-onset disease, SRT theoretically could lessen the production of substrates so that residual enzymatic activity could adequately manage the lower substrate burden. In more severe forms of disease, SRT theoretically could be part of a combination therapy. However, SRT has the potential to impair normal function by reducing the synthesis of galactosylceramide to levels that impede myelin function, or SRT could have other deleterious effects. Thus, multiple issues need to be resolved before this approach is ready for testing in humans. © 2016 Wiley Periodicals, Inc.

Albumin and multiple sclerosis.

Leakage of the blood-brain barrier (BBB) is a common pathological feature in multiple sclerosis (MS). Following a breach of the BBB, albumin, the most abundant protein in plasma, gains access to CNS tissue where it is exposed to an inflammatory milieu and tissue damage, e.g., demyelination. Once in the CNS, albumin can participate in protective mechanisms. For example, due to its high concentration and molecular properties, albumin becomes a target for oxidation and nitration reactions. Furthermore, albumin binds metals and heme thereby limiting their ability to produce reactive oxygen and reactive nitrogen species. Albumin also has the potential to worsen disease. Similar to pathogenic processes that occur during epilepsy, extravasated albumin could induce the expression of proinflammatory cytokines and affect the ability of astrocytes to maintain potassium homeostasis thereby possibly making neurons more vulnerable to glutamate exicitotoxicity, which is thought to be a pathogenic mechanism in MS. The albumin quotient, albumin in cerebrospinal fluid (CSF)/albumin in serum, is used as a measure of blood-CSF barrier dysfunction in MS, but it may be inaccurate since albumin levels in the CSF can be influenced by multiple factors including: 1) albumin becomes proteolytically cleaved during disease, 2) extravasated albumin is taken up by macrophages, microglia, and astrocytes, and 3) the location of BBB damage affects the entry of extravasated albumin into ventricular CSF. A discussion of the roles that albumin performs during MS is put forth.

Current Thoughts on Fat Grafting: Using the Evidence to Determine Fact or Fiction.

BACKGROUND: Autologous fat grafting is an increasingly popular procedure used for facial rejuvenation and body contouring. The purpose of this article is to perform an evidence-based review to determine fact from fiction for the hot topics in autologous fat grafting. METHODS: A comprehensive literature search was performed. The following key words were then searched: "fat grafting," "autologous fat grafting," "autologous fat transfer," "lipotransfer," "liposculping," and "lipofilling." The authors then assessed each modality individually for the level of evidence that exists and whether the majority of evidence supports or refutes it. RESULTS: A review of the literature demonstrated that there is no standard test for determining fat viability or volume augmentation after grafting. Furthermore, there is no difference in cell viability seen between syringe aspiration and liposuction pump aspiration harvest techniques (Level II). The decision to wash or centrifuge the fat plays very little role in fat graft survival (Level III). There is no difference between cell viability as a function of harvest location (Level IV). Nearly all studies show no significant effect of local anesthesia on adipocyte cells (Level IV). There are excellent data that support the fact that low-shear devices maintain fat structural integrity (Level IV). There is quality evidence that supports longevity of fat grafted to the breast (Level III). Two studies support large-volume fat grafting longevity but fail to prove their results using objective measures or with sufficiently large sample sizes (Level IV). External preexpansion devices improve total graft survival rate (Level IV). There is quality evidence to support that fat should be injected soon after harvesting, as properties of fat begin to change after processing (Level IV). Microneedling (preconditioning) before fat grafting has been demonstrated to improve fat survival (Level III). CONCLUSIONS: Currently, the highest levels of evidence derive from human studies of clinical trials and animal studies using human fat. The evidence presented here helps to address the need for accurate and quantitative viability assays. These assays would facilitate a systematic evaluation of each procedural step during fat graft harvest, processing, and grafting to improve the overall viability and predictability of fat grafts.

Plastic Surgery Mortality: An 11-Year, Single-Institution Experience.

BACKGROUND: Systematic reporting of mortality data is lacking in many surgical fields including plastic surgery. Current plastic surgery literature is largely limited to adverse events associated with specific procedures. Without mortality data, it is unclear how the recent growth of patient safety initiatives can rationally impact outcomes. METHODS: We evaluated 11 years of patient outcome data collected prospectively and updated monthly by our department. Paper records were entered into a Health Insurance Portability and Accountability Act-compliant digital database capable of prospectively maintaining future data. Data were reviewed for 5 surgical services in 4 different hospitals that comprise our department's activity. RESULTS: Between 2000 and 2011, a total of 60,834 cases were performed. In this time, a total of 829 (1.4%) negative outcome reports were identified. Of these, a total of 25 (0.04%) cases had an outcome of death (24) or brain death (1). Deaths were either directly or indirectly associated with cardiopulmonary causes, multisystem organ failure, sepsis, massive bleeding, CVA, saddle embolism, or unknown causes. CONCLUSIONS: This study is the largest reported series of cases performed by a single academic plastic surgery service to report overall mortality data.

Intersections of pathways involving biotin and iron relative to therapeutic mechanisms for progressive multiple sclerosis.

While there are a variety of therapies for relapsing remitting multiple sclerosis (MS), there is a lack of treatments for progressive MS. An early study indicated that high dose biotin therapy has beneficial effects in approximately 12-15% of patients with progressive MS. The mechanisms behind the putative improvements seen with biotin therapy are not well understood, but have been postulated to include: 1) improving mitochondrial function which is impaired in MS, 2) increasing synthesis of lipids and cholesterol to facilitate remyelination, and 3) affecting gene expression. We suggest one reason that a greater percentage of patients with MS didn't respond to biotin therapy is the inaccessibility or lack of other nutrients, such as iron. In addition to biotin, iron (or heme) is necessary for energy production, biosynthesis of cholesterol and lipids, and for some protective mechanisms. Both biotin and iron are required for myelination during development, and by inference, remyelination. However, iron can also play a role in the pathology of MS. Increased deposition of iron can occur in some CNS structures possibly promoting oxidative damage while low iron levels can occur in other areas. Thus, the potential, detrimental effects of iron need to be considered together with the need for iron to support metabolic demands associated with repair and/or protective processes. We propose the optimal utilization of iron may be necessary to maximize the beneficial effects of biotin. This review will examine the interactions between biotin and iron in pathways that may have therapeutic or pathogenic implications for MS.