Successful Novel Treatment of Granuloma Faciale Using CO2 Emulated Er:YAG Laser Ablation.

Granuloma faciale is a rare, benign inflammatory skin disease that has multiple medical treatment modalities due to its frequent unresponsiveness to treatment. This skin disease presents as a single, well-demarcated red-brown to violaceous, raised lesion, most commonly on the face, in middle-aged White men. Its etiology is unknown; sun exposure is thought to have some implications in its formation. Treatment modalities for granuloma faciale include topical therapy, intralesional injections, systemic therapies, phototherapy, lasers, cryotherapy, and surgical excision. In this article, we will highlight a rare case of granuloma faciale and its novel and successful treatment with a carbon dioxide emulated Er:YAG laser.

Necrotizing fasciitis of the breast managed by partial mastectomy and local tissue rearrangement.

Necrotizing fasciitis (NF) of the breast is a rare occurrence that is routinely misdiagnosed as an abscess or cellulitis, resulting in treatment delays. A total mastectomy is required when delays occur. We present a 53-year-old female with breast NF managed with a partial mastectomy and local tissue rearrangement.

Determinants of breast appearance and aging in identical twins.

BACKGROUND: Appearance, aging, and disorders of the breast are multifactorial. There are intrinsic, patient-specific characteristics, such as breast growth during puberty and propensity for breast cancer, which are primarily inherited. There are also environmental factors, which can be potentially controlled. Monozygotic twins provide an excellent research opportunity to examine the role of extrinsic factors in subjects with identical genetic predispositions. OBJECTIVES: The authors investigate the role and significance of various environmental and acquired factors on breast aesthetics. METHODS: Identical female twins were recruited during the Twins Days Festival in Twinsburg, Ohio, in 2009 and 2010. After consent was obtained, enrolled subjects completed a comprehensive survey on their medical and personal history. Standardized digital photographs were taken by medical photographers. Sixteen aesthetic breast features were subjectively rated by 6 plastic surgery residents blinded to the survey results. These ratings were then analyzed against survey data to determine the significance of different exogenous factors on breast appearance. RESULTS: A total of 161 pairs of identical female twins (n = 322) with a mean (SD) age of 47.6 (14.5) years were recruited. Twins who moisturized their skin daily had significantly fewer rhytids (P = .002). Twins who received hormone replacement therapy after menopause had more attractive breast shape, size, projection, areolar shape, and areolar size (P < .03). However, twins who had a higher body mass index, greater number of pregnancies, and larger cup sizes had significantly less attractive breasts (P < .05). Twins who smoked cigarettes and consumed alcohol also had significantly less attractive breasts (P < .05). Twins who breastfed had less attractive areolar size and shape but better skin quality than their counterparts who never breastfed (P < .03). Finally, there was a significantly higher incidence of breast pain in twins who primarily slept on their sides compared with twins who primarily slept on their backs (P < .008). CONCLUSIONS: This study implicates several environmental factors that significantly affect the aesthetic quality of breasts.

Mitochondrial abnormalities and oxidative imbalance in Alzheimer disease.

A number of mitochondrial and metabolic abnormalities were identified in the hippocampal neurons of Alzheimer disease compared to age-matched controls. Hippocampal neurons are the most vulnerable to disease-associated pathology (i.e., cell death and proteinaceous lesions) and contain numerous markers of oxidative stress. Interestingly we found that the levels of mitochondrial DNA and cytochrome oxidase-1 in these neurons are markedly increased compared with those of age-matched control brains, even though the number of mitochondria per neuron is decreased. We hypothesize that the increased levels of mitochondrial DNA and cytochrome oxidase-1 may reflect an attempt by oxidatively-challenged neurons to replicate mitochondria, albeit unsuccessfully, as a response to the energetic/oxidative stress. Indeed, in this context, numerous signs of mitosis are observed in pyramidal neurons. Mitotic signals that promote cell cycle re-entry might be expected to also signal the synthesis of new mitochondria. Alternatively, these abnormalities may indicate altered turnover of mitochondrial components as a result of reduced degradation of mitochondrial byproducts or altered mitochondrial transport that redistributes mitochondrial DNA and cytochrome oxidase-1 to the cell body.

Tau modifiers as therapeutic targets for Alzheimer's disease.

Fibrillogenesis is a major feature of Alzheimer's disease (AD) and other neurodegenerative diseases. Fibers are correlated with disease severity and they have been implicated as playing a direct role in disease pathophysiology. In studies of tau, instead of finding causality with tau fibrils, we found that tau is associated with reduction of oxidative stress. Biochemical findings show that tau oxidative modifications are regulated by phosphorylation and that tau found in neurofibrillary tangles is oxidatively modified, suggesting that tau is closely linked to the biology, not toxicity, of AD.

Contribution of redox-active iron and copper to oxidative damage in Alzheimer disease.

Metal-catalyzed hydroxyl radicals are potent mediators of cellular injury, affecting every category of macromolecule, and are central to the oxidative injury hypothesis of Alzheimer disease (AD) pathogenesis. Studies on redox-competent copper and iron indicate that redox activity in AD resides exclusively within the neuronal cytosol and that chelation with deferoxamine, DTPA, or, more recently, iodochlorhydroxyquin, removes this activity. We have also found that while proteins that accumulate in AD possess metal-binding sites, metal-associated cellular redox activity is primarily dependent on metals associated with nucleic acid, specifically cytoplasmic RNA. These findings indicate aberrations in iron homeostasis that, we suspect, arise primarily from heme, since heme oxygenase-1, an enzyme that catalyzes the conversion of heme to iron and biliverdin, is increased in AD, and mitochondria, since mitochondria turnover, mitochondrial DNA, and cytochrome C oxidative activity are all increased in AD. These findings, as well as studies demonstrating a reduction in microtubule density in AD neurons, suggest that mitochondrial dysfunction, acting in concert with cytoskeletal pathology, serves to increase redox-active heavy metals and initiates a cascade of abnormal events culminating in AD pathology.

Alzheimer disease: evidence for a central pathogenic role of iron-mediated reactive oxygen species.

Free radical formation, abnormalities in iron and copper distribution, and metal-catalyzed oxidation have all been noted in Alzheimer disease and are thought to play an important role in disease pathogenesis. Metal-catalyzed hydroxyl radical formation results in damage to every category of macromolecule found in the vulnerable neuronal populations in Alzheimer disease. In fact, redox activity resides within the cytosol of vulnerable neurons. Since oxidative damage represents one of the earliest pathological changes in Alzheimer disease, it is likely that aberrant redox activity is among the earliest changes in the transition to the disease state. In this review, we consider the wealth of evidence implicating a central role for metals in Alzheimer disease.

Microtubule reduction in Alzheimer's disease and aging is independent of tau filament formation.

Biochemical studies show that phosphorylated tau, like that found in paired helical filaments (PHFs), does not promote microtubule assembly leading to the view that PHF formation leads to microtubule deficiency in Alzheimer's disease (AD). However, although this issue is one of the most important aspects to further understanding the cell biology of AD, no quantitative examination of microtubule diminution in AD and its relationship with PHFs has been performed. To examine this issue directly, we undertook a morphometric study of brain biopsy specimens from AD and control cases. Ultrastructural analysis of neurons was performed to compare the microtubule assembly state in neurons of diseased and control cases and to examine the effect of PHF accumulation. We found that both number and total length of microtubules were significantly and selectively reduced in pyramidal neurons from AD in comparison to control cases (P = 0.000004) but that this decrement in microtubule density was surprisingly unrelated to PHFs (P = 0.8). Further, we found a significant age-dependent decrease in microtubule density with aging in the control cases (P = 0.016). These findings suggest that reduction in microtubule assembly is not dependent on tau abnormalities of AD and aging.

Apoptotic promoters and inhibitors in Alzheimer's disease: Who wins out?

A spectrum of apoptotic mediators are seen in neurons that are vulnerable in Alzheimer's disease (AD), leading many investigators to suggest that neuronal death in AD is mediated by an apoptotic process. Indeed, the environment of the AD brain is awash with proapoptotic mediators including amyloid-beta, oxidative stress, hydroxynonenal oxidants and metabolic alterations with concomitant energy failures. However, the phenotype that defines the terminal events that are pathogonomic of apoptosis, such as chromatin condensation, apoptotic bodies and membrane blebbing, are not seen in AD. Therefore, we speculated that, although AD presents with a proapoptotic environment, apoptosis does not proceed to completion. In this regard, we found that while the initiator phases of apoptosis were engaged, this does not lead to the activation of the terminal commitment phase necessary for apoptotic cell death. In other words, in AD, there is a lack of effective apoptotic signal propagation to distal effectors. This is a novel phenomenon (which we term abortosis) that represents an inhibition of apoptosis at the postinitiator stage in neurons that survive in AD.

Adventiously-bound redox active iron and copper are at the center of oxidative damage in Alzheimer disease.

Central to oxidative damage in Alzheimer disease is the production of metal-catalyzed hydroxyl radicals that damage every category of macromolecule. Studies on redox-competent copper and iron indicate that redox activity in Alzheimer disease resides exclusively within the cytosol of vulnerable neurons and that chelation with deferoxamine or DTPA removes this activity. We have also found that while proteins that accumulate in Alzheimer disease such as tau, amyloid beta, and apolipoprotein E possess metal-binding sites, metal-associated cellular redox activity is more dependent on metal-nucleic acid binding. Consistent with this finding is the large amount of cytoplasmic RNA in pyramidal neurons. Still, the source of metal-catalyzed redox activity is controversial. Heme oxygenase-1, an enzyme that catalyzes the conversion of heme to iron and biliverdin, is increased in Alzheimer disease suggesting increased heme turnover as a source of redox-active iron. Additionally, the role of mitochondria as a potential source of redox-active metals and oxygen radical production is assuming more prominence. In recent studies, we have found that while mitochondrial DNA and cytochrome C oxidase activity are increased in Alzheimer disease, the number of mitochondria is decreased, indicating accelerated mitochondria turnover. This finding, as well as preliminary studies demonstrating a reduction in microtubule density in neurons in Alzheimer disease suggests mitochondrial dysfunction as a potentially inseparable component of the initiation and progression of Alzheimer disease.

Alzheimer Disease and Oxidative Stress.

Research in Alzheimer disease has recently demonstrated compelling evidence on the importance of oxidative processes in its pathogenesis. Cellular changes show that oxidative stress is an event that precedes the appearance of the hallmark pathologies of the disease, neurofibrillary tangles, and senile plaques. While it is still unclear what the initial source of the oxidative stress is in Alzheimer disease, it is likely that the process is highly dependent on redox-active transition metals such as iron and copper. Further investigation into the role that oxidative stress mechanisms seem to play in the pathogenesis of Alzheimer disease may lead to novel clinical interventions.

Is Alzheimer's disease a mitochondrial disorder?

Cell bodies of neurons at risk of death in Alzheimer's disease (AD) have increased lipid peroxidation, nitration, free carbonyls, and nucleic acid oxidation. These oxidative changes occur in all vulnerable neurons and are reduced in neurons that contain neurofibrillary pathology. In this review, the authors provide a summary of recent work that demonstrates key abnormalities that may play a part in initiating and promoting neuronal oxidative damage. Mitochondrial abnormalities are clearly involved as a source of reactive oxygen species that culminates in perikaryal oxidative damage. However, because mitochondria in AD do not exhibit striking evidence of oxidative damage, as would be expected if they produced free radicals directly, the authors suspected that abnormal mitochondria are responsible for supplying a key reactant, that once in the cytoplasm, releases radicals. Because abnormal mitochondria, H2O2 and redox-active iron are juxtaposed in the same AD neuron, it has all the markings of a "radical factory." The proximal causes of mitochondrial abnormalities likely involve reentry into the cell cycle, where organellokinesis and proliferation results in an increase of mitochondria and intermediately differentiated cells, with a consequent increase in turnover. Supporting this, the authors have considerable in vivo and in vitro evidence for mitotic disturbances in AD.

Role of mitochondrial dysfunction in Alzheimer's disease.

Abnormalities in mitochondrial function relate to the spectrum of pathological changes seen in Alzheimer's disease. Here we review the causes and consequences of mitochondrial disturbances in Alzheimer's disease as well as how this information might impact on therapeutic approaches to this disease.

The role of iron and copper in the aetiology of neurodegenerative disorders: therapeutic implications.

Abnormalities in the metabolism of the transition metals iron and copper have been demonstrated to play a crucial role in the pathogenesis of various neurodegenerative diseases. Metal homeostasis as it pertains to alterations in brain function in neurodegenerative diseases is reviewed in this article in depth. While there is documented evidence for alterations in the homeostasis, redox-activity and localisation of transition metals, it is also important to realise that alterations in specific copper- and iron-containing metalloenzymes appear to play a crucial role in the neurodegenerative process. These changes provide the opportunity to identify pathways where modification of the disease process can occur, potentially offering opportunities for clinical intervention. As understanding of disease aetiology evolves, so do the tools with which diseases are treated. In this article, we examine not only the possible mechanism of disease but also how pharmaceuticals may intervene, from direct and indirect antioxidant therapy to strategies involving gene therapy.