PLoS One. 2011;6(11):e28145. Epub 2011 Nov 29.
Detecting Low Frequent Loss-of-Function Alleles in Genome Wide Association Studies with Red Hair Color as Example.
Liu F, et al
Multiple loss-of-function (LOF) alleles at the same gene may influence a phenotype not only in the homozygote state when alleles are considered individually, but also in the compound heterozygote (CH) state. Such LOF alleles typically have low frequencies and moderate to large effects. Detecting such variants is of interest to the genetics community, and relevant statistical methods for detecting and quantifying their effects are sorely needed. We present a collapsed double heterozygosity (CDH) test to detect the presence of multiple LOF alleles at a gene. When causal SNPs are available, which may be the case in next generation genome sequencing studies, this CDH test has overwhelmingly higher power than single SNP analysis. When causal SNPs are not directly available such as in current GWA settings, we show the CDH test has higher power than standard single SNP analysis if tagging SNPs are in linkage disequilibrium with the underlying causal SNPs to at least a moderate degree (r(2)>0.1). The test is implemented for genome-wide analysis in the publically available software package GenABEL which is based on a sliding window approach. We provide the proof of principle by conducting a genome-wide CDH analysis of red hair color, a trait known to be influenced by multiple loss-of-function alleles, in a total of 7,732 Dutch individuals with hair color ascertained. The association signals at the MC1R gene locus from CDH were uniformly more significant than traditional GWA analyses . The CDH test will contribute towards finding rare LOF variants in GWAS and sequencing studies.
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Dermatol Ther. 2011 Jul;24(4):432-42. doi: 10.1111/j.1529-8019.2011.01430.x.
Treatment of chemotherapy-induced Hair Loss.
Yeager CE, Olsen EA.
Chemotherapy-induced alopecia has been well documented as a cause of distress to patients undergoing cancer treatment. Despite the importance of hair loss to patients, however, patients often receive little more counseling than the advice to purchase a wig or other head covering for the duration of their treatment. Research into non-camouflage (wigs, turbans, and head scarves) treatment methods has been complicated both by a lack of a standardized methodology for evaluating hair loss and hair regrowth and by a lack of human trials. Nevertheless, scalp cooling as a method of preventing hair loss during chemotherapy and 2% topical minoxidil as a therapy for accelerating regrowth after chemotherapy are both effective non-camouflage options for treatment. Other proposed treatments for prevention of hair loss during chemotherapy have demonstrated promise in early trials, but these findings will need validation from rigorous further studies. The increasing number of reports of permanent alopecia not just with pre-bone marrow transplant, high-dose busulfan, and cyclophosphamide regimens but also with standard breast cancer chemotherapy regimens illustrates the importance of further research into treatment methods for chemotherapy-induced alopecia.
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Androgenic Alopecia ( Pattern Hair loss )
Abstract: Androgenic alopecia (AGA), or male pattern hair loss, is the most common form of hair loss and affects up to 50% of all men by the age of 50. This article looks at the pathophysiology, diagnosis and treatment (both medical and surgical) of AGA.
Amber S. Tully, Justin Schwartzenberger, James Studdiford
journal of men's health (Vol. 7, Issue 3, Pages 270-277)
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Am J Pathol. 2003 Mar;162(3):803-14.
Stress inhibits hair growth in mice by induction of premature catagen development and deleterious perifollicular inflammatory events via neuropeptide substance P-dependent pathways.
Arck PC, et al
It has been much disputed whether or not stress can cause hair loss (telogen effluvium) in a clinically relevant manner. Despite the paramount psychosocial importance of hair in human society, this central, yet enigmatic and controversial problem of clinically applied stress research has not been systematically studied in appropriate animal models. We now show that psychoemotional stress indeed alters actual hair follicle (HF) cycling in vivo, ie, prematurely terminates the normal duration of active hair growth (anagen) in mice. Further, inflammatory events deleterious to the HF are present in the HF environment of stressed mice (perifollicular macrophage cluster, excessive mast cell activation). This provides the first solid pathophysiological mechanism for how stress may actually cause telogen effluvium, ie, by hair cycle manipulation and neuroimmunological events that combine to terminate anagen. Furthermore, we show that most of these hair growth-inhibitory effects of stress can be reproduced by the proteotypic stress-related neuropeptide substance P in nonstressed mice, and can be counteracted effectively by co-administration of a specific substance P receptor antagonist in stressed mice. This offers the first convincing rationale how stress-induced hair loss in men may be pharmacologically managed effectively.
Extending our previous pilot study in telogen mouse skin,12 we show here for the first time that a well-defined psychoemotional stressor indeed alters actual HF cycling in vivo, ie, prematurely terminates the normal duration of hair growth in mice and up-regulates apoptosis and deleterious inflammatory events in and around the murine HFs. This provides the first solid pathophysiological mechanism for how stress may actually cause telogen effluvium and/or may even be involved in triggering the development of alopecia areata: 1) induction of premature catagen induction; 2) up-regulation of keratinocyte apoptosis in the hair bulb and bulge, the most damage-sensitive epithelial component of the HF; 3) induction of mast cell degranulation; 4) attraction of potentially damaging perifollicular infiltrates of activated macrophages home in on the bulge, the site of HF epithelial stem cells, thus reflecting an immunoactivation.
Furthermore, we show that most hair growth-inhibitory effects of stress can be imitated by the prototypic stress-related neuropeptide, SP, and, with respect to premature catagen onset, increased apoptosis and MHC class II+ cell infiltrates, can be counteracted effectively by co-administration of a specific SP receptor antagonist.
To date, SP has been implicated in diverse pathophysiologies, especially diseases of the central nervous system, which have been examined in the greatest detail.21,54,55 Although SP is best known as a pain-mediating neuropeptide, it also controls various behavioral, neurochemical, and cardiovascular responses to stress26,27,55-58 and exerts a wide range of immunomodulating properties.55,59-61 The development of small molecule antagonists of the SP-preferring tachykinin NK1 receptor during the past decade32,49 offers an important opportunity to exploit these molecules as novel therapeutic agents for hair growth disorders. In addition, recent clinical trials have confirmed the efficacy of NK1 receptor antagonists to alleviate depression and emesis but, surprisingly, not pain.62 In the future, clinical trials, targeted to appropriate patient populations, ie, patients with telogen effluvium or alopecia areata, may establish the therapeutic potential of novel neuropeptide ligands in such hair growth disorders.
In the present study we compared a well-established CBA/J mouse model for stress-related research (based on activation of the immune system and hypothalamo-pituitary-adrenal axis),16,23 with the in hair research widely used mouse strain C57BL/6.14,40,41,47 Published data indicate that different strains of mice react differently to various methods of stress application, ie, restraint stress affects C3H/HeJ, however, CBA/J or A/J mice proved resistant to restraint stress.16 By contrast, noise stress would affect CBA/J mice and C57BL/6 mice, both of which have been used in the present study.16,63 Comparing different strains in stress models, one might further question the hearing ability of the genetically different strains of mice, particularly when an audio stressor has been used. In our present study we observed that both strains, CBA/J and C57BL/6, showed high similarities in their response to stress/SP and skin immune environment. This is supported by published data indicating that C57BL/6 mice at the age of 6 weeks, as used in the present study, showed the same susceptibility to noise than CBA/J mice at the same age.64
An important focus of research on stress-induced hair regrowth inhibition is to identify stress-vulnerable areas of the HF. One such area might be the residence of stem cell areas within the skin, because stem cells are vital for the homeostasis of self-renewing tissues and their manipulation may have wide-ranging consequences.49 Rodent HF stem cells have been localized to the follicle bulge, whereas the location of human HF stem cells is less clear, and their characterization has been hampered by a lack of cellular markers for the bulge area.49 These cells acquire the ability to produce a new hair.65 The up-regulation of TUNEL+ cells in this key area of the HF, the bulge, by stress, as observed in the present study, is particularly striking because this region is one of the most sensitive targets for hair growth inhibitory agents and an abnormally high number of apoptotic cells in the epithelial stem cell region of the bulge carries the risk of permanent HF loss by programmed organ deletion. This observation further supports our previously published data on increased signs of apoptosis in stressed mice with all HFs in resting telogen stage.12 Thus, we propose that such delicate area as the bulge region of the cycling HF is one key target for immune cells, particularly activated macrophages and mast cells, activated by systemic stress mediators and that have the potential to damage the HF morphology by up-regulation of apoptosis through the secretion of inflammatory cytokines, ie, tumor necrosis factor-, interleukin-1ß, and interferon-.66-69 Longitudinal studies are now required to elucidate if a stress-triggered attack of HF stem cells would be associated with permanent or reversible hair growth inhibition. Further, based on our current data, we cannot differentiate whether the apoptotic cells in the bulge region are really stem cells or may be transient amplifying cells. Therefore we hope that the findings of the present study may foster research with label-retaining cells,70 which would tell us whether we are dealing with stem cells or not.
Clinical experience has long suggested that psychological factors play a role in triggering or exacerbating hair loss. The present study now reports the first experimental evidence available in the literature that psychoemotional stress indeed negatively affects the cycling activity of HFs as well as their immune environment in vivo, thus strongly suggesting the concept that stress-induced hair loss is a clinical reality that should and can be treated. Once confirmed for the human system, the data presented here together with the recent emergence of NK1 antagonists as promising anti-depressants, SP receptor antagonists might serve a dual clinical role, ie, for alleviating both stress-induced hair loss itself, and secondary the depressive mood that comes with it.
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J Eur Acad Dermatol Venereol. 2010 Jul 13.
Lipid peroxidation/antioxidant activity in patients with alopecia areata.
Abdel Fattah NS, et al
Aetiopathogenesis of hair loss in alopecia areata (AA) is not fully understood and many factors have been assumed. Oxidant/antioxidant disequilibrium has been proposed with controversies between results. Objectives The aim of this study was to determine lipid peroxidation/antioxidant activity in patients with AA and to determine its clinical significance. Methods Fifty non-obese patients with AA and 50 age-, gender- and body mass index-matched controls (25 patients with severe grade acne vulgaris representative of an oxidative stress condition and 25 healthy volunteers), were included. Levels of malondialdehyde (MDA), indicator of lipid peroxidation and antioxidant activity of superoxide dismutase (SOD), were spectrophotometrically measured in blood from all subjects and in scalp tissues from 10 patients with AA. Results No significant differences in MDA levels and SOD activity existed between patients with AA and those with acne. However, significantly higher MDA levels and lower SOD activity were found in patients with AA compared with healthy controls. Within patients with AA, lipid peroxidation/antioxidant parameters showed significant differences with disease duration, pattern and extent of lesions. Significant positive correlations also existed between tissue and blood SOD activity and between tissue and blood MDA levels of the 10 studied patients with AA. Conclusions Increased lipid peroxidation and defective SOD activity exist in patients with AA. Addition of drugs with antioxidative effects seems to be valuable in treatment.
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Dermatol Online J. 2010 15:3.
Does D matter? The role of vitamin D in hair disorders and hair follicle cycling.
Amor KT, et al
BACKGROUND: The role of vitamin D in the proliferation and differentiation of keratinocytes is well known within the field of dermatology. OBJECTIVE: To evaluate the role that vitamin D and the vitamin D receptor play in the hair cycle and assess how this can be clinically applied to the treatment of hair loss and hair disorders. METHODS: A MEDLINE search was preformed to find relevant articles pertaining to vitamin D, the vitamin D receptor, and hair loss and hair regrowth. RESULTS: The vitamin D receptor, independent of vitamin D, plays an important role in hair cycling, specifically anagen initiation. The role of vitamin D in hair follicle cycling is not as well understood. LIMITATIONS: The review is broad and there are limited human studies available to date. CONCLUSION: Additional studies to evaluate the role of vitamin D in the hair cycle should be done. Treatments that up regulate the vitamin D receptor may be successful in treating hair loss and are a potential area of further study.
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