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Update on the Genetics of Androgenetic Alopecia, Female Pattern Hair Loss, and Alopecia Areata: Implications for Molecular Diagnostic Testing Pedram Yazdan, MD Androgenetic alopecia, female pattern hair loss, and alopecia areata are among the most common forms of nonscarring hair loss encountered in clinical practice. Although the exact pathogenesis of these forms of alopecia remains to be clarified, genetic factors appear to have a significant contribution to their pathogenesis. Current treatment strategies are limited and their effectiveness remains modest at best. This review summarizes the current purported pathogenesis and recent genetic discoveries relating to these forms of alopecia. The role of molecular diagnostic testing is also discussed in relation to its future clinical utility for the prediction of developing hair loss, the diagnosis of the type of alopecia, prediction of disease severity, development of novel therapeutic and preventative targeted treatments, as well as determination of response to therapy. Semin Cutan Med Surg 31:258-266 © 2012 Frontline Medical Communications KEYWORDS androgenetic alopecia, female pattern hair loss, alopecia areata, genetics, molecular diagnostic testing, therapy H air loss is a common clinical problem in dermatologic practices, yet complex in etiology. Patients are often anxious about the clinical diagnosis and whether effective treatments exist. Among the various forms of alopecia, androgenetic alopecia ([AGA] also known as male pattern hair loss), female pattern hair loss (FPHL), and alopecia areata (AA) are among the most common forms of nonscarring hair loss encountered by clinicians. Additionally, there are significant psychosocial burdens faced by many patients with these forms of alopecia.1,2 Despite their high prevalence, effective treatment that halts the progression of hair loss and allows for substantial hair regrowth remains a challenge for many patients because our current knowledge of the full spectrum of biomolecular mechanisms underlying these conditions remains modest at best.3,4 To date, the etiology of these alopecias is unclear and genetic factors appear to play a significant role in their pathogenesis. Remarkable advances in genomic discovery along with the ever growing usage of molecular diagnostic testing for enhanced diagnosis, prognosis, and treatment of many other diseases are Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL. Conflict of Interest Disclosures: The author has completed and submitted the ICMJE form for disclosure of potential conflicts of interest and none were reported. Correspondence Author: Pedram Yazdan, MD, Department of Dermatology, Northwestern University, 676 North St. Clair Street, Suite 1600, Chicago, IL 60611. E-mail: [email protected] 258 made every day. However, the diagnosis and classification of alopecia is still currently based on the correlation of clinical history, examination, and when necessary scalp biopsy for histopathologic evaluation. Moreover, in certain cases, the clinical and histopathologic features may be ambiguous, making it difficult to render a definitive diagnosis.5-9 Currently, there are limited ancillary techniques available to allow for more accurate diagnoses in such cases as well as accurately predicting the severity, natural coarse, and treatment response of alopecias. Therefore, reliance on clinical and histopathologic features in this regard has been unpredictable.5,10,11 The aim of this article is to review the current understanding of the genetics of these 3 forms of nonscarring alopecias and to discuss how this information and future molecular advancements may allow for the development of ancillary molecular diagnostic testing for patients with hair loss. Such tests will ultimately allow for the prediction of risk of developing alopecia, accurate diagnosis and classification, prognosis of disease severity, development of novel therapeutic and preventative targeted treatments, as well as determination of response to therapy. Androgenetic Alopecia and Female Pattern Hair Loss Pathophysiology The most common form of hair loss affecting men is AGA. As many as 50% of Caucasian men are affected by age 5012-14 1085-5629/12/$-see front matter © 2012 Frontline Medical Communications http://dx.doi.org/10.1016/j.sder.2012.08.003 Implications for molecular diagnostic testing and up to 80% by age 70.15 The use of the medical term AGA reflects the current knowledge regarding the important role of both androgens and genetic inheritance in this form of alopecia.16 The association between androgens and AGA was first noted in 400 BC by Hippocrates, who observed that eunuchs never developed patterned baldness. In the 1940s, Hamilton16 showed that AGA did not develop in men who were castrated before puberty or in early adolescence, or those with severe testicular insufficiency. When testosterone was administered, baldness could be induced in those who were genetically predisposed (ie, family history of baldness), and when testosterone was discontinued, the alopecia did not progress, however, neither did the hair loss reverse. These observations support androgens as a prerequisite for the development of AGA in genetically susceptible men. Testosterone is the major circulating androgen in men and is metabolized to dihydrotestosterone (DHT) in tissues. DHT is thought to be the key androgen required for the induction of AGA.17 The conversion of testosterone to DHT in hair follicles is predominately mediated by the enzyme 5␣-reductase, which exists as 2 isoforms, types I and II. Both isoforms are found in scalp follicles; however, the conversion of testosterone to DHT in hair follicles is predominately mediated by type II 5␣-reductase, and it has been shown that men who are genetically deficient in type II 5␣-reductase do not experience AGA.18 On the scalp, androgen sensitivity and the distribution of androgen receptors are region specific, and this may explain why the occipital scalp is resistant to the effects of androgens and is usually spared even in the most severe case of AGA. FPHL is somewhat less common than AGA, affecting up to 25% of women under age 5019 and up to 40% of women by age 70.20 Although the androgen-dependent nature of AGA in men is well established, the relationship of androgens to the development of FPHL is more complex. Although women with hyperandrogenism certainly have a high incidence of FPHL (up to 86%), many women with FPHL do not have the elevated blood level of androgen hormones.19 Women without circulating androgens may also develop FPHL,21 which raises the possibility for nonandrogen-dependent mechanisms and could explain why some women with FPHL do not respond to androgen inhibition therapy. The role of estrogens in scalp hair growth has not been as extensively studied as that of androgens, and there are different views on whether estrogens are stimulatory or inhibitory to hair growth. Clinically, the increased prevalence of FPHL after menopause implies a possible stimulatory role for estrogens in hair growth.22 High-systemic estrogen levels in pregnancy are speculated to partially account for the prolongation of anagen, whereas plummeting estrogen levels in the postpartum period may in part account for the simultaneous conversion of hair follicles into the telogen phase, resulting in the condition telogen gravidarum.23 Lower estrogen levels because of aromatase inhibitor therapy have also been observed to induce hair loss. Topical estrogen applications have been widely used in some European countries as hair-growth stimulants in FPHL. Conversely, other studies show that estrogens are inhibitory to hair growth. In mouse models, the 259 administration of estrogen agonists has been shown to produce a profound and prolonged inhibition of hair growth through telogen arrest, whereas estrogen antagonists stimulated hair growth through the initiation of anagen.24,25 Additional evidence for an inhibitory role of estrogen in FPHL is the finding of an aromatase gene variant associated with circulating estrogen levels that occur at higher frequencies in women with FPHL when compared with unaffected women (discussed in more detail later in the text).26 Both AGA and FPHL are indistinguishable on a histologic level and result from altered hair follicle cycling and progressive miniaturization of the hair follicles. In both conditions, the duration of the anagen phase shortens, whereas the duration of the telogen phase remains the same or lengthens, causing a reduction in the anagen to telogen ratio from around 10-12:1 to 5:1. Because hair length is determined by the anagen phase, each passage through the cycle causes the length of the new anagen hair to be shorter than its predecessor. Eventually, the anagen phase becomes so short that it does not allow time for the new hair to acquire enough length to reach the skin surface. Telogen hairs, which now make up an increasing percentage of the total hairs, are more loosely anchored to the follicle than anagen hairs, leading to increased hair shedding. In addition, the latency period between telogen hair shedding and anagen regrowth becomes longer, ultimately leading to a reduction in the number of hairs present on the scalp. Follicular miniaturization also occurs in both AGA and FPHL, where the size of the follicle is reduced with each consecutive cycle leading to hairs that are narrower and shorter and of smaller diameter over time. Thus, a proportion of the large terminal follicles become miniaturized, making hair significantly finer and more susceptible to falling out. Although the pathophysiology of AGA and FPHL remains to be fully established, the alterations that occur within the hair follicle appear to some extent to be androgen mediated in AGA, and in some cases of FPHL, with androgen-independent mechanisms, possibly contributing to hair loss in both conditions as well. Genetics of Androgenetic Alopecia and Female Pattern Hair Loss With Implications for Molecular Diagnostic Testing AGA and FPHL are associated with strong heritability; however, the exact mode of inheritance of AGA and FPHL remains to be fully elucidated. Twin studies have shown that the development of hair loss is predominately determined by genetic predisposition.27 However, because of the high prevalence of AGA and FPHL, the increased risk of developing alopecia with increasing numbers of affected relatives, the wide distribution of age at onset, and the range of severity of the alopecia among affected individuals strongly suggest that this condition is not controlled by 1 gene (single gene traits rarely occur with a frequency ⬎ 1 in 1000), rather follows a polygenic mode of inheritance.27,28 Like many polygenic human disorders, the ultimate phenotypic expression of AGA and FPHL is likely dependent on the complex interplay between a number of genes throughout the genome. Each of 260 these genes may contribute variably to the risk of hair loss in one's lifetime and may determine the age of onset, progression, patterning, and severity of the alopecia. The genetic predisposition of AGA and FPHL and the role of androgens in its pathogenesis lead early genetic association studies to focus on chromosomes 2 and 5, which are the sites of the 5␣-reductase enzyme genes, SRD5A2 and SRD5A1, respectively. However, it has been determined that no significant difference in allele, genotype, or haplotype frequencies exists between young bald men and older nonbald male controls, suggesting no association with the genes encoding the 2 5␣-reductase isozymes and AGA.29 Attention was then turned to the androgen receptor gene (AR) located on the X-chromosome (Xq11-12) and belonging to a family of nuclear transcription factors whose aminoterminal domain (exon 1) is required for transcriptional activation. Ellis et al30 demonstrated the polymorphism in the AR gene and its association with susceptibility to the development of AGA in men. Specifically, a particular single-nucleotide polymorphism (SNP) in exon 1, known as StuI (rs6152, restriction fragment length polymorphism [RFLP], E211 G ⬎ A), is strongly associated with AGA in Caucasian men. The StuI RFLP in exon 1 was found to be present in 98% of young balding men and 92% of older balding men but was also found in 77% of nonbalding older men. As a large proportion of nonbald men carry this marker, it has been postulated that these men must lack other necessary causes of AGA, hence supporting a polygenic pathogenesis for this condition.30 This particular SNP also cannot account for father-to-son transmission of AGA because it is located on the X-chromosome and men inherit this chromosome maternally. Additionally, the StuI RFLP marker is flanked by 2 highly polymorphic triple-repeat sequences: a polyglutamine triplet repeat (CAG) that lies proximally and a polyglycine triplet repeat (GGN) that lies distally to StuI. Studies have found shorter CAG triplet repeats to be associated with the development of male AGA,30,31 with conflicting data regarding the role of GGN repeats. Hillmer et al32 have suggested an association between shorter GGN repeats and AGA; however, Ellis et al33 found that the AR GGN repeat polymorphism did not independently confer susceptibility to AGA. Interestingly, the StuI RFLP is noncoding and does not appear to lead to the phenotypic consequence of AGA by itself. However, the strong association of this marker with AGA may be explained if it acts as a marker for the inheritance of another functional SNP migrating together with it throughout generations via linkage disequilibrium (LD). Multiple comprehensive studies of SNPs34-37 and copy number variations38 of the AR gene region by various groups have thus far failed to identify a functional variant in LD that could be responsible for this strong association. Although the highly polymorphic CAG and GGN triplet repeats in exon 1 of the AR gene may possibly be in LD with the StuI RFLP, they are not thought to be functional variants responsible for this association.33 Currently, it has been hypothesized that the association between the AR gene and AGA involves variation in regulatory elements of noncoding DNA that may reside upstream or downstream of the AR gene region.10 Recently, 2 P. Yazdan independent loci containing SNPs located in the upstream and downstream intergenic regions of the AR gene were mapped and each were found to be independently associated with AGA.39 However, further studies are needed to identify functional variants in the noncoding regions around the AR gene that contribute to AGA. It has been estimated that the genetic variations in the AR gene may account for up to 40% of the heritability of AGA.32 The fact that the vast majority of men with premature hair loss have the predisposing AR gene variant suggests that inheriting this variant seems to be a necessary prerequisite for developing AGA. However, because the same predisposing copy of the AR gene variant is seen so commonly in older men without AGA, it is unlikely to be sufficient by itself to cause hair loss. In addition, up to 60% of the genetic predisposition remains unexplained, indicating that there are likely other genes contributing to the risk profile of AGA. In contrast to candidate gene methods, genome-wide genetic studies survey the entire genome in a nonbiased way for evidence of genetic contributions to disease. This methodology identifies genes on the basis of their position in the genome and does not depend on understanding the functionality of those genes. Therefore, these types of studies are particularly powerful methods for evaluating disease mechanisms when much remains unknown about how or why the disease occurs. With the recent advent of the genome-wide association studies (GWAS) and in keeping with the purported polygenic transmission of this condition, several other susceptibility loci have been found to be associated with AGA. Prodi et al36 recently identified a locus near the androgen receptor at Xq11-12 containing the ectodysplasin A2 receptor gene (EDA2R), which was found to be independently and strongly associated with AGA. It has been postulated that EDA2R could influence the onset of AGA through the activation of the NF-B pathway or by c-Jun, which has been shown to be critical for AR transactivation.40 However, the association of EDA2R with AGA could not be replicated in an Australian population.39 A possible explanation for the inability to replicate this association may be attributable to population stratification. In 2 other GWAS, a significant correlation was found between 5 SNPs on chromosome 20p11 and the development of early onset AGA (⬍ 40 years of age), suggesting that this locus may play a role in a yet to be identified androgen-independent pathway.34,37 The SNPs identified in these studies lie adjacent to the paired box 1 gene, which is expressed in skin, hair, and scalp, and is, therefore, a good candidate gene for AGA. In the studied populations, it was also determined that 1 in 7 men who harbored the AGAassociated SNPs at both chromosome 20p11 and AR had a 7-fold increased risk of developing AGA.37 However, because this susceptibility locus is located within a gene-poor region, the significance of these findings in relation to AGA are yet unknown. An AGA susceptibility locus has also been mapped to chromosome 3q26 in a population of German men; however, no known genes in this region are involved in hair biology.35 A more recent GWAS has demonstrated a potentially new susceptibility locus among German and Australian men, re- Implications for molecular diagnostic testing vealing 2 SNPs located at 7p21.1 within the histone deacetylase 9 (HDAC9) gene that are associated with AGA.41 One of these SNPs demonstrated a strong association, especially among men who were severely affected by AGA. In general, members of the histone deacetylase gene family modulate the chromatin structure thereby acting as key regulators of gene transcription. It has been postulated that HDAC9 may interact with the AR gene, thereby regulating its transcriptional activity, possibly in a tissue-specific manner.41 However, caution should be exercised in considering HDAC9 as a true causative gene for AGA because no direct effects of the associated variants have been demonstrated to date. It is possible that the associated variants or unidentified true causative variant(s) may be located in a regulatory element of a more distant gene. Further studies are necessary to investigate these hypotheses. There are fewer reported genetic association studies for FPHL in comparison with AGA. The genetic association studies for FPHL have not been able to reproduce the same strong association with the AR gene as found with AGA. Therefore, it is not clear whether the AR gene is also similarly pathogenic for FPHL. Whether an association between FPHL and the AR gene exists is difficult to interpret because of its location on the X-chromosome rendering 1 of the 2 gene copies prone to X-chromosome inactivation. The analyses of the association of FPHL to the AR gene using samples of peripheral blood from patients in certain studies make drawing a direct comparison with the changes occurring at the level of the hair follicle tissue difficult because X-chromosome inactivation is tissue specific. One study did examine the relationship between the StuI RFLP in exon 1 of the AR gene; however, no association was found between this SNP and FPHL.42 In another study, a weak association was found between FPHL and the AGAassociated susceptibility locus at chromosome 20p11.37 The implications of these findings are unknown at this time, and the authors of the study concluded that it is necessary to investigate this possible association in larger and carefullyphenotyped cohorts. The CAG repeat-length polymorphism in exon 1 in the AR gene has been linked with the development of androgen-related skin disorders, including acne, hirsutism, and FPHL in women with elevated androgen levels.31,43 However, in these studies, peripheral blood was used as the tested sample in the analyses rather than scalp hair follicles. The results generated from these studies do not take into consideration the effects of tissue-specific X-chromosome inactivation thereby limiting the strength of association of CAG repeat-length polymorphism and FPHL. There has been recent evidence for the role of the aromatase gene (CYP19A1) in FPHL. The CYP19A1 gene encodes the enzyme aromatase that is responsible for the conversion of androgens to estrogens, thereby regulating the balance of sex steroid hormone levels within the hair follicles. Yip et al26 found a nonfunctional SNP (rs4646) located in the 5'-untranslated region of the CYP19A1 gene. The frequency of this SNP was found to be higher in women (particularly in younger women) affected by FPHL and, in an unrelated study, was found to be associated with higher circulating 261 estrogen levels in women.44 The same group demonstrated that variation involving SNPs in the gene encoding for the estrogen receptor beta 2 (ESR2) may be associated with developing FPHL. ESR2 is the predominant estrogen receptor within the hair follicle and thought to be the principle mediator of estrogenic effects in hair growth.45 These findings support the view that estrogens may be involved in the pathogenesis of FPHL. However, measurement of sex steroid levels within the hair follicles would be necessary for future verification of these results. As a result of the advancement of genetic data for AGA, there are additional studies to determine if associations exist with treatment response and specific genetic findings. The current mainstay of therapy for AGA is finasteride, which is a potent synthetic inhibitor of 5␣-reductase type II. There are a limited number of studies that have postulated a genetic basis for the variable response to finasteride therapy for AGA. In a small study of 9 men with AGA, the messenger RNA expression of several cytokines believed to regulate hair growth was analyzed in follicular dermal papillae before and after finasteride therapy.46 A positive response to finasteride therapy was found to be associated with increased expression of the insulin-like growth factor 1. Wakisaka et al47 demonstrated a possible association between the AR gene CAG/GGC triplet repeats and response to finasteride among Japanese men. In this study, a sum of ⱕ 40 CAG plus GGC triplet repeats in the AR gene was associated with improved response to finasteride despite the test group presenting with more severe AGA. These results were verified in a second study whereby 70% of men with a marked response to finasteride had CAG repeat lengths ⬍ 22, whereas 70% of those with only minimal drug response had CAG repeat lengths ⬎ 22.48 There are limited numbers of similar studies with respect to FPHL. A recent study by Yamazaki et al49 was not able to show differences in CAG repeat numbers in association with finasteride therapy. However, in a 6-month pilot of 13 patients, Keene and Goren50 demonstrated that women with greater androgen sensitivity (⬍ 24 cytosine, adenine, and guanine [CAG] repeats) were likely to have a significant response to finasteride compared with patients treated with placebo, and also compared with patients with normal androgen sensitivity (ⱖ 24 CAG repeats) based on epigenetic-weighted evaluation of the CAG alleles. Currently, additional studies are necessary to firmly establish the possible genetic associations in regard to the efficacy of finasteride therapy in both AGA and FPHL as well as the applicability of this test for clinical use. The results of the genetic studies described previously in the text have been incorporated into the clinical evaluation and treatment of AGA and FPHL. Based on the information gleaned from these studies, screening tests have been developed for AGA and FPHL by a California based company, HairDx LLC (Irvine, California, USA), and are designed to provide patients with a risk estimate for developing AGA or FPHL. The end goal is to allow for earlier detection because long-term treatment with finasteride has been demonstrated to decrease the likelihood of developing further visible hair loss in some patients.51 This test uses a cheek swab and evaluates for the StuI SNP in the AR gene in men. Reports from 262 this company indicate that when integrating the family history of AGA from a patient's father, it can help improve the predictive value of the HairDx test. It is claimed that those with a father having a history of AGA who test positive for the AR variant have a ⬎ 80% chance of developing AGA, and those with a father without any history who test negative for the AR variant have ⬎ 90% chance of not developing AGA.52 For young patients concerned about hair loss, this test may help to define the value of early treatment initiation. For women, there is a different genetic test that evaluates for the number of CAG repeats within the AR gene and is used to predict a woman's risk of developing FPHL.52 The company references the study by Sawaya et al,31 which found that ⬍ 2% of women with ⬎ 23 CAG repeats developed FPHL, whereas approximately 98% of women with ⬍ 16 CAG repeats had FPHL. In women with intermediate numbers of CAG repeats between 16 and 23, the association with FPHL was not as apparent. According to HairDx LLC, this test could be used to reassure a woman whose CAG repeats are ⬎ 23 that she is unlikely to develop FPHL, and those with ⬍ 16 CAG repeats may be considered as candidates for initiating therapy for FPHL. Although these genetic tests are currently available for patients, it is important to be aware of their limitations. To date, only a relatively small portion of the heritability of AGA and FPHL has been explained by variation in the AR gene, which makes the clinical relevance of such tests uncertain at this time. Because genetic testing for AGA and FPHL relies predominately on the AR gene variation, the tests do not take into consideration the polygenic contributions from other causative genes and the possible role of epigenetic mechanisms.4 Genetic testing for AGA is based on genotyping for the StuI SNP in the AR gene, which is a nonfunctional SNP. This particular AR gene SNP does not lead to any alteration in gene protein or function, nor has it been linked to a functional SNP that does produce functional alterations. Additionally, a positive gene test result can be found in a high percentage of men ⱖ 50 years of age who have no evidence of hair loss as well as in the majority of balding men, leading to an uncertain clinical significance of a positive test result and ambiguity regarding whether to initiate treatment. By contrast, a negative test should not change the treatment offered to a patient. Therefore, for young patients concerned about hair loss, this test may have some potential in helping to define the value of early treatment initiation. However, it must be noted that because only a portion of AGA heritability can be explained by AR gene variation, testing the AR genetic variation alone does not accurately predict risk for developing AGA. Genetic testing for FPHL risk estimates are currently based on CAG repeat polymorphism in exon 1 of the AR gene, and the strength of this association with FPHL risk is also uncertain at this time. Alopecia Areata Pathophysiology AA is the most frequent cause of inflammatory hair loss, affecting an estimated 4.5 million people in the United P. Yazdan States.53 The prevalence of AA in the United States is approximately 0.1% to 0.2% of the population with an average lifetime risk of developing AA estimated at 2%.54 Additionally, 1 patient in 5 with AA has reported another family member with the disease. AA affects both children and adults and hair of all colors.55 The disease is uncommon in children ⬍ 3 years of age; however, most patients are relatively young, up to 66% are younger than 30 years of age, and only 20% are older than 40 years of age with no significant sex predilection. AA is also among the most prevalent autoimmune disorders leading to disfiguring hair loss and is associated with an increased overall risk of other autoimmune disorders (16%).56,57 The likely mechanism of this disease is probably because of the collapse of the immune privilege of the hair follicle and subsequent autoimmune defect.58 From a clinical perspective, the natural course of AA is unpredictable. Approximately 30% to 50% of patients with AA will recover their hair loss within 1 year; and 15% to 25% will progress to total loss of scalp hair (alopecia totalis) or loss of the entire scalp and body hair (alopecia universalis), from which full recovery is uncommon (10%).11 Despite the high prevalence and the psychosocial burden of AA, there are currently no evidence-based treatments with only a few available therapies that have been tested in placebo-controlled trials.59 Additionally, there are no therapies that are approved by the Food and Drug Administration for the treatment of AA, and treatments are considered "off label." Current treatment choices are frequently based on the age of the patient as well as the extent and duration of their disease. Treatments include a variety of topical, intralesional, and systemic agents.60 An analysis of 17 trials by the Cochrane Skin Group, published in the online Cochrane Database of Systematic Reviews, concluded that "overall, none of the interventions showed significant treatment benefit in terms of hair growth when compared with placebo."59 The current limited information about the underlying genetics and complete pathomechanism of the disease presents a major challenge in identifying novel effective treatments. The purported pathomechanism of AA is the collapse of the immune privilege of a previously healthy hair follicle.61,62 AA can occur in genetically predisposed individuals when proinflammatory signals (including substance P and interferon-␥) that are known to upregulate major histocompatibility complex class Ia expression in the hair follicle expose previously sequestered hair-follicle–associated autoantigens to preexisting autoreactive CD8⫹ T-cells.62-64 The lymphocytic infiltrate can then attack the hair follicle if costimulatory signals and interaction with others cells, such as CD4⫹ T-cells and mast cells, occurs.61,62 Because only anagen hair follicles are attacked in AA, the autoantigens may be formed and presented only during this phase of the hair cycle.65 In acute AA, histologic examination reveals a characteristic dense perifollicular lymphocytic inflammatory infiltrate around the terminal bulb portion of the anagen hair follicle. There are numerous examples from murine-derived models of AA supporting this hypothesized pathomechanism.58,66-69 Recent studies have also implicated other pro- Implications for molecular diagnostic testing inflammatory factors as well as natural killer (NK) cells, NK-cell–stimulating ligands, and NK-cell receptors (NKG2D) in the pathogenesis of AA.65,70 Hair follicles in AA have also been shown to overexpress the major histocompatibility complex class I polypeptide-related sequence A (MICA) protein, an important NKG2D agonist, whereas MICA expression in the normal hair follicle is much more limited.65,71 Increased NKG2D-mediated signaling contributing to the pathogenesis of AA is highlighted by the genetic association between AA and NKG2D-activating ligands from the MICA family, specifically the cytomegalovirus UL16-binding protein 3, which is upregulated around the affected hair follicles in AA.70 Genetics of Alopecia Areata With Implications for Molecular Diagnostic Testing The development of AA has a strong genetic component supported by the observation of heritability among first-degree relatives,72 twin studies,73 and studies on murine models.74 Additional support for a genetic component of AA comes from the fact that a history of atopy and autoimmune disease is associated with an increased risk of developing a severe subtype of AA.56,75 Familial cases of AA are also often characterized by a poorer prognosis with more rapid disease progression, more frequent relapses, and greater resistance to therapy in comparison with sporadic cases.75,76 The first genetic studies in AA were candidate-gene association studies, usually testing for a single gene that was chosen on the basis of a previous hypothesis about its function (typically in another autoimmune disease), tested for association in a small sample of cases and controls, and being biased by choices of candidate genes. Before GWAS, as with most autoimmune diseases, candidate gene studies have implicated associations of AA to genes residing in the human leukocyte antigen (HLA) region, including HLA-DQB1, HLA-DRB1, NOTCH4, and MICA, in addition to genes outside of the HLA region, including protein-tyrosine-phosphatase nonreceptor type 22, involved in negative regulatory effects on T-cell activation.58 One of the most promising areas of AA research has emerged from several recent large GWAS, which have identified a number of susceptibility loci associated with AA, in the form of SNPs, across several regions of the genome and implicating genes of the immune system as well as genes that are unique to the hair follicle itself.70,77 Specifically, the key genes found in the GWAS include those linked to T-cell proliferation and hair follicle genes that activate the NKG2D ligand, which can trigger autoimmunity. Interestingly, the risk loci revealed in the GWAS share associations with other forms of autoimmunity, including rheumatoid arthritis, type I diabetes, celiac disease, Crohn disease, systemic lupus erythematosus, multiple sclerosis, and psoriasis.78,79 A GWAS of 20 families by Martinez-Mir et al77 identified at least 4 susceptibility loci on chromosomes 6, 10, 16, and 18. On chromosome 6, 1 susceptibility locus was found at 6p 263 that corresponds to the HLA locus, whereas the region on chromosome 16 overlaps with a region near a susceptibility locus for Crohn disease. The susceptibility locus for AA on chromosome 18p also contains a psoriasis-susceptibility region. In a major recent GWAS, Petukhova et al70 evaluated 1054 patients and 3278 control subjects and identified 139 SNPs significantly associated with AA. The genomic regions not only encompassed the HLA region but also included genes that control the activation and proliferation of regulatory T-cell, cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), interlukin (IL), IL-2/IL-21, IL-2 receptor A (IL2RA; CD25) and Eos (known to play a crucial role in regulatory T-cell development). A strong association to AA was also found within the cytomegalovirus UL16-binding protein gene cluster on chromosome 6q25.1, encoding a class of ligands for activating NKG2D, which is highly expressed on NK cells and some CD8⫹ cells, and stimulates their activity. Previous studies have demonstrated excessive activity of NKG2D-expressing cells in the peripheral blood and lesional skin of AA patients as well as strong upregulation of MICA in lesional AA hair follicles.65,70 CTLA4 is a costimulatory molecule that is involved in the negative regulation of T-cell activation. The high expression of CTLA4 in patients with AA by GWAS has also been found in other autoimmune diseases, underscores the fact that AA shares pathways with other autoimmune conditions, and supports the concept of a strong autoimmune component to AA.80,81 Two GWAS intrafollicularly expressed genes, peroxiredoxin 5 and syntaxin 17, were found to be associated with AA,70 which points to the potential of follicular autoantigens playing a role in the pathobiology of the AA. In the most recent GWAS, an intronic region of spermatogenesis-associated protein 5 has been suggested as yet another novel susceptibility loci for AA,82 as well as IL-13 and KIAA0350/CLEC16A.83 IL-13 is a member of the cytokine group and is synthesized by activated T helper 2 cells. It is an essential effector in the recruitment of inflammatory cells and is thought to activate immunoglobulin E as well as the production and secretion of mucin. The variant rs20541, which achieved genome-wide significance, has been reported to be associated with autoimmune diseases, such as psoriasis, arthritis, and asthma.84-86 KIAA0350/CLEC16A is located on chromosome 16p13 and encodes a protein without a presently known function. It is mainly expressed in immune cells and assumed to be of crucial importance in the immunemodulating processes.87 Recent studies have shown that specific genetic variants of the KIAA0350/CLEC16A gene confer susceptibility to certain autoimmune disorders, such as multiple sclerosis and type 1 diabetes,88,89 providing further evidence that certain autoimmune disorders and AA may have shared etiologies. Although recent advancements have been made in our understanding of the genetic changes associated with AA, there are currently no molecular tests available for the diagnosis, prognosis, and treatment of patients with this disease. Although translational research in the study of AA is in its infancy, there have been several recent studies using molecular techniques that may have important clinical utility in the P. Yazdan 264 future. Lueking et al90 have combined protein microarray technology with the use of large cDNA expression libraries to profile the autoantibody repertoire of sera from AA patients against a human protein array consisting of 37,200 redundant recombinant human proteins. Eight autoantigens were identified among the AA patients by protein chip technology and were successfully confirmed by Western blot analysis. These proteins included SCG 10, GLCDAC05, ␣-endosulfine, NOL8, FGFR3, dematin, signal recognition particle subunit 14, and endemic pemphigus foliaceus autoantigen. FGFR3 is known to be expressed in the superbasal layers and the inner layers of hair follicles, and is strongly related to hair disorders. However, the possible pathophysiologic roles of the other detected proteins in AA remain to be defined. The 8 autoantigens were arrayed on protein microarrays to generate a disease-associated protein chip, purported to facilitate the detection of potential autoantigens in AA and in the discrimination of AA from other inflammatory skin disorders, making it potentially suitable for fast diagnosis. With the use of this disease-associated protein chip, the authors reported accurate identification of AA in 90% of their cases when compared with sera from patients with psoriasis or hand-and-foot eczematous dermatitis. To date, there have been 2 studies examining peripheral blood and lesional skin samples from AA patients. These studies have demonstrated distinct gene expression patterns, suggesting that gene expression profiling could potentially be used to determine transcriptional signatures related to genetic susceptibility to the disease, phenotypic expression of the disease, and disease severity.91,92 Additionally, Coda et al93 integrated the findings from the recent GWAS with their transcriptional microarray data from the blood and skin of AA patients. The goal was to find potential molecular links connecting the putative AA susceptibility loci to phenotypic expression and clinical heterogeneity of the disease. This group found several differentially-expressed genes encoded within putative AA genetic loci, suggesting that distinct genetic loci with statistically significant altered gene expression are apparent in the peripheral blood and skin of patients with AA. This finding may have useful clinical application relevant to disease classification and variable expression of the disease. John et al94 have confirmed that genetic variants in CTLA4 are strongly associated with AA, and their findings also suggest that it has the strongest effect in patients with a severe form of the disorder. Therefore, CTLA4 may be a potentially useful clinical marker for disease severity in the future. The recent advances achieved in understanding the genetic basis of AA have also opened new avenues for development of new therapies based on the underlying purported mechanism of AA. Potential future therapeutic opportunities may involve targeting key inducers of hair-follicle immuneprivilege collapse, such as substance P receptor antagonists and interferon-␥ antagonists.95 There may also be a role for treatments targeting NK cells, NK and CD8⫹ T cellactivating receptors (NKG2D), and their endogenous ligands (MICA, UL16-binding protein 3).95 Additionally, by virtue of the common molecular pathways shared by AA and other autoimmune diseases, new therapies for AA may also involve classes of drugs and biologics currently under development or being used for other autoimmune diseases. The genetic data implying CTLA4 in the pathogenesis of AA has an interesting correlate to a study by Carroll et al,96 which revealed that monoclonal antibodies against CTLA4 were effective in preventing AA in a mouse model of the disease. As antiCTLA4 antibodies deserve exploration as a potential new therapeutic approach in AA, clinical trials are pending to test the efficacy of the safety of abatacept (a fusion protein with the extracellular domain of CTLA4 fused with human immunoglobulin 1).60 Abatacept is a medication approved by the Food and Drug Administration currently in clinical use for rheumatoid arthritis, and it selectively modulated the costimulatory signal required for full T-cell activation. It is hypothesized that abatacept may block the T-cell activation in AA. Conclusions The future of molecular diagnostic testing for AGA, FPHL and AA will likely play a prominent role in the prediction and diagnosis of hair loss, severity of disease, determination of response to therapy, and in identifying candidate targets for novel therapeutic approaches. However, genetic testing for these conditions currently remains limited. The current gold standard in diagnosis of these alopecias is by clinical history, examination, and, when necessary, scalp biopsy for histopathologic evaluation. Although in most cases the diagnosis of these alopecias can be ascertained by these modalities, there are cases whereby the clinical and histopathologic features may be ambiguous, making a definitive diagnosis difficult.6-8 Additionally, the course and severity of the hair loss is unpredictable in most cases, and currently, there are no reliable and validated clinical or histologic features that can provide patients with prognostic information. It is conceivable that once the underlying genetic risk profiles of these forms of hair loss are more fully established, this information can potentially be used to aid in more definitively elucidating the pathogenesis of the hair loss. This would likely open more avenues for the development of molecular diagnostic testing that could be used as adjunctive tools to clinical and histopathologic examination, allowing for a more accurate and timely diagnosis. The establishment of molecular diagnostic testing for alopecia will also allow for the risk stratification of patients with respect to the development and severity of hair loss. Finally, molecular diagnostic testing will advance the field of pharmacogenetics for alopecia aiding in the development of therapeutic and preventative targeted therapies as well as determination of the treatment response allowing for personalization of treatment for patients with hair loss. References 1. Alkhalifah A, Alsantali A, Wang E, et al: Alopecia areata update: Part I. Clinical picture, histopathology, and pathogenesis. J Am Acad Dermatol 62:177-188, 2010; quiz 89-90 2. Alfonso M, Richter-Appelt H, Tosti A, et al: The psychosocial impact of hair loss among men: A multinational European study. Curr Med Res Opin 21:1829-1836, 2005 3. Petukhova L, Cabral RM, Mackay-Wiggan J, et al: The genetics of alo- Implications for molecular diagnostic testing 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. pecia areata: What's new and how will it help our patients? Dermatol Ther 24:326-336, 2011 Ellis J: Future directions: Gene polymorphism diagnostics relavant to hair, in Trueb R, Tobin D (eds): Aging Hair. London, Springer, 2010, pp 291-332 Dy LC, Whiting DA: Histopathology of alopecia areata, acute and chronic: Why is it important to the clinician? Dermatol Ther 24:369374, 2011 Eudy G, Solomon AR: The histopathology of noncicatricial alopecia. Semin Cutan Med Surg 25:35-40, 2006 Han A, Mirmirani P: Clinical approach to the patient with alopecia. Semin Cutan Med Surg 25:11-23, 2006 Hoss DM, Grant-Kels JM: Diagnosis: Alopecia areata or not? Semin Cutan Med Surg 18:84-90, 1999 Stefanato CM: Histopathology of alopecia: A clinicopathological approach to diagnosis. Histopathology 56:24-38, 2010 Trueb RM, Tobin DJ: Aging Hair. Berlin, Springer, 2010, p 270 Tosti A, Bellavista S, Iorizzo M: Alopecia areata: A long term follow-up study of 191 patients. J Am Acad Dermatol 55:438-441, 2006 Rhodes T, Girman CJ, Savin RC, et al: Prevalence of male pattern hair loss in 18-49 year old men. Dermatol Surg 24:1330-1332, 1998 Norwood OT: Male pattern baldness: Classification and incidence. South Med J 68:1359-1365, 1975 Hamilton JB: Patterned loss of hair in man; types and incidence. Ann N Y Acad Sci 53:708-728, 1951 Gan DC, Sinclair RD: Prevalence of male and female pattern hair loss in Maryborough. J Investig Dermatol Symp Proc 10:184-189, 2005 Hamilton JB: Effect of castration in adolescent and young adult males upon further changes in the proportions of bare and hairy scalp. J Clin Endocrinol Metab 20:1309-1318, 1960 Kaufman KD: Androgens and alopecia. Mol Cell Endocrinol 198:8995, 2002 Jenkins EP, Andersson S, Imperato-McGinley J, et al: Genetic and pharmacological evidence for more than one human steroid 5 alpha-reductase. J Clin Invest 89:293-300, 1992 Olsen EA: Female pattern hair loss. J Am Acad Dermatol 45 Suppl 3:S70-S80, 2001 Birch MP, Messenger JF, Messenger AG: Hair density, hair diameter and the prevalence of female pattern hair loss. Br J Dermatol 144:297-304, 2001 Orme S, Cullen DR, Messenger AG: Diffuse female hair loss: Are androgens necessary? Br J Dermatol 141:521-523, 1999 Lynfield YL: Effect of pregnancy on the human hair cycle. J Invest Dermatol 35:323-327, 1960 Simpson D, Curran MP, Perry CM: Letrozole: A review of its use in postmenopausal women with breast cancer. Drugs 64:1213-1230, 2004 Ohnemus U, Uenalan M, Inzunza J, et al: The hair follicle as an estrogen target and source. Endocr Rev 27:677-706, 2006 Oh HS, Smart RC: An estrogen receptor pathway regulates the telogenanagen hair follicle transition and influences epidermal cell proliferation. Proc Natl Acad Sci USA 93:12525-12530, 1996 Yip L, Zaloumis S, Irwin D, et al: Gene-wide association study between the aromatase gene (CYP19A1) and female pattern hair loss. Br J Dermatol 161:289-294, 2009 Nyholt DR, Gillespie NA, Heath AC, et al: Genetic basis of male pattern baldness. J Invest Dermatol 121:1561-1564, 2003 Ellis JA, Harrap SB: The genetics of androgenetic alopecia. Clin Dermatol 19:149-154, 2001 Ellis JA, Stebbing M, Harrap SB: Genetic analysis of male pattern baldness and the 5alpha-reductase genes. J Invest Dermatol 110:849-853, 1998 Ellis JA, Stebbing M, Harrap SB: Polymorphism of the androgen receptor gene is associated with male pattern baldness. J Invest Dermatol 116:452-455, 2001 Sawaya ME, Shalita AR: Androgen receptor polymorphisms (CAG repeat lengths) in androgenetic alopecia, hirsutism, and acne. J Cutan Med Surg 3:9-15, 1998 Hillmer AM, Hanneken S, Ritzmann S, et al: Genetic variation in the 265 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. human androgen receptor gene is the major determinant of common early-onset androgenetic alopecia. Am J Hum Genet 77:140-148, 2005 Ellis JA, Scurrah KJ, Cobb JE, et al: Baldness and the androgen receptor: The AR polyglycine repeat polymorphism does not confer susceptibility to androgenetic alopecia. Hum Genet 121:451-457, 2007 Hillmer AM, Brockschmidt FF, Hanneken S, et al: Susceptibility variants for male-pattern baldness on chromosome 20p11. Nat Genet 40: 1279-1281, 2008 Hillmer AM, Flaquer A, Hanneken S, et al: Genome-wide scan and fine-mapping linkage study of androgenetic alopecia reveals a locus on chromosome 3q26. Am J Hum Genet 82:737-743, 2008 Prodi DA, Pirastu N, Maninchedda G, et al: EDA2R is associated with androgenetic alopecia. J Invest Dermatol 128:2268-2270, 2008 Richards JB, Yuan X, Geller F, et al: Male-pattern baldness susceptibility locus at 20p11. Nat Genet 40:1282-1284, 2008 Cobb JE, White SJ, Harrap SB, et al: Androgen receptor copy number variation and androgenetic alopecia: A case-control study. PLoS One 4:e5081, 2009 Cobb JE, Zaloumis SG, Scurrah KJ, et al: Evidence for two independent functional variants for androgenetic alopecia around the androgen receptor gene. Exp Dermatol 19:1026-1028, 2010 Bubulya A, Wise SC, Shen XQ, et al: C-Jun can mediate androgen receptor-induced transactivation. J Biol Chem 271:24583-24589, 1996 Brockschmidt FF, Heilmann S, Ellis JA, et al: Susceptibility variants on chromosome 7p21.1 suggest HDAC9 as a new candidate gene for malepattern baldness. Br J Dermatol 165:1293-1302, 2011 el-Samahy MH, Shaheen MA, Saddik DE, et al: Evaluation of androgen receptor gene as a candidate gene in female androgenetic alopecia. Int J Dermatol 48:584-587, 2009 Ali I, Wojnarowska F: Physiological changes in scalp, facial and body hair after the menopause: A cross-sectional population-based study of subjective changes. Br J Dermatol 164:508-513, 2011 Haiman CA, Dossus L, Setiawan VW, et al: Genetic variation at the CYP19A1 locus predicts circulating estrogen levels but not breast cancer risk in postmenopausal women. Cancer Res 67:1893-1897, 2007 Yip L, Zaloumis S, Irwin D, et al: Association analysis of oestrogen receptor beta gene (ESR2) polymorphisms with female pattern hair loss. Br J Dermatol 166:1131-1134, 2012 Tang L, Bernardo O, Bolduc C, et al: The expression of insulin-like growth factor 1 in follicular dermal papillae correlates with therapeutic efficacy of finasteride in androgenetic alopecia. J Am Acad Dermatol 49:229-233, 2003 Wakisaka N, Taira Y, Ishikawa M, et al: Effectiveness of finasteride on patients with male pattern baldness who have different androgen receptor gene polymorphism. J Investig Dermatol Symp Proc 10:293294, 2005 Sato A, Arima Y, Kojima Y, et al: Correlation between polymorphic CAG-repeats in the androgen receptor gene and therapeutic efficacy of finasteride in androgenetic alopecia. Skin Surg 17:80-86, 2008 Yamazaki M, Sato A, Toyoshima KE, et al: Polymorphic CAG repeat numbers in the androgen receptor gene of female pattern hair loss patients. J Dermatol 38:680-684, 2011 Keene S, Goren A: Therapeutic hotline. Genetic variations in the androgen receptor gene and finasteride response in women with androgenetic alopecia mediated by epigenetics. Dermatol Ther 24:296-300, 2011 Kaufman KD, Rotonda J, Shah AK, et al: Long-term treatment with finasteride 1 mg decreases the likelihood of developing further visible hair loss in men with androgenetic alopecia (male pattern hair loss). Eur J Dermatol 18:400-406, 2008 HairDx. Available at: http://www.hairdx.com. Accessed July 17, 2012 McMichael AJ, Pearce DJ, Wasserman D, et al: Alopecia in the United States: Outpatient utilization and common prescribing patterns. J Am Acad Dermatol 57 Suppl 2:S49-S51, 2007 Safavi K: Prevalence of alopecia areata in the first national health and nutrition examination survey. Arch Dermatol 128:702, 1992 Finner AM: Alopecia areata: Clinical presentation, diagnosis, and unusual cases. Dermatol Ther 24:348-354, 2011 266 56. Barahmani N, Schabath MB, Duvic M, et al; National Alopecia Areata Registry: History of atopy or autoimmunity increases risk of alopecia areata. J Am Acad Dermatol 61:581-591, 2009 57. Chu SY, Chen YJ, Tseng WC, et al: Comorbidity profiles among patients with alopecia areata: The importance of onset age, a nationwide population-based study. J Am Acad Dermatol 65:949-956, 2011 58. Gilhar A, Paus R, Kalish RS: Lymphocytes, neuropeptides, and genes involved in alopecia areata. J Clin Invest 117:2019-2027, 2007 59. Delamere FM, Sladden MM, Dobbins HM, et al: Interventions for alopecia areata. Cochrane Database Syst Rev 2:CD004413, 2008 60. Miteva M, Tosti A: Treatment options for alopecia: An update, looking to the future. Expert Opin Pharmacother 13:1271-1281, 2012 61. Paus R, Nickoloff BJ, Ito T: A "hairy" privilege. Trends Immunol 26:3240, 2005 62. Paus R, Slominski A, Czarnetzki BM: Is alopecia areata an autoimmuneresponse against melanogenesis-related proteins, exposed by abnormal MHC class I expression in the anagen hair bulb? Yale J Biol Med 66: 541-554, 1993 63. Ito T, Ito N, Bettermann A, et al: Collapse and restoration of MHC class-I-dependent immune privilege: Exploiting the human hair follicle as a model. Am J Pathol 164:623-634, 2004 64. Siebenhaar F, Sharov AA, Peters EM, et al: Substance P as an immunomodulatory neuropeptide in a mouse model for autoimmune hair loss (alopecia areata). J Invest Dermatol 127:1489-1497, 2007 65. Ito T, Ito N, Saatoff M, et al: Maintenance of hair follicle immune privilege is linked to prevention of NK cell attack. J Invest Dermatol 128:1196-1206, 2008 66. Gilhar A, Landau M, Assy B, et al: Mediation of alopecia areata by cooperation between CD4⫹ and CD8⫹ T lymphocytes: Transfer to human scalp explants on Prkdc(scid) mice. Arch Dermatol 138:916922, 2002 67. Gilhar A, Ullmann Y, Berkutzki T, et al: Autoimmune hair loss (alopecia areata) transferred by T lymphocytes to human scalp explants on SCID mice. J Clin Invest 101:62-67, 1998 68. McElwee KJ, Freyschmidt-Paul P, Hoffmann R, et al: Transfer of CD8(⫹) cells induces localized hair loss whereas CD4(⫹)/CD25(-) cells promote systemic alopecia areata and CD4(⫹)/CD25(⫹) cells blockade disease onset in the C3H/HeJ mouse model. J Invest Dermatol 124:947-957, 2005 69. McElwee KJ, Spiers EM, Oliver RF: In vivo depletion of CD8⫹ T cells restores hair growth in the DEBR model for alopecia areata. Br J Dermatol 135:211-217, 1996 70. Petukhova L, Duvic M, Hordinsky M, et al: Genome-wide association study in alopecia areata implicates both innate and adaptive immunity. Nature 466:113-117, 2010 71. Natarajan K, Dimasi N, Wang J, et al: Structure and function of natural killer cell receptors: Multiple molecular solutions to self, nonself discrimination. Annu Rev Immunol 20:853-885, 2002 72. McDonagh AJ, Tazi-Ahnini R: Epidemiology and genetics of alopecia areata. Clin Exp Dermatol 27:405-409, 2002 73. Jackow C, Puffer N, Hordinsky M, et al: Alopecia areata and cytomegalovirus infection in twins: Genes versus environment? J Am Acad Dermatol 38:418-425, 1998 74. Sundberg JP, Silva KA, Li R, et al: Adult-onset alopecia areata is a complex polygenic trait in the C3H/HeJ mouse model. J Invest Dermatol 123:294-297, 2004 75. Goh C, Finkel M, Christos PJ, et al: Profile of 513 patients with alopecia areata: Associations of disease subtypes with atopy, autoimmune disease and positive family history. J Eur Acad Dermatol Venereol 20: 1055-1060, 2006 P. Yazdan 76. Colombe BW, Price VH, Khoury EL, et al: HLA class II antigen associations help to define two types of alopecia areata. J Am Acad Dermatol 33:757-764, 1995 77. Martinez-Mir A, Zlotogorski A, Gordon D, et al: Genome-wide scan for linkage reveals evidence of several susceptibility loci for alopecia areata. Am J Hum Genet 80:316-328, 2007 78. Gregersen PK, Olsson LM: Recent advances in the genetics of autoimmune disease. Annu Rev Immunol 27:363-391, 2009 79. Zhernakova A, van Diemen CC, Wijmenga C: Detecting shared pathogenesis from the shared genetics of immune-related diseases. Nat Rev Genet 10:43-55, 2009 80. Muto M, Deguchi H, Tanaka A, et al: Association between T-lymphocyte regulatory gene CTLA4 single nucleotide polymorphism at position 49 in exon 1 and HLA-DRB1*08 in Japanese patients with psoriasis vulgaris. J Dermatol Sci 62:70-71, 2011 81. Singh TP, Schön MP, Wallbrecht K, et al: 8-methoxypsoralen plus ultraviolet A therapy acts via inhibition of the IL-23/Th17 axis and induction of Foxp3⫹ regulatory T cells involving CTLA4 signaling in a psoriasis-like skin disorder. J Immunol 184:7257-7267, 2010 82. Forstbauer LM, Brockschmidt FF, Moskvina V, et al: Genome-wide pooling approach identifies SPATA5 as a new susceptibility locus for alopecia areata. Eur J Hum Genet 20:326-332, 2012 83. Jagielska D, Redler S, Brockschmidt FF, et al: Follow-up study of the first genome-wide association scan in alopecia areata: IL13 and KIAA0350 as susceptibility loci supported with genome-wide significance. J Invest Dermatol 132:2192-2197, 2012 84. Beghé B, Hall IP, Parker SG, et al: Polymorphisms in IL13 pathway genes in asthma and chronic obstructive pulmonary disease. Allergy 65:474-481, 2010 85. Bottema RW, Nolte IM, Howard TD, et al: Interleukin 13 and interleukin 4 receptor-␣ polymorphisms in rhinitis and asthma. Int Arch Allergy Immunol 153:259-267, 2010 86. Bowes J, Eyre S, Flynn E, et al: Evidence to support IL-13 as a risk locus for psoriatic arthritis but not psoriasis vulgaris. Ann Rheum Dis 70: 1016-1019, 2011 87. Martínez A, Perdigones N, Cénit MC, et al: Chromosomal region 16p13: Further evidence of increased predisposition to immune diseases. Ann Rheum Dis 69:309-311, 2010 88. Nischwitz S, Cepok S, Kroner A, et al: More CLEC16A gene variants associated with multiple sclerosis. Acta Neurol Scand 123:400-406, 2011 89. Zoledziewska M, Costa G, Pitzalis M, et al: Variation within the CLEC16A gene shows consistent disease association with both multiple sclerosis and type 1 diabetes in Sardinia. Genes Immun 10:15-17, 2009 90. Lueking A, Huber O, Wirths C, et al: Profiling of alopecia areata autoantigens based on protein microarray technology. Mol Cell Proteomics 4:1382-1390, 2005 91. Subramanya RD, Coda AB, Sinha AA: Transcriptional profiling in alopecia areata defines immune and cell cycle control related genes within disease-specific signatures. Genomics 96:146-153, 2010 92. Coda AB, Qafalijaj Hysa V, Seiffert-Sinha K, et al: Peripheral blood gene expression in alopecia areata reveals molecular pathways distinguishing heritability, disease and severity. Genes Immun 11:531-541, 2010 93. Coda AB, Sinha AA: Integration of genome-wide transcriptional and genetic profiles provides insights into disease development and clinical heterogeneity in alopecia areata. Genomics 98:431-439, 2011 94. John KK, Brockschmidt FF, Redler S, et al: Genetic variants in CTLA4 are strongly associated with alopecia areata. J Invest Dermatol 131: 1169-1172, 2011 95. Gilhar A, Etzioni A, Paus R: Alopecia areata. N Engl J Med 366:15151525, 2012 96. Carroll JM, McElwee KJ, E King L, et al: Gene array profiling and immunomodulation studies define a cell-mediated immune response underlying the pathogenesis of alopecia areata in a mouse model and humans. J Invest Dermatol 119:392-402, 2002
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Hotels in New Delhi
666 Accommodations in New Delhi
Hotel Hyatt Regency DelhiNew Delhi 10.3 km from city centre 2040 reviews
This 5 star hotel is located in the city centre of New Delhi and was established in 1982. It is a short drive away from the Connaught Place.
Hotel Radisson Blu Marina Connaught PlaceNew Delhi 800 m from city centre 927 reviews
Designed by internationally renowned architect Thom Catallo, this heritage, boutique hotel features premium brand amenities, attentive...
Hotel Taj PalaceNew Delhi 6.9 km from city centre 2489 reviews
All the rooms are elegantly appointed and offer guests an array of amenities such as internet connection,speaker phones with...
Hotel JiviteshNew Delhi 3.3 km from city centre 0 reviews
A stay at Hotel Jivitesh places you in the heart of New Delhi, convenient to Laxminarayan Temple and Red Fort. This hotel is within close...
Hotel Amrapali GrandNew Delhi 3 km from city centre 0 reviews
With a stay at Hotel Amrapali Grand in New Delhi, you'll be in a shopping district and convenient to Laxminarayan Temple and Birla Mandir...
Hotel The Claridges New DelhiNew Delhi 4.4 km from city centre 1823 reviews
Claridges rooms are larger than deluxe and have also benefited from a recent renovation and are appointed to a high standard. Rooms are...
Piccadily Hotel New DelhiNew Delhi 14.3 km from city centre 1059 reviews
With a stay at The Piccadily in New Delhi (West Delhi), you'll be minutes from Janakpuri District Centre. This 5-star hotel is within the...
The Leela Ambience Convention Hotel DelhiNew Delhi 8.1 km from city centre 0 reviews
The hotel is a 45 minutes drive from Airport, and can be easily accessed by the National Highway 8 . The Hotel Complex is also...
Hotel The Grand New DelhiNew Delhi 13.8 km from city centre 1015 reviews
This 4 star hotel is located within the city of New Delhi. It is a short drive away from the Qutub Minar. The Hotel has a coffee shop, an...
WelcomHotel DwarkaNew Delhi 17.6 km from city centre 1500 reviews
A stay at WelcomHotel Dwarka places you in the heart of New Delhi, convenient to Dada Dev Mandir. This 5-star hotel is within the...
Hotel Park Inn By Radisson New Delhi Ip ExtensionNew Delhi 8.8 km from city centre 0 reviews
A stay at Park Inn by Radisson New Delhi IP Extension places you in the heart of New Delhi, convenient to Swaminarayan Akshardham Temple....
Hotel Alpine TreeNew Delhi 58 reviews
With a stay at Hotel Alpine Tree in New Delhi (Aerocity), you'll be close to AMBI Mall and DLF Emporio Vasant Kunj. This hotel is within...
Shangri-La's - Eros HotelNew Delhi 1.8 km from city centre 2500 reviews
Room rates are for superior category rooms. Superior rooms are medium in size and in excellent condition. White duvets are accented by...
The Eros HotelNew Delhi 9.8 km from city centre 945 reviews
Feel at home with 28 m2 stylish and contemporary air conditioned guestrooms with king size beds with modern bathroms with a range of...
Hotel jüSTa Panchsheel ParkNew Delhi 9.9 km from city centre 556 reviews
The accommodations at the Residence Panchsheel Park hotel are comfortable. These are fitted with modern amenities. The rooms and suites...
Hotel The Lalit New DelhiNew Delhi 497 m from city centre 0 reviews
The rooms are very large, in good condition, and offer amenities expected from international travellers. Club rooms offer additional...
Accommodations in New DelhiLocated in a strategic location during its long history, New Delhi, Indias capital is now one of the most densely populated cities in the world, in which tradition and modernity walk hand in hand. The city is a melting pot of different cultures and different religions, as is the case with the whole of India.
New Delhi, situation in the golden triangle, is an immortal, holy city where visitors can let their imagination run wild. It is the starting point for many excursions to the surrounding areas, and is, in itself, a city filled with charm where one can lose oneself for many days.
Unlike the regions located further to the south of the country, New Delhi has a semi-arid, sub-tropical climate with enormous contrasts in temperature between the summer and the winter. During the monsoon season in the summer, the rainfall is extremely heavy and this is not the best time to visit the country.
The attractions of the city include Jama Masjid or the largest mosque in India, the Raj Ghad or the Ghandi memorial and the temple of Bangla Sahib. Other interesting sites are the Hindu temple of Birla, the Parliament building and the old British colonial district or Victoria tower. However, on arriving at New Delhi, it is a good idea to venture beyond its borders and visit the city of Jaipur, the rose of Rajasthan, Samode, Amber, Fatehpur Sikri, Agra, or Benares to admire all the charms that India has to offer, and in particular the northern part of the country.
As many rightly say, India is a paradise on earth and New Delhi is the main gateway to that paradise.
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In New Delhi we will have clear sky, soft clothing is advised as the temperatures will be warm throughout the day.
- Monday
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Points of Interest in New Delhi
- Train station - New Delhi
- Airport - New Delhi-Indira Gandhi
- India Gate
- New Delhi (city center)
- Red Fort

subset: commoncrawl


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Manufacturers of polyurethane (PU) materials are under increasing pressure to create additives which enable high quality production with fewer environmental emissions.
One such company that appears to be leading the way is Air Products. The North American industrial gas firm has recently developed low emission non-fugitive catalysts. These catalysts are designed specifically for application in the automotive and slabstock sectors.
Steve Hulme, Global Marketing Manager of PU Chemicals at Air Products explained some of the challenges involved in the hunt: "When developing low emission catalysts, the biggest challenge has been to fulfill the physical property standards of flexible foams used in automotive seating, in particular to meet properties after humid aging of the foam."
According to Air Products, demand for non-emission catalyst technology has spread globally in the past decade and this is expected to continue. Steve Hulme added, "Initial interest in non-fugitive catalyst technology came from the European automotive industry, but this has since spread to flexible stabstock and rigid foams. We are now seeing an increased demand for this advanced technology from furniture and bedding producers in Asia, for example, which are supplying markets in the EU and US."
In Europe, Air Products is launching two next generation non-emission catalysts at UTECH 2012, Dabco® NE1090 and Dabco BA305. Both these new products have been designed specifically to produce non-emission molded TDI foam that can meet the humid age specification that is required by automotive OEMs.
"The technology will close a gap that foam manufacturers have been looking for since many years", explained Steve Hulme, "and will be another milestone in 50 years of Air Products´ catalyst developments for the polyurethane industry". New catalysts and surfactants for rigid and flexible foam applications will also be showcased.


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Finish the sentence that begins "What I've always wanted to say is…"
Grow up. Just grow up.
I'm tired of hearing how bad life is. I am tired of hearing poor me. I am tired of hearing how unhappy you are. Just grow up.
Take control of your situation. Stop whining and DO SOMETHING.
Thank you – I feel better now.


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Remi is kindly sponsored by Sue.
" I'm Remi and I'm small and cute as a button! I don't take up much room, I quite like kids, and I passed my cat test so I have the potential to live with kitties if you have either of those at your house.I love to play quite a lot and consider myself a bit of a puppy still. I would much rather race around a garden or race to the couch than race around a track. Do you have a couch I could put my paws on? I hear every greyhound needs one of those and I haven't been on one yet, and I'm only nearly three. My birthday is in May, so maybe you could give me one as a birthday present? You could? Quick! Get onto those volunteers at GR firstname.lastname@example.com"
- Desexed, microchipped, vaccinated, heartworm tested and treated
- Located in Sydney
- Not yet cat tested
- Adoption cost $350


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Lord Hain detailed alleged abuse claims about Arcadia Group owner Sir Philip Green under parliamentary privilege at the House of Lords today.
In October last year, Hain named Green as the businessman behind an injunction against the Daily Telegraph, which stopped the newspaper naming him in a report following an eight-month investigation into allegations of bullying, racism and sexual harassment.
In a statement to the House of Lords today, Hain said there were "hundreds" of alleged complaints made about the retail tycoon.
The complaints listed involved inappropriate "touching", "grabbing" and "slapping" of women.
Arcadia Group has since responded, stating that these comments are "unfounded".
In an official statement, the company said: "There have never been hundreds of complaints as stated by Lord Hain, additionally, Sir Philip has not been present in the London head offices for nearly a year."
Responding to Hain's latest claims, Green said today: "To abuse parliamentary privilege in this way at this time knowing the damage it can cause is beyond irresponsible."
Green has always "categorically and wholly" denied the claims.
In a statement made at the time of he was accused, Green said: "I am not commenting on anything that has happened in court or was said in parliament today. To the extent that it is suggested that I have been guilty of unlawful sexual or racist behaviour, I categorically and wholly deny these allegations. Arcadia and I take accusations and grievances from employees very seriously and in the event that one is raised, it is thoroughly investigated."
Arcadia Group said it has a grievance policy in place across the business for any colleagues wishing to raise any concerns.
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To be or not to be disruptive or adaptive at work? Here are 5 tips to help you find your way.
4 fun freebies for the office
Work + play = #bestofficeEVER
(VAULT) Stronger 2015
Have you plotted down your new year resolutions yet? Perhaps 2015 is the year to surprise yourself with a new challenge like triathlon, a multi-sport race including swimming, biking and running. "Triathlon probably made me a better person," celebrity triathlete Drew Arellano said to describe his seven years of being into triathlon. To further his … Continue reading (VAULT) Stronger 2015
(VAULT) LSGH Campaigns
More than anything, I find it so amusing that I actually salvaged these lovely scanned copies of print articles. Gary V Back Home LSGH @ 50 One La Salle Foundation
(VAULT) Getting into triathlon: from competitive races to helping each other
One of the fast-growing sporting trends in the country is Triathlon. From just a small community of athletes, it has now grown into a bigger network of sports enthusiasts who races competitively but trains as a community. Do you want to try out triathlon as a new hobby? It's the perfect time to challenge yourself. … Continue reading (VAULT) Getting into triathlon: from competitive races to helping each other
How to be productive in 5 ways
You will never have enough time for everything… but you can always manage your time better.
Weekly worK inspo
I'm never really the type who gets bit by the Monday blues BUT if you are, here's 5 quotes I lifted from IG that best sums up how I'd like this week to be. Hope you find some inspo from these quotes as well! Follow my worK space Spotify playlist
3 apps to help you to never forget things
This pretty much might sound like "back-up the back-up! When work gets overwhelming, it's easy to slide into oblivion and all of a sudden, find yourself a bit lost or worse, having overlooked a few things. Yes, it happens, but there are many ways to avoid the dilemma. Here are some of my favorite work hacks … Continue reading 3 apps to help you to never forget things
Medium page
My worK space is also on Medium!
For her
This is for her, that girl who never really lost the fire.


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Bourne's Energy
Bourne's Energy is a locally owned and operated business that takes great pride in its integrity, loyalty and quality of workmanship. Bourne's Energy is large enough to see to all residential and commercial heating requirements, yet small enough to care for the individual needs of all our customers. All requests are taken into full consideration under the watchful eyes of president, Peter Bourne. It is this hands-on operation that distinguishes Bourne's from its competitors.
Our company is proud to provide 24-hour emergency service 365 days a year to all its customers. Bourne's Energy supplies home heating biofuel, propane, kerosene, biodiesel, air-conditioning, solar hot water, energy efficiency home audits, full plumbing service and heating installation.
Bourne's Energy's concern and commitment to community, environment and social awareness knows no bounds. For every gallon of propane our American Breast Cancer "pink" propane truck delivers, we are proud to donate 1 cent to the ABCF and then an additional 1/2 cent for every gallon delivered is donated to local cancer networks. In addition, Bourne's Energy donates 1 cent for every gallon delivered from our United Way biofuel delivery truck to the Lamoille United Way and Green Mountain United Way.
In our efforts to be "green", we are able to use the internet for ecobilling and you can even check your account on-line at your convenience. Also, for every customer that signs up for ecobilling, Bourne's Energy donates $0.15 to a charity or non-profit organization. We look forward to having you as one of our loyal and valued customers.


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- Flights + Hotel
- Cruises
St. Petersburg / Clearwater HolidaysReference WW38597
Book your St Petersburg or St Pete's as it's better known, & Clearwater holiday today and you'll soon be jetting off to this sun-drenched peninsula separating the Gulf of Mexico from Tampa Bay, St. Petersburg and Clearwater are where holidaymakers head to if they're after that quintessential beach holiday.
With 35 miles of spectacular award-winning white-sand beaches and an average 361 days of sunshine per year, you are sure to find the perfect spot to soak up the sun whenever you visit St. Petes Clearwater. From the pristine Caladesi Island in the North to Fort De Soto State Park in the South, we have a wide variety of amazing beaches where families and couples can play or relax next to the crystal clear waters of the Gulf of Mexico. Then why not head for Pier 60 on Clearwater Beach where musicians, performers and other colourful characters gather for the daily festival to celebrate the incredible sunsets we are famous for.
So what are you waiting for? With a fantastic choice of hotels to choose from then just pick up the phone and speak to our travel experts today to book your holidays to St Petersburg and Clearwater.
Top hotels in St Petersburg / Clearwater
Top 5 Things To Do
St. Petersburg / Clearwater Holiday Highlights
When to Visit
- Jan
- Feb
- Mar
- Apr
- May
- Jun
- Jul
- Aug
- Sep
- Oct
- Nov
- Dec
- Currency US Dollars ($)
- Flying time from UK 10 1/2 Hours
- Primary Language English
- Passport & Visas Brits must have a full 10-year British Passport that's valid for six months after you return to the UK.


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Business Communication and Soft Skills Laboratory Manual
by D. Sudha Rani
Publisher: Pearson India
Release Date: September 2011
View table of contents
Start reading
Book Description
Business Communication and Soft Skills Laboratory Manual
provides hands-on experience of business and professional situations. It imparts the required communication and soft skills through group activities and peer group assessment essential for effective communication and personality development. This ensures long-term employability of students entering the professional domain and professionals striving for consistency and success in their jobs. This is also an effective tool for students and teachers to use a communicative approach to business communication.
Table of Contents
Title page
About the Author
Section I Introduction
Chapter 1. Selection Process of Companies
Chapter 2. Essential Qualities of a Suitable Employee
Section II Introduction to Soft Skills
Chapter 3. Effective Communication Skills
Chapter 4. Presentation Skills
Chapter 5. Public Speaking
Chapter 6. Letter Writing
Chapter 7. Group Discussion
Chapter 8. Interview Skills
Chapter 9. Application Writing
Chapter 10. Essay Writing
Chapter 11. Report Writing
Chapter 12. Leadership Skills
Chapter 13. Socializing Skills


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UW-L Academy of Business Administration adroitness and agents visited four above Fox Valley breadth employers, including the Green Bay Packers, Schneider, Kohler Co. and Grande Cheese. in August. Here, the accumulation tours Lambeau Field.
Many acceptance acquaint University of Wisconsin-La Crosse Accessory Abettor Adam Hoffer they are absorbed in application their business degrees to assignment for the Green Bay Packers afterwards graduation. What admonition should he accord them?
Hoffer went to the antecedent backward this summer, allurement several alumni who assignment for the Packers, including the team's new accepted manager, alum Brian Gutekunst, what admonition they would offer.
Hoffer was on a Academy of Business Administration acreage cruise in August to four above Fox Valley breadth employers, organized by Academy of Business Administration Dean Laura Milner, UW-L Development Officer Jay Scott and UW-L Alumni Association Administrator Janie Morgan.
Milner has organized added able development events, including trips to Ashley Furniture and Harmony Enterprises.
"The CBA is consistently attractive to body industry partnerships," Milner says. "These adroitness acreage trips accommodate adroitness able development, ensuring acknowledgment to accepted business practices, as able-bodied as a two-way altercation with industry about what accurately they are attractive for in our graduates and what abilities they are accouterment to our acceptance who participate in internships with them."
CBA adroitness and agents additionally toured accessories and abstruse what academy adventures alumni begin analytical to their career success.
"We heard afresh and afresh about the accent of networking and connections," says Maggie McDermott, UW-L accessory abettor of marketing. "A key takeaway for me is continuing to assignment adamantine to affix acceptance with businesses alike admitting it takes a lot of assignment and time."
UW-L adroitness and agents asked alum Brian Gutekunst, accepted administrator of the Packers, as able-bodied as added Packers staff, about what they attending for back hiring.
Gutekunst got his aboriginal internship aloof for the Packers in summer 1997 from a articulate advocacy from UW-L arch football drillmaster at the time, Roger Harring. Gutekunst had congenital a accord with Harring as his abettor drillmaster for two years afterwards he afflicted his accept as a football player.
"If it wasn't for apprenticeship for Roger as a student, that advocacy wouldn't accept happened," Gutekunst said. "To me, you charge to asperse yourself in what you appetite to do. Get all of the acquaintance you can and see area your passions lie."
Many alumni accent the amount of such career-like adventures in academy whether through internships, advance work, abstraction abroad, semester-long analysis projects or part-time jobs.
Krissy Zegers, '02, Packers Hall of Fame and Stadium Tour manager, is complex in hiring abounding academy students. She says accepting accordant acquaintance is the best benign affair acceptance gluttonous application with the Packers can do.
"If you appetite to do accounts for the Green Bay Packers, anticipate about what accomplishments are you bringing to the organization," she said. "For lot our internships here, we accept acceptance who accept had sometimes three or four internships afore coming."
The Packers agents associates weren't the alone UW-L alumni to allotment how an internship and added work-related acquaintance was a cardinal aboriginal step.
Joy Langreder, '93, animal ability administrator for Schneider, a busline and acumen casework aggregation based in Green Bay, says a UW-L economics abettor fabricated her acquainted of her aboriginal internship. That befalling to become a animal assets intern for the burghal of La Crosse was the alpha of her added than 20-year HR career. She additionally advised away and aing assorted clubs at UW-L.
"There was abundant to accept from at UW-L, and the things I did helped me to acreage my aboriginal job," she says. "I didn't apprehend I was architecture a resume at the time."
On the trip, adroitness additionally fabricated cross-departmental access with one addition and with employers. The access are already consistent in means to added advance their courses.
"I enjoyed accepting Wisconsin-based examples for the classroom," says Nese Nasif, a UW-L abettor abettor of marketing. "I saw approach in activity everywhere I went."
Higher apprenticeship has a big appulse on the action and abridgement of the Coulee Region. Campus Connection appears on Sundays in the La Crosse Tribune during the abatement and bounce semesters to spotlight apprentice and adroitness achievements at the UW-La Crosse, Viterbo and Western Technical College. The campuses accommodate these appearance on a alternating basis.
Seven Solid Evidences Attending Business Administration Resume Sample Is Good For Your Career Development | Business Administration Resume Sample – business administration resume sample
| Delightful to my own blog, in this occasion I'm going to demonstrate concerning business administration resume sample


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- Undergraduate
- Graduate
- Alumni
- Research/Facilities
- About Us
- Apply Now
Graduate Program - Apply
Application Deadlines
Applications may be submitted at any time. However, for full consideration of financial support, applications must be received by the Department by January 15. Matriculation is fall semester only.
What Materials Are Required?
- Official online OSU Graduate College Application (and pay the application fee)
- Transcripts with bachelor's degree conferred or pending, as well as transcripts for any graduate coursework or degree(s)
- GRE (or GMAT) score report (Note: OSU's GRE institution code is 6546.)
- All international students must also submit scores from the TOEFL exam or the IELTS (academic stream) exam; the exam must have been taken within the last two years.
- Statement of background and goals (2-3 page statement; indicating why you have applied to the program at OSU and which faculty members you would like to work with, if admitted.)
- Recommendations letters from at least three references.
- Curriculum Vitae/Resume
In addition, Ph.D. program applicants must submit:
- Research paper in English that demonstrates technical writing skills and the ability to analyze and synthesize literature
Applicants in the area of Interior Design must submit:
- Portfolio
What Are the Program's Admission Requirements?
The DHM graduate faculty members consider a variety of factors when making an admission
recommendation, and academic background (i.e., the courses you have taken as an undergraduate)
and test scores will be considered along with your statement of goals.
Applicants must have:
- GPA - The department prefers a minimum cumulative Grade Point Average of 3.0 undergraduate for admission to the masters program and 3.5 graduate for admission to the PhD program (on a 4.0 scale)
- GRE/GMAT - The department prefers a minimum 3.5 score on the analytical writing portion of the exam, but scores on the verbal and quantitative components will also be considered.
- For international students, the university and department require a minimum score of 79 on the internet-based TOEFL (iBT) or an IELTS academic stream score of at least 6.5.
- For Interior Design M.S. degree applicants, an undergraduate degree in interior design, interior architecture, architecture, landscape architecture, facility management or industrial/product design is required; for Interior Design Ph.D. applicants, one degree in interior design, interior architecture, architecture, landscape architecture, facility management or industrial/product design is required.
For application process and inquiries, contact
Dr. Gina Gould Peek, DHM Graduate Program Coordinator &
Associate Professor & Cooperative Extension Housing and Consumer Specialist
Oklahoma State University
443 Human Sciences
Stillwater, OK 74078
Phone: 405-744-9521


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http://ashland.oregon.localsguide.com/wp-content/uploads/2016/06/Screen-Shot-2016-06-27-at-9.51.50-AM.png 407 448 Zagorska Oasis http://ashland.oregon.localsguide.com/wp-content/uploads/2018/05/logo-1-300x76.png Zagorska Oasis2017-01-26 14:54:012017-01-26 14:55:20For the Body, From the Heart
For the Body, From the Heart
We have love-centered spa specials during the month of February for couples and singles alike!
Lover's Special
• Side by side rose petal foot soak & scrub
• 30 minute couple's reflexology
• complimentary champagne & Belgian chocolates in our Salt Cave Sanctuary
Luxury for One: 24K Gold Facial
• 99.99% pure 24K gold leaf
• Champagne + Black Truffle Toner
• Caviar + Pearl Serum
• red LED light therapy
• complimentary champagne & Belgian chocolates in our Salt Cave Sanctuary
Introductory Special: $199 until February 28th
Call us at 541-810-8877 to learn more, or to book an appointment. Or book online at www.ZagorskaOasis.com. We are located at 111 E Main in Ashland, downstairs from Sew Creative.


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Complementary Alternative Medicine (CAM) is just what it sounds like. Something to complement the AED regimen you're already on. And perhaps take an extra step (with your doctor's go-ahead) to alleviate seizures.
There are lots of alternatives, so I'll touch on the most popular ones here. (Somehow, I don't think you're going to be turning to stones or amulets for relief!)
Interestingly, The Epilepsy Foundation of Arizona did a survey and it revealed that half of the people with epilepsy had tried CAM at some time for seizure control. Almost half used them for other reasons.
Overall, people found CAM to be generally beneficial to their health. The most helpful were stress reduction, yoga, and botanicals (herbs). Nonetheless, half of the patients taking botanicals had an increase in their seizures.
One third of the patients felt that CAM helped treat their epilepsy better than the AED. However, very few patients considered stopping the AED. Almost all of the patients stated they would feel comfortable informing their physician about CAM use.
"Modern medical therapy often fails, yet modern medical therapy exists because complementary and alternative medicine often fails. Both sides have to recognize each other." Dr. Orrin Devinsky
You can have medication without meditation. Most of us do.
You can do meditation without medication. Most of us wouldn't and shouldn't take that risk.
But together, they can enhance one another.
Meditation has long been touted as a holistic approach to pain relief. And studies show that long-time meditators can tolerate quite a bit of pain.
Now researchers at Wake Forest Baptist Medical Center have found you don't have to be a lifelong Buddhist monk to pull it off. Novices were able to tame pain after just a few training sessions.
Sounds a bit mystical, we know, but researchers using a special type of brain imaging were also able to see changes in the brain activity of newbies. Their conclusion? "A little over an hour of meditation training can dramatically reduce both the experience of pain and pain-related brain activation," says Fadel Zeidan, a neuroscientist and the study's lead author. That finding's a first, Zeidan says….


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April Celebration: library Appreciation
April 23, 2018
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The almost silent working space of the library is filled with noises of flipping papers and quiet chatter as students work with their friends or by themselves. Librarians quietly sit at the front desk, waiting for one of the 600 students to come check out a book and explore what is inside.
The library is a place where students collaborate and a place to quietly focus. Amy Pine, Library Media specialist, shows students that even with new technology, including the 238 audiobooks with the library.
"We have an electronic library [at the LZHS library], but I'd say 95 percent of all of our checkouts are hard copy books. That students prefer to actually have a book in their hand, than to use the e-books," said Pine.
The library contains exactly 983 electronic books, 20,000 hard copy books, an online magazine collection and 26 databases for students to use, according to Pine. Madelyn Malouski, freshman, say that with all these resources, the library has become a meaningful place to students.
"To me, the library is a quiet place where I can relax, read, and talk with friends," Malouski said. "I have always liked the LZHS library compared to others because there is plenty of room to study, use the computers if you need to, and I know that the librarians at LZHS will always be able to find me a book that I will like."
For books, many students read popular genre and author's recommended to them by friends, the library staff uses monthly library journals such as Booklist, School Library Journal, and Voya as well as monitoring new releases on yalit.com to keep the library updated and "in style" for the teen readers, according to Pine.
"I like to have popular materials in the library as close to the day they hit store shelves as possible. For nonfiction we are actually working on weeding the selection since a lot of our material is dated and most students do research using the databases, which are always current," said Pine. "Right now I only order popular nonfiction and know much in the way of reference since we have so much digital content. I spend a lot of time in classrooms teaching students how to use the databases for specific research projects as well as helping them select books for independent reading projects in classes like Contemporary Literature and World Literature."
For students, the library is not just a place to work on class work but also a place to work as a job. For Maja Keska, library aid, the library is not only a workplace, but somewhere to get immersed with the books and to become an important part of the library .
"I check books in and out for people, renew books, but them back on shelves. It's very exciting, I also like organizing the drawers behind the desk, but that's just me," said Keska. "I became a library assistant because my friend and I wanted to do it together, it sounded fun, and I thought it would get me into reading, which it did."
Although the library isn't doing anything special for this month of appreciation, the librarians hope that students see the libraries importance all year round.
"I appreciate there being a month long celebration of the library, but I hope that students and teachers see the library as a resource that is important to them all year long. I guess that why we don't do anything major for this one month, because I feel that everything that we do all year round is to hopefully promote the library," said Pine.
This is Marissa's first year on staff and second year in the journalism program. As a sophomore, Marissa likes to take long walks to the fridge and spends...


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The weather can't seem to make up its mind whether it's winter or spring, but this soup (inspired by the soup you'll frequently find at WaterCourse Foods) is good no matter what the temperature is outside. The curry and spices add a little heat, and the coconut milk smooths that out while balancing the acidity of the tomatoes. Best of all, it's fast and easy (but you'll need a blender!).
See also: - Dairy-free cream of broccoli soup for a warm-up on Meatless Monday - Split-pea soup to help chase away winter for Meatless Monday - Homemade mock chicken stock for a kitchen staple on Meatless Monday
You will need:
3 tablespoons olive oil 3 small onions 1 teaspoon salt 1 tablespoon curry powder 1 teaspoon cumin 1 teaspoon coriander 1/2 teaspoon red pepper flakes 2 28-ounce cans whole tomatoes 3 cups water 1 14-ounce can coconut milk
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1. Heat the oil in a large pot over medium heat. 2. Peel and thinly slice the onion. Add the onion and the salt to the heated oil. Stir until the onion is coated with the oil and salt. Cook for ten minutes or so, until the onion is soft. Perfect. 3. Add the curry powder, cumin, coriander and red pepper flakes. Stir until the onion is coated with the spices. 4. Add the two cans of tomatoes, juices included, and stir. 5. Add the water and stir. (First, swirl the water in the tomato cans to make sure you get all the goodness.) 6. Bring to a boil, then simmer, uncovered, for fifteen minutes or so. 7. After the fifteen minutes is up, blend the soup in batches (or use an immersion blender). Beautiful. Return the blended soup to the pot. 8. Add the coconut milk. Stir until thoroughly combined and cook for another five to ten minutes. Serve warm with crusty bread, a grilled-cheese sandwich (if you do cheese) or just on its own!
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As it appears this forum is now a source of information for the mainstream media, we should start providing positives along with the negatives. With that in mind, I propose we report our trip-to-stranding ratio. Here's mine (which I gleaned from CARWINGS):
Successful trips = 350
Strandings = 0
Punts = 1
A "stranding" is where you run out of power before reaching a charging station
A "punt" is where you probably could have made the trip in your EV, but chickened out and drove an oil-burner instead


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This year we are holding services on two consecutive Sundays to mark the season of Harvest.
On Sunday 21st October 11:00am we shall focus on our World Church partnership through Commitment for Life
On Sunday 28th October 11:00am we shall hold our Harvest Thanksgiving Service followed by a bring and share lunch. Gifts of suitable food will be received that will be used in the Helensburgh & Lomond Foodbank to support members of our local community in need.


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Thank you to the thousands of people across Solihull who supported our candidates in this years local elections. We are delighted that Cllr Glenis Slater was successfully re-elected in Elmdon, and Ade Adeyemo and Jo Fairburn have now joined the council for Lyndon and Olton respectively.
A huge thank you also to our brilliant team of candidates:
Elmdon- Glenis Slater
Dorridge and Hockley Heath- Paul Fairburn
Lyndon- Ade Adeyemo
Olton- Jo Fairburn
Shirley East- Peter Lee
Shirley South- Antony Rogers
Shirley West- Bradley Tucker
Silhill- Jan Mason
St Alphege- Martin Smith
Did you vote in this year's local elections?
If you submit this form, the Liberal Democrats, locally and nationally, may use information in it, including your political views, to further our objectives, share it with our elected representatives and contact you in future using any of the means provided. Some contacts may be automated. You may opt out of some or all contacts or exercise your other legal rights by contacting us. Further details are in our Privacy Policy at www.libdems.org.uk/privacy


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