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Carbon fiber reinforced plastics (CFRPs) gained high interest in industrial applications because of their excellent strength and low specific weight. The stacking sequence of the unidirectional plies forming a CFRP laminate, and their thicknesses, primarily determine the mechanical performance. However, during manufacturing, defects, e.g., pores and residual stresses, are induced, both affecting the mechanical properties. The objective of the present work is to accurately measure residual stresses in CFRPs as well as to investigate the effects of stacking sequence, overall laminate thickness, and the presence of pores on the residual stress state. Residual stresses were measured through the incremental hole-drilling method (HDM). Adequate procedures have been applied to evaluate the residual stresses for orthotropic materials, including calculating the calibration coefficients through finite element analysis (FEA) based on stacking sequence, laminate thickness and mechanical properties. Using optical microscopy (OM) and computed tomography (CT), profound insights into the cross-sectional and three-dimensional microstructure, e.g., location and shape of process-induced pores, were obtained. This microstructural information allowed for a comprehensive understanding of the experimentally determined strain and stress results, particularly at the transition zone between the individual plies. The effect of pores on residual stresses was investigated by considering pores to calculate the calibration coefficients at a depth of 0.06 mm to 0.12 mm in the model and utilizing these results for residual stress evaluation. A maximum difference of 46% in stress between defect-free and porous material sample conditions was observed at a hole depth of 0.65 mm. The significance of employing correctly calculated coefficients for the residual stress evaluation is highlighted by mechanical validation tests.

Cracks developing within a masonry structure induce changes in its strain field that can be measured for damage identification purposes through the adoption of strain-based structural health monitoring techniques. “Smart bricks” are strain-sensing piezoresistive clay bricks that can be used for this purpose. Along these lines, the paper investigates their use for strain field reconstruction and damage identification in masonry walls subjected to in-plane compressive loading. Experiments are first carried out to select the smart brick formulation and to demonstrate its effectiveness in estimating strain in compression. Then, an application of a network of smart bricks for monitoring a masonry wall eccentrically loaded in its plane is presented. Strains measured by the embedded smart bricks are benchmarked against those provided by strain gauges and further interpreted by means of a non-linear 3D model discretized with the finite element method. The strain field of the monitored structural element is reconstructed by spatially interpolating the strain measurements from smart bricks with a Kriging-based approach, while damage identification is achieved by defining a specific strain-based damage identifying feature. The obtained results clearly demonstrate that smart bricks significantly outperform strain gauges for strain field reconstruction and damage identification in masonry structures.

Obtaining the mesostructure of concrete from X-ray computed tomography (CT) requires segmentation of the data into distinct phases, a process complicated by the limited contrast between aggregates and mortar matrix. This paper explores the possibility to add baryte or hematite into the concrete mixture to enhance the contrast between cement paste and aggregates in CT, thus allowing for a semi-automatic segmentation. Raw and segmented CT images of plain and modified concrete mixtures are obtained and compared to assess the validity of the proposed approach. Characterization tests are also performed in order to ensure that the concrete characteristics are not appreciably affected by the presence of the enhancers.

Alopecia areata (AA) is one of the most common forms of human hair loss. Although genetic studies have implicated autoimmune processes in AA etiology, understanding of the etiopathogenesis is incomplete. Recent research has implicated microRNAs, a class of small noncoding RNAs, in diverse autoimmune diseases. To our knowledge, no study has investigated the role of microRNAs in AA. In this study, gene-based analyses were performed for microRNAs using data of the largest genome-wide association meta-analysis of AA to date. Nominally, significant P-values were obtained for 78 of the 617 investigated microRNAs. After correction for multiple testing, three of the 78 microRNAs remained significant. Of these, miR-30b/d was the most significant microRNA for the follow-up analyses, which also showed lower expression in the hair follicle of AA patients. Target gene analyses for the three microRNAs showed 42 significantly associated target genes. These included IL2RA, TNXB, and ERBB3, which had been identified as susceptibility loci in previous genome-wide association studies. Using luciferase assay, site-specific miR-30b regulation of the AA risk genes IL2RA, STX17, and TNXB was validated. This study implicates microRNAs in the pathogenesis of AA. This finding may facilitate the development of future treatment strategies.

This paper presents an isogeometric formulation for frictionless contact between deformable bodies, based on the recently proposed concept of the third medium. This concept relies on continuum formulations not only for the contacting bodies but also for a fictitious intermediate medium in which the bodies can move and interact. Key to the formulation is a suitable definition of the constitutive behavior of the third medium. In this work, based on a number of numerical tests, the role of the material parameters of the third medium is systematically assessed. We also assess the rate of spatial convergence for higher-order discretizations, stemming from the regularization of the non-smooth contact problem inherent to the third medium approach. Finally, problems with self contact are considered and turn out to be an attractive application of the method.

In this paper, a phase-field model for ductile fracture previously proposed in the kinematically linear regime is extended to the three-dimensional finite strain setting, and its predictions are qualitatively and quantitatively compared with several experimental results, both from ad-hoc tests carried out by the authors and from the available literature. The proposed model is based on the physical assumption that fracture occurs when a scalar measure of the accumulated plastic strain reaches a critical value, and such assumption is introduced through the dependency of the phase-field degradation function on this scalar measure. The proposed model is able to capture the experimentally observed sequence of elasto-plastic deformation, necking and fracture phenomena in flat specimens; the occurrence of cup-and-cone fracture patterns in axisymmetric specimens; the role played by notches and by their size on the measured displacement at fracture; and the sequence of distinct cracking events observed in more complex specimens.

Isogeometric collocation methods have been recently proposed as an alternative to standard Galerkin approaches as they provide a significant reduction in computational cost for higher-order discretizations. In this work, we explore the application of isogeometric collocation to large deformation elasticity and frictional contact problems. We first derive the non-linear governing equations for the elasticity problem with finite deformation kinematics and provide details on their consistent linearization. Some numerical examples demonstrate the performance of collocation in its basic and enhanced versions, differing by the enforcement of Neumann boundary conditions. For problems with strong singularities, enhanced collocation is shown to outperform basic collocation and to lead to a spatial convergence behavior very similar to Galerkin, whereas for weaker or no singularities enhanced and basic collocation may give very similar results. A large deformation contact formulation is subsequently developed and tested in the frictional setting, where collocation confirms the excellent performance already obtained for the frictionless case. Finally, it is shown that the contact formulation in the collocation framework passes the contact patch test to machine precision in a three-dimensional setting with arbitrarily inclined non-matching discretizations, thus outperforming most of the available contact formulations and all those with pointwise enforcement of the contact constraints.

The search for lightning is an important item on the agenda for the future exploration of Titan. Thunder, as a direct lightning signature, can be used, together with electromagnetic signals, to corroborate and quantify lightning. Using Cassini-Huygens data and model predictions, the main characteristics of thunder produced by a potential 20 km cloud-to-ground tortuous discharge are obtained and discussed. The acoustic power released right after the discharge decreases with increasing altitude, owing to the ambient pressure and temperature gradients. Ray tracing is used to propagate sound waves to the far field. Simulated thunder waveforms are characterized by fairly long codas—on the order of tens of seconds—arising from the small acoustic absorption (∼10−4dB/km). In the low-loss environment, the principal thunder arrival will likely have a large signal-to-noise ratio ensuring a high detection selectivity. The spectral content depends on the amount of energy released during the discharge. For an energy density of 5 kJ/m, the dominant contribution lies between 50 and 80 Hz; for 500 kJ/m, it shifts to lower frequencies between 10 and 30 Hz.

This paper deals with the role of the muscle fibres and extracellular matrix (ECM) components when muscle tissue is subjected to compressive loads. To this end, dissected tissue samples were tested in compression modes which induced states of fibres in compression (I), in tension (II) or at constant length (III), respectively. A comparison of the stress responses indicated that the tissue behaviour is significantly different for these modes, including differences between the modes (I) and (III). This contradicts the paradigm of many constitutive models that the stress response can be decomposed into an isotropic part relating to the ECM and an anisotropic fibre part the contribution of which can be neglected under compression. Conversely, the results provide experimental evidence that there is an anisotropic contribution of the fibre direction to the compressive stress. Interpreting these results in terms of recent microscopical studies, potential connections between the observed behaviour and the structure of muscle ECM are established.

Dowling-Degos disease (DDD) is an autosomal-dominant genodermatosis characterized by progressive and disfiguring reticulate hyperpigmentation. We previously identified loss-of-function mutations in KRT5 but were only able to detect pathogenic mutations in fewer than half of our subjects. To identify additional causes of DDD, we performed exome sequencing in five unrelated affected individuals without mutations in KRT5. Data analysis identified three heterozygous mutations from these individuals, all within the same gene. These mutations, namely c.11G>A (p.Trp4(∗)), c.652C>T (p.Arg218(∗)), and c.798-2A>C, are within POGLUT1, which encodes protein O-glucosyltransferase 1. Further screening of unexplained cases for POGLUT1 identified six additional mutations, as well as two of the above described mutations. Immunohistochemistry of skin biopsies of affected individuals with POGLUT1 mutations showed significantly weaker POGLUT1 staining in comparison to healthy controls with strong localization of POGLUT1 in the upper parts of the epidermis. Immunoblot analysis revealed that translation of either wild-type (WT) POGLUT1 or of the protein carrying the p.Arg279Trp substitution led to the expected size of about 50 kDa, whereas the c.652C>T (p.Arg218(∗)) mutation led to translation of a truncated protein of about 30 kDa. Immunofluorescence analysis identified a colocalization of the WT protein with the endoplasmic reticulum and a notable aggregating pattern for the truncated protein. Recently, mutations in POFUT1, which encodes protein O-fucosyltransferase 1, were also reported to be responsible for DDD. Interestingly, both POGLUT1 and POFUT1 are essential regulators of Notch activity. Our results furthermore emphasize the important role of the Notch pathway in pigmentation and keratinocyte morphology.

Female pattern hair loss (FPHL) is a common hair loss disorder in women and has a complex mode of inheritance. The etiopathogenesis of FPHL is largely unknown; however, it is hypothesized that FPHL and male pattern baldness [androgenetic alopecia (AGA)] share common genetic susceptibility alleles. Our recent findings indicate that the major AGA locus, an X-chromosome region containing the androgen receptor and the ectodysplasin A2 receptor (EDA2R) genes, may represent a common genetic factor underlying both early-onset FPHL and AGA. This gives further support for the widespread assumption of shared susceptibility loci for FPHL and AGA. However, we could not demonstrate association of further AGA risk loci, including 20p11, 1p36.22, 2q37.3, 7p21.1, 7q11.22, 17q21.31, and 18q21.1, with FPHL. Interestingly, a recent study identified four novel AGA risk loci in chromosomal regions 2q35, 3q25.1, 5q33.3, and 12p12.1. In particular, the 2q35 locus and its gene WNT10A point to an as-yet unknown involvement of the WNT signaling pathway in AGA. We hypothesized that the novel loci and thus also the WNT signaling may have a role in the etiopathogenesis of FPHL and therefore examined the role of these novel AGA risk loci in our FPHL samples comprising 440 German and 145 UK affected patients, 500 German unselected controls (blood donors), and 179 UK supercontrols. Patients and controls were genotyped for the top two single nucleotide polymorphisms at each of the four AGA loci. However, none of the genotyped variants displayed any significant association. In conclusion, the results of this study provide no support for the hypothesis that the novel AGA loci influence susceptibility to FPHL.

Several (standardized) measurements require an omnidirectional sound source. Traditionally used sources offer either high power and flat frequency response, but limited omnidirectionality, or excellent point source characteristics with very irregular frequency response and limited power. In this paper, the development and performance of a different kind of source, consisting of two broadband speakers in face-to-face configuration, each with smooth conical enclosure, are presented. The proposed source, radiating the sound from a ring-like area, has a useable frequency range of 150 Hz–10 kHz, with 106 dB sound power and good uniformity of pressure with angle. Data from two commercial sources is presented for comparison.

An inverse finite element method (iFEM) to estimate material parameters from compression tests of soft materials is presented, where alginate hydrogel was used as a phantom material. The method applies if the boundary conditions at the loaded surfaces are not ideal, i.e. neither free of friction nor fully constrained, as it may be the case in most realistic testing set-ups. Assuming a linear friction law, the friction coefficient μ was considered unknown and estimated in a first step by minimising the difference between the contours of the sample, obtained by optical measurements, and the simulated shape. Force–displacement data were used in a second step to determine the parameters of the constitutive law. Staggering these two steps, both friction and material parameters were identified by optimisation. Skipping the first step and predefining μ instead, a unique parameter set could only be clearly identified if the deviations of the contours were considered in addition to the deviations in the force–displacement data. Finally, forward FEM calculations with differently shaped specimens were used to verify the goodness of the obtained parameter sets.

Bei der Hyperhidrose handelt es sich um eine ortlich umschriebene oder generalisiert auftretende ubermasige Schweisbildung mit Krankheitswert. Da das ubermasige Schwitzen oftmals schon im Kindesalter beginnt, stellt die Hyperhidrose eine bedeutsame Erkrankung des Kindes- und Jugendalters dar. Daruber hinaus liegt haufig eine therapeutische Herausforderung vor, da die meisten handelsublichen Therapeutika nicht fur das Kindes- und Jugendalter zugelassen sind.

Hypotrichosis simplex (HS) comprises a group of hereditary isolated alopecias that are characterized by a diffuse and progressive loss of hair starting in childhood and shows a wide phenotypic variability. We mapped an autosomal-dominant form of HS to chromosome 1q31.3-1q41 in a Spanish family. By direct sequencing, we identified the heterozygous mutation c.1A>G (p.Met1?) in SNRPE that results in loss of the start codon of the transcript. We identified the same mutation in a simplex HS case from the UK and an additional mutation (c.133G>A [p.Gly45Ser]) in a simplex HS case originating from Tunisia. SNRPE encodes a core protein of U snRNPs, the key factors of the pre-mRNA processing spliceosome. The missense mutation c.133G>A leads to a glycine to senile substitution and is predicted to disrupt the structure of SNRPE. Western blot analyses of HEK293T cells expressing SNRPE c.1A>G revealed an N-terminally truncated protein, and therefore the mutation might result in use of an alternative in-frame downstream start codon. Subcellular localization of mutant SNRPE by immunofluorescence analyses as well as incorporation of mutant SNRPE proteins into U snRNPs was found to be normal, suggesting that the function of U snRNPs in splicing, rather than their biogenesis, is affected. In this report we link a core component of the spliceosome to hair loss, thus adding another specific factor in the complexity of hair growth. Furthermore, our findings extend the range of human phenotypes that are linked to the splicing machinery.

Female pattern hair loss (FPHL) is a common disorder with a complex mode of inheritance. Although understanding of its etiopathogenesis is incomplete, an interaction between genetic and hormonal factors is assumed to be important. The involvement of an androgen-dependent pathway and sex steroid hormones is the most likely hypothesis. We therefore selected a total of 21 variants from the steroid-5-alpha-reductase isoforms SRD5A1 and SRD5A2, the sex steroid hormone receptors ESR1, ESR2 (oestrogen receptor) and PGR (progesterone receptor) and genotyped these in a case-control sample of 198 patients (145 UK; 53 German patients) and 329 controls (179 UK; 150 German). None of these variants showed any significant association, either in the overall UK and German samples or in the subgroup analyses. In summary, the present results, while based on a limited selection of gene variants, do not point to the involvement of SRD5A1, SRD5A2, ESR1, ESR2 or PGR in FPHL.

The performance of microphone arrays outdoors is influenced by the environmental conditions. Numerical simulations indicate that, while horizontal arrays are hardly affected, direction-of-arrival (DOA) estimation with vertical arrays becomes biased in presence of ground reflections and sound speed gradients. Turbulence leads to a huge variability in the estimates by reducing the ground effect. Ground effect can be exploited by combining classical source localization with an appropriate propagation model (ground effect inversion). Not only does this allow the source elevation and range to be determined with a single vertical array but also it allows separation of sources which can no longer be distinguished by far field localization methods. Furthermore, simulations provide detail of the achievable spatial resolution depending on frequency range, array size and localization algorithm and show a clear advantage of broadband processing. Outdoor measurements with one or two sources confirm the results of the numerical simulations.

Alopecia areata (AA) is a common hair loss disorder, which is thought to be a tissue-specific autoimmune disease. Previous research has identified a few AA susceptibility genes, most of which are implicated in autoimmunity. To identify new genetic variants and further elucidate the genetic basis of AA, we performed a genome-wide association study using the strategy of pooled DNA genotyping (729 cases, 656 controls). The strongest association was for variants in the HLA region, which confirms the validity of the pooling strategy. The selected top 61 single-nucleotide polymorphisms (SNPs) were analyzed in an independent replication sample (454 cases, 1364 controls). Only one SNP outside of the HLA region (rs304650) showed significant association. This SNP was then analyzed in a second independent replication sample (537 cases, 657 controls). The finding was not replicated on a significant level, but showed the same tendency. A combined analysis of the two replication samples was then performed, and the SNP rs304650 showed significant association with P=3.43 x 10(-4) (OR=1.24 (1.10-1.39)). This SNP maps to an intronic region of the SPATA5 (spermatogenesis-associated protein 5) gene on chromosome 4. The results therefore suggest the SPATA5 locus is a new susceptibility locus for AA. European Journal of Human Genetics (2012) 20, 326-332; doi:10.1038/ejhg.2011.185; published online 26 October 2011

The transfer function method is a procedure to determine the surface impedance of grounds in-situ. Disadvantageously, it is very sensitive to errors in the magnitude and phase of the measured transfer function at frequencies below about 500 Hz. One source of these errors is the differences in the frequency responses and calibration of the two microphones used. Two methods routinely used for impedance tube measurements are employed to reduce these errors: One microphone is subsequently placed at the two measurement positions or the measurement is done with two microphones in "normal" and "switched" position. The two microphone / switched positions technique leads to credible impedance estimates down to 100 Hz on the investigated ground of medium impedance. The one microphone / switched positions technique, on the other hand, shows a comparable performance only for small source-microphone distances, low wind speed and background noise.

The transfer function method is a procedure to measure the surface impedance of grounds in situ. In this article, the influence of measurement errors on the predicted surface impedance is investigated numerically. Even small errors in the range of accuracy of common measurement equipment can lead to significant errors in the impedance. This is especially true for errors in the transfer function at frequencies below about 500 Hz and for highly reflecting grounds. To a lesser degree, errors in the measurement geometry contribute to the uncertainty of the estimated impedance. To minimize these effects, an improved geometry is suggested for the frequency range 100–400 Hz significantly reducing the average error. However, even with this optimized geometry the average error for high impedance grounds, like compacted silt, in this frequency range will be around 50%. Therefore, the use of the transfer function method cannot be recommended in this case unless the requirements in accuracy are very low for a specific application or particular favourable measurement conditions are given.

Transport, fracture and their interaction in concrete are complex phenomena of great practical relevance for the durability of civil engineering structures. Due to the heterogeneous nature of the materials, encompassing a wide range of length scales, multiscale approaches are essential. In this paper, we outline some recent research results and open issues in this field. First, we present a microscale model which aims at simulating chloride diffusion and binding in cement. Then, we outline a mesoscale model addressing coupling between cracking and diffusion. Finally, we discuss open issues in the acquisition of the mesoscale geometry from X-ray computed tomography techniques., RILEM Technical Letters, 1, ISSN:2518 -0231

Acoustic surface impedance of sound absorbing materials can be measured by several techniques such as the impedance tube for normal impedance or the Tamura method for normal and oblique surface impedance. In situ, the acoustic impedance is mostly measured by use of impulse methods or by applying two-microphone techniques. All these techniques are based on the determination of the sound pressure at specific locations. In this paper, the authors use a method which is based on the combined measurement of the instantaneous sound pressure and sound particle velocity. A brief description of the measurement technique and a detailed analysis of the influence of the calibration, the source type, the source height, the sound incidence angle, and the sample size are included.

Background Familial aggregation of alopecia areata (AA) has been previously described, but systematic studies with information obtained directly from family members have yet to be undertaken. Objective We sought to study the pattern of familial aggregation of AA by assessing the affection status of patients' relatives. The study included 206 index patients with a total of 1029 first-degree and 2625 second-degree relatives. Methods First-degree relatives were directly interviewed, whereas information on second-degree relatives was obtained by interviewing the index patients and their first-degree relatives. Results Estimated lifetime risks were 7.1% in siblings, 7.8% in parents, and 5.7% in offspring. The risk in second-degree relatives was slightly higher than the reported population risk. Age at onset in index patients and first-degree relatives was significantly correlated. Limitations Using patients drawn from specialized hair clinics may have produced results showing a higher proportion of early onset and severe cases. Conclusion The familial aggregation of AA supports the role of genetic factors in the development of the disease. In addition, our data indicate genetic factors might contribute to the age at onset of AA.

Dowling-Degos disease (DDD) is an autosomal dominant genodermatosis characterized by progressive and disfiguring reticulate hyperpigmentation of the flexures. We performed a genomewide linkage analysis of two German families and mapped DDD to chromosome 12q, with a total LOD score of 4.42 ( theta =0.0) for marker D12S368. This region includes the keratin gene cluster, which we screened for mutations. We identified loss-of-function mutations in the keratin 5 gene (KRT5) in all affected family members and in six unrelated patients with DDD. These represent the first identified mutations that lead to haploinsufficiency in a keratin gene. The identification of loss-of-function mutations, along with the results from additional functional studies, suggest a crucial role for keratins in the organization of cell adhesion, melanosome uptake, organelle transport, and nuclear anchorage.

Androgenetic alopecia (AGA), or male-pattern baldness, is the most common form of hair loss. Its pathogenesis is androgen dependent, and genetic predisposition is the major requirement for the phenotype. We demonstrate that genetic variability in the androgen receptor gene (AR) is the cardinal prerequisite for the development of early-onset AGA, with an etiological fraction of 0.46. The investigation of a large number of genetic variants covering the AR locus suggests that a polyglycine-encoding GGN repeat in exon 1 is a plausible candidate for conferring the functional effect. The X-chromosomal location of AR stresses the importance of the maternal line in the inheritance of AGA.

DNA mismatch repair is a postreplicative DNA repair cascade ensuring genomic integrity. Inactivating germline mutations in DNA mismatch repair genes are responsible for hereditary non-polyposis colorectal carcinoma syndrome (HNPCC), which predisposes to various types of visceral cancer. Most associated tumors exhibit high-grade microsatellite instability. Some patients develop skin tumors of the sebaceous glands. This combined occurrence is known as Muir-Torre syndrome, which has a high probability of an underlying DNA mismatch repair defect. This is also true for individuals selected solely on the basis of sebaceous neoplasias, tumors with the highest frequency of high-grade microsatellite instability. This article focuses on the recent advances in molecular diagnostics for the detection of DNA mismatch repair defects in patients with sebaceous neoplasias, and the potential significance for the secondary prevention of visceral cancer in these patients.

Sebaceous gland neoplasias are the cutaneous manifestation of the Muir–Torre syndrome, which is known to be a phenotypical variant of hereditary nonpolyposis colorectal cancer. Both hereditary nonpolyposis colorectal cancer and Muir–Torre syndrome are caused by inherited DNA mismatch repair defects. As a prominent molecular genetic feature, all tumors associated with a DNA mismatch repair defect exhibit high microsatellite instability. So far, the frequency of DNA mismatch repair defects in patients selected solely on the basis of a sebaceous gland tumor has never been determined. In order to estimate this frequency, we assessed microsatellite instability with up to 10 microsatellite markers in a newly collected unselected series of 25 sebaceous gland neoplasias (six sebaceous adenomas, 16 sebaceous epitheliomas, three sebaceous carcinomas) in comparison to 32 sebaceous gland hyperplasias from unrelated patients. As many as 15 of the 25 sebaceous gland neoplasias (60%), but only one of the 32 sebaceous gland hyperplasias (3%), exhibited high microsatellite instability. Thus, in our study, the majority of patients with a sebaceous gland neoplasia in contrast to patients with a sebaceous gland hyperplasia are highly suspicious for an inherited DNA mismatch repair defect. On the basis of the subsequently collected tumor histories, nine of the 15 patients with a high microsatellite unstable sebaceous gland neoplasia were identified to have Muir–Torre syndrome. In none of these cases, however, were the clinical Amsterdam criteria for diagnosing hereditary nonpolyposis colorectal cancer fulfilled. In the sebaceous tumors of the remaining six patients, high microsatellite instability was an incidental finding. In two of these six patients, single relatives were known to be affected with internal cancer; however, their family histories were not suggestive of Muir–Torre syndrome or hereditary nonpolyposis colorectal cancer. In comparison with microsatellite instability screening studies in a variety of other randomly selected tumors, our study identifies sebaceous gland neoplasias as tumors with the highest frequency of high microsatellite instability reported so far, whereas sebaceous gland hyperplasia rarely exhibits high microsatellite instability. Therefore, screening for microsatellite instability in sebaceous gland neoplasias will be of great value in the detection of an inherited DNA mismatch repair defect, which predisposes to various types of internal cancers.

Alopecia areata (AA) is a prevalent autoimmune disease with 10 known susceptibility loci. Here we perform the first meta-analysis of research on AA by combining data from two genome-wide association studies (GWAS), and replication with supplemented ImmunoChip data for a total of 3,253 cases and 7,543 controls. The strongest region of association is the major histocompatibility complex, where we fine-map four independent effects, all implicating human leukocyte antigen-DR as a key aetiologic driver. Outside the major histocompatibility complex, we identify two novel loci that exceed the threshold of statistical significance, containing ​ACOXL/​BCL2L11(​BIM) (2q13); ​GARP (​LRRC32) (11q13.5), as well as a third nominally significant region ​SH2B3(​LNK)/​ATXN2 (12q24.12). Candidate susceptibility gene expression analysis in these regions demonstrates expression in relevant immune cells and the hair follicle. We integrate our results with data from seven other autoimmune diseases and provide insight into the alignment of AA within these disorders. Our findings uncover new molecular pathways disrupted in AA, including autophagy/apoptosis, transforming growth factor beta/Tregs and JAK kinase signalling, and support the causal role of aberrant immune processes in AA.

Muir-Torre syndrome (MTS) is a rare autosomal-dominant disorder characterized by the predisposition to both sebaceous skin tumors (or multiple keratoacanthomas) and internal malignancies. A subtype of MTS is allelic to hereditary nonpolyposis colorectal cancer and is caused by germline mutations in the DNA mismatch repair genes MSH2 or MLH1. In these cases both internal and skin tumors show characteristic microsatellite instability (MSI). The aim of the present study was to determine whether immunohistochemical examination of MSH2 or MLH1 protein expression in MTS-associated skin tumors can be used as a diagnostic screening tool to identify patients with germline mutations in MSH2 or MLH1. In the present study 28 skin lesions from 17 patients (20 sebaceous gland tumors, 4 sebaceous hyperplasias, 3 keratoacanthomas, and 1 squamous cell carcinoma) were tested immunohistochemically with antibodies against MSH2 and MLH1. Eighteen of these tumors were from eight patients with known MSH2 germline mutations, two tumors were from a patient with a germline mutation in MLH1, and eight microsatellite stable sporadic skin tumors served as controls. One sample had to be excluded because of a lack of immunoreactivity. All eight microsatellite stable tumors expressed both DNA repair proteins. In 15 of the tumors from MSH2 germline mutation carriers, loss of MSH2 expression was observed, one tumor showed reduced MSH2 expression, and one tumor displayed positive immunoreactivity to MSH2. Both tumors of the MLH1 germline mutation carrier showed loss of the MLH1 protein. In conclusion, our findings demonstrate that immunohistochemical testing of MTS-related skin tumors is a reliable screening method with high predictive value for the diagnosis of the DNA mismatch repair-deficient MTS.

Manfred Schroeder was a man with many interests. Between the years 1966 and 1967, he invented devices for measuring the surface impedance of materials as well as the vocal tract impedance. At the time, he would only consider normal incidence; however, he already anticipated that the behavior of materials at grazing incidence would have relevance to room acoustics, a field of research he is well known for.

BACKGROUND: Hypotrichosis of the Marie Unna type (HMU) is a rare autosomal dominant disorder characterized by male-pattern hair loss with childhood onset and anomalies of the hair shaft. OBJECTIVES: We aimed to evaluate a number of chromosomal loci as possible candidate regions for HMU. METHODS: A linkage analysis was performed in a large German family using microsatellite markers spanning candidate regions on chromosomes 8, 12 and 17. RESULTS: We found that the HMU locus maps to chromosomal region 8p21 in a 13.01-cM interval between markers D8S1145 and D8S1771. This interval harbours the hairless gene (HR). Mutational analysis of HR on the genomic and transcript levels revealed no pathogenic mutation. CONCLUSIONS: Our findings, together with a recent report of two unrelated families of Dutch and British origin, provide evidence for a hair growth regulatory gene distinct from HR in chromosomal region 8p21.

Hypotrichosis simplex of the scalp (HSS) is an autosomal dominant form of isolated alopecia causing almost complete loss of scalp hair, with onset in childhood. After exclusion of candidate regions previously associated with hair-loss disorders, we performed a genomewide linkage analysis in two Danish families and localized the gene to chromosome 6p21.3. This was confirmed in a Spanish family, with a total LOD score of 11.97 for marker D6S1701 in all families. The combined haplotype data identify a critical interval of 14.9 cM between markers D6S276 and D6S1607. Localization of the locus for HSS to 6p21.3 is a first step toward identification of the gene. The gene will give important insights into the molecular and cellular basis of hair growth on the scalp.

Familial juvenile polyposis (FJP) is a hamartomatous polyposis syndrome characterized by the appearance of juvenile polyps in the gastrointestinal tract. Patients with this syndrome are at an increased risk for cancer of the colon, stomach, and pancreas. Recently, germline mutations in the SMAD4/DPC4 gene (official symbol MADH4) have been found in the majority of patients suffering from FJP. We have examined 11 unrelated patients with FJP for MADH4 germline mutations by direct sequencing of genomic DNA encompassing all 11 exons of the gene. Besides a novel mutation (959-960delAC at codon 277, exon 6) in one patient, we observed a 4-bp deletion (1372-1375delACAG) in exon 9 in two unrelated patients. Examination with microsatellite markers flanking MADH4 supports an independent origin of the mutation in these two families. The same 4-bp deletion in exon 9 has previously been described in three out of nine patients examined for MADH4 mutations. Our results combined with these previous data demonstrate that a unique 4-bp deletion in exon 9 of MADH4 accounts for about 25% of all FJP cases and that other MADH4 mutations occur in an additional 15% of patients. Genes Chromosomes Cancer 25:403-406, 1999.

BACKGROUNDClinical diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) is based on a typical family history. As molecular genetic testing is predominantly restricted to these families, gene carriers not meeting the clinical criteria may be missed.AIMSTo examine the value of microsatellite instability (MSI) as a tool to increase the likelihood for uncovering a mismatch repair germline mutation in patients with colorectal cancer and to identify a genotype-phenotype relation in families with verified mutations.METHODSSystematic search for germline mutations (hMSH2 and hMLH1 genes) was performed in 96 patients: 57 fulfilled the Amsterdam criteria (group 1) and 12 the looser HNPCC criteria (group 2). Seventeen patients showed familial clustering of cancers (group 3) and 10 patients under 50 years had sporadic cancer (group 4), the latter of whom all exhibited MSI+ tumours.RESULTSA similar proportion of germline mutations was found in patients who fulfilled the clinical criteria of HNPCC and had MSI+ tumours (groups 1 and 2; 15/39) compared with patients who did not meet these clinical criteria but who had MSI+ tumours (groups 3 and 4; 8/27 patients). Affected relatives of patients with hMLH1 mutations showed a significantly higher frequency of colorectal cancer but a lower frequency of endometrium cancer than those with hMSH2 mutations.CONCLUSIONSMSI in tumour tissue is a useful criterion for selecting patients who should be tested for germline mutations in the mismatch repair genes hMSH2 and hMLH1 irrespective of their family history. Among carriers of hMSH2 mutations the tumour spectrum was broader than among carriers of hMLH1 mutations.

We carried out a genome-wide association study in 296 individuals with male-pattern baldness (androgenetic alopecia) and 347 controls. We then investigated the 30 best SNPs in an independent replication sample and found highly significant association for five SNPs on chromosome 20p11 (rs2180439 combined P = 2.7 x 10(-15)). No interaction was detected with the X-chromosomal androgen receptor locus, suggesting that the 20p11 locus has a role in a yet-to-be-identified androgen-independent pathway.

Richner-Hanhart syndrome (tyrosinemia type 2) is an inborn error of tyrosine metabolism which is clinically characterized mainly by oculocutaneous symptoms including corneal opacities and keratosis palmoplantaris. Skin symptoms usually develop after the first year of life. We report a neonate in whom already on the third day of life diagnosis of Richner-Hanhart syndrome could be suspected because of elevated tyrosine levels in newborn screening by tandem mass spectrometry. Analysis of the tyrosine aminotransferase gene revealed a homozygous missense mutation p.R433W (c.1297C>T). An 8-year-old brother with persistent plantar hyperkeratotic plaques of the soles of yet unknown origin was subsequently identified to be also affected with Richner-Hanhart syndrome. This demonstrates that early diagnosis of Richner-Hanhart syndrome is possible in neonates by extended newborn screening. Early introduction of dietary treatment is a prerequisite to reduce the risk of clinical symptoms.

SummaryComplete or partial congenital absence of hair (congenital alopecia) may occur either in isolation or with associated defects. The majority of families with isolated congenital alopecia has been reported to follow an autosomal-recessive mode of inheritance (MIM 203655). As yet, no gene has been linked to isolated congenital alopecia, nor has linkage been established to a specific region of the genome. In an attempt to map the gene for the autosomal recessive form of the disorder, we have performed genetic linkage analysis on a large inbred Pakistani family in which affected persons show complete absence of hair development (universal congenital alopecia). We have analyzed individuals of this family, using >175 microsatellite polymorphic markers of the human genome. A maximum LOD score of 7.90 at a recombination fraction of 0 has been obtained with locus D8S258. Haplotype analysis of recombination events localized the disease to a 15-cM region between marker loci D8S261 and D8S1771. We have thus mapped the gene for this hereditary form of isolated congenital alopecia to a locus on chromosome 8p21-22 (ALUNC [alopecia universalis congenitalis]). This will aid future identification of the responsible gene, which will be extremely useful for the understanding of the biochemistry of hair development.

In a search for germline mutations in the DNA mismatch repair genes hMSH2 and hMLH1 in Chinese patients with colorectal cancer we identified a novel missense mutation (V384D) in exon 12 of the hMLH1 gene in 4 out of 26 individuals. This mutation had not been observed in any of 109 German patients who either fulfill the clinical criteria of hereditary nonpolyposis colorectal cancer or had developed colorectal cancer at an early age. In a second series of experiments, DNA samples of 80 healthy Japanese and 100 healthy Germans were examined for the presence of the V384D mutation. It was observed in 4 Japanese, but in none of the German individuals. Thus, the V384D mutation seems to be confined to the East-Asian population. Since this missense mutation occurs at a less conserved region of the hMLH1 gene, it may represent a nonfunctional polymorphism. However, a role in the pathogenesis of colorectal cancer cannot be ruled out from the present study.

The Min (multiple intestinal neoplasia) mouse with a germline mutation in the adenomatous polyposis coli gene serves as an animal model for familial adenomatous polyposis coli (FAP). The number and age at onset of colorectal adenomas varies in the offspring of Min mice crossed with other strains. The murine gene for the secretory phospholipase A2 (PLA2G2A) was found to be the main candidate for these variations. To test the hypothesis of a correlation between PLA2G2A gene alterations and human tumor development, we screened 14 patients with FAP and 20 patients with sporadic colorectal cancer for germline and somatic PLA2G2A gene mutations. None of the individuals with FAP showed PLA2G2A germline alterations. However, a germline mutation was observed in one patient with an apparently sporadic colorectal tumor; the wildtype allele was somatically lost in the tumor of this patient.

The Muir-Torre syndrome (MTS) is a rare autosomal-dominant condition characterized by the occurrence of sebaceous skin lesions and internal tumours in a patient. It has been demonstrated that at least a subgroup of MTS exhibits clinical and molecular genetic features of hereditary nonpolyposis colorectal cancer, including microsatellite instability in skin and visceral tumours, because of mutations in DNA mismatch repair genes. We have identified germline mutations in the hMSH2 gene in two unrelated MTS patients ascertained because of their skin tumours. Our results, together with published MTS cases, support the hypothesis that MTS with its characteristic skin lesions is confined to mutations in the hMSH2 gene.

Female pattern hair loss (FPHL) is a common hair loss disorder in women with a complex mode of inheritance. Its etiopathogenesis is poorly understood. Widespread assumptions of overlapping susceptibility variants between FPHL and male pattern baldness (androgenetic alopecia) and a crucial role of androgens or distinct sexual steroid hormones in the development of FPHL could neither be clearly demonstrated nor completely excluded at the molecular level up to date. Interestingly, recent studies suggested an association of metabolic syndrome-including obesity, hyperlipidaemia, hypertension and diabetes mellitus type 2 or abnormally high fasting blood glucose-with FPHL. Of note, mutations in the melanocortin 4 receptor gene (MC4R) have been identified in patients with morbid obesity. Interestingly, this neuropeptide receptor has been detected amongst others in the dermal papilla of the hair follicle. As almost half of our FPHL patients of German origin present with adipositas and/or obesity, we hypothesized as to whether FPHL could be associated with variants of the MC4R gene. Thus, we genotyped a total of six variants from MC4R in our case-control sample comprising 245 UK patients of German and UK origin. However, based on our present study none of the genotyped MC4R variants displayed any significant association, neither in the overall UK and German samples nor in any subgroup analyses. In summary, these results do not point to an involvement of MC4R in FPHL.