Neurological symptoms and natural course of xeroderma pigmentosum

We have prospectively followed 16 Finnish xeroderma pigmentosum (XP) patients for up to 23 years. Seven patients were assigned by complementation analysis to the group XP-A, two patients to the XP-C group and one patient to the XP-G group. Six of the seven XP-A patients had the identical mutation (Arg228Ter) and the seventh patient had a different mutation (G283A). Further patients were assigned to complementation groups on the basis of their consanguinity to an XP patient with a known complementation group. The first sign of the disease in all the cases was severe sunburn with minimal sun exposure in early infancy. However, at the time the diagnosis was made in only two cases. The XP-A patients developed neurological and cognitive dysfunction in childhood. The neurological disease advanced in an orderly fashion through its successive stages, finally affecting the whole nervous system and leading to death before the age of 40 years. Dermatological and ocular damage of the XP-A patients tended to be limited. The two XP-C patients were neurologically and cognitively intact despite mild brain atrophy as seen by neuroimaging. The XP-G patients had sensorineural hearing loss, laryngeal dystonia and peripheral neuropathy. The XP-C patients had severe skin and ocular malignancies that first presented at pre-school age. They also showed immunosuppression in cell-mediated immunity. Neurological disease appears to be associated with the complementation group and the failure of fibroblasts to recover RNA synthesis following UV irradiation, but not necessarily to the severity of the dermatological symptoms, the hypersensitivity of fibroblasts to UVB killing or the susceptibility of keratinocytes to UVB-induced apoptosis

The desmosome and pemphigus

Desmosomes are patch-like intercellular adhering junctions (“maculae adherentes”), which, in concert with the related adherens junctions, provide the mechanical strength to intercellular adhesion. Therefore, it is not surprising that desmosomes are abundant in tissues subjected to significant mechanical stress such as stratified epithelia and myocardium. Desmosomal adhesion is based on the Ca2+-dependent, homo- and heterophilic transinteraction of cadherin-type adhesion molecules. Desmosomal cadherins are anchored to the intermediate filament cytoskeleton by adaptor proteins of the armadillo and plakin families. Desmosomes are dynamic structures subjected to regulation and are therefore targets of signalling pathways, which control their molecular composition and adhesive properties. Moreover, evidence is emerging that desmosomal components themselves take part in outside-in signalling under physiologic and pathologic conditions. Disturbed desmosomal adhesion contributes to the pathogenesis of a number of diseases such as pemphigus, which is caused by autoantibodies against desmosomal cadherins. Beside pemphigus, desmosome-associated diseases are caused by other mechanisms such as genetic defects or bacterial toxins. Because most of these diseases affect the skin, desmosomes are interesting not only for cell biologists who are inspired by their complex structure and molecular composition, but also for clinical physicians who are confronted with patients suffering from severe blistering skin diseases such as pemphigus. To develop disease-specific therapeutic approaches, more insights into the molecular composition and regulation of desmosomes are required

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Genetic architecture of human plasma lipidome and its link to cardiovascular disease

Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P <5 x10(-8)), 10 of which associate with CVD risk including five new loci-COL5A1, GLTPD2, SPTLC3, MBOAT7 and GALNT16 (false discovery rate<0.05). We identify loci for lipid species that are shown to predict CVD e.g., SPTLC3 for CER(d18:1/24:1). We show that lipoprotein lipase (LPL) may more efficiently hydrolyze medium length triacylglycerides (TAGs) than others. Polyunsaturated lipids have highest heritability and genetic correlations, suggesting considerable genetic regulation at fatty acids levels. We find low genetic correlations between traditional lipids and lipid species. Our results show that lipidomic profiles capture information beyond traditional lipids and identify genetic variants modifying lipid levels and risk of CVD

Psoriasis Causes Significant Economic Burden to Patients

INTRODUCTION: Psoriasis results in expenses to patients from many cost sources. Psoriasis treatments may result in considerable time and traveling costs, yet many studies fail to account for these costs. The objective of this study was to evaluate the multidimensional economic burden of psoriasis to patients. METHODS: The study was based on 232 Finnish patients with psoriasis or psoriatic arthritis visiting a tertiary level dermatological clinic during a 1-year study period between October 1, 2009 and September 30, 2010. The data were based on a patient questionnaire, clinical data from the medical records and reimbursement data from the Finnish Social Insurance Institution. Item costs were based on true costs charged from the patients and all time cost estimates were based on the Human Capital Approach method. RESULTS: 199 patients with psoriasis and 33 with psoriatic arthritis were included in the study. Total costs were higher for patients receiving traditional systemic medications or phototherapy than those not receiving such treatment. Travel costs and travel time costs accounted for more than 60% of the costs of phototherapy. Skin care at home was time consuming and thus caused significant burden to patients. The majority of the visit costs arose from hospital visits and only a small proportion were attributed to visiting primary health care providers. CONCLUSION: Visit charges and other patient co-payments were estimated to play a minor role in the total cost of psoriasis incurred by patients, while travel costs and lost time comprised the majority of the costs, which should not be omitted in future studies regarding costs of treatments. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13555-014-0053-2) contains supplementary material, which is available to authorized users

Iän tuomat iho-ongelmat

Tiivistelmä Ikääntyminen aiheuttaa rakenteellisia ja toiminnallisia muutoksia eri elimiin, myös ihoon. Monien ihosairauksien esiintyvyys kasvaa ikääntyessä (1). Nykyiselläänkin ihotaudit aiheuttavat kuolemaan johtamattomista sairauksista neljänneksi eniten tautitaakkaa sairauden vuoksi menetettyinä toimintakykyisinä elinvuosina mitaten (disability adjusted life years, DALY) (2). Väestön vanhetessa tämä taakka lisääntyy. Väestötason tutkimuksia ikäihmisten ihosairauksien yleisyydestä on niukasti. Noin 4 000 potilaan sairaalarekisteristä tehdyn tutkimuksen mukaan yleisimpiä olivat ekseemat, ihoinfektiot, kutina ja ihosyövät (3). Myös hyvänlaatuisten ihokasvainten, kuten seborrooisten keratoosien (rasvaluomien), kirsikkaluomien ja lentigojen, määrä lisääntyy iän karttuessa (4). Tässä katsauksessa käsittelemme tavanomaisia iän tuomia iho-ongelmia. Krooniset alaraajahaavat sekä lääkeaineihottumat on jätetty katsauksesta pois.Abstract Skin problems in the elderly Aging causes many structural changes in the skin and affects its functionality. Therefore, many skin diseases are more common in the older population. Measured on the DALY index (disability adjusted life years), skin diseases are the fourth most common disease group causing disability. The most common skin diseases in older adults are eczemas, skin infections, pruritus and malignant diseases. Skin aging can be divided into chronological aging and photoaging. Smoking, air pollutants and exposure to ultraviolet radiation are the most significant factors in skin aging. Dry skin is the most common cause of pruritus in the elderly but sometimes systemic diseases can be the cause and they must be excluded. Asteatotic eczema is a common skin disease found particularly in the elderly population. It is caused by structural changes in the skin and excessive washing with soap. It can be prevented by applying moisturizing cream daily. Sometimes corticosteroid creams or ultraviolet light treatment are needed. Seborrhoeic dermatitis is most common in older people and possibly caused by a weakened immune system. As many as half of the elderly population are estimated to have dermatitis in skinfolds. The term MASD (moistureassociated skin damage) is used when moisture and chemicals break the skin’s protective barrier. It is treated with washing and careful drying of the skinfolds. Sometimes local antimycotics are needed because of secondary infection. Skin infections caused by bacteria, viruses and fungi are common in the elderly because of their weakened immune system. Malignant and premalignant lesions are becoming more common due to aging of the population. The prevalence of actinic keratosis varies according to age, skin phototype and residence. Some actinic keratoses evolve to Bowen’s disease and eventually to squamous cell carcinoma. Diagnosis is confirmed by biopsy. Actinic keratoses with mild dysplasia can be treated topically. Otherwise treatment by a dermatologist is needed. Patients’ ability to function must be considered when treating older patients