Atopic dermatitis shows significant cutaneous comorbidity: results from large-scale investigations in the working population.

BACKGROUND: Atopic dermatitis (AD) is one of the most common chronic inflammatory diseases of the skin. Rare large-scale data have been published on the prevalence of concomitant dermatoses. OBJECTIVE: To analyse the prevalence and cutaneous comorbidity of AD in Germany. METHODS: A cross-sectional study on voluntary whole-body skin checks by trained dermatologists in over 400 companies throughout Germany reflecting the adult working population was conducted. Prevalence ratios (PR) were calculated to compare dermatological comorbidity in employees with and without current AD. A logistic regression analysis controlling for age, sex and skin type revealed odds ratios (OR) of the occurrence of skin diseases in AD. RESULTS: A total of N = 118 939 people were examined between 2006 and 2017 (43.2% female, mean age 43.2 ± 10.7 years, min. age 16 years, max. age 70 years). AD (point prevalence) was identified in 1.45% (men: 1.50%, women 1.39%) and decreased significantly with age. Self-reported lifetime prevalence of AD was 4.95% (men: 3.72%, women: 6.55%). The following skin diseases were significantly more frequent in people with current AD: Contact dermatitis (PR: 3.38), hand eczema (PR: 4.62), exsiccation dermatosis (PR: 2.19), folliculitis (PR: 1.95) and port-wine stains (PR: 1.49). Among those, folliculitis was the most frequent (prevalence in AD 16.42%). Controlled for age, sex and skin type, AD was significantly associated with - among others - hand eczema (OR: 3.96; 95% CI: 2.95-5.32), contact dermatitis (OR: 2.97; 95% CI: 1.50-5.88) and exsiccation dermatosis (OR: 1.78; 95% CI: 1.30-2.44). Psoriasis was significantly less frequent in people with AD (OR: 0.61; 95% CI: 0.39-0.94). CONCLUSION: In summary, cutaneous comorbidity is frequent and of great importance in people with AD, suggesting the need for comprehensive, dermatologically guided diagnostics in AD.

Regional variations in the use of statutory skin cancer screenings in Germany: population-based spatial multisource analysis.

BACKGROUND: Due to the increasing incidence of skin cancer, programmes for the prevention of skin cancer have been developed and implemented in Germany. However, utilization of skin cancer screenings shows marked regional differences. Reasons and predictors of such variations are unclear. OBJECTIVES: The objective of the study is to identify predictors for regional use of skin cancer screening variations in Germany. METHODS: Analysis of the population set of ambulatory claims data (2009-2015) of the statutory health insurances (SHI) in Germany (70.2 million people in 2015). Skin cancer screening utilization rate was determined on county level. Descriptive, cluster and multivariate analyses were performed to identify spatial patterns in skin cancer screening utilization. RESULTS: Overall, 6.5-7.9 million people participated in skin cancer screenings. Utilization rates of people ≥35 years of age were 9.74% (2009) and 10.96% (2015). Marked regional variations were identified between the counties. Dermatologists in Saxony and Westphalia-Lippe as well as general practitioners in Lower Saxony and North Rhine showed particularly high utilization rates. Multiple regression analyses demonstrated e.g. positive associations between the skin cancer screening utilization rates and employees with higher vocational qualifications and shorter travel time by car to the nearest major urban centre. CONCLUSION: Utilization rates of skin cancer screening vary largely in Germany with specific spatial patterns. Multivariate analyses demonstrate associations with socio-economic and geographical determinants. The results indicate the importance of health policy measures. These should be used in a more targeted manner in the regions in order to increase utilization of skin cancer screening.

Perception and determinants of stigmatization of people with psoriasis in the German population.

BACKGROUND: Perception of psoriasis in the general population is characterized by knowledge deficits and prejudice against those affected. The extent and possible predictors of stigmatizing attitudes remain unclear. OBJECTIVES: The aim was to assess prejudices and stigmatization of people with psoriasis and to identify sociodemographic and attitude-related variables accounting for stigmatization. METHODS: Representative telephone surveys of 2004 (in 2017) and 2001 (in 2018) adults using a standardized questionnaire. Descriptive analyses were applied to living area, age, gender, educational status, general knowledge and attitudes about psoriasis. Logistic regression analyses were carried out to determine which variables are associated with the assessment of prejudices of 'others' against people with psoriasis. Those prejudices were specified by the following statements: 'they should take better care of themselves', 'don't want to touch people with psoriasis' and 'disgusted by psoriasis'. RESULTS: The majority of those surveyed (74%) believe that people with psoriasis are disadvantaged. Similarly, a majority (69%) said that most people find psoriasis disgusting, do not want to touch people with psoriasis (59%) and think that people with psoriasis need to take better care of themselves (45%). 'Willing to enter a relationship with an affected person' (OR = 0.330, P = 0.029), higher age (OR = 1.027, P <0.001) and male gender (OR = 1.263, P = 0.034) proved to be significantly associated with 'psoriasis is disgusting'. Education (OR = 1.648, P = 0.016) and lower age (OR = 0.847, P  <0.001) are significantly associated with 'they need to take better care of themselves'. CONCLUSIONS: Data suggest that stigmatization of skin diseases is still entrenched. This overview shows the need for interventions against stigmatization of those affected. Results imply that gender, age and education level and related health literacy of the target groups of respective interventions should be taken into account.

Epidemiology and dermatological comorbidity of seborrhoeic dermatitis: population-based study in 161 269 employees.

BACKGROUND: Seborrhoeic dermatitis is a common but epidemiologically poorly researched chronic skin disease. OBJECTIVES: To characterize the prevalence and dermatological comorbidity of seborrhoeic dermatitis in Germany. METHODS: In the course of voluntary company skin checks, full-body examinations were carried out in more than 500 companies by experienced dermatologists and documented electronically. RESULTS: In total, 161 269 participants were included (men 55·5%, mean age 43·2 ± 10·9 years). Seborrhoeic dermatitis was identified in 3·2% (men 4·6%, women 1·4%). A significant difference was found between age groups (2·0% in < 35; 3·6% in 35-64; 4·4% ≥ 65 years). The most frequent concomitant skin conditions were: folliculitis [17·0%, 95% confidence interval (CI) 15·9-18·1], onychomycosis (9·1%, 95% CI 8·3-10·0), tinea pedis (7·1%, 95% CI 6·3-7·8), rosacea (4·1%, 95% CI 3·6-4·7), acne (4·0%, 95% CI 3·4-4·5) and psoriasis (2·7%, 95% CI 2·3-3·2). Regression analysis revealed the following relative dermatological comorbidities when controlling for age and sex: folliculitis [odds ratio (OR) 2·1, 95% CI 2·0-2·3], contact dermatitis (OR 1·8, 95% CI 1·1-2·8), intertriginous dermatitis (OR 1·8, 95% CI 1·4-2·2), rosacea (OR 1·6, 95% CI 1·4-1·8), acne (OR 1·4, 95% CI 1·2-1·7), pyoderma (OR 1·4, 95% CI 1·1-1·8), tinea corporis (OR 1·4, 95% CI 1·0-2·0), pityriasis versicolor (OR 1·3, 95% CI 1·0-1·7) and psoriasis (OR 1·2, 95% CI 1·0-1·5). CONCLUSIONS: Seborrhoeic dermatitis is a common disease, which is more prevalent in men and older people, and it has an increased rate of dermatological comorbidity. However, absolute differences in the prevalence of comorbidities are small and negligible. Nevertheless, the findings underline the need for integrated, complete dermatological diagnostics and therapy.

Prevalence, predictors and comorbidity of dry skin in the general population.

BACKGROUND: Dry skin is a frequent and multifaceted condition which can be associated with skin irritation, itch, patient discomfort and manifest skin disease. In spite of being frequent, little is known about the epidemiology of dry skin in the population. OBJECTIVE: To determine the prevalence of dry skin in the German adult population. METHODS: Data of 48 630 employed persons were assessed on a cross-sectional level in whole-body examinations by experienced dermatologists during company-based skin screenings conducted in 343 German companies. Next to the current dermatologic findings, age, gender, allergies, atopic diseases and the skin type were assessed. RESULTS: In total, n = 14 300 persons (29.4%) were rated as having xerotic skin. Older age but not gender was associated with xerosis. In the regression analyses controlling for age and gender, dry skin was a significant predictor for: axillary dermatitis (OR: 4.51; CI 2.70-7.54), atopic eczema (OR: 3.99; CI 3.42-4.65), exsiccation eczema (OR: 2.96; CI 2.40-3.65), psoriasis (OR: 1.57; CI 1.38-1.78), plantar warts (OR: 1.42; CI 1.26-1.60), seborrhoeic dermatitis (OR: 1.28; CI 1.16-1.42) and atopic disposition (OR: 1.17; CI 1.12-1.22). CONCLUSION: Dry skin is a frequent condition in the adult general population and needs special attention. Known risk factors may facilitate identifying patients at risk for deterioration.

Decreasing sunbed use in the German population between 2001 and 2015: survey in 155 679 working persons.

BACKGROUND: UV radiation is a proven cause of skin cancer. Use of sunbeds has been shown to provide an attributable risk. OBJECTIVE: To evaluate the proportion of regular sunbed use in Germany based on large-scale population-based surveys over 15 years. METHODS: Skin cancer screenings by dermatologists were conducted between 2001 and 2015 in more than 500 German companies, including a clinical examination and interviews on the risk behaviour related to sunburns and sunbeds. RESULTS: Among 155 679 persons included regular sunbed use significantly declined from 11.0% in 2001 to 1.6% in 2015 (P < 0.001). There were significantly higher rates of sunbed use in women (12.5%/2.0%) vs. men (7.3%/1.3%; P < 0.001), in younger persons and in participants with darker skin (type II and III) vs. fair skin (type I). Individuals with sunburns in childhood were significantly more often sunbed users (5.1% vs. 4.6%; P = 0.002). A remarkable decline of sunbed use was observed after 2009 (7.0% in 2001-2008 and 2.2% in 2009-2015). This reduction occurred in the time of a legal ban of sunbed use for minors but also with the start of the national skin cancer screening programme. CONCLUSION: Use of sunbeds in the German adult population has dropped by more than 85% in the past decade. Primary prevention, including the large public awareness following the legal ban of sunbed use for young people and the effects of the statutory skin cancer screening programme may have contributed to this.

[Primary prevention in the context of skin cancer screening]. / Primärprävention im Rahmen des Hautkrebsscreenings.

BACKGROUND: The skin cancer screening program in Germany is used for early identification of skin tumours with the aim of a lower-risk removal and avoidance of progression. OBJECTIVES: The aim of the study is to investigate the extent to which skin cancer screening (SCS) has an additional effect on dissemination of information on primary prevention. METHODS: This question was examined from the point of view of screening participants and dermatologists. The proportion of appropriately informed persons among persons who have been screened was determined based on a survey of a representative sample of the German standard population of 1004 persons; the provision of information on primary preventive behaviour was based on a survey of dermatological practices (n = 444). Both surveys were evaluated descriptively. RESULTS: Of those who underwent SCS (n = 397), the majority (74%) stated that information on protection against UV radiation was provided during the screening. Among dermatologists offering SCS (n = 424), 70% stated that they personally informed all SCS participants about measures preventing skin cancer, and 46% always or predominantly provided written material after conducting SCS. CONCLUSION: In addition to secondary prevention, SCS also has an important primary preventive function; however there is potential for improvement, since about a quarter of the SCS participants do not receive any information on preventive behaviour from the examining physician. The extent to which this information is actually applied by the SCS participants should be investigated in a longitudinal study.

[Social rights claims for malignant melanoma patients : Providing patient information in German dermatological practices]. / Sozialrechtliche Ansprüche beim malignen Melanom : Aufklärung von Patienten in deutschen dermatologischen Praxen.

BACKGROUND: Treatment of patients with malignant melanoma includes informing the patients about their rights regarding social/disability benefits. In particular, every patient has the right to rehabilitation treatment according to SGB V and IX (SGB: Sozialgesetzbuch; Social Security Code) and to an examination regarding the classification of the disability. OBJECTIVES: The present study examines the extent to which patients with invasive malignant melanoma are informed after initial diagnosis about their social rights to medical rehabilitation measures and the classification of disability. MATERIALS AND METHODS: In the course of a survey in 2014, n = 1800 German dermatological practices were contacted and provided a standardized questionnaire on several care-relevant questions, including the aforementioned ones. RESULTS: Evaluable questionnaires were submitted by n = 424 practices. In all, 52% of dermatologists stated that they regularly provided information on the right to rehabilitation, 15% sometimes, 41% rarely or never. Furthermore, 44% of dermatologists regularly, 17% sometimes and 38% rarely or never informed their patients about the classification of disability. Relevant differences were found in regional comparisons. CONCLUSIONS: Practicing dermatologists seem to transfer the information requirement to the clinics involved in the treatment. It would be beneficial if the information were also provided again by the dermatologists in private practice. In view of the known limited capacity to receive new information from patients with newly diagnosed melanoma, repeated counselling appears to be more patient-friendly.

Cost-of-illness of psoriasis - results of a German cross-sectional study.

BACKGROUND: Though psoriasis poses a substantial chronic socio-economic burden, few studies have addressed the economic impact in Germany. OBJECTIVES: The objective was to evaluate the annual costs of psoriasis in Germany from the societal perspective. METHODS: A cross-sectional study was performed in randomly selected German dermatology practices and clinics in 2013/2014 using standardized questionnaires of illness-related costs. Costs were grouped by perspective and category as well as analysed by sex and age. Group differences were tested by non-parametric tests. RESULTS: Complete data were obtained from 1158 patients in 132 centres. Annual average costs for patients with psoriasis: total costs € 5543 ± € 8044, systemic treatment costs (paid by the statutory health insurances [SHI]) € 3733 ± € 7322, out-of-pocket costs € 224 ± € 406, total SHI costs € 4940 ± € 7533, direct costs € 5164 ± € 7581 and indirect costs € 379 ± € 2087. Significant higher costs in male and significant lower costs in 65+-year-old patients were found. CONCLUSIONS: Psoriasis induces a considerable economic burden. Between 2003 and 2014, costs have markedly shifted from hospital, out-of-pocket and indirect costs towards systemic drug costs.

Association of atopy and tentative diagnosis of skin cancer - results from occupational skin cancer screenings.

BACKGROUND: The relationship between atopic conditions and carcinoma of the skin has been described inconsistently. Population-based data providing information on atopic diseases as well as on skin cancer are sparse. OBJECTIVE: To determine the correlation between atopy and prevalence of precanceroses, non-melanoma skin cancer and malignant melanoma (MM), while taking into account known risk factors for skin cancer. METHODS: Data from occupational skin cancer screenings were analysed in a cross-sectional study. Dermatologists performed whole body examinations and collected medical histories. Subjects comprised all employees (16-70 years) examined from 2006 to 2014. 'Atopy' was defined by clinical screening diagnosis and/or by participant-reported, pre-existing atopic dermatitis, allergic asthma or other specified allergies confirmed by a physician. Tentative screening diagnoses of skin cancer related to actinic keratosis, basal cell carcinoma and malignant melanoma. RESULTS: The study cohort comprised 90 265 employees (mean age 43 ± 11 years, 58.5% male), 30.7% of whom were ever diagnosed with an atopic disease. Persons with atopic conditions recorded in their medical history and at the time of screening had a significantly lower prevalence of actinic keratosis (AK), basal cell carcinoma (BCC) and MM. After controlling for age, sex and relevant risk factors (skin type, childhood sun burns), atopy remained significantly protective against BCC (OR 0.77) and MM (OR 0.53). CONCLUSION: Design limitations of the study include that all findings of skin cancer were based on clinical examination only and must therefore be considered tentative diagnoses. Furthermore, owing to the cross-sectional study design, causal pathways cannot be proven. However, analyses of data from such a large and general population-based cohort afford valuable insights into the relationship between atopic diseases and skin cancer. They provide the grounds for prospective cohort studies to evaluate and dissect the underlying mechanism.

Barriers to guideline-compliant psoriasis care: analyses and concepts.

Despite the availability of effective therapeutics and evidence-based treatment guidelines, a substantial proportion of patients with moderate-to-severe psoriasis does not receive appropriate care. This under-provision of health care may cause further worsening of health, remarkable limitations of the patient's quality of life, and indirect costs for the health care system. In order to provide guideline-compliant care for every psoriasis patient, it is important to identify barriers obstructing optimal care. Studies have identified various barriers on the physician's and on the patient's side; however, respective studies approached only single barriers, and not all of them in the context of psoriasis. Other publications that describe barriers systematically did not focus on psoriasis either. The objective of this literature review was to identify barriers and facilitators, based on studies analysing quality of care and single barriers, resulting in a comprehensive model of causal factors. Our analyses revealed three categories of barriers - patient-related, physician-related and external factors: On the patient side, we found non-adherence to therapies to be an important barrier, often in close association with psychiatric factors. Barriers on the physician's side predominantly are incomplete knowledge of the guidelines as well as the complexity of psoriasis comorbidity. In some countries, payment for patients with complex disease status is poor and inconsistent reimbursement regulations potentially interfere with optimal care. The current analysis indicates that most barriers are interdependent. Thus, measures approaching related barriers simultaneously are required. To improve care for psoriasis patients, further studies systematically addressing all potentially relevant barriers in conjoint are needed.

Psoriasis registries worldwide: systematic overview on registry publications.

BACKGROUND: Safety and efficacy of new treatments are analyzed in clinical trials but their capacity to show potential effects of long-term treatment and more than short latency of onset is limited. To meet this challenge, patient registries (of treatments or diseases) collect prospective data of real-world patients in daily practice without tight selection of patients. OBJECTIVE: The aim of this article was to identify existing psoriasis patient registries by published articles and evaluation of monitored treatment classes, patients, research questions addressed, and measurement instruments implemented. MATERIALS & METHODS: A systematic review of Medline (PubMed) and Embase (Ovid) databases for publications on psoriasis patient registries, including cross-validation was conducted October 2015. RESULTS: 14 patient registries for long-term observation of psoriasis patients in real-world care were identified. Registries were established since 2005, the majority is located in Europe. The number of published studies from single registries ranged from 1 to 10. Most registries include patients treated by conventional systemics as well as biologics. The number of patients analyzed ranged from 35 to >12 000 patients. The publications mostly addressed safety issues or treatment outcomes, followed by baseline description, drug survival, predictor analyses, and treatment patterns. CONCLUSION: A variety of local, national, and international patient registries collect longitudinal data on (systemic) psoriasis treatment. The number of publications reflect the main registry objectives of safety and effectiveness, with additional therapy-related investigations being addressed as well. Based on the information from publications, the combination of data from these registries will involve many methodological challenges. To gain comparability and combinability of cohorts and data across registries, further harmonization of data collection is demanded.

Alterations in expression of glutamatergic transporters and receptors in sporadic Alzheimer's disease.

Excitatory neurotransmitter dysfunction has been discussed to be involved in the pathophysiology of Alzheimer's disease (AD). In the current study we investigated gene and protein expression patterns of glutamatergic receptors and transporters in brains of AD patients in various stages of disease using gene chip arrays, real time PCR and immunohistochemistry. We found marked impairment in the expression of excitatory amino acid transporters (EAAT1 and EAAT 2) at both gene and protein levels in hippocampus and gyrus frontalis medialis of AD patients, already in early clinical stages of disease. The loss of EAAT immunoreactivity was particularly obvious in the vicinity of amyloid plaques. In contrast, EAAT expression was up-regulated in the cerebellum of these patients. Furthermore, a significant up-regulation of the glutamatergic kainate (GRIK4) receptor observed by gene arrays was confirmed by quantitative RT-PCR in late stages in the hippocampus of AD patients. Moreover, there were down-regulations of other glutamatergic receptors such as NMDA (GRINL1A) and AMPA (GRIA4) receptors. Our data show marked changes in the functional elements of the glutamatergic synapses such as glutamatergic receptors and transporters and indicate impaired glutamate clearing rendering neurons susceptible to excess extracellular glutamate and support further the involvement of excitotoxic mechanisms in the pathogenesis of AD.

Dermatological comorbidity in psoriasis: results from a large-scale cohort of employees.

The field of dermatological comorbidity in psoriasis is only passively explored with contradictory results. Objective of this study was to further investigate the complex field of psoriasis and associated skin diseases by identifying skin comorbidity patterns in an extensive cohort of employees in Germany. Retrospective analysis of data deriving from occupational skin cancer screenings was conducted. From 2001 to 2014 German employees between 16 and 70 years from different branches underwent single whole-body screenings by trained dermatologists in their companies. All dermatological findings and need for treatment were documented. Point prevalence rates and their 95% confidence intervals were computed. Logistic regression analysis was performed to calculate odds ratios (OR) of single dermatological diseases to occur together with psoriasis controlled for age and sex. Data from 138,930 persons (56.5% male, mean age 43.2) were evaluated. Psoriasis point prevalence was 2.0%. Of those 20.6% had unmet treatment needs of their disease. Onychomycosis was the most frequent dermatological comorbidity with a prevalence of 7.8%. Regression analysis found rosacea (OR = 1.40, 95% CI 1.13-1.72) and telangiectasia (OR = 1.25, 95% CI 1.10-1.41) to be significantly associated with psoriasis. 17.2% of psoriasis patients had at least one further finding requiring treatment. The highest treatment needs were found for onychomycosis (3.4%), tinea pedis (3.1%), and verruca plantaris (1.0%). It can be concluded that persons with psoriasis are at increased risk to suffer from comorbid skin diseases, which should be considered in treatment regimens. Particular attention should be paid to fungal diseases of the feet.

Suppression of v-fms-induced transformation by overexpression of a truncated T-cell protein tyrosine phosphatase.

Rat 2 cells stably transformed by murine v-fms (pB5 cells) were infected with retroviruses containing a human cDNA encoding either a full-length human T-cell protein tyrosine phosphatase (TC.PTP) or a truncated form (delta C11.PTP) in which an 11-kDa carboxy-terminal extension had been removed. This segment is responsible for enzyme localization and regulation. Clonal cell lines were isolated following G418 selection and their transforming properties analysed; pB5 cells containing the vector alone or TC.PTP remained transformed. These cells grew readily in soft agar, formed tumors in nude mice and were morphologically indistinguishable from the parental pB5 cells. In contrast, cells expressing delta C11.PTP showed dramatic changes in cell morphology, loss of anchorage-independent growth in soft agar and reduced or lack of tumor formation in nude mice. Both increases and decreases in tyrosine phosphorylation of specific proteins in the cells overexpressing the truncated enzyme were detected. These results indicate that coexpression of the deregulated, soluble tyrosine phosphatase with a constitutively active, oncogenic receptor tyrosine kinase leads to the suppression of the transformed phenotype.

Structural fluctuations and conformational entropy in proteins: entropy balance in an intramolecular reaction in methemoglobin.

The reversible intramolecular binding of the distal histidine side chain to the heme iron in methemoglobin is of special interest due to the very large negative reaction entropy which overcompensates the large reaction enthalpy. It may be considered as a prominent example of the ability of proteins (including enzymes) to provide global entropy in a local process. In this work new experiments and model calculations are reported which aim at finding the structural elements contributing to the reaction entropy. Geometrical studies prove the implication of the 20 residue E-helix being shifted by more than 2 A. Vibrational entropies are calculated by a procedure derived from the method of Karplus and Kushik. It turns out that neither the histidine alone nor the complete E-helix contribute more than 15 per cent of the required entropy.

Coagulation assay with improved specificity to factor V mutants insensitive to activated protein C.

The prevalence of a new hereditary defect in the protein C anticoagulant pathway, the factor V-Leiden, has been reported to range between 20% to 60% in familial thrombophilia. In addition to differences in patient groups, these very divergent numbers might also be due to the detection method applied. In most studies a modified APTT was used, where activated protein C (APC) is added simultaneously with the start of the clotting reaction. However, this method is also influenced by other factors like protein S, factor VIII or lupus anticoagulants. Furthermore, heparin or oral anticoagulant therapy might interfere. We tried to develop a coagulation assay dependent only on those mutant forms of factor V stable against proteolytic attack by APC. For this purpose, samples were first diluted with a factor V deficient plasma (f.V-dp). Then, coagulation was initiated either on the intrinsic pathway (APTT) or on the extrinsic pathway (PT) or, by directly activating factor X (RVVT). Additionally, APC was added, which prolongation of the clotting time. Deficiencies in protein S or the presence of factor V-Leiden resulted in a less pronounced clotting time prolongation. Titration of protein S-deficient plasma samples with f.V-dp diminished this effect. In contrast, in samples with factor V-Leiden the difference to the clotting time obtained with normal plasma even increased in the order APTT>>RVVT>PT. In the APTT-based method high concentrations of factor VIII shortened the clotting times, thus mimicking a factor V-Leiden defect. This could be compensated for up to 4 U/ml factor VIII by using a f.V-dp containing factor VIII at physiological concentration. Neither unfractionated nor LMW-heparin (up to 2 U/ml) interfered with the determination. In a brief investigation on 16 plasma samples from patients under oral anticoagulation 5 (30%) showed a similar behaviour as observed with normal plasma from factor V-Leiden carriers. These results let us suggest that by simply mixing the patient sample with a factor V-deficient plasma factor V-Leiden might be detected also in patients under oral anticoagulant therapy. Inherited disorders of protein C or protein S are well known as thrombotic risk factors (1). The recent investigations by Dahlbäck et al. (2) led to the discovery of a new hereditary defect in the protein C anticoagulant pathway: the factor V-Leiden (3). This mutation renders activated factor V stable against proteolytic attack by activated protein C (APC). The reports on the prevalence of this mutation in thrombophilic patients show a considerable variation between 21% (4) and 64% (5).(ABSTRACT TRUNCATED AT 400 WORDS)

Isoform diversity of phosphorylase kinase alpha and beta subunits generated by alternative RNA splicing.

We have sequenced rabbit cDNAs that encode one isoform of the alpha subunit and two isoforms of the beta subunit of phosphorylase kinase, in addition to the single isoform from fast skeletal muscle that has been characterized to date for each subunit. All these isoforms are generated by alternative RNA splicing. The alpha subunit sequence obtained from slow skeletal muscle (soleus) is characterized by an internal deletion of 59 amino acids. This deletion is predominant in mRNA from slow muscle, heart, and uterus and accounts for the smaller alpha subunit variant (alpha') characteristic of phosphorylase kinase purified from slow muscle and heart. The beta subunit mRNA can be differentially spliced at two sites. In all tissues (except skeletal muscle) that were analyzed, an internal segment encoding 28 amino acids of the muscle sequence is replaced by a homologous sequence of identical length, presumably through the use of mutually exclusive exons. In brain and some other tissues, the deduced N-terminal sequence of the beta subunit is also changed. This is achieved by an insertion into the mRNA sequence that interrupts the initial reading frame after 25 codons and starts a new reading frame, encoding a different N terminus of 18 amino acids. This modification probably affects the major regulatory phosphorylation site of the beta subunit.