The genetic basis for most patients with pustular skin disease remains elusive.

BACKGROUND: Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause or contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP). OBJECTIVES: To better understand the disease relevance of these genes, we screened our cohorts of patients with pustular skin diseases [primarily GPP and palmoplantar pustular psoriasis (PPP)] for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN. METHODS: Coding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients - 61 with GPP, two with acute generalized exanthematous pustulosis and four with acrodermatitis continua of Hallopeau. We screened IL36RN and AP1S3 for intragenic copy-number variants and 258 patients with PPP for coding changes in AP1S3. Eleven heterozygous IL36RN mutations carriers were analysed for a second noncoding IL36RN mutation. Genotype-phenotype correlations in carriers/noncarriers of IL36RN mutations were assessed within the GPP cohort. RESULTS: The majority of patients (GPP, 64%) did not carry rare variants in any of the three genes. Biallelic and monoallelic IL36RN mutations were identified in 15 and five patients with GPP, respectively. Noncoding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype-phenotype correlation observed for IL36RN mutation carriers was early age at disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutation carriers. CONCLUSIONS: The identification of IL36RN mutation carriers harbouring additional rare variants in CARD14 or AP1S3 indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest that, in heterozygous IL36RN mutation carriers, there are additional disease-causing genetic factors outside IL36RN.

Evidence for genetic overlap between adult onset Still's disease and hereditary periodic fever syndromes.

OBJECTIVE: Adult onset Still's disease (AOSD) is a severe, autoimmune disease that can be challenging to treat with conventional therapeutics and biologicals in a considerable number of cases. Therefore, there is a high need to understand its pathogenesis better. As major clinical symptoms overlap between AOSD and hereditary periodic fever syndromes (HPFS), we analysed four known HPFS genes in AOSD. METHODS: We performed Sanger sequencing and quantitative analysis of all coding regions of MEFV, TNFRSF1A, MVK and NLRP3 in 40 AOSD patients. All rare coding variants (n = 6) were evaluated for several aspects to classify them as benign to pathogenic variants. Statistical analysis was performed to analyse whether variants classified as (likely) pathogenic were associated with AOSD. RESULTS: We identified three rare variants in MEFV, one previously not described. Association to the three likely pathogenic MEFV variants was significant (p c = 2.34E- 03), and two of the three carriers had a severe course of disease. We observed strong evidence for significant association to mutations in TNFRSF1A (p c = 2.40E- 04), as 5% of patients (2/40) carried a (likely) pathogenic variant in this gene. Both of them received a biological for treatment. CONCLUSION: Our results indicate TNFRSF1A as a relevant gene in AOSD, especially in patients with a more challenging course of disease, while causal variants remain to be identified in the majority of patients.

Micro-trace fossils reveal pervasive reworking of Pliocene sapropels by low-oxygen-adapted benthic meiofauna.

Animal burrowers leave an indelible signature on the sedimentary record in most marine environments, with the seeming exception of low-oxygen environments. In modern sedimentary settings, however, sub-millimetre-sized benthic animals (meiofauna) are adapted to low oxygen and even sulfidic conditions. Almost nothing is known about their impact on ancient marine sediments because they leave few recognizable traces. Here we show, in classic Pliocene-aged anoxic facies from the Mediterranean, the first reported trace fossil evidence of meiofaunal activity and its relation to changing oxygenation. A novel approach utilizing electron imaging of ion-polished samples shows that meiofauna pervasively reworked sediment under oxygen-depleted conditions that excluded macrofauna, fragmenting organic laminae and emplacing 15- to 70-µm-diameter faecal pellets without macroscopically influencing the fabric. The extent of reworking raises the question: how pervasively altered are other sediments presently assumed to lack animal influence and how far into the geological record does this influence extend?

Predicting protein function from structure: unique structural features of proteases.

We have noted consistent structural similarities among unrelated proteases. In comparison with other proteins of similar size, proteases have smaller than average surface areas, smaller radii of gyration, and higher C(alpha) densities. These findings imply that proteases are, as a group, more tightly packed than other proteins. There are also notable differences in secondary structure content between these two groups of proteins: proteases have fewer helices and more loops. We speculate that both high packing density and low alpha-helical content coevolved in proteases to avoid autolysis. By using the structural parameters that seem to show some separation between proteases and nonproteases, a neural network has been trained to predict protease function with over 86% accuracy. Moreover, it is possible to identify proteases whose folds were not represented during training. Similar structural analyses may be useful for identifying other classes of proteins and may be of great utility for categorizing the flood of structures soon to flow from structural genomics initiatives.

Predicting garment pattern dimensions from photographic and anthropometric data.

Traditional linear measurements (lengths and circumferences taken over the body surface with a tape measure) were compared with measurements of frontal and lateral view photographs for usefulness in determining pattern dimensions for the upper torso of the female body form. The statistical regression models developed indicated that, while linear measurements provided slightly more accuracy in predicting a few of the pattern dimensions, the photographic measurements were more accurate in predicting others, particularly pattern angles. Photographic measurements hold promise as an alternative to the more intrusive linear measurements for predicting pattern dimensions.

[Fractures of the clavicle: classification, diagnosis, therapy]. / Klavikulafrakturen: Einteilung, Diagnose, Therapie.

Clavicular fracture is one of the most frequent skeletal lesions. In most cases the median third of the clavicula is affected (this is due to the peculiar biomechanical structure). Accompanying lesions and complications of clavicular fractures are rare. A total of 13 x-ray diagnostic techniques are described for clavicular fractures. X-ray film should, as a matter of principle, always be taken in two planes. Definitely the major part of clavicular fractures are treated conservatively (rucksack dressing), whereas surgery is reserved for few and strictly defined indications.

Separation of immature and adult rat hepatocytes into distinct subpopulations by centrifugal elutriation.

Several subpopulations of hepatocytes with increasing cell diameters were isolated, the smaller cells were attributed to the periportal area, the larger ones to the perivenous region. Profiles of total cytochrome P-450, benzphetamine N-demethylation and ethoxyresorufin O-deethylation, cytochrome c-reductase, glucose-6-phosphatase and GPT activities were determined. With adult hepatocytes an increasing cytochrome P-450 concentration with increasing cell diameter could be observed, paralleled by increasing activities of monooxygenases. Glucose-6-phosphatase and GPT also revealed increasing activities with increasing cell diameter, but cytochrome c-reductase did not show a distinct zonation. Immature hepatocytes (age 11-15 days) were smaller, more fragile, and could not be isolated with the same enzyme solution as adult hepatocytes. They did not show any zonation of cytochrome P-450 whereas the zonation of the monooxygenases was almost fully developed. For cytochrome c-reductase a zonation with higher activities in the perivenous cells could be demonstrated, in contrast to the lack of zonation in adult rats. Glucose-6-phosphatase showed a decline with increasing cell diameter in immature hepatocytes, whereas GPT did not show any zonation. In rats aged 20 days the zonation of these parameters in liver was in between younger and older animals.