Position statement for a pragmatic approach to immunotherapeutics in patients with inflammatory skin diseases during the coronavirus disease 2019 pandemic and beyond.

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, a novel RNA virus that was declared a global pandemic on 11 March 2020. The efficiency of infection with SARS-CoV-2 is reflected by its rapid global spread. The SARS-CoV-2 pandemic has implications for patients with inflammatory skin diseases on systemic immunotherapy who may be at increased risk of infection or more severe infection. This position paper is a focused examination of current evidence considering the mechanisms of action of immunotherapeutic drugs in relation to immune response to SARS-CoV-2. We aim to provide practical guidance for dermatologists managing patients with inflammatory skin conditions on systemic therapies during the current pandemic and beyond. Considering the limited and rapidly evolving evidence, mechanisms of action of therapies, and current knowledge of SARS-CoV-2 infection, we propose that systemic immunotherapy can be continued, with special considerations for at risk patients or those presenting with symptoms.

Three-dimensional simulation of viscous-flow agglomerate sintering.

The viscous-flow sintering of different agglomerate particle morphologies is studied by three-dimensional computer simulations based on the concept of fractional volume of fluid. For a fundamental understanding of particle sintering characteristics, the neck growth kinetics in agglomerate chains and in doublets consisting of differently sized primary particles is investigated. Results show that different sintering contacts in agglomerates even during the first stages are not completely independent from each other, even though differences are small. The neck growth kinetics of differently sized primary particles is determined by the smaller one up to a size difference by a factor of approximately 2, whereas for larger size differences, the kinetics becomes faster. In particular, the agglomerate sintering kinetics is investigated for particle chains of different lengths and for different particle morphologies each having ten primary particles and nine initial sintering contacts. For agglomerate chains, the kinetics approximately can be normalized by using the radius of the fully coalesced sphere. In general, different agglomerate morphologies show equal kinetics during the first sintering stages, whereas during advanced stages, compact morphologies show significantly faster sintering progress than more open morphologies. Hence, the overall kinetics cannot be described by simply using constant morphology correction factors such as fractal dimension or mean coordination number which are used in common sintering models. However, for the first stages of viscous-flow agglomerate sintering, which are the most important for many particle processes, a sintering equation is presented. Although we use agglomerates consisting of spherical primary particles, our methodology can be applied to other aggregate geometries as well.

Microarray analysis of RpoS-mediated gene expression in Escherichia coli K-12.

The alternative sigma factor RpoS controls the expression of many stationary-phase genes in Escherichia coli and other bacteria. Though the RpoS regulon is a large, conserved system that is critical for adaptation to nutrient deprivation and other stresses, it remains incompletely characterized. In this study, we have used oligonucleotide arrays to delineate the transcriptome that is controlled by RpoS during entry into stationary phase of cultures growing in rich medium. The expression of known RpoS-dependent genes was confirmed to be regulated by RpoS, thus validating the use of microarrays for expression analysis. The total number of positively regulated stationary-phase genes was found to be greater than 100. More than 45 new genes were identified as positively controlled by RpoS. Surprisingly, a similar number of genes were found to be negatively regulated by RpoS, and these included almost all genes required for flagellum biosynthesis, genes encoding enzymes of the TCA cycle, and a physically contiguous group of genes located in the Rac prophage region. Negative regulation by RpoS is thus much more extensive than has previously been recognized, and is likely to be an important contributing factor to the competitive growth advantage of rpoS mutants reported in previous studies.

[Late diagnosis of Curschmann-Steinert myotonic dystrophy in a female patient with dilated cardiomyopathy and in her son]. / Späte Diagnose einer myotonen Dystrophie Curschmann-Steinert bei einer Patientin mit Dilatativer Kardiomyopathie und ihrem Sohn.

A 41 year old woman presented with dyspnoea at rest and swollen legs in the emergency room of our centre. She reported a history of slowly progressing dyspnoea and oedema in the legs. Physical examination showed signs of biventricular congestive heart failure and dysmorphia of the face. Routine laboratory examination revealed elevated CK levels without significant elevations of the CK-MB isoform. ECG showed complete left bundle branch block and first degree atrioventricular block. Echocardiography and angiography showed markedly reduced left ventricular systolic function, the ejection fraction was 25%. Coronary angiography excluded CAD and there was no evidence for congenital or valvular heart disease. The patient also reported a history of a serious complication during emergency general anaesthesia and cataracts of both eyes. Because of the clinical and chemical findings, the history of cataracts and complications during general anaesthesia, a systemic congenital disease of the muscular tissue was suspected. Molecular studies revealed a trinucleotide amplification at the myotonic dystrophy locus 19q 13.3, so the diagnosis myotonic dystrophy Curschmann-Steinert was established. The sixteen year old son of the patient suffered from an at this time unknown disease with retardation, muscular weakness and myotonia of the face. The diagnosis myotonic dystrophy was evident because of the clinical signs and the family history.

Characterization and clinical relevance of a new complement-fixing antibody--anti-M8--in patients with primary biliary cirrhosis.

A new complement-fixing antimitochondrial antibody--anti-M8--was detected in patients with primary biliary cirrhosis. Anti-M8 was only found in association with anti-M2, however, not all anti-M2 positive patients had anti-M8. Thus, among 66 anti-M2 positive patients, 29 were also positive for anti-M8, whereas sera from patients who had the complement-fixing anti-M2 and anti-M4 antibodies in parallel always strongly reacted with the M8 antigen. This group was previously described as mixed form. The M8 antigen was isolated either from human liver mitochondria or pig kidney microsomes and could be clearly distinguished from the M4 antigen. In contrast to M4, M8 was trypsin sensitive and banded at sucrose densities from 1.16 to 1.24, while M4 was found at densities from 1.08 to 1.14. Like M4, the M8 antigen also co-purified with outer mitochondrial membranes. Fifty-three patients with primary biliary cirrhosis have been followed over a period of up to 16 years and were classified according to their complement-fixing antimitochondrial antibody profile. At the time of the first diagnosis, 95% of 31 patients being anti-M2 positive, but anti-M8 negative (antimitochondrial antibody Profile I) were in Stage I or II. In contrast, only 61% of 13 patients being anti-M2 and anti-M8 positive (antimitochondrial antibody Profile II) and 44% of 9 patients with anti-M2, anti-M8 and anti-M4 in parallel (antimitochondrial antibody Profile III) belonged to Stage I or II.(ABSTRACT TRUNCATED AT 250 WORDS)

Natural course of primary biliary cirrhosis. I. A morphological, clinical and serological analysis of 103 cases.

Clinical, biochemical and serological data obtained in 103 patients with primary biliary cirrhosis (PBC) were analysed with respect to the four defined morphological stages. Evaluation of the initial biopsies (99 needle biopsies/4 wedge biopsies) revealed that most patients were in stage I (focal bile duct destruction). Unequivocal distinction between stages I and II was possible in most cases, while considerable overlapping of criteria was observed in stages II to IV. Morphological cholestasis, a characteristic sign of stage IV was already found in 7% of PBC I cases. Four out of 12 autopsy specimens showed micronodular biliary cirrhosis (Hanot's type) and eight specimens had a macronodular type of biliary cirrhosis. No predominant clinical symptoms were found in patients with PBC I or II, but pruritus was observed in about 30%. Increased serum alkaline phosphatase (AP) and IgM levels as well as a positive antimitochondrial antibody (AMA) test were typical features of all stages in up to 80-90%, but patients with normal AP or IgM or negative AMA have been observed, especially in stages I and II. Five of 57 patients at stage I had increased bilirubin levels and in three patients IgM and IgG were simultaneously elevated in stage I. The natural course of PBC, as it is reflected in histological staging, was studied in 30 patients in whom biopsies were regularly taken over a period of 2-18 years. About 80% of PBC I-cases lasted between 1 and 7 years before reaching stage II, while another 5-10 years were necessary for the development of stage III-IV. Thus it appears that in the vast majority of patients PBC lasts about 10-15 years and in some instances even more than 20 years. The finding in stage I and II of normal AP indicates a benign course, while morphological and biochemical cholestasis seems to be associated with a rather progressive course.

[Explorative laparoscopy or laparotomy? (author's transl)]. / Explorative Laparoskopie oder Laparotomie

Explorative laparoscopy is an endoscopic examination of the abdominal cavity which, with the modern endoscopy tables, permits a considerably improved survey than formerly. Within one year, 105 patients were examined and a suspected tumor was confirmed 20 times in 57 patients. Metastases were sought 23 times in patients known to have a primary tumor, and demonstrated 11 times. The differential diagnosis of cholestasis was made 18 times, 6 times a negative cholecystogram required further clarification. Two of these showed an inoperable, infiltrating, growing carcinoma of the gall bladder. For the purpose of classification of lymphogranulomata, laparoscopy shows the advantage over laparotomy of careful magnifying observation of the surface of the liver which can be repeated as often as desired.