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The ICD-10-GM coding system used in the German healthcare system only captures a minority of rare disease diagnoses. Therefore, information on the incidence and prevalence of rare diseases as well as necessary (financial) resources for the expert care required for evidence-based decisions by health insurers, care providers, and politicians are lacking. Furthermore, the missing information complicates and sometimes even precludes the generation of scientific knowledge on rare diseases. Therefore, starting in 2023, all in-patient cases in Germany with a rare disease diagnosis must be coded by an ORPHAcode using the Alpha-ID-SE file.The file Alpha-ID-SE links the ICD-10-GM codes to the internationally established ORPHAcodes for rare diseases. Commercially available software tools progressively support the coding of rare diseases. In several centers for rare diseases linked to university hospitals, IT tools and procedures were established to realize a complete coding of rare diseases. These include financial incentives for the institutions providing rare disease codes, systematic queries asking for rare disease codes during the coding process, and a semi-automated coding process for all patients with a rare disease previously seen at the institution. A combination of the different approaches probably results in the most complete coding.To get the complete picture of rare disease epidemiology and care requirements, a specific and unique coding of out-patient cases is also desirable. Furthermore, a structured reporting of phenotype is required, especially for complex rare diseases and for yet undiagnosed cases., (© 2022. The Author(s).)

We report upon PanelDesign, a framework to support the design of diagnostic next generation DNA sequencing panels with epidemiological information. Two publicly available resources, namely Genomics England PanelApp and Orphadata, were combined into a single data set to allow genes in a given NGS panel to be ranked according to the frequency of the associated diseases, thereby highlighting potential core genes as defined by the Eurogenetest/ESHG guidelines for diagnostic next generation DNA sequencing. In addition, PanelDesign can be used to evaluate the contribution of different genes to a given disease following ACMG (American College of Medical Genetics) technical standards.

PD-L1/PD-1 blocking antibodies have demonstrated therapeutic efficacy across a range of human cancers. Extending this benefit to a greater number of patients, however, will require a better understanding of how these therapies instigate anticancer immunity. Although the PD-L1/PD-1 axis is typically associated with T cell function, we demonstrate here that dendritic cells (DCs) are an important target of PD-L1 blocking antibody. PD-L1 binds two receptors, PD-1 and B7.1 (CD80). PD-L1 is expressed much more abundantly than B7.1 on peripheral and tumor-associated DCs in patients with cancer. Blocking PD-L1 on DCs relieves B7.1 sequestration in cis by PD-L1, which allows the B7.1/CD28 interaction to enhance T cell priming. In line with this, in patients with renal cell carcinoma or non-small cell lung cancer treated with atezolizumab (PD-L1 blockade), a DC gene signature is strongly associated with improved overall survival. These data suggest that PD-L1 blockade reinvigorates DC function to generate potent anticancer T cell immunity., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

We report three cases of severe olmesartan-associated chronic diarrhea with weight loss and malassimilation syndrome. Histologically, a sprue-like enteropathy was diagnosed in each case, while serological tests for celiac disease were negative. After stopping the medication, symptoms improved within a few days. Histologically, remission was documented after 3 months. Olmesartan-associated enteropathy is an underestimated entity and an important differential diagnosis in patients with chronic diarrhea.

Clinical practice guidelines (CPGs) for rare diseases (RDs) are scarce, may be difficult to identify through Internet searches and may vary in quality depending on the source and methodology used. In order to contribute to the improvement of the diagnosis, treatment and care of patients, Orphanet (www.orpha.net) has set up a procedure for the selection, quality evaluation and dissemination of CPGs, with the aim to provide easy access to relevant, accurate and specific recommendations for the management of RDs. This article provides an analysis of selected CPGs by medical domain coverage, prevalence of diseases, languages and type of producer, and addresses the variability in CPG quality and availability. CPGs are identified via bibliographic databases, websites of research networks, expert centres or medical societies. They are assessed according to quality criteria derived from the Appraisal of Guidelines, REsearch and Evaluation (AGREE II) Instrument. Only open access CPGs and documents for which permission from the copyright holders has been obtained are disseminated on the Orphanet website. From January 2012 to July 2015, 277 CPGs were disseminated, representing coverage of 1,122 groups of diseases, diseases or subtypes in the Orphanet database. No language restriction is applied, and so far 10 languages are represented, with a predominance of CPGs in English, French and German (92% of all CPGs). A large proportion of diseases with identified CPGs belong to rare oncologic, neurologic, hematologic diseases or developmental anomalies. The Orphanet project on CPG collection, evaluation and dissemination is a continuous process, with regular addition of new guidelines, and updates. CPGs meeting the quality criteria are integrated to the Orphanet database of rare diseases, together with other types of textual information and the appropriate services for patients, researchers and healthcare professionals in 40 countries., Competing Interests: The authors have declared that no competing interests exist.

Extracorporeal photopheresis (ECP) constitutes a promising treatment for patients with steroid-refractory acute graft-versus-host disease (aGvHD) after allogeneic stem cell transplantation and for patients with graft rejection after solid organ transplantation (SOT). There is an increasing body of evidence that modulation of lymphocyte subsets might play a crucial role in the mechanism of action in ECP. We therefore analyzed immunological effects concomitantly with clinical findings in patients under ECP therapy using multicolor flow cytometry. In a patient with steroid-refractory aGvHD and a patient with progressive bronchiolitis obliterans syndrome (BOS) after double-lung transplantation, clinical responses to ECP therapy were paralleled by an increase of CD4 + CD25hiFoxP3 + regulatory T cells and a decrease of T(EMRA) (CD3 + CD8+ CD45RA+ CD62L+ effector memory T) cells as well as of natural killer (NK)T cells. In summary, immunomonitoring of T cell subsets can elucidate the mechanism of action in ECP.

Objective: To investigate the relation of residual worst lead ST segment elevation (WL-STE) after ST segment myocardial infarction (STEMI) with infarct size and microvascular injury assessed by cardiovascular magnetic resonance (CMR) imaging., Background: WL-STE in patients with acute reperfused STEMI has been shown to identify high risk patients for major adverse cardiovascular events (MACE). However, the relation of WL-STE with myocardial damage is unknown., Methods: In this multicentre study we analysed ECG data 90 min after primary percutaneous coronary intervention (PCI) in 763 STEMI patients. WL-STE was defined as the absolute magnitude of STE in the most affected lead on the post-PCI ECG. Patients were categorised into three groups (<1 mm, 1-2 mm, and ≥2 mm). CMR was performed within 1 week after infarction for comprehensive assessment of myocardial damage using a standardised protocol. The primary clinical endpoint was MACE defined as death, reinfarction, and new congestive heart failure within 12 months after infarction., Results: WL-STE <1 mm, 1-2 mm, and ≥2 mm was present in 155 (20%), 328 (43%), and 280 (37%) patients, respectively. Myocardial damage determined by CMR demonstrated a graded relationship of infarct size (median (IQR) 13.3 (6.2-20.3)%LV vs 13.7 (7.6-21.3)%LV vs 22.5 (15.6-31.2)%LV, p<0.001), the myocardial salvage index (60.8 (37.0-84.5) vs 55.0 (36.6-73.9) vs 42.7 (26.2-58.2), p<0.001), and microvascular obstruction (0.0 (0.0-0.9)%LV vs 0.0 (0-1.0)%LV vs 1.2 (0.0-3.6)%LV, p<0.001) across the three groups. WL-STE ≥2 mm was strongly associated with MACE 12 month after infarction (HR 1.93, 95% CI 1.11 to 3.37; p=0.02)., Conclusions: This largest CMR study to date correlating post-PCI WL-STE with markers of myocardial damage demonstrates that WL-STE is significantly associated with infarct size, myocardial salvage, microvascular obstruction, and MACE in a high risk STEMI population., Trial Registration Number: NCT00712101., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Primary mediastinal B-cell lymphoma (PMBL) is characterized by aberrant activation of JAK/STAT-signaling resulting in constitutive presence of phosphorylated STAT6 (pSTAT6). In primary PMBL samples pSTAT6 is only expressed in a sub-population of lymphoma cells in a pattern that is reminiscent of that of the BCL6 oncogene. Double-fluorescence staining was carried out to determine the association between these two proteins in ten primary PMBL cases and three available PMBL cell line models. Surprisingly, only a minute fraction of double-positive nuclei was observed, while each sample contained considerable fractions of single-positive pSTAT6 and BCL6 nuclei. The intratumoral coexistence of BCL6+/pSTAT6- and BCL6-/pSTAT6+ subpopulations suggests a negative interaction between these factors. In silico screening of the STAT6 /BCL6 promoters for DNA consensus binding sites identified five STAT-binding-sites in the BCL6 promoter. We confirmed STAT6 binding to the BCL6 promoter in vitro and in vivo by band shift / super shift assays and chromatin immunoprecipitations. Using BCL6 luciferase reporter assays, depletion of STAT6 by siRNA, and ectopic overexpression of a constitutive active STAT6 mutant, we proved that pSTAT6 is sufficient to transcriptionally repress BCL6. Recently developed small molecule inhibitors 79-6 and TG101348 that increases BCL6 target gene expression and decreases pSTAT6 levels, respectively, demonstrate that a combined targeting results in additive efficacy regarding their negative effect on cell viability. The delineated pSTAT6-mediated molecular repression mechanism links JAK/STAT to BCL6-signaling in PMBL and may carry therapeutic potential.

Collectively, rare diseases are of major public health impact, but research on rare diseases poses major challenges. There are many deterrents for researchers to initiate rare disease projects and for funding agencies to grant support. It can be expected that rare disease research is underfunded, but no systematic assessments on rare disease funding practices were found in the literature. The recipients of grants for rare disease research were identified through the research reports of four German medical faculties, and data on external funding of individual projects were obtained through questionnaires and database mining. Response rates to questionnaires were unsatisfactory. The analysis was thus concentrated on a single faculty, Hannover Medical School, for which 100% data ascertainment was obtained. External funding for rare disease research at this faculty comprises 5.8% of all external research funding in 2006, and 3.8% in 2007. As the first study of this kind, this survey indicates enormous deficits and inequities in rare disease research.

Marfan syndrome is an autosomal dominant disorder involving different organ systems. Marfan syndrome type 1 (MFS1) is caused by mutations in the FBN1 gene. Heterozygosity for mutations in the TGFBR1 or TGFBR2 genes cause Loeys-Dietz syndrome (LDS) types 2A and 2B that overlap with MFS1 in their clinical features. The phenotype of MFS1 is defined by the Ghent nosology, which classifies the clinical manifestations in major and minor criteria. Dural ectasia is one of the major criteria for Marfan syndrome but it is rarely tested for. We here report 22 novel and 9 recurrent mutations in the FBN1 gene in 36 patients with clinical features of Marfan syndrome. Sixty patients with identified mutations in the FBN1 gene and three patients with mutations in the TGFBR1 or TGFBR2 genes were examined for dural ectasia. Forty-seven of the 60 patients (78%) with MFS1 showed the dural ectasia criterion and 13 (22%) did not. Thirty-three (55%) patients were suspected of having Marfan syndrome and 24 (73%) of them had dural ectasia. Two of the three patients with LDS had dural ectasia.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder characterized by manifestations in the cardiovascular, skeletal, ocular, and other organ systems. MFS type1 (MFS1) is caused by mutations in the gene encoding fibrillin (FBN1). Recently, the transforming growth factor-beta receptor-2 gene, TGFBR2, has been shown to be associated with a second type of this disorder with typically mild or absent ocular involvement (MFS type 2; MFS2). Several point mutations were found in the highly conserved serine/threonine kinase domain of TGFBR2. Mutations in both TGFBR1 and TGFBR2 are associated with Loeys-Dietz aortic aneurysm syndrome (LDS). We searched for TGFBR1 and TGFBR2 mutations in 41 unrelated patients fulfilling the diagnostic criteria of Ghent nosology or with the tentative diagnosis of Marfan syndrome, in whom mutations in the FBN1 coding region were not identified. In TGFBR1, two mutations and two polymorphisms were detected. In TGFBR2, five mutations and six polymorphisms were identified. Reexamination of patients with a TGFBR1 or TGFBR2 mutation revealed extensive clinical overlap between patients with MFS1, MFS2, and LDS.

Marfan syndrome (MFS; OMIM#154700) is a connective tissue disorder characterized by manifestations in the ocular, skeletal and cardiovascular systems. MFS is caused by mutation in the fibrillin-1 gene (FBN1; OMIM#134797) and more than 550 mutations have been identified so far. FBN1 is approximately 230 kb in size and contains three evolutionarily conserved alternatively spliced exons B, A and C at the 5'end. In a first systematic attempt to associate sequence variations in the FBN1 5' alternatively spliced exons with MFS, we investigated 41 individuals fulfilling the diagnostic criteria of Ghent nosology or with features of MFS including at least one major criterion or involvement of two organ systems but not fulfilling a strict interpretation of the Ghent nosology, and known to be negative for mutations in the FBN1 exons 1-65 as well as the TGFBR2 and TGFBR1 coding regions. We identified five novel and one previously reported variants in the six unrelated probands and provide preliminary evidence for their role in pathogenesis.

Marfan syndrome (MFS) is an autosomal-dominant disorder of the fibrous connective tissue that is typically caused by mutations in the gene coding for fibrillin-1 (FBN1), a major component of extracellular microfibrils. The clinical spectrum of MFS is highly variable and includes involvement of the cardiovascular, skeletal, ocular, and other organ systems; however, the genotype-phenotype correlations have not been well developed. Various screening methods have led to the identification of about 600 different mutations (FBN1-UMD database; www.umd.be). In this study we performed SSCP and/or direct sequencing to analyze all 65 exons of the FBN1 gene in 116 patients presenting with classic MFS or related phenotypes. Twenty-nine novel and nine recurrent mutations were identified in 38 of the analyzed patients. The mutations comprised 18 missense (47%), eight nonsense (21%), and five splice site (13%) mutations. Seven further mutations (18%) resulted from deletion, insertion, or duplication events, six of which led to a frameshift and subsequent premature termination. Additionally, we describe new polymorphisms and sequence variants. On the basis of the data presented here and in a previous study, we were able to establish highly significant correlations between the FBN1 mutation type and the MFS phenotype in a group of 76 mutation-positive patients for whom comprehensive clinical data were available. Most strikingly, there was a significantly lower incidence of ectopia lentis in patients who carried a mutation that led to a premature termination codon (PTC) or a missense mutation without cysteine involvement in FBN1, as compared to patients whose mutations involved a cysteine substitution or splice site alteration., (Copyright 2005 Wiley-Liss, Inc.)

Mutations in the gene encoding fibrillin-1 (FBN1) cause Marfan syndrome (MFS) and other related connective tissue disorders. In this study we performed SSCP to analyze all 65 exons of the FBN1 gene in 76 patients presenting with classical MFS or related phenotypes. We report 7 missense mutations, 3 splice site alterations, one indel mutation, one nonsense mutation and two mutations causing frameshifts: a 16bp deletion and a single nucleotide insertion. 5 of the missense mutations (Y1101C, C1806Y, T1908I, G1919D, C2251R) occur in calcium-binding Epidermal Growth Factor-like (EGFcb) domains of exons 26, 43, 46 and 55, respectively. One missense mutation (V449I) substitutes a valine residue in the non-calcium-binding epidermal growth factor like domain (EGFncb) of exon 11. One missense mutation (G880S) affects the "hybrid" motif in exon 21 by replacing glycine to serine. The 3 splice site mutations detected are: IVS1-1G>A in intron 1, IVS38-1G>A in intron 38 and IVS46+5G>A in intron 46. C628delinsK was identified in exon 15 leading to the substitution of a conserved cysteine residue. Furthermore two frameshift mutations were found in exon 15 (1904-1919del ) and exon 63 (8025insC) leading to premature termination codons (PTCs) in exon 17 and 64 respectively. Finally we identified a nonsense mutation (R429X) located in the proline rich domain in exon 10 of the FBN1 gene. Y1101C, IVS46+5G>A and R429X have been reported before., (Copyright 2002 Wiley-Liss, Inc.)

In healthy children plasma ammonia concentrations show values from 12.3 to 57.2 mumol/l (80%-range) (group I). We also measured plasma ammonia in epilepsy patients with valproate therapy (group II) and epilepsy patients treated with other anticonvulsiva (group III). In a fourth group there were children with various cerebral lesions without episodes and without anticonvulsiva therapy. There were significant differences between group I and group II and group II and group IV respectively. But no significant differences were found between the patients who were treated with valproate and the patients with cerebral lesions. The data does not allow the plasma ammonia concentration to be taken as a control parameter in children treated with valproate. Ammonia estimation at the beginning of therapy, however, may be used as risk indicator.

The effects of natural secretin (90%) and synthetic secretin as well as impure (10%) and pure (99%) cholecystokinin-pancreozymin (CCK) on net absorption of water, electrolytes, and glucose in human jejunum were studied in 31 normal subjects. An intestinal perfusion technique with a triple-lumen tube was used. Net absorption of water and solute was significantly inhibited by both hormones only with larger doses, pure CCK being less active than impure CCK. A dose-dependent response of water and electrolyte absorption to graded doses of pure CCK was observed, without concomitant inhibition of glucose absorption with lower doses. The findings suggest that secretin and CCK may not be of physiologic importance regarding intestinal absorption in man. The definite changes in intestinal motility and transit rate caused by these hormones seem more likely to result in a reduction of intestinal absorption and an increase in the secretion of water and electrolytes along the proximal small bowel.

A screening study for coronary disease, chronical bronchitis, diabetes mellitus, hypertension, peripheral circulatory disturbance and overweight is described. 2429 persons aged over 40 years and working in two factories were studied. Typical laboratory tests, a short standardised examination by a physician and a questionnaire were used. In a 10 per cent sample the questionnaire was repeated by an interview and the serum was sent to the laboratory not only by mail, but also by a special car transport in a cooled transport box. The results of the laboratory tests are presend according to age, sex and factory. The family doctor had to be informed in nearly 70 per cent of the men and about 60 per cent of the women because of at least one suspicious symptom or sign. There was a pathological value of glucose in the urine in 14.7 per cent, a rise of glucose in the blood (above 113 mg per cent) in 5.7 per cent, of triglicerides (above 181 mg per cent) in 12.6 per cent, of cholesterol (above 264 mg per cent) in 15.4 per cent, of uric acid (male above 7.7 mg per cent, female above 7.1 mg per cent) in 6.8 per cent, of creatinine (above 1.3 mg per cent) in 6.4 per cent and the presence of albumin in urine in 2.2 per cent of the cases.

Parameters of collagen metabolism were investigated in guinea pigs, both untreated and treated with glucocorticoids. One series consisted of animals housed under normal conditions, the others of SPF animals from the same strain. There are marked differences in certain parameters, including the hydroxyproline content and the reaction of the collagen to glucocorticoids.

The mucosal extracellular space in rat small intestine is determined with inulin-14C, mannitol-14C and unlabeled 2-deoxy-D-glucose in control animals and after an intravenous secretin load. The mannitol and 2-deoxy-D-glucose spaces in control animals are significantly greater than the inulin space. After secretin the three investigated markers show different, in part adverse, alterations of the mucosal extracellular space. These different results may be due to the composition of the incubation medium and to a distinct effect of secretin on the distribution of the employed markers.

The bulk of water and electrolyte absorption takes place in the human jejunum from isotonic solutions, and is determined largely by special transport mechanisms for different monosaccharides, amino acids and dipeptides. This is of considerable significance for regaining the large volumes of fluid delivered to the small intestine during the digestion of food. Small changes in intraluminal pH do not significantly influence the absorptive function of the jejunum and are rapidly compensated by the buffering capacity of the gut. The maintenance of an isotonic as well as neutral intraluminal milieu seems to be essential to the physiological processes of intestinal absorption.

The effects of synthetic human gastric I (SHG I) and gastrin-like pentapeptide (PG) on jejunal water, electrolyte, and glucose absorption were studied in 11 normal subjects. The i.v. administration of graded doses of SHG I increased plasma gastrin levels similar to those after food intake and in the Zollinger-Ellison syndrome. SHG I and PG caused no significant changes in the net movement of water and solute. The findings indicate that gastrin has no direct effect on intestinal absorption in normal man, and does not account for the mechanism of diarrhea in the Zollinger-Ellison syndrome.

The exactitude of some widely used laboratory tests (triglycerids, cholesterol, glucose, uric acid, creatinine) is examined in a situation relevant for practising physicians. Different statistical methods for reporting errors are compared. Accuracy and precision are useful measures for the quality of analytic procedures. They are not sufficient for medical judgement for a single patient, since sampling procedures, type of sample or transport and storage of sample are not considered in accuracy and precision. Such sources of error can largely devaluate the quality of accuracy and precision and of the analytic procedures. Error coefficients are proposed as a new method of reporting laboratory errors. The mathematical model starts with an analysis of variance and total error, technical error and transport error are defined. The study shows that the error introduced by transporting serum via postal service compared to that conveyed in a cooled transport box by a special car is considerable. It is nearly impossible for a physican to use single laboratory value for a rational decision "normal-not normal" if the values are based on samples which are sent by postal service and if the values lie in the broad borderline between the normal and pathological area. This is especially true for creatinine (transport error 47.0 per cent) and uric acid (transport error 38.7 per cent), but not so much for cholesterol (22.9 per cent), triglicerids (14.3 per cent) and glucose (13.3 per cent). Variables with high transport error like creatinine should not be used in screening programs, as long as the transport is made by postal service and the method is not improved. The agreements between the answers of a questionnaire and of an interview are analysed with the same patients (n=235). These agreements lie between 98.7 per cent and 61.7 per cent depending on the single question. The exactitude of medical questionnaires is in the same size order as the exactitude of laboratory tests-at least when the sample is sent by postal service.

Considering the multitude of tests in clinical chemistry and hematology, their low diagnositc sensitivity and specifity, and the low incidence of the diseases in a non selected population it is not possible presently to recommend a general screening procedure based on the definition of the reference, the methodological reproducibility and the diagnostic information of a test procedure it is possible to calculate the number of requests necessary to get any desired number of pathological results. "Tell me how many pathological results you want and I'll tell you how many requests you need". In order to get an optimal diagnostic information for clinical chemistry and hematological tests, it is necessary to increase the prevalence by proper selection of the patients and then to order test procedures specific for the suspected disease.

LP-X was investigated in the serum of 221 patients with and without cholestasis. The diagnostic sensitivity and the diagnostic specificity of the test were 0.9 and 0.88, respectively. When this test is used on a non-selected collective, however, the predictive value of the positive test is very low, whereas negative results have a high diagnostic value. Thus, in practice, LP-X is more suitable for the exclusion, rather than the detection of cholestasis.

The influence of the bacterial flora of the intestine and of cytostatic drugs on the intestinal xylose and glucose absorption in the rat is studied by a perfusion technique in vivo. Conventional, germfree and decontaminated animals show no different xylose absorption rates while the galactose absorption is decreased in germfree and decontaminated animals compared to conventional rats. Three days after a single injection of cytostatic drugs the xylose absorption is diminished in conventional and decontaminated animals compared to untreated rats. In germfree rats no effect of cytostatics on the xylose absorption can be proved. The galactose absorption is unchanged after cytostatics in conventional and decontaminated animals, but increased in germfree rats.

The amylase activity in serum, the amylase excretion and the amylase-creatinine-ratio was investigated in 25 volunteers monthly for one year and daily for two weeks. The intraindividual variation of the amylase-activity in serum showed only small oscillations. The large refernce value of the group and the need to use individual reference values prefer the 24 hour amylase excretion as a diagnostic tool. The amylase-creatinine-ratio showed individual and seasonal large variations. Therefore the ratio is not suitable for diagnostic questions.

In a workshop conference of the German Society for Clinical Chemistry, clinical chemical parameters, which are important in preventive medicine, were discussed for three common diseases, diabetes mellitus, gout and chronic liver diseases. In addition the analytical and diagnostic reliability was evaluated for each of these parameters.

Repeated intravenous injections of 2.0 clinical units (CU) secretin per kg body weight showed no effect on jejunal glucose absorption and net water movement in perfusion studies in vivo. The in vitro uptake of galactose and 3-O-methylglucose was not altered by a secretin load given 12 min before sacrifice. The values for Km and Vmax were identical after secretin and in a control group. The conflicting results of different authors concerning the effect of secretin on net water movement and solute absorption may be due to differences in experimental techniques, different, mostly pharmacological doses of the hormone, and a diverse response of heterogeneous species.

Specific pathogen free guinea pigs were treated with varying dosis of fluocortolone for 15 days. The treated animals showed the same per cent weight gain as the controls. The total hydroxyproline content of the skin and the hydroxyproline content in different collagen fractions was the same in treated and untreated animals. Thus fluocortolone seems to have no specific effect on the synthesis or the breakdown of collagen in the guinea pig skin. Also the physical development of the animals, kept under defined conditions, failed to show a catabolic effect of of fluorcortolone.

The uptake of the shortest six fatty acids (acetic to octanoic) was studied in vitro, using everted segments of rat jejunum. The marked influence of medium-pH and fatty acid chain-length suggests that non-ionic diffusion through the lipoid membrane is quantitatively the most important way of transport, but ionic diffusion through the membrane as well as transport through hydrophilic pores also seem to play a role. Though fatt acids evidently are accumulated in the tissue-fluid, and saturation kinetics, competitive inhibition and sodium- as well as energy-dependence apparently are observed, the transport mechanism is assumed to involve solely passive diffusion, - the concept of a carrier-mediated transport for short and medium chain fatty acids seems improbable.

The seasonal, intra- und interindividual variation of the creatinine and urea concentrations in serum and urine and the clearances of these compounds were examined monthly for one year in 25 healthy volunteers. In contrast to the other parameters (serum urea, clearance and excretion of creatinine and urea), the variations in serum-creatinine concentration were small and statistically unsignificant. The variations of the urinary excretion and the clearance of creatinine and urea is due to seasonal variations in the output of the kidney.

A rat jejunal segment of 15 cm length was perfused single pass with a 3 mmol/l sucrose solution 4 times daily at 8.00, 14.00, 20.00 and 2.00. One group of rats was fed ad libitum, a second group was "meal fed" between 14.00 and 18.00. Sucrose absorption reached its maximum at 8.00 in the rats fed ad libitum whereas it was spread over a period of six hours (20.00-2.00) in the meal fed rats. The activity of sucrase in mucosal scrapings reached its peak at feeding time.

After an oral load of 10 g polyethylene glycol, its concentration in the urine was measured by gas chromatography. The coefficient of variation of the imprecision between run was about 11%. The urinary excretion was 25% of the administered dose with a coefficient of variation of the interindividual variation 26% and the intraindividual variation between 13% and 29%.

The influence of circulatory conditions, point of blood withdrawal (arterial, central or peripheral venous) and the plasma-serum relation on 29 clinical chemical and hematological parameters were studied with 22 polytraumatized patients. The conditions studied significantly affect the results, and must be taken into consideration in evaluating the results and their comparison to reference values. This is especially important for the determination of the catalytic activities of creatine kinase, aspartate and alanine aminotransferases, and alkaline phosphatase in centralized-circulatory patients, for the total protein the electrophoretic fractions and analyses of blood gas as a function of the point of blood withdrawal, and for the total protein, gamma-globulins and potassium when plasma is analysed instead of serum.

Widely used methods in diagnostical and experimental gastroenterology like measuring the protein-and DNA-content and the activity of alkaline phosphatase and sucrase of intestinal mucosa were adapted to a microliter system and partly automatized. With "artificial" control material a system for statistical quality control was established. Lastly the results on up to three years experience with this control system were presented showing an imprecision within run below 5% and an in-imprecision between run below 8% in all methods.