ECFS standards of care on CFTR-related disorders: Diagnostic criteria of CFTR dysfunction.

The spectrum of disorders involving CFTR (cystic fibrosis transmembrane conductance regulator) dysfunction correlates with a continuous gradient of CFTR function defined by the combination of two allelic CFTR variants. CFTR-related disorders are clinical entities with features of cystic fibrosis (CF) and evidence for presence of CFTR dysfunction but not meeting criteria for diagnosis of CF. Individuals with CFTR-RDs demonstrate a wide range of CFTR activity and are still under-recognized or misclassified. The level of CFTR dysfunction may be measured in vivo (sweat testing, nasal potential difference measurements) and/or by ex vivo tests (intestinal current measurement), or indirectly indicated by CFTR variants, as alteration in sequence of the CFTR gene translates into CFTR dysfunction. CFTR bioassays can aid in the diagnosis of individuals with CF, but we lack parameters to differentiate CF from CFTR-RD. In the era of the CFTR modulators and their potential clinical benefit, it is of utmost importance to diagnose CFTR-RD as unambiguously as possible. We therefore propose the following to define compatible CFTR dysfunction in a person with a suspected diagnosis of CFTR-RD : (1) evidence of CFTR dysfunction in vivo or ex vivo in at least two different CFTR functional test types, or (2) One CFTR variant known to reduce CFTR function and evidence of CFTR dysfunction in vivo or ex vivo in at least two different CFTR functional test types, or (3) Two CFTR variants shown to reduce CFTR function, with at most one CF-causing variant.

Functional Restoration of CFTR Nonsense Mutations in Intestinal Organoids.

BACKGROUND: Pharmacotherapies for people with cystic fibrosis (pwCF) who have premature termination codons (PTCs) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are under development. Thus far, clinical studies focused on compounds that induce translational readthrough (RT) at the mRNA PTC location. Recent studies using primary airway cells showed that PTC functional restoration can be achieved through combining compounds with multiple mode-of-actions. Here, we assessed induction of CFTR function in PTC-containing intestinal organoids using compounds targeting RT, nonsense mRNA mediated decay (NMD) and CFTR protein modulation. METHODS: Rescue of PTC CFTR protein was assessed by forskolin-induced swelling of 12 intestinal organoid cultures carrying distinct PTC mutations. Effects of compounds on mRNA CFTR level was assessed by RT-qPCRs. RESULTS: Whilst response varied between donors, significant rescue of CFTR function was achieved for most donors with the quintuple combination of a commercially available pharmacological equivalent of the RT compound (ELX-02-disulfate or ELX-02ds), NMD inhibitor SMG1i, correctors VX-445 and VX-661 and potentiator VX-770. The quintuple combination of pharmacotherapies reached swelling quantities higher than the mean swelling of three VX-809/VX-770-rescued F508del/F508del organoid cultures, indicating level of rescue is of clinical relevance as VX-770/VX-809-mediated F508del/F508del rescue in organoids correlate with substantial improvement of clinical outcome. CONCLUSIONS: Whilst variation in efficacy was observed between genotypes as well as within genotypes, the data suggests that strong pharmacological rescue of PTC requires a combination of drugs that target RT, NMD and protein function.

Effect of adding B-vitamins to vitamin D and calcium supplementation on CpG methylation of epigenetic aging markers.

BACKGROUND AND AIM: B-vitamins may influence DNA methylation. We studied the effects of vitamin D + Ca + B versus D + Ca on epigenetic age markers and biological age. METHODS AND RESULTS: Participants (mean ± SD of age = 68.4 ± 10.1 years) were randomized to receive 1200 IE vitamin D3 plus 800 mg Ca-carbonate alone (n = 31) or with 0.5 mg B9, 50 mg B6, and 0.5 mg B12 (n = 32). The CpG methylation of 3 genes (ASPA, ITGA2B, and PDE4C) and the changes in methylation were compared between the groups after 1 year. The changes of ASPA methylation from baseline were higher in the D + Ca + B than in the D + Ca group (1.40 ± 4.02 vs. -0.96 ± 5.12, respectively; p = 0.046, adjusted for age, sex, and baseline methylation). The changes in PDE4C from baseline were slightly higher in the D + Ca + B group (1.95 ± 3.57 vs. 0.22 ± 3.57; adjusted p = 0.062). Methylation of ITGA2B and its changes from baseline were not different between the intervention groups. Sex-adjusted odds ratio of accelerated aging (chronological age < biological age at 1 year) was 5.26 (95% confidence interval 1.51-18.28) in the D + Ca + B compared with the D + Ca group. Accelerated aging in both groups was associated with younger age. In the D + Ca + B group, it was additionally associated with lower baseline homocysteine. CONCLUSIONS: Vitamin D + Ca + B and D + Ca differentially affected epigenetic age markers, although the effect size appeared to be small after 1 year. B-vitamins effect in young subjects with low homocysteine requires further investigation. ClinicalTrials.gov ID: NCT02586181.

CCR6/CCL20 chemokine expression profile in distinct colorectal malignancies.

Originally, chemokines and their G-protein-coupled receptors were described to regulate multiple physiological functions, particularly tissue architecture and compartment-specific migration of white blood cells. Now, it is established that the chemokine/chemokine receptor system is also used by cancer cells for migration and metastatic spread. Here, we examined the relative levels of CC-chemokine CCL20 and its corresponding receptor CCR6 in resection specimens from patients with different malignant and non-malignant colorectal diseases as well as in colorectal liver metastases (CRLM). CCL20/CCR6 mRNA and protein expression profiles were assessed by quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) in resection specimens from patients with ulcerative colitis (UC, n = 15), colorectal adenoma (CRA, n = 15), colorectal adenocarcinoma (CRC, n = 61) and colorectal liver metastases (CRLM, n = 16). Corresponding non-diseased tissues served as control. In contrast to UC tissues, the CCL20/CCR6 system showed a distinct upregulation in CRA, CRC and CRLM related to corresponding non-affected tissues (P < 0.05, respectively). Furthermore, CRA, CRC and CRLM tissue samples displayed significantly higher protein amounts of CCL20 in comparison with UC specimens (P < 0.05, respectively). Our results strongly suggest an association between CCL20/CCR6 expression and the induction of CRA, CRC and the development of CRLM. Therefore, CCL20 and CCR6 may provide potential targets for novel treatment strategies of CRC.

A scoring system for the assessment of angiographic findings in non-occlusive mesenteric ischemia (NOMI).

PURPOSE: To establish a standardized scoring system for angiographic findings in patients with non-occlusive mesenteric ischemia (NOMI). MATERIALS AND METHODS: In 36 patients (mean age: 72 years), 53 angiographies of the superior mesenteric artery (SMA) were performed for suspected NOMI after cardiac or major aortic surgery. All examinations were performed using a standardized DSA technique. Two experienced radiologists performed a consensus reading blinded to the clinical information, on two occasions with an interval of two weeks. In order to investigate the reproducibility of the criteria, the images were assessed once by an intensivist and a medical student. Image analysis was performed with respect to vessel morphology, reflux of contrast medium into the aorta, small bowel parenchymal contrast enhancement and distension and the delay between arterial injection and portal vein filling. RESULTS: Almost perfect intra-observer correlation was obtained for the assessment of the contrast medium reflux (κ = 0.82) and substantial correlation for the time of portal vein filling (κ = 0.66). Moderate correlations were obtained for the vessel morphology (κ = 0.51), small bowel enhancement (κ = 0.63) and distension (κ = 0.53). Contrast medium reflux into the aorta (κ = 0.77 and 0.63) and the time of portal vein filling (κ = 0.42 and 0.58) resulted in the highest inter-observer correlations between the radiologists and the intensivist as well as the radiologists and the student. CONCLUSION: In patients with suspected NOMI, using our scoring system yields high intra- and inter-observer correlations, allowing a standardized evaluation of angiographic findings.

Acupuncture to alleviate chemotherapy-induced nausea and vomiting in pediatric oncology - a randomized multicenter crossover pilot trial.

BACKGROUND: We investigated whether acupuncture as a supportive antiemetic approach reduces the need for antiemetic rescue medication during highly emetogenic chemotherapy in pediatric oncology. We report on a multicenter crossover study at 5 tertiary hospitals in Germany. PROCEDURE: Twenty-three children (13.6 y,+/- 2.9) receiving highly emetogenic chemotherapy for treatment of solid malignant tumors were included. Patients were randomly allocated to receive acupuncture treatment during either the second or third identical chemotherapy course together with standard antiemetic medication. The main outcome measure was the amount of additional antiemetic medication during chemotherapy. Secondary outcome measure was the number of episodes of vomiting per course. RESULTS: Fourty-six chemotherapy courses with or without acupuncture were compared. The need for rescue antiemetic medication was significantly lower in acupuncture courses compared to control courses (p=0.001) Episodes of vomiting per course were also significantly lower in courses with acupuncture (p=0.01). Except for pain from needling (4/23) no side effects occurred. Patients acceptance of acupuncture was high. CONCLUSIONS: Acupuncture as applied here seems to be effective in preventing nausea and vomiting in pediatric cancer patients.

Clinical pathways in general surgery. Development, implementation, and evaluation.

OBJECTIVES: To emphasize the importance of the view of business process management for development and implementation of clinical pathways, and to evaluate their effectiveness in reducing cost and effort as well as enhancing patient satisfaction. METHODS: We describe the development and implementation of pathways with methods of process management and the design and realization of an evaluation study in the setting of a surgical department. For this study 67 patients treated without clinical pathways were compared with 62 patients treated using pathways. RESULTS: The approach explicitly enhances the development and implementation of clinical pathways. The introduction of pathways reduces length of hospital stay, number of laboratory tests, number of consultations, and number of imaging procedures. Patient satisfaction is improved. CONCLUSIONS: Depending on design and setting, the introduction of clinical pathways may be a very promising method to improve the inpatient service at a hospital and so to react to the challenges of increasing competition in medical care.

Use of HL7 to integrate a HIS-subsystem: limits and possibilities.

Modern computer-based hospital information systems are mostly distributed with several heterogeneous subsystems connected together by specialized communication services. The common standard to integrate subsystems is HL7. By the example of subsystem integration for a pulmonary function test lab, we discuss the possibilities of HL7, the limits we encountered and how we overcame these.

How to select a clinical information system.

Modern computer-based hospital information systems are mostly distributed with several information subsystems connected together by communication services. A single subsystem may be developed or purchased ("make" or "buy"). Before the purchase of hard- and software it is necessary to check out whether the product fits the requirements concerning the functionality and especially the integration in the hospital information system. This selection process is difficult and tedious and requires thus a simple and flexible technique. An appropriate approach for the comparison of clinical information systems before implementation based on the SMARTER method is described here, in hospital and its practicability is demonstrated with an example.

Expression pattern of galectin-3 in neural tumor cell lines.

Galectin-3 is a member of the galectin family of beta-galactoside-specific animal lectins. Here we show that galectin-3 is constitutively expressed in 15 out of 16 glioma cell lines tested, but not by normal or reactive astrocytes, oligodendrocytes, glial O-2A progenitor cells and the oligodendrocyte precursor cell line Oli-neu. Galectin-3 is also expressed by one oligodendroglioma cell line, but not by primitive neuroectodermal tumor and 4 neuroblastoma cell lines tested so far. In all galectin-3 expressing cell lines, the lectin is predominantly, if not exclusively, localized intracellularly and carries an active carbohydrate recognition domain (shown for C6 rat glioma cells). Moreover, in contrast to primary astrocytes, glioma cells do not or only weakly adhere to substratum-bound galectin-3, probably reflecting an unusual glycosylation pattern. Our findings indicate that the expression of galectin-3 selectively correlates with glial cell transformation in the central nervous system and could thus serve as a marker for glial tumor cell lines and glial tumors.

Clinical workstations supporting evidence-based medicine.

The application of the principles of evidence-based medicine is based on a rigorous analysis of clinical research tailored to the individual characteristics of a specific patient. Thus the physician must have information about the patient and about the latest results of clinical research simultaneously. We present a computer-based clinical workstation offering sources for both kinds of information: the current patient data is delivered by access to the electronic patient record and the results of research may be searched at the Internet, Intranet, or other online databases. Performing an evaluation study we are testing this configuration in the setting of a university hospital. The physicians are interviewed about their use of the single information sources and their consequences for clinical research and evidence-based medicine. We hope to show that in spite of some technical and methodological problems the clinical workstation is a promising tool for decision-making at the clinical workplace.

Medical information processing: an interactive course for the Internet.

Medical students in Germany have to study the basics of medical information processing within a special curriculum which is part of the ecological course. This curriculum offers an introduction to principles of medical informatics. Starting with a conventional textbook, a computer-based training (CBT) program has been developed using the technologies of the internet and the World Wide Web (WWW). Features of the program include a well structured presentation of the information within the software and a high degree of interactivity. Early experiences suggest that this program enhances the learning in the domain of medical information processing. The program may be viewed via the URL: htfp.//www.med-rz.uni-sb.de/med_fak/imbei/pro jekt.

Connexin transfection induces invasive properties in HeLa cells.

Gap-junctional coupling of tumor cells facilitates their invasion into normal tissue as was further investigated with connexin-transfected HeLa cells by an in vitro assay. Wild-type HeLa cells are coupling deficient and did not show invasive properties when multicell spheroids were confronted with precultured embryonic chicken heart fragments. After transfection with cDNA of Cx31, Cx40, or Cx43, these cells were homotypically coupled; Cx40- and Cx43-transfected HeLa cells also were heterotypically coupled with embryonic chicken heart cells in monolayer coculture. Transfected clones revealed invasive properties in the chicken heart in vitro assay. However, the pattern of invasion differed between these transfectants: After 4 days Cx43-transfected HeLa cells were found in the central part of heart spheroids; Cx40- and Cx31-transfected HeLa cells, however, did not invade the central core but were detected in the outer part of heart spheroids. We conclude that connexin expression supports invasion of tumor cells into normal tissue, but heterotypic gap-junctional coupling is not required for this process.

Application of clinical workstations: functionality and usability.

Clinical workstations are software systems that support physicians and nurses in all their specific activities concerned with the medical care of inpatients. In the university hospital of Saarland, we are testing several commercial systems so as to whether they can give such comprehensive support. For their evaluation, we developed a list of criteria grouped in functions to support the physicians, functions to support the nurses, and general functions, together with a grading schema. Besides scope and quality of functions, the acceptance of clinical workstations strongly depends on organizational environment and human factors. To evaluate these conditions, we interviewed all people concerned with the system, using a checklist. The following are examples of problems that we detected: "Facts" (new design of work flow, eg, for examination or nursing procedures); some tasks have to be performed twice; reaction to emergencies; frequent changes of staff. Technical deficiencies (response times too long; mobile data collection was insufficient due to width of display and lack of data consistency, eg, during the doctor's visit). Psychological factors (fear of using computers; statements such as "Medical work cannot be planned" or "Too few benefits from the system"; in view of increasing "transparency," no use for electronic scheduling; insufficient understanding of work flow of automated tasks). The consequences of this study are the introduction of clinical workstations in hospital needs, as well as reengineering the business processes of the ward as a careful and intensive training of staff. This article will present and discuss methods and results of this evaluation study.

Communication services for a distributed hospital information system.

Planning principles and development are described of a communication server which controls and performs all information exchange between distributed and heterogeneous applications in a hospital information system. The analysis is based on business process modeling. At present, the core of the server uses a commercial product (Cloverleaf). This allows to connect both old systems with no or few interface features and new systems with modern interface facilities (such as HL7). Prerequisites, functions, and configuration of the server software are described in detail. Experiences, advantages, and disadvantages are discussed.

Object-oriented modeling of hospital information systems.

We have chosen an object-oriented approach for the modeling of a hospital information system; this avoids some disadvantages of the classic methods (i.e., a combination of Structured Analysis and Entity-Relationship-Model). The primary goal of this procedure was to find and represent the needs of communication in the computer-based part of the information system and, with that, to configure an information server that handles all the interactions. Furthermore, we wanted to develop communication interfaces for the application programs on an object-oriented level.

Human atrial natriuretic peptide in patients with type 1 diabetes mellitus: is it related to the development of diabetic nephropathy?

There is controversy as to whether increased plasma levels of human atrial natriuretic peptide (hANP) in patients with type 1 diabetes mellitus may contribute to the development of diabetic nephropathy. Therefore, we decided to conduct two studies to examine the relationship of hANP levels to urinary albumin excretion and blood pressure. In a cross-sectional study, 83 randomly selected type 1 diabetic patients were investigated. 19 of the patients had increased urinary albumin excretion. 45 healthy volunteers served as controls. In a longitudinal study, 19 type 1 diabetic patients were examined for one year at monthly intervals. An increased risk of eventually developing diabetic nephropathy was identified in 7 out of these patients by repeatedly revealing increased urinary albumin excretion. On the average, hANP levels were increased in type 1 diabetic patients in comparison to controls (P < 0.001). In both studies, hANP levels were positively related (P < 0.05) to mean arterial blood pressure. There was no correlation between hANP levels and metabolic control. hANP levels lay within normal range irrespective of normal or elevated urinary albumin excretion provided that mean arterial blood pressure was normal. In the longitudinal study, increased urinary albumin and alpha-1-microglobulin excretion preceded the increase in both hANP levels and mean arterial blood pressure. Although hANP levels were evidently not related to the disease mechanisms of early diabetic nephropathy, it is tempting to speculate that hANP may contribute to the vicious circle connecting diabetic kidney disease to hypertension once that its levels are increased by elevated blood pressure.

[The role of human atrial natriuretic peptide on pathogenesis of nephropathy in patients with type I diabetes mellitus]. / Zum Einfluss des humanen atrialen natriuretischen Peptids auf die Pathogenese der Nephropathie bei Patienten mit Typ-I-Diabetes mellitus.

Divergent findings in recent clinical and experimental studies have caused considerable controversy as to whether or how elevated plasma levels of human atrial natriuretic peptide (hANP) may contribute to the pathogenesis of diabetic nephropathy in type I diabetic patients. Therefore, we decided to examine potential changes of urinary albumin excretion (UAE), urinary excretion of alpha-1-microglobulin (A-1-M), mean arterial blood pressure (MAP), hANP levels, creatinine clearance and HbA1 in the course of a prospective one-year study in 19 patients (13 females, six males, age 29 +/- 2 years). All patients had intensified insulin treatment. Seven patients at increased risk for eventually developing nephropathy (group 1) were identified by repeatedly showing elevated UAE ( > 30 mg/24 h). The other patients served as controls (group 2). Patients in group 1 differed from those in group 2 in increased A-1-M (maximal difference, 10.1 +/- 1.5 vs. 5.5 +/- 1.0 mg/l, p < 0.01). In the second half of the study, 43% of the MAP measurements in group 1 exceeded 100 mmHg in comparison to 19% in group 2 (p < 0.01). Simultaneously, 38% of the hANP levels in plasma in group 1 were higher than 25 pg/ml (upper limit of normal range) in comparison to 15% in group 2 (p < 0.05). There were no differences in creatinine clearance between both groups. 58% of the HbA1 concentrations measured in group 1 in the course of the study exceeded 8.5% in comparison to 47% in group 2 (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)