[Our moral ancestors: determining adjustment sets in causal diagrams with ease]. / Die moralischen Vorfahren: Adjustierungsmengen in Kausaldiagrammen schnell und einfach berechnen.

This article is concerned with the application of causal diagrams (also called DAGs) to the following 2 tasks, which are often faced in epidemiology: (1) a posteriori verification of the adjustment performed in an empirical study; (2) a priori identification of appropriate covariate sets for adjustment during study design. Causal diagram theory provides several methods for solving both of these tasks. However, some of these methods are computationally highly demanding, and thus cannot be carried out by hand and even pose problems for fast modern computers. In order to ease everyday work with causal diagrams, we discuss here the most efficient method known to date for performing the stated tasks. This method is based on the so-called "ancestor moral graph" construction by Lauritzen et al. and enables epidemiologists to solve at ease even large causal diagrams with dozens of variables and associations. Moreover, the presented method is well-suited for implementation in computer software, like it has been done in the DAG program and its graphical counterpart DAGitty.

Adrenal insufficiency is a contraindication for omalizumab therapy in mast cell activation disease: risk for serum sickness.

Omalizumab is an effective therapeutic humanized murine IgE antibody in many cases of primary systemic mast cell activation disease (MCAD). The present study should enable the clinician to recognize when treatment of MCAD with omalizumab is contraindicated because of the potential risk of severe serum sickness and to report our successful therapeutic strategy for such adverse event (AE). Our clinical observations, a review of the literature including the event reports in the FDA AE Reporting System, the European Medicines Agency Eudra-Vigilance databases (preferred search terms: omalizumab, Xolair®, and serum sickness) and information from the manufacturer's Novartis database were used. Omalizumab therapy may be more likely to cause serum sickness than previously thought. In patients with regular adrenal function, serum sickness can occur after 3 to 10 days which resolves after the antigen and circulating immune complexes are cleared. If the symptoms do not resolve within a week, injection of 20 to 40 mg of prednisolone on two consecutive days could be given. However, in MCAD patients whose adrenal cortical function is completely suppressed by exogenous glucocorticoid therapy, there is a high risk that serum sickness will be masked by the MCAD and evolve in a severe form with pronounced damage of organs and tissues, potentially leading to death. Therefore, before the application of the first omalizumab dose, it is important to ensure that the function of the adrenal cortex is not significantly limited so that any occurring type III allergy can be self-limiting.

The tumour microenvironment shapes dendritic cell plasticity in a human organotypic melanoma culture.

The tumour microenvironment (TME) forms a major obstacle in effective cancer treatment and for clinical success of immunotherapy. Conventional co-cultures have shed light onto multiple aspects of cancer immunobiology, but they are limited by the lack of physiological complexity. We develop a human organotypic skin melanoma culture (OMC) that allows real-time study of host-malignant cell interactions within a multicellular tissue architecture. By co-culturing decellularized dermis with keratinocytes, fibroblasts and immune cells in the presence of melanoma cells, we generate a reconstructed TME that closely resembles tumour growth as observed in human lesions and supports cell survival and function. We demonstrate that the OMC is suitable and outperforms conventional 2D co-cultures for the study of TME-imprinting mechanisms. Within the OMC, we observe the tumour-driven conversion of cDC2s into CD14+ DCs, characterized by an immunosuppressive phenotype. The OMC provides a valuable approach to study how a TME affects the immune system.

Adjustment for time-invariant and time-varying confounders in 'unexplained residuals' models for longitudinal data within a causal framework and associated challenges.

'Unexplained residuals' models have been used within lifecourse epidemiology to model an exposure measured longitudinally at several time points in relation to a distal outcome. It has been claimed that these models have several advantages, including: the ability to estimate multiple total causal effects in a single model, and additional insight into the effect on the outcome of greater-than-expected increases in the exposure compared to traditional regression methods. We evaluate these properties and prove mathematically how adjustment for confounding variables must be made within this modelling framework. Importantly, we explicitly place unexplained residual models in a causal framework using directed acyclic graphs. This allows for theoretical justification of appropriate confounder adjustment and provides a framework for extending our results to more complex scenarios than those examined in this paper. We also discuss several interpretational issues relating to unexplained residual models within a causal framework. We argue that unexplained residual models offer no additional insights compared to traditional regression methods, and, in fact, are more challenging to implement; moreover, they artificially reduce estimated standard errors. Consequently, we conclude that unexplained residual models, if used, must be implemented with great care.

Prostate cancer tissue is masked by bicalutamide: a case report.

Prostate cancer is the most common malignant tumor in men. Recently, a slightly decreased frequency of margin positivity following neoadjuvant bicalutamide treatment due to tumor shrinkage was reported. Trials investigating other anti-androgens in the past also reported lower frequencies of surgical margin positivity, but patients outcome has not improved. In this case, local recurrence was confirmed by needle biopsy in a patient five years following radical prostatectomy for prostate adenocarcinoma. After therapy with 50 mg bicalutamide for a month, the tumour was resected. Despite of detailed histological work-up and immunohistochemistry cancer suspicious lesions were not found. We think that bicalutamide may be capable of masking prostate cancer cells.

Renal agenesis in an alpaca cria.

A 4-day-old alpaca cria presented for inappetence that responded to symptomatic treatment. The cria re-presented with acute signs of inappetence and azotaemia. The azotaemia persisted despite intravenous fluid therapy. There was no right kidney on ultrasound and there appeared to be perirenal oedema around the left kidney. A diagnosis of right renal agenesis and acute renal failure of the left kidney was made. The cria failed to improve and was euthanased. Necropsy examination confirmed right renal agenesis and agenesis of the right ureter and right renal artery. A section of left kidney submitted for histological examination revealed diffuse, acute, marked tubular degeneration and nephrosis. The cause of the renal failure in the left kidney was not determined.

Aggressive angiomyxoma of the prostate mimicking benign prostatic hyperplasia.

Aggressive angiomyxoma (AAM) is a locally invasive soft tissue tumor with a high risk of local recurrence but without metastatic spread. The mesenchymal tumor is relatively site-specific and has a peak incidence in females in their 2nd or 4th decade. Only few cases in males have been reported in the literature. We describe what we think is the first case of an aggressive angiomyxoma arising in the prostate presenting with classical symptoms of benign prostatic hyperplasia.

Lactic acid secretion by human neutrophils. Evidence for an H+ + lactate- cotransport system.

The pathway by which L-lactate (Lac) crosses the plasma membrane of isolated human neutrophils was investigated. The influx of [14C]Lac from a 2 mM Lac, 145 mM Cl-, 5.6 mM glucose medium was approximately 1.5 meq/liter of cell water.min and was sensitive to the organomercurial agent mersalyl (apparent Ki approximately 20 microM), to alpha-cyano-4-hydroxycinnamate (CHC), the classical inhibitor of monocarboxylate transport in mitochondria, and to UK-5099 (apparent Ki approximately 40 microM), a more potent analogue of CHC. Transport was also strongly blocked (greater than 80%) by 1 mM of either 3,5-diiodosalicylic acid, MK-473 (an indanyloxyacetate derivative), or diphenyl-amine-2-carboxylate, and by 0.4 mM pentachlorophenol, but not by 1 mM ethacrynic acid, furosemide, or the disulfonic stilbenes SITS or H2DIDS. One-way [14C]Lac efflux from steady-state cells amounted to approximately 6 meq/liter.min and was likewise affected by the agents listed above. Influx, which was membrane potential insensitive and Na+ independent, displayed a strong pH dependence: extracellular acidification enhanced uptake while alkalinization inhibited the process (pK' approximately 5.7 at 2 mM external Lac). The rate of [14C]Lac influx was a saturable function of external Lac, the Km being approximately 7 mM. Steady-state cells exhibited an intracellular Lac content of approximately 5 mM and secreted lactic acid into the bathing medium a a rate of approximately 4 meq/liter.min. Secretion was completely suppressed by 1 mM mersalyl which inactivates the carrier, leading to an internal accumulation of Lac. That the Lac carrier truly mediates an H+ + Lac- cotransport (or formally equivalent Lac-/OH- exchange) was documented by pH-stat techniques wherein an alkalinization of poorly buffered medium could be detected upon the addition of Lac; these pH changes were sensitive to mersalyl. Thus, the Lac carrier of neutrophils possesses several features in common with other monocarboxylate transport systems in erythrocytes and epithelia.

Blood and Cerebrospinal Fluid α-Tocopherol and Selenium Concentrations in Neonatal Foals with Neuroaxonal Dystrophy.

BACKGROUND: Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (NAD/EDM) is a neurodegenerative disorder affecting genetically predisposed foals maintained on α-tocopherol (α-TP)-deficient diet. OBJECTIVE: Intramuscular α-TP and selenium (Se) administration at 4 days of age would have no significant effect on serum or cerebrospinal fluid (CSF) α-TP in healthy foals. Serum and CSF α-TP, but not Se, would be significantly decreased in NAD/EDM-affected foals during first year of life. ANIMALS: Fourteen Quarter horse foals; 10 healthy foals supplemented with 0.02 mL/kg injectable α-TP and Se (n = 5) or saline (n = 5) at 4 days of age and 4 unsupplemented NAD/EDM-affected foals. METHODS: Complete neurologic examinations were performed, blood and CSF were collected before (4 days of age) and after supplementation at 10, 30, 60, 120, 180, 240, and 360 days of age. Additional blood collections occurred at 90, 150, 210, and 300 days. At 540 days, NAD/EDM-affected foals and 1 unsupplemented healthy foal were euthanized and necropsies performed. RESULTS: Significant decreases in blood, CSF α-TP and Se found in the first year of life in all foals, with most significant changes in serum α-TP from 4-150 days. Dam α-TP and Se significantly influenced blood concentrations in foals. Injection of α-TP and Se did not significantly increase CSF Se, blood or CSF α-TP in healthy foals. NAD/EDM-affected foals had significantly lower CSF α-TP through 120 days. CONCLUSIONS AND CLINICAL IMPORTANCE: Injection of α-TP and Se at 4 days of age does not significantly increase blood or CSF α-TP. Despite all 14 foals remaining deficient in α-TP, only the 4 genetically predisposed foals developed NAD/EDM.

Lymphatic Interventions for Treatment of Chylothorax.

PURPOSE: To determine effectiveness of lymphatic interventional procedures for treatment of chylothorax. MATERIAL AND METHODS: Analysis of interventions performed from 2001 to 2014. RESULTS: In 21 patients with therapy resistant chylothorax a lymphatic radiological intervention was attempted, which could be performed in 19 cases: 17 thoracic duct embolizations (15 transabdominal, one transzervical and one retrograde transvenous procedure), 2 percutaneous destructions of lymphatic vessels, one CT-guided injection of ethanol next to a duplicated thoracic duct. Fourteen of seventeen (82.3 %) of the technically successful embolizations lead to clinical cure. This encluded three patients with prior unsuccessful surgical thoracic duct ligation. Also the injection of ethanol was clinically effective. Complications were a bile peritonitis requiring operation, and one clinical deterioration of unknown cause. CONCLUSION: Interventional lymphatic procedures allow for effective treatment in many cases of chylothorax, and should be considered early during treatment. KEY POINTS: • Thoracic duct embolization is an effective treatment method for chylothorax. • If embolization is impossible, percutaneous lymphatic destruction or injection of sclerosants/tissue adhesive next to the thoracic duct may be tried.

Infantile fibromatosis of the neck with intracranial involvement: MR and CT findings.

CT and MR imaging studies were performed in a 3-year-old boy with infantile fibromatosis arising from the infratemporal fossa and extending into the middle cranial fossa. On CT scans, the lesion was hyperattenuating (44-49 Hounsfield units [HU]), enhancing significantly after application of contrast material (63-66 HU). The MR images showed a multilobulated lesion of heterogeneous signal intensity. The tumor was markedly hypointense on T2-weighted images and slightly hypointense on T1-weighted images relative to brain tissue, iso- or slightly hyperintense relative to tongue muscle on both T2- and T1-weighted images, and enhanced strongly after administration of gadopentetate dimeglumine.

[Value of selective MIP reconstructions in respiratory triggered 3D TSE MR-cholangiography on a workstation in comparison with MIP standard projections and single-shot MRCP]. / Stellenwert selektiver MIP-Rekonstruktionen einer atemgetriggerten 3D-TSE-MR-Cholangiographie an einer Workstation gegenüber den MIP-Standardprojektionen und einer Single-Shot-MRCP.

PURPOSE: Comparison of anatomical visualisation and diagnostic value of selective MIP reconstructions of respiratory triggered 3D-TSE-MRCP versus standard MIP reconstructions and single-shot MRCP. MATERIAL AND METHODS: 50 patients with pancreaticobiliary disease were examined at 1.5 Tesla (ACS NT II, Philips Medical Systems) using a breath-hold single-shot (SS) and a respiratory triggered 3D-TSE-MRCP technique in 12 standard MIP projections. Additional selective MIP reconstructions with different slice thickness (2, 4, 10 cm) and projections were performed on a workstation. Visualization of the pancreaticobiliary system and the diagnostic value of the examinations were analysed. RESULTS: Single-shot and 3D-TSE in standard projections showed comparable anatomical visualisation. On selective MIP reconstructions the biliary system (SS p < 0.002; 3D-TSE p < 0.000) and the periampullary region (SS p < 0.000; 3D-TSE p < 0.003) were more clearly seen than on SS and standard MIP reconstructions. Furthermore, superior visualisation of the pancreatic duct could be achieved with additional selective MIP reconstructions in contrast to standard MIP (p < 0.003). Sensitivity and diagnostic accuracy showed superior results for selective and standard MIP reconstructions, but no significant differences between the three techniques were found. CONCLUSION: SS and standard MIP reconstructions showed comparable anatomical visualisation. Selective MIP postprocessing on a workstation offers a better visualisation of the pancreaticobiliary system and is useful for detecting pathological alterations.

[DIL vena cava filter. Initial experiences in 15 patients]. / DIL Vena-Cava-Filter. Erste Erfahrungen bei 15 Patienten.

DIL filters were permanently inserted through the cubital vein, using a 7-F catheter, in 15 patients and were followed up for six months in 12 patients. One filter could not be opened and 4 others were only partly open. Clinically there were no recurrences of pulmonary emboli. There were no complications from the correctly placed filters. Amongst the 4 incompletely expanded filters, two caused perforation of the cava, in one the cava thrombosed and in another the filter migrated to the bifurcation of the pulmonary artery. It follows that unexpanded filters should not be placed in the cava. Measurements in 10 patients showed the cava reduced to less than 10 mm lumen. In two cases the reduction of lumen was only slight, measuring more than 15 mm. The effect of the reduction in the lumen remains to be compared with that achieved by other filters.

[Magnetic resonance tomography of the kidney: the testing of new pulse sequences and comparison with CT in the differential diagnosis of space-occupying lesions]. / Magnetresonanztomographie der Niere: Erprobung neuer Pulssequenzen und Vergleich mit der CT in der Differentialdiagnose von Raumforderungen.

PURPOSE: To evaluate new pulse sequences (turbo-spin-echo [TSE] and turbo-field-echo [TFE] sequences) for study protocol optimisation and to assess the role of MRI in the differential diagnosis of renal tumours. METHODS: In six volunteers MRI of the kidney was performed at 0.5 T using a conventional T2 weighted spin-echo (SE) sequence (TR/TE 1800/90 ms) and three different TSE sequences (TR 1800-5000 ms, TE 90-150 ms). Additionally CT and MRI was performed in 34 patients with 41 renal masses. Two readers evaluated both images regarding the differentiation between malignant and benign masses. RESULTS: The pilot study showed that the heavily T2-weighted TSE sequence (TR/TE 5500/150 ms) was superior to other sequences with regard to image quality and differentiation of the corticomedullary junction. In the clinical study malignant tumours were correctly classified with CT and MRI in 86.4% and 95.5% of the cases, whereas the accuracy in the diagnosis of benign lesions of CT and MRI was 73.7% and 89.5%, respectively. CONCLUSION: Using new puls sequences MRI is superior to CT in the differential diagnosis of renal tumours. MRI is superior to CT in the differentiation between complicated cysts and cystic or hypovascular renal cell carcinomas.

[Diagnostic imaging of vascular leiomyosarcomas]. / Bildgebende Diagnostik von vaskulären Leiomyosarkomen.

Primary vascular leiomyosarcomas are very rare tumors, with the venous variety most often arising from the inferior caval vein and the arterial variety from the pulmonary artery. The tumors show either an exclusive intra- or extravascular pattern or a mixed growth pattern. The clinical symptoms depend on tumor location, with intraluminal tumors of the inferior caval vein causing edema or a Budd-Chiari syndrome. Leiomyosarcomas of the pulmonary artery can mimic chronic central or recurrent peripheral pulmonary embolism. Contrast enhanced spiral CT with multiplanar reconstruction is the diagnostic method of choice when a vascular leiomyosarcoma is suspected. MRI with MR-angiography can be added. If a tumor of undetermined origin shows a broad contact with a vessel and/or an intraluminal component, possible primary vascular leiomyosarcoma should be included in the differential diagnosis.

[Stent implantation as a palliative therapeutic measure in tumor-induced stenoses of the large veins of the body]. / Stentimplantation als palliative Therapiemassnahme bei tumorinduzierten Stenosen der grossen Körpervenen.

PURPOSE: Self-expandable metallic stents were used to treat patients with malignant venous obstructions to determine their effectiveness in producing symptomatic palliation. METHODS: 20 patients with a total of 28 tumour-induced obstructions of the superior vena cava (n = 13), the inferior vena cava (n = 4), the subclavian (n = 4), the innominate (n = 5) and the iliac veins (n = 2) were treated with self-expandable metallic stents. 38 Gianturco stents and 21 Wallstents were applied. Patients were heparinised during the procedure and up to three days afterwards. RESULTS: In all patients correct positioning of the stents was achieved. In 16 patients stent placement resulted in relief of their symptoms. In 8 patients the symptoms completely disappeared without recurrence until death as a result of tumour progression. The follow-up ranged from 10 days to 14 months. In 8 still living patients no re-obstruction occurred (follow-up average three months). In one patient thrombotic stent occlusion occurred 6 days after the procedure; the v. cava superior was reopened again by local urokinase therapy. Three patients finally developed re-occlusion due to tumour progression. In one patient stent placement was complicated by migration of the Gianturco stent one day after stent implantation and reocclusion of the subclavian vein. CONCLUSION: The application of self-expandable metallic stents in patients with malignant venous obstruction is a useful palliative therapy.

[Carbon dioxide (CO2) as contrast medium for the new installation and follow-up of a TIPS]. / Kohlendioxid (CO2) als Kontrastmittel zur Neuanlage und Kontrolle von TIPS.

PURPOSE: To determine the efficacy of CO2 as negative contrast medium compared with iodinated contrast medium in creation and control of TIPS. MATERIAL AND METHODS: CO2 was used during TIPS procedures in 33 patients. In 21 patients a wedged hepatic venography was obtained for planning the shunt tract. Additional TIPS-control DSA was performed in 42 cases by direct portal venography to verify the TIPS function and patency. In all cases CO2 gas was used in addition to iodinated contrast medium. RESULTS: CO2 produced excellent wedged hepatic venographies in all patients. Visualisation of the portal veins and collaterals was superior to iodinated contrast medium. The TIPS-control DSA performed with CO2 were comparable to those performed with iodinated contrast medium. Complications were not observed in our study. CONCLUSION: CO2 is an effective contrast medium for TIPS procedures. In particular the visualisation of portal veins performed by CO2-wedged hepatic venography is superior to iodinated contrast medium.

[CT angiography hemodynamically relevant to renal artery stenosis. Evaluation of AXIAL, MPR, MIP and SSD reconstruction procedures under standard investigation conditions]. / CT-Angiographie hämodynamisch relevanter Nierenarterienstenosen. Evaluation der Rekonstruktionsverfahren AXIAL, MPR, MIP und SSD unter standardisierten Untersuchungsbedingungen.

PURPOSE: To evaluate the various reconstruction methods of helical-CT angiography for the assessment of hemodynamically relevant renal artery stenoses in comparison to i.a. DSA. METHODS: In 76 renal arteries the reconstruction modalities AXIAL, MRP, MIP and SSD of helical-CT angiography were compared with the results of i.a. DSA for the determination of the grade and location of the stenosis. RESULTS: The highest accuracy of stenosis grading was 76% with AXIAL reconstruction. In 8% of the cases grading of the stenosis was not evaluable by the AXIAL reconstruction. In these cases, a higher sensitivity in the detection of hemodynamically relevant stenoses (> grade II, > 50%) was achieved with the reconstruction mode MPR (96%) than with MIP (92%). In 51% of the cases the reconstruction mode SSD was not suitable for any diagnosis of renal artery stenosis because of overlying calcified plaques. CONCLUSIONS: The evidence of hemodynamically relevant stenosis in helical-CT angiography in comparison to i.a. DSA succeeds most reliable by using the reconstruction modality AXIAL in combination with MPR. The MIP reconstruction provides information about the anatomy of the renal arteries within one image.

[The nitinol stent as a palliative measure in inoperable carcinoma of the esophagus and cardia. Possibilities and limitations of the procedure]. / Der Nitinolstent als Palliativmassnahme bei inoperablem Osophagus- und Kardiakarzinom. Möglichkeiten und Grenzen des Verfahrens.

Nitinol stents were used in ten patients as palliative treatment for carcinoma of the esophagus and the cardia. Following insertion of the stent the severity of dysphagia decreased on average from 3.2 to 1.5 (on a scale from 0-4). Difficulties with stent opening and passage through the gut were found particularly in the region of metal sutures at esophago-jejunal anastomoses. One stent, which had been obstructed by mucosal folds, had to be removed and replaced. One stent which had been incorrectly placed was extended by introducing a second stent by a coaxial technique. During the period of observation, six patients died after an average of 4.6 months. The palliative effect of the stent lasted on average for eleven weeks. In two patients the tumour grew beyond the stent and in three there was tumour growth into the stent.

[MRI dacryocystography after applying gadolinium-containing eyedrops]. / MRT-Dakryozystographie nach Applikation gadoliniumhaltiger Augentropfen.

PURPOSE: To determine the efficacy of MRI for the lacrimal drainage system after conjunctival application of gadolinium-DTPA solution. MATERIAL AND METHODS: MRI dacryocystography of 32 nasolacrimal duct systems was performed in 16 patients additional to digital subtraction dacryocystography. The gadolinium solution was prepared by diluting the commercially available gadolinium-DTPA (Magnevist, Schering AG, Berlin) 1:10 in sterile saline solution. 3 x 2 drops of this contrast medium were instilled bilaterally immediately before MRI scanning. RESULTS: MRI dacryocystography provided detailed information on the nasolacrimal duct system in all 32 cases. In 16 cases localisation and functional degree of nasolacrimal duct obstruction or stenosis was determined reliably. In 15 cases normal nasolacrimal duct system showed no contrast enhancement. In one case stenosis of the canaliculus was observed. CONCLUSION: MRI dacryocystography provides detailed morphological soft tissue information of the lacrimal drainage system. Local conjunctival application of gadolinium solution allows functional tests of the lacrimal duct system in patients suffering from epiphora.