Catheter ablation in ASymptomatic PEDiatric patients with ventricular preexcitation: results from the multicenter "CASPED" study.

BACKGROUND: As there are limited data about the clinical practice of catheter ablation in asymptomatic children and adolescents with ventricular preexcitation on ECG, we performed the multicenter "CASPED" (Catheter ablation in ASymptomatic PEDiatric patients with Ventricular Preexcitation) study. METHODS AND RESULTS: In 182 consecutive children and adolescents aged between 8 and 18 years (mean age 12.9 ± 2.6 years; 65% male) with asymptomatic ventricular preexcitation, a total of 196 accessory pathways (APs) were targeted. APs were right sided (62%) or left sided (38%). The most common right-sided AP location was the posteroseptal region (38%). Ablation was performed using radiofrequency (RF) energy (93%), cryoablation (4%) or both (3%). Mean procedure time was 137.6 ± 62.0 min with a mean fluoroscopy time of 15.6 ± 13.8 min. A 3D mapping or catheter localization system was used in 32% of patients. Catheter ablation was acutely successful in 166/182 patients (91.2%). Mortality was 0% and there were no major periprocedural complications. AP recurrence was observed in 14/166 patients (8.4%) during a mean follow-up time of 19.7 ± 8.5 months. A second ablation attempt was performed in 20 patients and was successful in 16/20 patients (80%). Overall, long-term success rate was 92.3%. CONCLUSION: In this retrospective multicenter study, the outcome of catheter ablation for asymptomatic preexcitation in children and adolescents irrespective of antegrade AP conduction properties is summarized. The complication rate was low and success rate was high, the latter mainly depending on pathway location. The promising results of the study may have future impact on the ongoing risk-benefit discussion regarding catheter ablation in the setting of asymptomatic preexcitation in children and adolescents.

An unexpected role for a Wnt-inhibitor: Dickkopf-1 triggers a novel cancer survival mechanism through modulation of aldehyde-dehydrogenase-1 activity.

It is widely accepted that canonical Wnt (cWnt) signaling is required for the differentiation of osteoprogenitors into osteoblasts. Furthermore, tumor-derived secretion of the cWnt-antagonist Dickkopf-1 (Dkk-1) is known to cause bone destruction, inhibition of repair and metastasis in many bone malignancies, but its role in osteosarcoma (OS) is still under debate. In this study, we examined the role of Dkk-1in OS by engineering its overexpression in the osteochondral sarcoma line MOS-J. Consistent with the known role of Dkk-1 in osteoblast differentiation, Dkk-1 inhibited osteogenesis by the MOSJ cells themselves and also in surrounding tissue when implanted in vivo. Surprisingly, Dkk-1 also had unexpected effects on MOSJ cells in that it increased proliferation and resistance to metabolic stress in vitro and caused the formation of larger and more destructive tumors than controls upon orthotopic implantation. These effects were attributed in part to upregulation of the stress response enzyme and cancer stem cell marker aldehyde-dehydrogenase-1 (ALDH1). Direct inhibition of ALDH1 reduced viability under stressful culture conditions, whereas pharmacological inhibition of cWnt or overexpression of ALDH1 had a protective effect. Furthermore, we observed that ALDH1 was transcriptionally activated in a c-Jun-dependent manner through a pathway consisting of RhoA, MAP-kinase-kinase-4 and Jun N-terminal Kinase (JNK), indicating that noncanonical planar cell polarity-like Wnt signaling was the mechanism responsible. Together, our results therefore demonstrate that Dkk-1 enhances resistance of OS cells to stress by tipping the balance of Wnt signaling in favor of the non-canonical Jun-mediated Wnt pathways. In turn, this results in transcriptional activation of ALDH1 through Jun-responsive promoter elements. This is the first report linking Dkk-1 to tumor stress resistance, further supporting the targeting of Dkk-1 not only to prevent and treat osteolytic bone lesions but also to reduce numbers of stress-resistant tumor cells.

Always expect the unexpected: lung abscess due to pseudomonas aeruginosa mimicking pulmonary aspergilloma in acute B-cell leukemia.

We report on a case of Pseudomonas aeruginosa sepsis and consecutive lung abscess in a 13-year-old patient with acute B-cell leukemia. At first, radiographic findings strongly suggested presence of pulmonary aspergilloma and only microbiological testing of the surgically enucleated mass revealed the correct underlying pathogen and confirmed final diagnosis.

[Castleman's disease : a rare differential diagnosis for Heerfordt's syndrome]. / M. Castleman : Eine seltene Differenzialdiagnose zum Heerfordt-Syndrom.

A 50-year-old male patient demonstrated an existing left proptosis for several weeks. The patient was suffering from physical exhaustion and had lost considerable weight. Furthermore, we observed greatly enlarged parotid and submandibular glands on both sides. MRI of the neck showed multiple, sharply circumscribed lesions in the major salivary glands and both lacrimal glands as well as in the orbit. Initially we suspected Heerfordt's syndrome, a manifestation of sarcoidosis, but laboratory diagnosis could not reveal a pathological erythrocyte sedimentation rate or an increased ACE titer. After exploratory excision from the right submandibular gland, histological examination revealed Castleman's disease. Therefore, we initiated an immunomodulatory therapy with interleukin-6 receptor antagonists.Castleman's disease is one of the very rare, benign, lymphoproliferative processes that have a tendency to turn malignant. Isolated findings of Castleman's disease should be completely resected. There are no clear treatment strategies for multiple localizations of Castleman's disease. The approaches range from systemic glucocorticoid therapy with chemotherapy to immunomodulatory treatment. In contrast to isolated findings, the prognosis for multicentric occurrence is unfavorable.

Thrombosis of the aorta abdominalis in infants--diagnosis and thrombolytic therapy.

Aortic thrombosis is rarely observed in neonates and infants. Underlying conditions include the presence of umbilical artery catheters, thrombosed aneurysm of the ductus arteriosus, sepsis and different states of inherited thrombophilia. Treatment options include anticoagulation, thrombolytic therapy and thrombectomy. Due to the lack of large studies, neither diagnosis nor treatment of neonatal aortic thrombosis are standardized.From 2008-2010, 1 neonate and 1 infant were admitted to our hospital with symptomatic aortic thrombosis.In both patients, diagnosis was made by Doppler ultrasound. Both patients were effectively treated with recombinant tissue type plasminogen activator. Diagnosis and treatment of 2 infants with symptomatic aortic thrombosis are discussed and the literature is reviewed.Since aortic thrombosis is a life-threatening condition, early diagnosis by Doppler ultrasound is mandatory to initiate treatment without delay. Thrombolytic therapy is a safe measure to treat this condition if administered with caution and if the patient has not suffered from serious complications such as mesenteric infarction or renal failure prior to begin of therapy.

Improved lentiviral transduction of human mesenchymal stem cells for therapeutic intervention in pancreatic cancer.

Genetic modification of human bone marrow mesenchymal stem cells (MSC) is highly valuable for their exploitation in basic science and therapeutic applications, for example in cancer. We present here a new, fast and easy-to-use method to enrich a functional population of lentiviral (LV)-transduced MSC expressing enhanced green fluorescent protein (eGFP). We replaced the eGFP gene by a fusion gene of puromycin acetyltransferase and eGFP. Upon LV gene transfer and puromycin selection, we quickly obtained a pure transduced MSC population, in which growth, differentiation capacity and migration preferences were not compromised. Furthermore, we are the first to report the migration velocity of MSC among which 30% were moving and velocity of about 15 mum h(-1) was not altered by LV transduction. Manipulated MSC underwent senescence one passage earlier than non-transduced cells, suggesting the use for therapeutic intervention in early passage numbers. Upon tail vein application in nude mice, the majority of LV-transduced MSC could be detected in human orthotopic pancreatic tumor xenografts and to a minor extent in mouse liver, kidney and lung. Together, LV transduction of genes to MSC followed by puromycin selection is a powerful tool for basic research and improves the therapeutic prospects of MSC as vehicles in gene therapy.

Metabolic control as reflected by HbA1c in children, adolescents and young adults with type-1 diabetes mellitus: combined longitudinal analysis including 27,035 patients from 207 centers in Germany and Austria during the last decade.

INTRODUCTION: While the central role of HbA1c levels for the prediction of micro- and macrovascular complications in patients with type 1 diabetes is generally accepted; recommendations in current guidelines and the level of metabolic control actually achieved during routine care differ widely. Limited information is available on factors that influence metabolic control in the pediatric age group and during the transition from pediatric to adult diabetes care. In a large prospective multicenter database (DPV-Wiss), 338,330 individual HbA1c measurements from 27,035 patients with type-1 diabetes (94,074 observation years) were recorded between 1995 and 2005. Data were anonymously transmitted from 207 institutions. HbA1c values were mathematically standardized to the DCCT normal range (4.05-6.05%). The SAS 9.1 software was used for statistical analysis using nonparametric statistics. Median HbA1c for all measurements was 7.8%, with a strong effect of diabetes duration: median HbA1c at onset was 9.1%, during the first 2 years of diabetes 7.1% with a subsequent increase to 7.9% in patients beyond the remission phase (>2 years, 20,314 patients); a strong age dependency was present. HbA1c above the recommended guidelines was found in 23%. For all age groups, girls/women had higher HbA1c values compared to boys (mean difference 0.1%, p<0.0001). Seasonal variation was remarkably small with the lowest HbA1c values in September (mean: 7.86%) and highest values in January (8.08%; p<0.0001). Some improvement in HbA1c was observed comparing three periods: 1995-1997, 1998-2000 and 2001-2005; after remission the median HbA1c decreases from 8.5% to 7.6%. In a multivariate model, a significant influence on HbA1c was detected for age (p<0001), duration of diabetes (p<0.0001), gender (p<0.02), minority status (p<0.0001), season (p<0.0001), treatment period (p<0.0001), insulin therapy (p<0.0001) and center effect (p<0.0001). CONCLUSIONS: Both patient-related and treatment-related variables have a strong influence on metabolic control achieved in pediatric and young adult patients with T1DM. In contrast to wide-spread belief, metabolic control is only marginally better in summer compared to winter. Some improvement in metabolic control was observed during the last 10 years.

Radiation dose of the lens in trans-sphenoidal pituitary surgery: pros and cons of a conventional setup using fluoroscopic guidance and CT-based neuronavigation.

BACKGROUND AND PURPOSE: We determined the radiation dose in patients' lenses during pituitary surgery with either conventional fluoroscopy or CT-guided neuronavigation. MATERIALS AND METHODS: Thermoluminescent dosimeters (TLD-100H) were attached to the lenses of an anthropomorphic Alderson-Rando head phantom. Simulation of the conventional setup of continuous fluoroscopy (61 kV peak, 2.01 mAs) with collimation and automatic exposure control was used with 1 TLD being removed every 5 seconds, followed by another experiment with 1 being removed every 30 seconds. For CT-guided neuronavigation, a spiral of 3-mm-thick sections without gap was performed (140 kV, 220 mA). Patients' charts (n = 87) were reviewed in terms of radiation exposure and perioperative complications. RESULTS: Radiation dose is distance-dependent (P < .002), with an exposure-time-dependent linear increase (R(2) = 99.27, P < .0001) close to the primary beam only. The radiation dose of the CT (mean, 39.39 mGy) was fivefold higher compared with the maximal time of 3 minutes (8 mGy) reached in our patients by using the conventional setup. CT offers more detailed 3D anatomy available at any time intraoperatively. Tolerance doses needed to develop cataracts were not reached, and perioperative complications occurred without significant differences (Mann-Whitney U test, P = .39) using either method. Continuous use of fluoroscopy reached the mean value of CT after 14.33 minutes. CONCLUSION: Neuronavigation provides better anatomic information and avoids repetitive exposure and accumulation to the staff, with the disadvantage of an increased radiation exposure to the patient causing at least no acute harm. Long-term effects are hard to prove but cannot be neglected either.

Is the frequency of self-monitoring of blood glucose related to long-term metabolic control? Multicenter analysis including 24,500 patients from 191 centers in Germany and Austria.

Blood glucose measurements are generally accepted components of a modern diabetes self-management. The value of self-monitoring of blood glucose (SMBG) is, however, discussed controversially and only a few studies addressed the efficacy of SMBG under real-life conditions so far. In order to investigate whether the frequency of SMBG is related to long-term metabolic control, data from the DPV-Wiss-database, a standardized,prospective, computer-based documentation of diabetes care and outcome, were analyzed for patients with type 1(n = 19,491) and type 2 (n = 5,009) diabetes from 191 centers in Germany and Austria. Local HbA1c reference ranges were mathematically adjusted to the DCCT reference. For each patient, data from the most recent year of diabetes care were used. On average,patients with type 1 diabetes performed 4.4 blood glucose measurements/day. Corrected for age, gender, diabetes duration,on intensified (>or=4 daily injections or CSII) therapy (HbA1c reduction of 0.32% for one additional SMBG/day) compared to patients on conventional (1-3 daily injections) therapy(HbA1c-reduction of 0.16% for one additional SMBG/day). In 2,021 patients with insulin-treated type 2 diabetes (2.7 measurements/day), more frequent SMBG was associated with better metabolic control (HbA1c-reduction of 0.16% for one additionalSMBG/day, p < 0.0001), while in 2,988 patients on OAD or diet alone (2.0 measurements/day), more frequent blood glucose measurements were associated with higher HbA1c-levels(HbA1c-increase of 0.14% for one additional SMBG/day,p < 0.0001). These data indicate that more frequent SMBG are associated with better metabolic control in both, patients with type 1 and insulin-treated type 2 diabetes. Since no benefit ofSMBG on metabolic control was found in patients with type 2 diabetes on OAD or diet alone, SMBG should primarily be recommended for those patients with suboptimal metabolic control whereas the benefit of SHBG in non-insulin-treated patients with adequate HbA1c-levels remains uncertain.insulin therapy and center difference, the SMBG frequency was associated with better metabolic control (HbA1c-reduction of0.26% for one additional SMBG/day, p < 0.0001). HbA1c-reduction with higher frequency of SMBG was more pronounced in patients Blood glucose measurements are generally accepted components of a modern diabetes self-management. The value of self-monitoring of blood glucose (SMBG) is, however, discussed controversially and only a few studies addressed the efficacy of SMBG under real-life conditions so far. In order to investigate whether the frequency of SMBG is related to long-term metabolic control, data from the DPV-Wiss-database, a standardized,prospective, computer-based documentation of diabetes care and outcome, were analyzed for patients with type 1(n = 19,491) and type 2 (n = 5,009) diabetes from 191 centers in Germany and Austria. Local HbA1c reference ranges were mathematically adjusted to the DCCT reference. For each patient, data from the most recent year of diabetes care were used. On average,patients with type 1 diabetes performed 4.4 blood glucose measurements/day. Corrected for age, gender, diabetes duration,insulin therapy and center difference, the SMBG frequency wasassociated with better metabolic control (HbA1c-reduction of 0.26% for one additional SMBG/day, p < 0.0001). HbA1c-reduction with higher frequency of SMBG was more pronounced in patients on intensified (>or= 4 daily injections or CSII) therapy (HbA1c reduction of 0.32% for one additional SMBG/day) compared to patients on conventional (1-3 daily injections) therapy(HbA1c-reduction of 0.16% for one additional SMBG/day). In 2,021 patients with insulin-treated type 2 diabetes (2.7 measurements/day), more frequent SMBG was associated with better metabolic control (HbA1c-reduction of 0.16% for one additionalSMBG/day, p < 0.0001), while in 2,988 patients on OAD or diet alone (2.0 measurements/day), more frequent blood glucose measurements were associated with higher HbA1c-levels(HbA1c-increase of 0.14% for one additional SMBG/day, p < 0.0001). These data indicate that more frequent SMBG are associated with better metabolic control in both, patients with type 1 and insulin-treated type 2 diabetes. Since no benefit of SMBG on metabolic control was found in patients with type 2 diabetes on OAD or diet alone, SMBG should primarily be recommended for those patients with suboptimal metabolic control whereas the benefit of SHBG in non-insulin-treated patients with adequate HbA1c-levels remains uncertain.

Transplantation of mesenchymal stromal cells on mineralized collagen leads to ectopic matrix synthesis in vivo independently from prior in vitro differentiation.

BACKGROUND: Tissue engineering using mesenchymal stromal cells (MSC) represents a promising approach for bone regeneration. Nevertheless, the optimal constructs have yet to be determined. It still remains unclear if there is a benefit of in vitro differentiation of MSC prior to transplantation or if undifferentiated MSC hold the optimal potential concerning new tissue formation. METHODS: After isolation and in vitro expansion, MSC were seeded on mineralized collagen sponges and transplanted in a heterotopic SCID mice model (n=12). While group A contained undifferentiated MSC, in group B cells were cultivated for 14 days in vitro under osteogenic conditions prior to implantation. Results were compared with non-loaded scaffolds (group C). Animals were killed for investigation at 4 and at 8 weeks. RESULTS: In situ hybridization demonstrated integration of MSC for up to 8 weeks in groups A and B. Histology revealed significantly more extracellular matrix synthesis in MSC-seeded scaffolds containing calcium phosphate and collagen type I at 4 and 8 weeks after transplantation compared with unloaded controls. At a biochemical level, higher levels of specific alkaline phosphatase expression were detected in MSC-loaded scaffolds (P<0.05). Scaffolds containing undifferentiated and differentiated MSC did not appear to differ in terms of matrix synthesis and protein expression, while the number of avital cells was significant higher in those probes loaded with differentiated MSC (P<0.01). DISCUSSION: The integration of transplanted cells and MSC-associated matrix synthesis encourages the use of MSC-loaded mineralized collagen for tissue engineering of bone. Furthermore, our data suggest that in vitro differentiation of MSC does not have a positive influence in terms of improved matrix synthesis.

[Prophylactic parathyroidectomy for familial parathyroid carcinoma]. / Das familiäre Nebenschilddrüsenkarzinom Indikation zur prophylaktischen Parathyreoidektomie?

In contrast to primary hyperparathyroidism, parathyroid carcinoma is a rare disease. In patients with hyperparathyroidism jaw tumor (HPT-JT) syndrome, caused by germline mutations in HRPT2, the development of parathyroid carcinoma is estimated to be 10-15%. This review summarizes the clinical and molecular genetic data of about 100 patients in the literature and three of our own cases. Unfortunately, osteofibromas, which might enable timely diagnosis of HPT-JT syndrome, occur in only about 30% of patients; about 80% have uniglandular disease. Based on the current data, a general recommendation to perform prophylactic parathyroidectomy cannot be given. However, thorough screening of patients at risk is mandatory. Of note in patients thought to have sporadic parathyroid carcinoma, germline HRPT2 mutations are found in up to 20%. Hence, any patient with parathyroid carcinoma should undergo HRPT2 mutation analysis.

[Are chest radiographs justified in pre-employment examinations? Presentation of legal position and medical evidence based on 1760 cases]. / Ist die Röntgenthoraxaufnahme bei Neueinstellungen gerechtfertigt? Darstellung von Rechtslage und medizinischer Evidenz in 1760 Fällen.

BACKGROUND: The legal and medical basis for chest radiographs as part of pre-employment examinations (PEE) at a University Hospital is evaluated. The radiographs are primarily performed to exclude infectious lung disease. METHODS: A total of 1760 consecutive chest radiographs performed as a routine part of PEEs were reviewed retrospectively. Pathologic findings were categorized as "nonrelevant" or "relevant." RESULTS: No positive finding with respect to tuberculosis or any other infectious disease was found; 94.8% of the chest radiographs were completely normal. Only five findings were regarded as "relevant" for the individual. No employment-relevant diagnosis occurred. CONCLUSIONS: The performance of chest radiography as part of a PEE is most often not justified. The practice is expensive, can violate national and European law, and lacks medical justification.

Evaluation of the validity of the UN SADT H.4 test for solid organic peroxides and self-reactive substances.

Many self-accelerating decomposition temperatures (SADTs) of solid organic peroxides and self-reactive substances have been determined with the UN test method H.4, which is a scaled down test in a small Dewar vessel. For solid organic peroxides and solid self-reactive substances Fierz has questioned this procedure in a recent paper. Fierz concluded that the Dewar test results should not be extrapolated to beyond 8l packages, owing to the thermal insulation value of solids. On the other hand, long term experience with the test, with a great variety of solid organic peroxides and self-reactive substances show about equal critical temperatures in the small Dewar vessel and on 50 kg scale. In the present work, we first checked, by numerical simulations, the Dewar scale versus the larger scale, in a way comparable with Fierz' method: both scales are simulated by spheres, consisting of a number of annular layers, for the large scale the usual external heat loss term is used but for the small scale the outside heat transfer is strongly limited. The outcome of these simulations, covering a variety of physical parameters, supports the concerns expressed by Fierz. After this, we performed accurate cooling and heating experiments with solid organic peroxide in the usual Dewar vessel, provided with a large set of thermocouples. The results of these experiments showed that the simulation model for the Dewar vessel has to be changed from a spherical analogue to a short cylinder of solid material with heat exchange mainly via its top (U(top) approximately 3.5 W/(m(2)K), overall heat transfer coefficient) and some heat exchange (U(side) approximately 0.29 W/(m(2)K)) through its cylindrical and bottom part. With this "modified cylinder" model (being neither an infinitely long cylinder nor a slab) of the Dewar vessel, we found that the UN method H.4 enables an accurate prediction of the SADT, with small deviations of 0+/-2.5 degrees C. Further, by performing a truly three-dimensional (3D) finite element calculation in FEMLAB, the new heat characteristics of the Dewar vessel as well as a 50 kg package of dilauroyl peroxide, a solid organic peroxide, were checked. The outcome was compared with the critical ambient temperatures known for various package sizes, which agreed well.

[Allogenic transplantation of human mesenchymal stem cells for tissue engineering purposes: an in vitro study]. / Allogene Transplantationsmöglichkeiten humaner mesenchymaler Stammzellen. Eine In-vitro-Studie zur Knochenregeneration.

Due to their plasticity and high proliferation capacity in vitro, human mesenchymal stem cells (MSC) are promising candidates for tissue engineering approaches of mesenchymal tissues like bone, cartilage, or tendon. Undifferentiated MSC do not express immunologically relevant cell surface markers. They inhibit the proliferation of allogeneic T-cells in vitro and elicit no immune response after allogeneic or xenogenic transplantation. Thus, MSC ought to be seen as immunoprivileged or immunomodulating cells. Here, we characterize the immune status and -behavior of MSC and MSC-derived osteogenic precursors in order to evaluate the usefulness of allogeneic MSC for tissue engineering of bone. Human MSC were isolated from bone marrow of hematologically normal voluntary donors. Osteogenic differentiation was induced by adding dexamethasone, ascorbic acid and beta-glycerophosphate. After 0, 8, 16 and 24 days, MSC were co-cultivated with allogeneic mononuclear cells. In parallel, the expression of immunologically relevant cell surface markers was monitored by flow cytometry. Undifferentiated and differentiated MSC did not stimulate allogeneic lymphocytes. MSC were negative for MHC-II, CD40, CD40L, CD80 (B7-1) and CD86 (B7-2), positive for MHC-I, and kept this expression pattern during osteogenic differentiation. Our results support the hypothesis that MSC are immunoprivileged cells which are potentially at disposal for HLA-incompatible cell replacement therapies.

Development of leiomyosarcoma from primary leiomyoma?

Kidney leiomyosarcoma represents a rare variety of malignant kidney tumours. In this paper, we report on a patient with an inoperable leiomyosarcoma. Since this neoplasm is very rare, there is very little information on this type of malignancy. We present the symptoms, radiological findings, diagnostic criteria and differential diagnosis of the tumour. Leiomyosarcoma exhibits aggressive biological behaviour and has a poor prognosis. We have found that the treatment of choice is a radical nephrectomy.

[Comparative study of life quality in patients with cycloid and schizophrenic psychoses]. / Vergleichsuntersuchung zur Lebensqualität bei Probanden mit zykloiden und schizophrenen Psychosen.

BACKGROUND: Cycloid psychoses represent a nosological entity not adequately recognised by contemporary psychiatry. They show full recovery after each episode and thus have a favourable prognosis. METHODS: Course, psychiatric status, social function, and quality of life (QoL) of 33 patients with cycloid psychosis and 44 schizophrenics were compared (CGI, PANSS, GAF, Strauss-Carpenter,WHOQOL-BREF).Also, 48 controls were asked to rate their QoL. RESULTS: The schizophrenics developed symptoms earlier in life (P=0.009) and were hospitalized longer (P=0.001) and more frequently(P=0.01) than patients with cycloid psychosis. The latter showed better scores in the applied scales (P<0.0001). In QoL measures, cycloid psychotic patients were more satisfied than schizophrenic patients in three of four domains(P<0.01). Only in one domain did they differ from controls (P<0.01). CONCLUSION: Cycloid psychoses display better course, outcome, and QoL than schizophrenia.Thus, they appear to present a useful concept deserving more clinical and scientific attention.