[Hyperthyroid and acute tonsillitis in a 23-year-old woman]. / Hyperthyreose und akute Tonsillitis bei einer 23-jährigen Patientin.

A 23-year-old woman with preexisting Graves' disease who received thiamazole treatment presented with fever, dysphagia, hyperthyroidism and leukopenia. With suspicion of thyreotoxicosis accompanied by drug-induced agranulocytosis she was successfully managed by plasmapheresis, G­CSF administration and inhibition of periphereal conversion of thyroid hormones. In due course she underwent thyroidectomy. Thiamazole is frequently associated with drug-induced agranulocytosis. Long-term therapy with thiamazole requires critical evaluation and alternatives should be considered early. Plasmapheresis is an adequate treatment option to achieve normal thyroid hormonal status.

Critical evaluation of rituximab rescue in 27 patients with different types of kidney disease.

AIM: Rituximab is increasingly being used in the treatment of patients with kidney disease. We evaluated our clinical experience at the Ulm University Hospital. METHODS: Since 2004, we have administered rituximab as rescue therapy to twenty-seven patients with kidney disease non-responsive to standard treatment. Indications for rituximab were progressive loss of kidney function in thirteen cases; nephrotic syndrome in five cases; humoral rejection after kidney transplantation in five cases and single cases of catastrophic antiphospholipid syndrome (CAPS), pre-emptive removal of ABO incompatible antibodies, pre-transplant removal of panel-reactive antibodies (PRA), and post-transplant lymphoproliferative disease (PTLD). Sixteen patients were treated with both, plasmapheresis and rituximab. RESULTS: Kidney function recovered in five of thirteen cases. Nephrotic syndrome response was observed in two of five cases. In two of five patients with humoral rejection, kidney transplant function could be preserved. Antiphospholipid antibodies, blood group A antibodies and panel reactive antibodies successfully were reduced, and remission was achieved in the case of the patient with PTLD. Four patients died (15%). Adverse events (N.=10) and infectious complications (N.=15) were most likely due to immunosuppression in general and not to rituximab alone. Toxic leukoencephalopathy was a serious but reversible complication in three cases and occurred particularly after the administration of high-dose rituximab (>375 mg/m2). CONCLUSION: Rituximab rescue was successful in 48% of our cases (13 of 27). Rituximab did not increase the complication risk of standard immunosuppression. But toxic leukoencephalopathy was identified as a significant rituximab complication.

Beneficial effects of intravenously administered N-3 fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a prospective randomized study.

BACKGROUND: Atrial fibrillation (AF) is a common complication after coronary artery bypass grafting operation (CABG). Experimental data have shown antiarrhythmic effects of n-3 polyunsaturated fatty acids (PUFA) on myocardial cells. Orally administered PUFA could significantly reduce the rate of postoperative AF. We assessed the efficacy of PUFA for the prevention of AF after CABG. PUFA were given intravenously to prevent variation in bioavailability. METHODS AND RESULTS: 52 patients were randomized to the interventional group, 50 served as controls. In the control group free fatty acids (100 mg soya oil/kg body weight/day) were infused via perfusion pump, starting on admission to hospital and ending at discharge from intensive care. In the interventional group PUFA were given at a dosage of 100 mg fish oil/kg body weight/day. Primary end point was the postoperative development of AF, documented by surface ECG. Secondary end point was the length of stay in the ICU. The demographic, clinical and surgical characteristics of the patients in the two groups were similar. Postoperative AF occurred in 15 patients (30.6 %) in the control and in 9 (17.3 %) in the PUFA group ( P < 0.05). After CABG, the PUFA patients had to be treated in the ICU for a shorter time than the control patients. No adverse effects were observed. CONCLUSIONS: Perioperative intravenous infusion of PUFA reduces the incidence of AF after CABG and leads to a shorter stay in the ICU and in hospital. Our data suggest that perioperative intravenous infusion of PUFA should be recommended for patients undergoing CABG.

[52-year-old patient with painful ascites following fall from a bicycle]. / 52-jähriger Patient mit schmerzhaftem Aszites nach Fahrradsturz.

A 52-year-old patient presented with a ruptured abdominal aortic aneurysm after bicycle trauma. He was treated with a vascular prosthesis. His postoperative recovery was complicated by acute renal failure with anuria for which he was commenced on dialysis. His main persistent symptoms were severe abdominal pain, nausea and vomiting as well as massive ascites. Despite several attempts of a diagnostic and therapeutic ascitic tap, we were initially unable to make a diagnosis. Following each attempted paracentesis, symptoms initially improved. Ascites did reaccumulate, however, and we had to continue with his dialysis. Measurement of creatinine in the ascitic fluid was the key to the correct diagnosis. The ascitic fluid creatinine was nearly 3 times higher than the serum creatinine. The consequent MRI scan of the abdomen with excretion urogram demonstrated a leakage of the left ureter at the junction of the proximal and the middle third of the ureter with contrast leaking into the surrounding fluid.

Should commercial organ donation be legalized in Germany? An ethical discourse.

OBJECTIVE: We evaluated the arguments pro and con concerning kidney sales from a German perspective. At present, we see social, medical, and ethical reasons why organ selling should not be legalized in Germany. DISCUSSION: Legalization of organ selling would weaken the principle of solidarity within the German health system. Conversely, profit making will undermine the principle of social justice. Within the present social system in Germany, there is no economic pressure to sell an organ to save life, and there is no medical need to buy a kidney. Also, there exists the risk that opening the market for organ sales will de-motivate potential directed organ donors. Relatives would have more doubts about giving their consent to donate organs of their deceased. Moreover, the historical experience with the "action T4" of the Nazi regime sensitized German society for the categorical imperative set forth by Immanuel Kant (1724-1804), namely that man is not a means, but an end to himself. By selling one's kidney, the donor uses himself as a means and as an instrument for the end result of gaining money. With directed organ donation, the welfare of the recipient is the end result. The pending reform of the German health system needs a more communitarian sense, which will be eroded should organs be sold and no longer donated as gifts. CONCLUSION: Germany's special historical experience and a deeply embedded consent toward ethical values give reason for the prohibition of organ selling in Germany.

Everolimus and mycophenolate mofetil sensitize human pancreatic cancer cells to gemcitabine in vitro: a novel adjunct to standard chemotherapy?

BACKGROUND/AIMS: Gemcitabine improves survival in pancreatic adenocarcinoma. A variety of drugs have been tested to potentiate gemcitabine treatment for pancreatic cancer cells. Two major immunosuppressive drugs, mycophenolate mofetil (MMF) and everolimus (RAD001) have been shown to exert an anti-tumoral effect, but their ability to sensitize human pancreatic cell lines during gemcitabine treatment remains unclear. We examined the effects of everolimus and MMF on gemcitabine-treated MiaPaCa and Panc-1 cell lines. METHODS: MiaPaCa and Panc-1 human pancreatic tumor cell lines were subjected to everolimus (0.001-1 microg/ml) or MMF (0.1-100 microg/ml) treatment in combination with gemcitabine (1-10(6) nM). Western blot analysis was performed for Panc-1 cells in the presence or absence of TGF-beta1 and different treatments: 0.1-100 muicro/ml MMF and 0.1-100 microg/ml everolimus. The antiproliferative effect of the treatment was assessed by BrdU test. The results were evaluated by two-way analysis of variance followed by post-hoc tests, and nonlinear regression analysis for dose-response rates. RESULTS: As expected, standard treatment doses of gemcitabine decreased proliferation dose-dependently. Everolimus increased the actual EC(50) response to gemcitabine treatment (1-10(3) nM) to as much as 83.1 and 82.1% in MiaPaCa and Panc-1 cell lines, respectively. Likewise, concomitant administration with MMF altered the EC(50) of gemcitabine treatment in MiaPaCa cell lines to values between 76.8 and 85.2% for doses of >or=1 microg/ml. Even the minor dose of MMF (0.1 microg/ml) increased the antiproliferative effect of gemcitabine by 43.5% for MiaPaCa and 42.4% for Panc-1 cells. In addition, treatment of Panc-1 cells with MMF (0.1-100 microg/ml) dose-dependently inhibited TGF-beta1-induced collagen expression. CONCLUSION: We found an overadditive antiproliferative effect of both MMF and everolimus in gemcitabine-treated MiaPaCa and Panc-1 cells in vitro, and an additional inhibitory effect of MMF on TGF-beta1-induced collagen type I expression. Interestingly, both the sensitizing effect of pancreatic cancer cells to gemcitabine treatment and the inhibition of collagen type I expression could be achieved by clinically feasible doses of everolimus and MMF. The use of these drugs is promising as a novel adjunct to standard chemotherapy.

Resolution of sirolimus-induced pneumonitis after conversion to everolimus.

BACKGROUND: Sirolimus-induced pneumonitis usually requires the complete cessation of sirolimus. Herein we have reported five cases of recovery from sirolimus pneumonitis after conversion from sirolimus to everolimus. PATIENTS: All five cases were comparable with regard to their clinical conditions. The ages were between 46 and 64 years. They had received kidney transplants 3 to 18 years earlier. In four cases, the reason for sirolimus therapy was toxicity due to calcineurin inhibitors on a transplant biopsy; three of the patients also displayed malignant tumors: renal cell carcinoma, spinocellular carcinoma, or melanoma. Their serum creatinine levels were elevated between 150 and 350 micromol/L. In all five cases, bronchoscopy disclosed lymphocytic pneumonitis and bronchiolitis obliterans. The immunosuppressive co-medications were prednisolone in three, azathioprine in one, and mycophenolate mofetil in four cases. The previous sirolimus dose was 1 to 4 mg/day, with sirolimus trough levels between 5 and 12 ng/mL. The patients were switched to everolimus at doses between 1 x 0.25 and 2 x 0.75 mg/day to achieve trough concentrations between 3 and 8 ng/mL. Pulmonary symptoms and radiological findings resolved completely within 1 to 4 weeks. CONCLUSION: Everolimus is more hydrophilic by virtue of differing from sirolimus by one hydroxyl group. Sirolimus-induced pneumonitis improved after conversion to everolimus.

Antiproliferative and overadditive effects of everolimus and mycophenolate mofetil in pancreas and lung cancer cells in vitro.

BACKGROUND: Everolimus inhibits the growth of several tumor cell lines in vitro as well as tumor growth in a rat model. Mycophenolate mofetil (MMF) inhibits growth of a Walker sarcoma in a rat model in vivo. Herein we tested the in vitro antiproliferative capacity of everolimus and MMF on a pancreatic tumor cell line Panc-1 and on a small cell lung cancer cell line ScLc. MATERIALS AND METHODS: Cells were cultured under standardized conditions. Everolimus was added in increasing doses from 0.005 to 500 microg/mL; MMF was used from 0.05 to 5000 microg/mL. For co-incubation experiments, we combined everolimus (0.005 microg/mL and 0.05 microg/mL) with five concentrations of MMF; and MMF (0.5 microg/mL and 5 microg/mL) with five concentrations of everolimus. The antiproliferative capacity was assessed by a BrdU incorporation assay. RESULTS: Everolimus and MMF inhibited BrdU incorporation into Panc-1 and ScLc in a dose-dependent fashion. A 50% inhibition was seen in Panc-1 only at 50 microg/mL everolimus, but in ScLc at 5 microg/mL everolimus. MMF was clearly more potent in Panc-1: 50% inhibition was observed at 5 microg/L. In ScLc, 40% inhibition of BrdU incorporation was seen only at 50 microg/L MMF. In co-incubation, an effective combination for both Panc-1 and ScLc was 5 microg/mL MMF with 0.005 microg/mL everolimus resulting in 50% inhibition of BrdU incorporation (P < .001). CONCLUSIONS: Everolimus and MMF showed dose-dependent antiproliferative effects in tumor cell lines in vitro both alone and in combination. The combined use of everolimus and MMF showed supra-additive effects at concentrations used for therapeutic immunosuppression in patients.

Clinical course after total parathyroidectomy without autotransplantation in patients with end-stage renal failure.

In patients with chronic renal failure, hyperparathyroidism is a common problem and surgical parathyroidectomy (PTX) is frequently required. The three different surgical approaches are subtotal PTX, total PTX with autotransplantation, and total PTX without autotransplantation. Recurrence of hyperparathyroidism varies from 5% to 80% in different studies for the first two surgical approaches. To minimize the risk for recurrence, and because we fear severe relapses with calciphylaxia, we perform total PTX without autotransplantation. From October 1993 to October 1997, 20 patients (9 men and 11 women) underwent total PTX without autotransplantation (median age, 52 years; range, 23 to 74 years; median dialysis time before PTX, 6.5 years; range, 1 to 22 years). All patients were supplemented with vitamin D analogues postoperatively. Patients were followed up for 1 to 48 months (median, 20 months). Bone pain, when present, disappeared within the first week after total PTX. Postoperatively, most patients had temporary hypocalcemia. In the long term, five patients had asymptomatic hypocalcemia. One patient, however, repeatedly had hypocalcemic seizures. Five patients developed asymptomatic hypercalcemia when supplemented with calcitriol. At the end of the individual's observation time, parathyroid hormone (PTH) levels were less than normal in six patients, normal in seven patients, and increased in seven patients despite total PTX. We conclude that total PTX should be reconsidered an option for the treatment of hyperparathyroidism secondary to renal failure. There was no evidence of clinical bone disease after total PTX. Apparently, remaining ectopic parathyroid tissue accounts for PTH levels after total PTX.

Pleiotropic effects of hepatocyte growth factor in proximal tubule involve different signaling pathways.

Hepatocyte growth factor (HGF) accelerates renal tubule cell regeneration and induces tubulogenic differentiation via the intracellular tyrosine kinase (TK) domain of its receptor, the proto-oncogene c-Met. We tested whether different signaling pathways may be involved by examining HGF binding and effects on cell proliferation, migration, scattering, and tubulogenic differentiation in the bipolar differentiating rabbit proximal tubule cell line PT-1 under serum-free conditions in the presence or absence of the protein TK inhibitors (PTKIs) herbimycin-A, genistein, methyl-2,5-dihydroxycinnamate, and geldanamycin. These PTKIs inhibit pp60(c-src), a nonreceptor TK involved in cell-growth control. HGF bound to a single high-affinity receptor class, increased microvilli numbers 1.5-fold, enhanced cell proliferation and migration 1.8-fold, and stimulated formation of tubule structures 2.2-fold. PTKI inhibited the mitogenic and motogenic effects of HGF with different potencies and comparable maximal effects but had no specific influence on HGF-induced tubulogenic cell differentiation. These data underline the importance of pp60(c-src) in mediating mitogenic and motogenic effects of HGF, whereas stimulation of tubulogenic cell differentiation may be transduced by a pp60(c-src)-independent pathway.

Different binding and degradation of proinsulin, insulin and insulin-like growth factor-1 (IGF-1) in cultured renal proximal tubular cells. Implications for the prolonged serum half-life of proinsulin.

Recent studies have reported that elevated proinsulin levels are indicative of an increased cardiovascular risk. Renal proximal tubular cells represent a major site for the metabolism of insulin-like hormones after glomerular filtration into the tubular lumen. To determine the binding and degradation of proinsulin in comparison with insulin and insulin-like growth factor-1 (IGF-1), we have used a rabbit proximal tubular cell line (PT-1). As confirmed by electron microscopy. PT-1 cells exhibit bipolar differentiation, demonstrating apical microvilli and invaginations of the basolateral membrane. To allow selective incubation of both compartments, cells were grown on filter membranes. Performing equilibrium binding assays with 125I-labelled hormones, severalfold higher binding was found at the apical than at the basolateral cell membrane, with the capacity range IGF-1 > insulin > proinsulin. Half-maximal displacement of 125I-labelled insulin and IGF-1 was observed at 0.6 and 2 nM, respectively, while crossover binding to the alternate receptor occurred with a 10- to 100-fold lower affinity. Half-maximal displacement of 125I-proinsulin binding was obtained at approx. 8 nM proinsulin and insulin, whereas IGF-1 was 10-fold less potent. The relative degradation of specifically bound tracer was lowest for proinsulin (apical 10%, basolateral: 13%). IGF-1 was degraded by 20% at the apical cell membrane, and up to 78% at the basolateral membrane. In contrast, almost the total amount of insulin bound was degraded at both membrane sites (apical 99%, basolateral: 83%). These results suggest separate insulin and IGF-1 receptors while proinsulin binds with high affinity to a third insulin-like receptor on the apical membrane of PT-1 cells.

The CardioOP-Data Clas (CDC). Development and application of a thesaurus for content management and multi-user teleteaching in cardiac surgery.

OBJECTIVES: Self-directed and customized medical education programs are gaining importance in health care instruction. We prototypically implemented a repository-driven online computer system (CardioOP) for teleteaching in Heart Surgery. It supports authoring and multiple re-use of multimedia data for different user groups in different instructional applications and therefore requires a process of content management. METHODS: We defined objectives for a terminological system to support semantic, cross-media type annotation and retrieval of learning objects: domain completeness, German (natural) language processing, multi-user concepts, extensibility and maintenance, content based annotation and technical implementation. Existing terminologies (ICD10, READ V3, Snomed III, UMLS 1997, MESH) have been analysed according to these objectives. RESULTS: We found that the analysed terminologies did not meet our criteria sufficiently. Therefore, we developed a domain-specific thesaurus, the CardioOP-DataClas (CDC). The application of the CDC within a database-driven authoring process using specifically developed tools is reported. CONCLUSIONS: Metadata play an important role in the effective discovery and search, access, integration and management of educational multimedia data in medicine but so far, there is no terminology to support content management for instructional multimedia. We prototypically designed and applied a thesaurus for the CardioOP educational system. Additional work is needed to evaluate the system in terms of user-friend-liness, concept coverage and information retrieval performance.

Measurement of myocardial oxygen tension: a valid and sensitive method in the investigation of transmyocardial laser revascularization in an acute ischemia model.

BACKGROUND: The effect of transmyocardial laser revascularization (TMLR) on microperfusion and oxygen supply was studied in an acute ischemia model, using 35 pigs, with 13 serving as controls. METHODS: Measurement of tissue oxygen tension was compared with the semiquantitative measurement of microperfusion using contrast echocardiography and infrared laser Doppler. All methods were used before and after coronary occlusion and after TMLR. Effects were measured in the ischemic area and in two ischemia independent areas. RESULTS: At baseline, oxygen partial pressure was 54.2 +/- 15.7 mmHg and decreased to 2.8 +/- 1.4 mmHg ( P < 0.05) after occlusion. After TMLR, oxygen tension increased to 27.3 +/- 8.5 mmHg ( P < 0.05) in the ischemic area, indicating a significant effect of TMLR on microperfusion and oxygen tension. Changes in regional oxygen tension corresponded to Levovist density changes in contrast echocardiography and changes in microperfusion measured by infrared laser Doppler. CONCLUSIONS: Our data indicate that measurement of tissue oxygen tension is a suitable experimental tool to assess the effect of TMLR on myocardial perfusion, which cannot be discriminated using clinical imaging methods.

Development and prospective evaluation of a multimedia teaching course on aortic valve replacement.

BACKGROUND: Participation in heart surgery requires procedural and factual knowledge and intensive preparation. There is evidence in the literature that multimedia driven learning has advantages in medical fields where an understanding of complex temporal and spatial events plays an important role. This work describes the development and evaluation of a multimedia driven, online teaching course on aortic valve replacement for students and residents. METHODS: The instructional model followed a methodological approach with scalable information for different user groups. Various interactive multimedia development tools were employed. In a prospective study, 20 students and 10 residents were exposed to the program in a standardized environment. Both groups completed a 20-item multiple choice pre- and post-test. Psychometric evaluation with HILVE (Heidelberg inventory for the evaluation of teaching courses, 50 items) was performed. RESULTS: The multimedia course integrates more than 200 high quality surgical video and audio sequences, interactive 2 D and 3 D models, as well as illustrations and text. It is available at www.lamedica.de. Study time in the student group was 103 +/- 11 min and 70 +/- 10 min in the resident group. Mean number of correct responses to the knowledge pre-test was 6.23 +/- 2.71 in the student group and 12.2 +/- 2.66 in the resident group. Mean number of correct responses to the knowledge post-test was 15.24 +/- 2.06 in the student group ( p < 0.0001 vs. pre-test) and 17 +/- 2.98 in the resident group ( p = 0.004 vs. pre-test). The HILVE test showed positive results for teaching conditions, the program's instructional competence, student motivation and individual learning. CONCLUSION: Our data demonstrate that multimedia driven training can adapt to the individual needs of learners and improves procedural knowledge required for open heart surgery. Consequently, the whole course forms part of the training of residents and students.

[The role of anesthesiology in fast track concepts in colonic surgery]. / Die Aufgabe der Anästhesiologie bei der Umsetzung operativer "Fast track-Konzepte". Darstellung am Beispiel der Fast-track-Kolonchirurgie.

In the present study the "fast-track rehabilitation" protocol of the Charité university hospital for patients undergoing elective colonic resection is described. The underlying principles, clinical pathways and outcome data from 208 patients are shown. Particularly anesthesiological aspects of this multimodal approach, such as modified preoperative and postoperative fluid management, changed guidelines for preoperative fasting, effective analgetic therapy using epidural analgesia and avoiding high systemic doses of opioids, use of short-acting anesthetic agents, and maintenance of normothermia as well as normovolemia are presented and discussed. In comparison to outcome data before "fast-track rehabilitation" was established, the duration of postoperative hospital stay has been reduced from 12 to 5 days, the number of general complications (pneumonia, duodenal ulcer bleeding, urinary tract infection, cerebral, cardiac and renal dysfunction) decreased from 20% to 7%, whereas surgical complications remained constant at 17% (8% wound infections, 3% anastomotic insufficiency).

Postmitotic reassembly of the cell nucleus in whole cells: an electron-spectroscopic study.

By electron-spectroscopic imaging it is possible to visualize selectively the distribution of phosphorus-rich structures such as nucleosomes, ribosomes or other ribonucleoprotein particles. Using this method we re-examined assembly of the nucleus in telophase of dividing onion root cells and human HeLa cells. Our observations disagree considerably with conclusions drawn from work with cell-free systems. We consistently observed reassembly of nuclear envelope cisternae from vesicles in the cytoplasm without direct contact with chromatin. The preassembled envelope cisternae then enclosed the telophase chromosome mass, contacting the chromatin in some tracts, but also trapping cytoplasmic material such as ribosomes between chromosomes and envelope. Until a late stage in telophase the re-forming nuclear envelope left large gaps between the nuclear and the cytoplasmic compartments. Exclusion of cytoplasmic material from the re-assembling nucleus was facilitated by prenucleolar material, which accumulated in the deep furrows of the chromosomes and interchromosomal spaces. This material expanded considerably while the envelope was still open, in this way displacing cytoplasm non-selectively from the future nucleus. The model we propose for reassembly of the nucleus in whole cells does not postulate contact with and complete enclosure of chromosomes by the re-forming envelope, and suggests a decisive role for expanding prenucleolar material in the process of nucleocytoplasmic compartmentalization.

[Minimal Change Glomerulonephritis]. / Minimal Change Glomerulonephritis.

We report two cases of minimal change glomerulonephritis (synonyms: idiopathic nephrotic syndrom, minimal change disease). A 47-year old female patient was admitted to our unit with a relapsing nephrotic syndrome since childhood. Another patient, a 22-year old female, presented with moderately swollen legs that developed over several months and a complaint of frequent upper respiratory tract infections during the last year. In both cases we suspected a minimal change glomerulonephritis which can only be proven by renal biopsy. Therapeutic options comprise steroids, cyclosporin, tacrolimus or even cyclophosphamide, depending on the clinical presentation of the disease in the individual case.

[Heparin-associated platelet aggregation syndrome with skin necrosis during hemodialysis]. / Heparinassoziiertes Thrombozyten-Aggregationssyndrom mit Hautnekrosen bei Hmodialyse.

HISTORY AND CLINICAL FINDINGS: A 52-year-old man had been in terminal renal failure for 6 years. On haemodialysis under heparin without complications, acral skin necroses occurred. Even with low-molecular heparin anticoagulation further lesions developed. Within 12 weeks of haemodialysis being performed without heparin the necroses healed, but they recurred when heparin was again added for dialysis. On admission the patient was in poor general condition, with a weight of 55 kg (height 175 cm). LABORATORY INVESTIGATIONS: The heparin-induced platelet aggregation (HIPA) test was positive in the absence of thrombocytopenia. Na-heparin reacted positively in three out of four tests, but Danaparoid did not react. TREATMENT AND COURSE: The skin necroses once again healed after the heparinoid Danaparoid, which had not reacted in the HIPA test, had been substituted for heparin. CONCLUSION: This case illustrates that skin necroses, thrombocytopenia and thromboembolism can be independent signs of immunologically induced platelet aggregation.