[Therapy of myositis]. / Therapie der Myositiden.

Idiopathic inflammatory myopathy consists of dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM) and necrotizing autoimmune myopathy (NAM). At all stages of myositis, physiotherapy is effective in improving muscle strength, endurance and in maintaining joint motion. In DM and PM the therapy is initiated with glucocorticosteroids. Steroid-sparing agents (azathioprine, methotrexate and cyclosporin A) are added to prevent Cushing's syndrome or an unsatisfactory response. Therapy can also be escalated with intravenous immunoglobulins. Tacrolimus and mycophenolate mofetil (MMF) were effective in small case series. Cyclophosphamide is restricted to patients not responding to previous agents. For treatment intensification immunoglobulins can also be combined with MMF. There is not enough evidence to routinely recommend rituximab. The results with TNF-alpha inhibitors and plasmapheresis were negative or inconsistent. In DM skin involvement responds to sun blockers, antimalarials, topical corticosteroids or calcineurin inhibitors. In NAM statins should be discontinued and treatment with prednisone and immunosuppressants initiated. In IBM a therapeutic trial with prednisone, methotrexate or azathioprine may be warranted, especially in cases in which the serum creatine kinase (CK) is elevated or an inflammatory infiltrate is present in the muscle biopsy.

Cytogenetic patterns in multiple myeloma after a phase of preceding MGUS.

BACKGROUND: Presenting the same histological diagnosis, multiple myeloma (MM) shows a large genomic variety, resulting in variable times of overall survival. MATERIALS AND METHODS: To investigate major cytogenetic categories (any 14q-translocation, t(11;14), t(4;14), 13q-deletions, 17p-deletions) and their clinical consequences in MM after a pre-existing monoclonal gammopathy (MM post-MGUS), we performed a comparative analysis of 41 patients with MM post-MGUS and 287 patients with unknown prior history MM (U-MM). RESULTS: In MM post-MGUS, a t(11;14) was found to be more frequent than in U-MM (24% vs. 14%) and it was associated with significantly shortened survival (24 months vs. 70 months in U-MM; P = 0.01). MM post-MGUS was further characterized by a higher frequency of 13q-deletions only (absence of all other specific abnormalities; 28% vs. 12% in U-MM; P = 0.02). A 13q-deletion only was an indicator of long survival in MM post-MGUS (median not yet reached) as opposed to U-MM (median survival, 29 months; P = 0.001). 17p-deletions were infrequent in MM post-MGUS (3% vs. 16% in U-MM; P = 0.04). Survival times for patients with t(4;14) and/or 17p-deletions and other abnormalities were similar in both MM patient cohorts. CONCLUSIONS: Our data suggest that t(11;14) and 13q-deletions have distinct prognostic implications in the context of MM post-MGUS.

Evaluation of the safety and bioactivity of purified and semi-purified glucoraphanin.

The anti-carcinogenic effects of broccoli have been attributed to sulforaphane, the hydrolysis product of glucoraphanin (GRP). Here we determined if purified GRP, in the absence of the plant-derived hydrolyzing enzyme myrosinase, could affect pulmonary and hepatic ethoxyresorufin O-deethylase (EROD) and/or NAD(P)H-quinone oxidoreductase 1 (NQO1) activity. Male F344 rats were administered semi-synthetic, semi-purified or purified GRP (240 mg/kg: 550 micromol/kg rat daily for 4 days) by gavage. Hepatic and pulmonary NQO1 activity increased ( approximately 20%), but not EROD. Varying doses of semi-purified GRP (30, 60, or 120 mg/kg rat daily for 4 days) again caused no change in EROD activity, although a dose-dependent increase in NQO1 was seen. Urinary excretion of mercapturic acids showed no difference between preparations, and recovery increased with decreasing dose. Histopathologic examination revealed no abnormal tissues other than cecum, where inflammation was dose dependent; mild at 120 mg/kg and severe at 240 mg/kg, a greatly supra-physiological dose. We conclude that GRP 30-60 mg/kg p.o. is safe and effectively enhances NQO1 in all tissues evaluated.

Simultaneous measurement of pulmonary venous flow by intravascular catheter Doppler velocimetry and transesophageal Doppler echocardiography: relation to left atrial pressure and left atrial and left ventricular function.

OBJECTIVES: The aim of our study was to compare measurements of pulmonary venous flow velocity obtained either by transesophageal Doppler echocardiography or by intravascular catheter Doppler velocimetry. Furthermore, the relation among pulmonary venous flow velocity, left atrial compliance and left atrial pressure was evaluated. BACKGROUND: Data about the relation between left atrial pressure and pulmonary venous flow velocity are controversial. METHODS: A total of 32 patients undergoing elective open heart surgery for coronary artery bypass grafting were included prospectively in the study. Pulmonary venous flow velocity (Doppler catheter) and left atrial pressure (microtip pressure transducer) were recorded simultaneously with recordings of pulmonary venous flow velocity obtained by transesophageal Doppler echocardiography. RESULTS: Agreement between Doppler catheter and Doppler echocardiographic measurements of pulmonary venous flow velocity (n = 18 patients) was analyzed using the Bland-Altmann technique. The 95% limits of agreement were -0.16 to +0.11 m/s for systolic peak velocity, -0.14 to +0.09 m/s for diastolic peak velocity and -0.12 to +0.10 m/s for atrial peak velocity. The closest agreement between both methods was found for the ratio of systolic to diastolic peak velocity, the ratio of systolic to diastolic flow duration and the time from Q deflection on the electrocardiogram to maximal flow velocity. Mean left atrial pressure was strongly correlated with the ratio of systolic to diastolic peak velocity (r = -0.829), systolic velocity-time integral (r = -0.653), time to maximal flow velocity (r = 0.844) and the ratio of systolic to diastolic flow duration (r = -0.556). The ratio of systolic to diastolic peak velocity and the time to maximal flow velocity were identified as strong independent predictors of mean left atrial pressure. Left atrial compliance was not found to be an independent predictor of mean left atrial pressure. CONCLUSIONS: Flow velocity in the left upper pulmonary vein can be reliably recorded by transesophageal pulsed wave Doppler echocardiography. Our data reveal further evidence that mean left atrial pressure can be estimated by the pattern of pulmonary venous flow velocity.

Effect of first treatment with aminobisphosphonates pamidronate and ibandronate on circulating lymphocyte subpopulations.

Up to 60% of patients receiving their first infusion of the bisphosphonate pamidronate experience an acute-phase reaction. In this study, we used flow cytometry to determine the effects of pamidronate treatment on circulating lymphocyte subpopulations, and we investigated whether pamidronate and ibandronate treatment affect lymphocyte subpopulations differently. Twenty patients received a pamidronate infusion, 20 patients received intravenously injected ibandronate, and 10 controls received a clodronate infusion. Pamidronate treatment was followed by a significant increase in median body temperature at the 10-hour measurement and a significant decrease in counts of circulating lymphocytes, natural killer cells, T cells, and CD4+ and CD8+ T-cell subsets. Ibandronate treatment did not affect median body temperature, and it was associated at the 10-hour measurement with maximum increases in total lymphocyte count, B cells, T cells, and CD4+ and CD8+ T-cell subsets. Thus, there is a substantial difference in the hematologic response to initial treatments with pamidronate and ibandronate. Clodronate treatment did not induce changes in body temperature or significantly affect the number of circulating T cells and NK cells. The reduction in lymphocyte subsets after initial pamidronate therapy might be mediated by the release of tumor necrosis factor alpha, whose source in the acute-phase reaction could be T cells.

Novel serum markers of bone resorption: clinical assessment and comparison with established urinary indices.

Although urinary measurements of collagen degradation provide valid estimates of bone resorption, their clinical application is hampered by pronounced analytical and biological variability. Therefore, immunoassays for the determination of such parameters in serum have been developed. In this study, we assessed the performance of three new serum markers of bone turnover, i.e., C-terminal and N-terminal telopeptides of type I collagen (S-CTX and S-NTX) and bone sialoprotein. Results were compared with urinary total pyridinoline, total deoxypyridinoline, and urinary C-terminal telopeptides of type I collagen (U-CTX) and urinary N-terminal telopeptides of type I collagen (U-NTX). The study population included healthy men (n = 27), premenopausal (n = 30) and postmenopausal (n = 31) women, patients with hepatic dysfunction (HF, n = 24), renal failure (RF, n = 30), breast cancer without (BC-, n = 24) and with (BC+, n = 30) bone metastases, primary vertebral osteoporosis (OPO, n = 27), primary hyperparathyroidism (PHPT, n = 16), active Paget's disease of bone (n = 18), multiple myeloma (MM, n = 18), and patients with hypercalcemia of malignancy before and after treatment with pamidronate (HOM, n = 28). Changes in urinary and serum markers were similar in most metabolic bone diseases. However, differentiation between healthy controls and OPO, or PHPT, was improved by the serum markers. In MM, all serum and urinary markers were elevated (p < 0. 05 vs. controls). In BC+, skeletal involvement was reflected by significant increments in all indices (p < 0.01 vs. BC-), except U-CTX and S-CTX. In HOM, pamidronate-induced changes in biomarkers were most pronounced for U-CTX and S-CTX and S-NTX. HF and RF were associated with elevated levels of all serum markers (p < 0.05 vs. controls). In conclusion, measurements in serum reflect bone resorption to the same extent as the urinary indices. Since serum markers circumvent some of the limitations of urinary measurements, their use potentially improves the assessment of skeletal disorders.

Usefulness of carvedilol in unstable angina pectoris.

The safety and efficacy of adding oral carvedilol (25 mg twice daily) to standardized treatment of unstable angina was assessed in a multicenter, randomized, double-blind, placebo- controlled trial on 116 patients with acute unstable angina. Patients were monitored in an intensive care unit and underwent 48-hour Holter monitoring to assess transient ischemia. Carvedilol as adjunctive therapy resulted in a significant reduction of median heart rate (65 vs 75 beats/min, p <0.05), mean systolic blood pressure (133 vs 130 mm Hg, p <0.05), and mean rate-pressure product (8,337 vs 10,042, p <0.05). Carvedilol reduced the ischemic burden during 48 hours of treatment by 75% (49 vs 204 minutes), including a 36% reduction of patients with ischemic episodes (p <0.05), a 66% reduction of the mean number of ischemic episodes (8 vs 24, p <0.05), and a 76% reduction in the mean duration of ischemic episodes (50 vs 205 minutes, p <0.05). Side effects occurred in 8 of 59 patients (13.6%) in the carvedilol group and in 5 of 54 patients (8.8%) given placebo. Although not significant, the early onset of maximal blood pressure reduction and the delayed effect on heart rate were closely correlated to drug-induced hypotension and bradycardia in the carvedilol group. Thus, carvedilol as an adjunctive to standardized treatment effectively reduces heart rate and blood pressure, and thus the ischemic burden in patients with unstable angina pectoris, but requires close monitoring of patients at risk for bradycardia or hypotension.

Comparative tolerability of drug therapies for hypercalcaemia of malignancy.

The bisphosphonates are the treatment of choice in hypercalcaemia of malignancy. However, plicamycin (mithramycin) an calcitonin treatment may still be of value should bisphophonate treatment fail, and gallium nitrate has recently been introduced as an alternative therapy. We analysed the tolerability of different treatments based on articles identified in a Medline search covering the period 1979 through September 1998. Articles were included if they met two criteria: (i) quantitative assessment of adverse effects; (ii) inclusion of > or = 10 patients. Although bisphosphonates are generally well tolerated, elevation of serum creatinine level, nausea/vomiting and fever have been reported following their application. Patients receiving etidronate (n = 268) or clodronate (n = 127) more frequently experienced creatinine elevation (8 and 5%, respectively) than did patients receiving pamidronate (n = 424; 2%), aledronate (n = 79; 0%), or ibandronate (n = 203; <1%). The difference in the frequency of reported creatinine level elevations reached statistical significance only for etidronate (z-test: p < 0.001 versus pamidronate; p < 0.02 versus alendronate; p < 0.001 versus ibandronate). With regard to the frequency of creatinine level elevations, clodronate treatment did not differ significantly from treatment with pamidronate, alendronate and ibandronate. An exception among the bisphosphonates is tiludronate, which has been reported on s a treatment of hypercalcaemia in only 1 study (n = 19) resulting in 1 case of lethal and 1 case of manageable acute renal failure. Nausea and vomiting are rare adverse effects of bisphosphonate treatment but seem to be more frequent with first generation drugs: etidronate (8%) and clodronate (7%) versus pamidronate (2%) [p < 0.001 and 0.009, respectively] and versus ibandronate (<1%) [p< 0.002 and 0.02, respectively]. Bisphosphonates containing a nitrogen atom were associated with an acute phase reaction leading to reported fever in 16% of pamidronate, 20% of aledronate, and 11% of ibandronate-treated patients. The most frequently reported adverse effects of treatment with the cytostatic drug plicamycin were hepatotoxicity (26%), nausea/vomiting (23%), and serum creatinine level elevation (5%). Furthermore. plicamycin application was associated with bone marrow suppression and a bleeding tendency due to abnormalities in multiple clotting factors and platelet dysfunction. The use of calcitonin is limited more by the short duration of its therapeutic effect than by toxicities (most frequent: nausea/vomiting in 16% of treated cases). The few publications on gallium nitrate in the treatment of hypercalcaemia of malignancy characterise it as an efficient drug, which is, however, associated with a higher frequency of renal toxicity (10%) and of nausea and vomiting (14%) than are the bisphosphonates.

Diagnosis, localization and evaluation of malignancy of heart and mediastinal tumors by conventional and transesophageal echocardiography.

Transesophageal echocardiography is well established in detecting and diagnosing heart tumors. In contrast, its role in assessing presence, growth and evidence of malignancy of tumors originating from the mediastinal site remains widely uncertain. In a prospective and investigator-blind study, we evaluated 72 consecutive patients with cardiac and/or mediastinal tumor lesions to assess the diagnostic impact of transthoracic and transesophageal echocardiography in determining localization, growth and malignancy. All tumor lesions were diagnosed and carefully evaluated by computer tomography and/or magnetic resonance imaging prior to the study. Biopsy demonstrated a malignant tumor in 49 patients and a benign tumor in 23 patients. Transthoracic and transesophageal echocardiography were equally effective in visualizing tumors of the heart in 24 patients (92% vs 100%; N.S.). Tumors originating from the mediastinum were 2.9 times less likely to be detected by the transthoracic approach (p < 0.001). In these patients, transesophageal echocardiography was also superior in diagnosing myocardial infiltration (18 vs 4 patients, p < 0.001) and invasion or intracardiac growth of the tumor (13 vs 6 patients, p < 0.05). When compared to histological findings, transesophageal echocardiography predicted malignancy from the presence of tumor spread both in- and outside the heart, infiltration and invasion in 21/49 patients (43%), a false positive result was obtained in only 1/23 patients with a benign tumor. Conventional echocardiography predicted malignancy in only 4/49 patients (8%, p < 0.005). In conclusion, transesophageal echocardiography is increasingly used in patients with suspected mediastinal tumor lesions. Our study demonstrates, that transesophageal echocardiography is effective and superior to the conventional approach in predicting localization and growth of mediastinal tumors, as well as in accessing evidence of malignancy of the tumor.

Influence of particles on sonochemical reactions in aqueous solutions.

Numerous publications deal with the possible application of ultrasound for elimination of organic pollutants as a tool for water pollution abatement. Most of the experiments were performed in pure water under laboratory conditions. For developing technologies that hold promise it is necessary to investigate the effect of ultrasound in natural systems or waste water where particulate matter could play an important role. In this paper the influence of quartz particles (2-25 microm) on the chemical effects of ultrasound in aqueous system using a high power ultrasound generator (68-1028 kHz, 100 W, reactor volume 500 ml) is reported. In pure water in dependence on particle size, concentration and frequency the formation rate of hydrogen peroxide under Ar/O2 (4:1) shows a maximum using 206 kHz in presence of 3-5 microm quartz particles (4-8 g/l). Under these conditions the yield of peroxide is higher than without quartz. Additionally under N2/O2 (4:1) besides hydrogen peroxide the formation of nitrite/nitrate was measured. Compared to pure water quartz particle depressed the formation of nitrite/nitrate up to 10-fold but not the formation of H2O2. According to the results of H2O2 formation the elimination of organic compounds by sonolysis (206 kHz) and the influence of quartz particles were investigated. As organic compounds salicylic acid, 2-chlorobenzoic acid and p-toluenesulfonic acid were used. The influence of quartz on the oxidation of organic compounds (206 kHz) is similar to that on the formation of H2O2.

Localization of the Enzyme System Involved in Anaerobic Reduction of Azo Dyes by Sphingomonas sp. Strain BN6 and Effect of Artificial Redox Mediators on the Rate of Azo Dye Reduction.

The effect of different artificial redox mediators on the anaerobic reduction of azo dyes by Sphingomonas sp. strain BN6 or activated sludge was investigated. Reduction rates were greatly enhanced in the presence of sulfonated anthraquinones. For strain BN6, the presence of both cytoplasmic and membrane-bound azo reductase activities was shown.

[Electromechanical mapping as a platform for myocardial laser therapy]. / Elektromechanisches Mapping als Plattform für myokardiale Lasertherapie.

Percutaneous myocardial laser therapy is a new strategy for myocardial revascularization in patients with end-stage coronary artery disease. The laser impulse which is applied via a catheter creates small channels into ischemic myocardium from the endocardial surface. Different mechanisms such as angiogenesis, improved blood flow via open channels or neural stunning are discussed as the underlying mechanism. Precise identification and maneuvering of the laser catheter to the target zone is of crucial importance. By using a novel catheter-based, non-fluoroscopic, three-dimensional endocardial mapping system (NOGA, Biosense-Webster Co.) accurate simultaneous assessment of both local electrical activity and regional contractility can be obtained. The analysis of uni- or bipolar voltage and linear local shortening allows an exact differentiation of scar tissue from viable myocardium. In addition, due to the high spatial resolution of the NOGA system the application of laser channels at the same site can be avoided, which increases the safety of the procedure. To assess the efficacy of the NOGA based myocardial lasing procedure a multicenter randomized study (Euro-direct) is presently underway.

Reduction of azo dyes by redox mediators originating in the naphthalenesulfonic acid degradation pathway of Sphingomonas sp. strain BN6.

The anaerobic reduction of azo dyes by Sphingomonas sp. strain BN6 was analyzed. Aerobic conversion of 2-naphthalenesulfonate (2NS) by cells of strain BN6 stimulated the subsequent anaerobic reduction of the sulfonated azo dye amaranth at least 10-fold. In contrast, in crude extracts, the azo reductase activity was not stimulated. A mutant of strain BN6 which was not able to metabolize 2NS showed increased amaranth reduction rates only when the cells were resuspended in the culture supernatant of 2NS-grown BN6 wild-type cells. The same increase could be observed with different bacterial strains. This suggested the presence of an extracellular factor which was formed during the degradation of 2NS by strain BN6. The addition of 1,2-dihydroxynaphthalene, the first intermediate of the degradation pathway of 2NS, or its decomposition products to cell suspensions of the mutant of strain BN6 (2NS-) increased the activity of amaranth reduction. The presence of bacterial cells was needed to maintain the reduction process. Thus, the decomposition products of 1,2-dihydroxynaphthalene are suggested to act as redox mediators which are able to anaerobically shuttle reduction equivalents from the cells to the extracellular azo dye.

[The coexistence of 2 different neuroendocrine tumors of the upper gastrointestinal tract and pancreas]. / Koexistenz von zwei unterschiedlichen neuroendokrinen Tumoren des oberen Gastrointestinaltraktes und des Pankreas.

HISTORY AND CLINICAL FINDINGS: A 41-year-old obese patient presented with cramp-like abdominal pain, watery diarrhoea with partly digested food particles, projectile vomiting and newly diagnosed diabetes mellitus. For the preceding 6 years he had been treated for recurrent gastric and duodenal ulcers. Although the fasting gastrin level was raised and Zollinger-Ellison syndrome suspected, computed tomography (CT), magnetic resonance imaging (MRI) and coeliac angiography at another hospital had failed to discover a tumor. INVESTIGATIONS: Biochemical tests were unremarkable except for an increased GPT concentration, slight fasting hyperglycemia and hypertriglyceridemia. The gastrin and chromogranin A levels were markedly elevated (15,590 pg/ml and 584.2 U/l, respectively). Gastroscopy revealed, in addition to multiple small duodenal ulcers, a round polypoid mass (diameter of 0.7 cm) lateral to the papilla of Vater, histologically an APUDoma. Endoscopic retrograde cholangiopancreatography (ERCP) revealed a 0.5 cm long compression of the duct of Wirsung in the region of the head of the pancreas. Liver metastases were excluded by magnetic resonance imaging and computed tomography. Endosonography showed a ca. 4 mm space-occupying lesion in the region of the body of the pancreas. Octreotide scintigraphy demarcated two foci at the level of the head of the pancreas (somatostatin-receptor positive). TREATMENT AND COURSE: After a pylorus-preserving partial duodenopancreatectomy with lymph node dissection N1/N2, histology confirmed a gastrinoma of the duodenum and a glucagonoma of the pancreas (pT3pN1pMx). Postoperatively the patient became symptom-free and both the blood sugar level and the tumor marker were normal. CONCLUSION: Combined ERCP, endosonography and scintigraphy are more sensitive than other radiological examinations (CT and MRI) in diagnosing and localizing neuroendocrine tumours of the gastrointestinal tract. Despite the low incidence of such tumours, the possible synchronous occurrence of several such tumour should not be ignored.

Regional cerebral blood flow in patients suffering from post-traumatic stress disorder.

OBJECTIVE: The aim of the study was to determine whether regional cerebral blood flow in survivors of torture suffering from post-traumatic stress disorder (PTSD) differed significantly from that in healthy controls. METHOD: We examined the cerebral regional distribution of 99m-technetium-hexamethylpropyleneamineoxime (HMPAO) using single photon emission computed tomography (SPECT) in 8 patients and in 8 healthy controls. A semi-quantitative analysis was performed in which symmetrical regions of interest (ROI) were drawn in all subjects. RESULTS: Regional blood flow was markedly more heterogeneous in patients suffering from PTSD than in healthy controls. The differences are significant. CONCLUSION: Severe psychological trauma induced by torture can cause neurobiologic alterations that may contribute, even years after the original trauma, to a number of complaints commonly expressed by patients suffering from PTSD.

Biochemical markers of bone formation in patients with plasma cell dyscrasias and benign osteoporosis.

BACKGROUND: Myeloma-induced bone loss is related to an uncoupling of bone formation and bone resorption. The aim of the present study was to assess the potential clinical value of biochemical markers of bone formation in the work up of patients with plasma cell dyscrasias. METHODS: Serum total alkaline phosphatase, bone-specific alkaline phosphatase (BAP), and osteocalcin (OC) were measured in 43 patients with newly diagnosed multiple myeloma (MM), in 40 patients with monoclonal gammopathy of undetermined significance (MGUS), in 40 patients with untreated benign vertebral osteoporosis (OPO), and in 48 healthy adults. RESULTS: In MM and MGUS patients, serum BAP, but not serum OC, was lower than in healthy controls (P<0.05). Serum OC was higher in patients with OPO than in healthy controls (P<0.05). The strongest associations between markers were found in OPO patients and in healthy adults. MM patients with early-stage disease or without detectable osteolysis had decreased serum BAP values (P<0.05). Serum OC was higher in MM patients with stage III disease (P<0.05) than in healthy controls. MM patients with OPO-like bone involvement had lower BAP values than sex- and age-matched MGUS patients with OPO-like bone involvement and patients with benign OPO (P<0.05). CONCLUSIONS: In patients with plasma cell dyscrasias, serum BAP, rather than serum OC, appears to reflect a suppressed bone formation rate and may be helpful in the differentiation between benign and myeloma-induced OPO. However, the overall clinical use of biochemical markers of bone formation in patients with plasma cell dyscrasia appears limited.