Influence of inhibitors of eicosanoid metabolism on proliferation of rat hepatoma cells and on tumor-host interaction.

The influence of eicosanoids on the proliferation of hepatoma (HTC) cells was studied in culture and in tumor-bearing rats. The cells in culture demonstrated a capacity to metabolize arachidonic acid to eicosanoids including thomboxane B2 and the prostaglandins E2 and F2 alpha a. An effect of these eicosanoids on cell proliferation was suggested by the decreased cell division seen with an inhibitor of cyclooxygenase, flurbiprofen. A biphasic effect on the proliferation of HTC cells was observed with increasing concentrations of prostaglandin F2 alpha. These studies were extended to tumor-bearing rats where inhibitory effects on the early stages of tumor growth were seen with flurbiprofen. Bleeding times were decreased in tumor-bearing rats but were restored to control values by treatment with flurbiprofen and an inhibitor of thromboxane synthetase, OKY 046. These drugs and a thromboxane/endoperoxide receptor antagonist, SQ 29, 548, were not observed to have statistically significant effects on isotope-labeled water distribution but they had substantial effects on the maintenance of body weight by tumor-bearing rats. The data suggested that the cachexia of tumor-bearing animals may be mediated at least in part by the action of eicosanoids.

[Results of employing single crystal gammacamera and minicomputer in the first tracer passage to determine left-ventricular ejection fraction and wall motion (author's transl)]. / Einsatz von Einkristall-Gammakamera und Kleinrechner bei der ersten Radionuklid-Passage zur Bestimmung von Auswurffraktion und Wandbewegungen des linken Ventrikels.

Single crystal gammacamera and minicomputer were employed in 71 patients to determine left-ventricular ejection fraction (EF) (17 mCi 99mTc-HSA; 30 degrees RAO projection) by means of the first tracer passage. In 30 out of these patients, ventricular wall motion could be analyzed additionally because later on the gammacamera was equipped with a converging collimator. Comparison with cineventriculographically determined EF values revealed a good correlation (r = 0.91), not depending on left-ventricular wall motion pattern. Hereby, with first transit, high EFs were computed somewhat lower and low EFs were found somewhat higher. This non-limiting discrepancy is closely related to the influence of paracardiac "background"-radioactivity. Comparative analysis of segmental wall motion demonstrated agreement in 83% of the 90 segments examined. Therefore, it can be confirmed that performance of the first tracer passage for a evaluating segmental wall motion must not mandatorily be done with a multicrystal camera.

Enzymatic analysis and collagen content in endomyocardial biopsy samples of patients with congestive cardiomyopathy of unknown etiology.

Endomyocardial biopsy samples from patients suffering from congestive cardiomyopathy of unknown etiology (COCM) were analyzed for lactate dehydrogenase (LDH) isoenzyme distribution by microisoelectric focusing. In addition, the concentration of collagen in the biopsy samples was estimated by determination of hydroxyproline and proline. The results were correlated with the clinical and hemodynamic data of the patients. Increased activities of total LDH and LDH5--the worse the hemodynamic parameters, the higher the concentration of LDH5--indicate an enhanced anaerobic glycolysis in the myocardium of COCM patients. The close correlation between the hemodynamic data and the LDH isoenzyme pattern suggests an association between severity of COCM and impairment of aerobic metabolism. The results of the alteration in the LDH isoenzyme pattern were not influenced by the collagen content in the myocardial biopsy samples. Varying isoenzyme patterns in the different parts and wall layers of the normal heart show the necessity of analyzing biopsy samples only from comparable localizations.

[Heparin-associated type II thrombocytopenia as a cause of multiple thromboembolism complications]. / Heparin-assoziierte Thrombozytopenie Typ II als Ursache multipler thromboembolischer Komplikationen.

13 days after hysterectomy and subcutaneous treatment with unfractionated heparin (10000 IU daily) a 68 year old women developed a pulmonary embolism and deep vein thrombosis of the right leg. She thereupon received intravenous heparin (1000 IU/h). Eight days later she developed acute ischaemia of both legs, and Doppler examination revealed acute Leriche's Syndrome with thrombosis of both iliac arteries. Platelet count fell from, initially 152 x 10(9)/I, to 44 x 10(9)/I. Although heparin-associated thrombocytopenia type II was suspected a confirmation by demonstrating a heparin dependent antibody with the heparin-induced platelet activation (HIPA)-test failed and therefore crossreactivity of low molecular heparins or heparinoids could not be assessed. After discontinuation of heparin and iliacal artery thrombectomy a combination therapy with aspirin plus ticlopidine (500 mg/d respectively) was started and continued until phenprocoumon could exert its full effect. No recurrent thromboembolic events occurred, the platelet counts normalized and the patient fully recovered.

Clinical trial simulations in pediatric patients using realistic covariates: application to teduglutide, a glucagon-like peptide-2 analog in neonates and infants with short-bowel syndrome.

Teduglutide, a synthetic glucagon-like peptide-2 (GLP-2) analog with activity relating to the regeneration, maintenance, and repair of the intestinal epithelium, is currently being evaluated for the treatment of short-bowel syndrome (SBS), Crohn's disease, and other gastrointestinal disorders. On the basis of promising results from teduglutide studies in adults with SBS and from studies in neonatal and juvenile animal models, a pediatric multiple-dose phase I clinical study was designed to determine the safety, efficacy, and pharmacokinetics of teduglutide in pediatric patients with SBS who have undergone resection for necrotizing enterocolitis, malrotation, or intestinal atresia. This report details the application of clinical trial simulations coupled with a novel approach using generalized additive modeling for location, scale, and shape (GAMLSS) that facilitates the simulation of demographic covariates specific to the targeted patient populations. The goal was to optimize phase I dosing strategies and the likelihood of achieving target exposure and therapeutic effect.

[Isoniazid intoxication]. / Intoxikation mit Isoniazid.

HISTORY AND ADMISSION FINDINGS: A 55-year-old woman presented with sustained convulsions after the ingestion of an at first unknown amount of isoniazid, rifampin, ethambutol and alcohol. INVESTIGATION: At admission the patient had a severe metabolic acidosis. Blood tests showed changes caused by the hepatotoxicity of isoniazid. TREATMENT AND COURSE: Because diazepam was not efficacious in controlling the convulsions the patient was intubated. In response to the therapautic measures the convulsions stopped and metabolic acidosis was quickly compensated. Pyridoxine was given intravenously as an antidote. CONCLUSION: The rare intoxication with isoniazid demands immediate administration of pyridoxine and aggressive treatment of the convulsions.

[Primary diagnosis of an interrupted aortic arch in a 65-year old woman with hypertension]. / Erstdiagnose eines kompletten Aortenbogenverschlusses bei einer 65-jährigen Hypertonikerin.

HISTORY AND PHYSICAL EXAMINATION: A 65-year-old woman presented in a hypertensive crisis and with angina pectoris. She had a history of hypertension for several years and medication included five different antihypertensive drugs. On physical examination a faint systolic murmur was heard. Weak femoral pulses were felt, but not the arterial pulses distal to the groin. INVESTIGATIONS: An attempt to perform coronary arteriography failed because it was impossible to pass the catheter across the aortic arch. MR-angiography and cardiac catheterization via the brachial artery confirmed the diagnosis of a complete interruption of the aortic arch distal to the left subclavian artery and showed distinct collateral circulation predominantly via the internal mammary arteries. DIAGNOSIS AND THERAPY: Because of the age of the patient we assumed that the pathogenesis of this interruption of the aortic arch probably was progression and finally occlusion of an aortic coarctation. It was not possible to distinguish the findings from a true congenital atresia, because there was no histological examination. The patient rejected surgery and conservative therapy with frequent monitoring seemed justified, considering the good blood pressure adjustment and the extensive collateral vascularization. CONCLUSION: Patients with complete interruption of the aortic arch very rarely do reach late adult age without previous surgical intervention. Indeed, such a situation is only conceivable when there is a good collateral blood supply and no concomitant shunt defects. There is an indication for operation, but as there are insufficient follow-up data this should be weighed up carefully in elderly patients whose blood pressure is well controlled.

[Intracardial thrombus formation in heparin-associated thrombocytopenia type II]. / Intrakardiale Thrombenbildung bei Heparin-assoziierter Thrombozytopenie Typ II.

Deep vein thrombosis of the right leg occurred in a 77-year-old woman after percutaneous cardiac catheterization via the right femoral vein, performed to assess mitral valve disease with atrial fibrillation. She thereupon received intravenous heparin (1,000 IU/h; partial thromboplastin time 60-70s). 13 days later she developed a transient incomplete right brachiofacial hemiparesis with motor aphasia. Transthoracic echocardiography revealed a fresh left atrial thrombus. Platelet count fell from initially normal levels to 20 x 10(9)/l. Because type II heparin-associated thrombocytopenia was suspected heparin administration was discontinued and phenprocoumon administered. Heparin-dependent antibodies were demonstrated with the heparin-induced platelet activation test. Cross reactions occurred in vitro against all low-molecular heparins and heparinoid ORG 10172. The platelet count had become normal 17 days later, the leg veins had recanalized and the intraatrial thrombus had become much smaller. The patient declined cardiac surgery and was discharged on the 41st hospital day in satisfactory general condition on maintenance anticoagulant dosage.

[Lactacidosis in biguanide therapy: diagnosis and therapy. 4 cases compared to 179 cases in the world literature]. / Laktazidose bei Biguanidtherapie: Diagnostik und Therapie 4 Kasuistiken im Vergleich zu 179 Fällen der Weltiliteratur.

In 4 out of 9711 (= 1:2400) patients, lactice acidosis due to biguanides was diagnosed. Serum lactate concentration averaged 18.2 mmol/l and the pH value 6.87. All patients showed signs of renal insufficiency and three had congestive heart disease. In addition to treatment with biguanides, other factors might have contributed to the lactice acidosis in these patients: prolonged fasting, severe dehydration due to persistent vomiting, acute bronchopneumonia, and acute pyelonephritis. On addmission, two patients were in shock and all patients were semi-conscious or comatose. All patients were treated with bicarbonate and glucose/insulin. One patient was hemodialysed. Two of our four patients died. Oour four patients are compared with 179 patients in the literature with respect to mortality and prognosis of lactic acidosis due to biguanides.

[Heparin-induced thrombocytopenia. Diagnosis, clinical course and therapeutic alternatives]. / Heparin-induzierte Thrombozytopenie. Diagnostik, klinischer Verlauf und therapeutische Alternativen.

Heparins are common and have been widely used in prophylaxis and therapy of thromboembolic disorders for many years. Nevertheless, the serious side effect of heparin-induced thrombocytopenia type II (HIT II) has attracted attention only recently. First evidence of HIT II is a drop in platelet count below 100,000/mm3. Subsequently, thromboembolic complications occur 6-20 days after beginning heparin therapy. Overall mortality is 20-30% of patients with HIT II. Therefore, frequent platelet counts are required for early diagnosis. However, in cases of moderate or absent thrombocytopenia the diagnosis of HIT II can be difficult. Laboratory tests such as heparin-induced platelet activation (HIPA) test or heparin/PF4-antibody-ELISA have limited sensitivity and specificity. Therefore, with typical clinical findings, divergent laboratory results should be interpreted with caution. If HIT II is suspected, all heparins should be discontinued immediately. Due to a high cross reactivity rate with the heparin-dependent antibody, subsequent therapy with low molecular weight heparins (LMWH) is contraindicated. As treatment of choice danaparoid or recombinant hirudin may be administered. Oral anticoagulation should be started cautiously with an alternative immediate-acting antithrombotic agent. More widespread use of LMWH may reduce the incidence of HIT II in the future. Nevertheless, the main and most important factor in the prevention of this life-threatening complication is the awareness and caution of the clinician.

[Metastasizing pancreatic vipoma. Its diagnosis and therapy with the somatostatin analog octreotide]. / Metastasierendes Pankreas-VIPom. Diagnostik und Therapie mit dem Somatostatin-Analogon Octreotid.

HISTORY: An 82-year-old woman was hospitalized for anaemia of 4.8 g/dl after having suffered for about one year from watery treatment-resistant diarrhoea, causing a weight loss of ca. 10 kg. FINDINGS: Computed tomography, magnetic resonance imaging and endosonography revealed a 2.5 x 2.0 cm space-occupying mass in the body of the pancreas. Taking into account electrolyte abnormalities (potassium 2.7 mmol/l), marked metabolic acidosis (pH 7.16, base excess -20.3 mmol/l) and achlorhydria, an increased serum concentration of vasoactive peptide (VIP) of 548.5 pmol/l confirmed a VIPoma. Somatostatin-receptor scintigraphy also demonstrated a metastasis, 1.8 cm in diameter, in the region of the right ovary. TREATMENT AND COURSE: Under administration of somatostatin analogue octreotide (150 micrograms three times daily subcutaneously) the symptoms quickly disappeared and the stools as well as electrolyte and acid-base balances became normalized. After 5 months of treatment the levels of VIP, pancreatic enzymes and gastrin were within normal limits or clearly suppressed. There has been no recent evidence of tumour progression. CONCLUSION: This case demonstrates so far successful suppression of a metastasizing VIPoma with the somatostatin analogue octreotide, the metastasis having been revealed first by somatostatin-receptor scintigraphy.

Prostaglandin biosynthetic capacity of hepatomas with different growth rates.

1. Prostaglandin synthesis from [14C]arachidonate by microsomal fractions was measured with preparations from rat liver and from hepatomas of different growth rates. The highest rates of synthesis were observed with microsomal preparations from the rapidly growing hepatoma HTC. 2. Assay of endogenous levels of prostaglandins E2, F2 alpha and thromboxane B2 also indicated high levels in solid tumors of the HTC line. 3. With HTC cells in culture it was necessary to incubate in the absence of serum in order to detect prostaglandin synthesis. 4. The data indicated that, while prostaglandin synthesis was elevated in HTC cells, the synthesis of prostaglandins by a series of hepatomas was not closely correlated with the growth rates of the tumors.

[Assessment of left ventricular performance by single crystal gamma camera and first pass radionuclide angiography (author's transl)]. / Die Erfassung der Funktion des linken Ventrikels mit der Einkristall-Gammakamera im Rahmen der Ersten Radionuklidpassage

Employment of a single crystal gamma camera in first pass radionuclide angiography yields essential parameters of left ventricular performance. These are: global ejection fraction, end-diastolic, end-systolic and stroke volumes, regional wall motion and regional ejection fractions. Since the right anterior oblique (30 degree RAO) projection is used, results of this noninvasive method are comparable to findings from invasive contrast ventriculography. A critical evaluation of the comparative results (correlation r = 0.84 to 0.97 in global ejection fraction; r = 0.87 to 0.95 in end-diastolic volume; agreement in segmental wall motion analysis of 72 to 90%) justifies the use of a single crystal gamma camera in first pass radionuclide angiocardiography. At elevated heart rates, e.g. during exercise, the single crystal system yields information of limited value as compared with that of the multiple crystal system. As compared to other methods (e.g. equilibrium methods), short examination times (30 s) of first pass are advantageous. First pass radionuclide angiocardiography may directly precede equilibrium examinations. Within this sequence, it may be used to assess right ventricular function and lung circulation.

Light-chain binding sites on renal brush-border membranes.

Immunoglobulin light chains are low-molecular-weight proteins filtered at the renal glomerulus and catabolized within the proximal tubular epithelium. Excessive production and urinary excretion of light chains are associated with renal dysfunction. They also interfere with proximal renal tubule epithelial functions in vitro. We studied the binding of 125I-labeled kappa- and lambda-light chains, obtained from the urine of multiple myeloma patients, to rat and human renal proximal tubular brush-border membranes. Light-chain binding to brush borders was also demonstrated immunologically by flow cytometry. Computer analysis of binding data was consistent with presence of a single class of low-affinity, high-capacity, non-cooperative binding sites with relative selectivity for light chains on both rat and human kidney brush-border membranes. The dissociation constants of light chains ranged from 1.6 X 10(-5) to 1.2 X 10(-4) M, and maximum binding capacity ranged from 4.7 +/- 1.3 X 10(-8) to 8.0 +/- 0.9 X 10(-8) (SD) mol/mg protein at 25 degrees C. Kappa- and lambda-light chains competed with each other for binding with comparable affinity constants. Competition by albumin and beta-lactoglobulin, however, was much weaker, suggesting relative site selectivity for light chains. These binding sites probably function as endocytotic receptors for light chains and possibly other low-molecular-weight proteins.

[Typing of amyloidoses intra vitam by tissue biopsy using antibodies. Report on 2 patients]. / Typisierung von Amyloidosen intra vitam an der Gewebebiopsie mit Hilfe von Antikörpern. Bericht über zwei Patienten.

The value of the immunohistochemical classification of amyloid-syndromes has been illustrated in two patients with generalized amyloidosis. Chemical types and exact diagnosis were recognized in biopsies (and later necropsies) using antisera against different purified amyloid fibril proteins and the indirect immunoperoxidase technique. The first case, originally diagnosed as "perireticular" amyloid, was diagnosed as "Ak-amyloidosis with kappa-Bence-Jones-proteinuria without apparent B-cell malignoma", the second case as "AA-amyloidosis reactive to periodic fever". The diagnosis and possible therapeutic measures are discussed in the light of the new classification of amyloid syndromes.

[Strychnine poisoning]. / Strychninvergiftung.

HISTORY AND ADMISSION FINDINGS: A 46-year-old man presented two hours after ingestion of about 250 mg strychnine with severe violent, generalized convulsions, triggered by external stimuli. During the convulsion-free periods there were no abnormal signs in the physical examination. INVESTIGATION: The presence of strychnine was confirmed by urine analysis with gas chromatography-mass spectrometry. TREATMENT AND COURSE: Because diazepam as anticonvulsant of choice was not effective in abating the convulsions the patient was intubated. A combination with midazolam, fentanyl and pancuronium was effective in controlling the convulsions. The patient was discharged from ICU on day three. CONCLUSION: Fatal outcome of strychnine poisoning demands an aggressive management with early intubation, control of muscle tremors and prevention of rhabdomyolisis and renal failure.

[Intravascular ultrasound in recurrent myocardial ischemia and unremarkable coronary angiogram]. / Intravaskulärer Ultraschall bei rezidivierender Myokardischämie und unauffälligem Koronarangiogramm.

HISTORY AND CLINICAL FINDINGS: 3 months after sustaining an intramural anterior wall myocardial infarction (AWMI) a 57-year-old man was again admitted with the clinical and electrocardiographic (ECG) signs of an acute AWMI. As the activities of creatinine kinase (841 U/l) and of the myocardial isoenzyme (CKMB 143 U/l) were markedly elevated, thrombolysis with streptokinase was instituted. Subsequent left heart catheterization demonstrated discrete wall irregularity in the proximal branch of the anterior interventricular artery (PAIVA) and the right coronary artery, but no evidence of stenosing coronary heart disease. TREATMENT AND COURSE: Because of the discrepancy in the findings, intravascular ultrasound imaging (IVUI) was performed. It revealed an eccentric unstable plaque in the PAIVA with a minimal cross-sectional stenosis of 3.3 mm2 (50% luminal narrowing). After stent implantation under IVUI a good primary result was achieved (stent cross-sectional area 6.2 mm2). CONCLUSION: The usual cause of acute MI is rupture of an unstable, not flow-limiting and thus angiographically possibly "silent" plaque. IVUI can provide immediate assessment of atheromatous wall changes and can thus help to decide on further specific interventional measures.

Electrical proarrhythmia: induction of inappropriate atrial therapies due to far-field R wave oversensing in a new dual chamber defibrillator.

This case report describes delivery of atrial therapies during a sinus tachycardia in a new dual chamber implantable cardioverter defibrillator inappropriately caused by far-field oversensing of ventricular beats in the atrial channel. Upon classification of the PR interval pattern, the rate criterion for an atrial tachycardia was fulfilled, and the device initiated high-frequency burst pacing as the first stage of programmed tiered atrial therapies. Atrial fibrillation subsequently was induced by high-frequency burst pacing, and eventually a programmed 10-J shock was delivered for successful termination of atrial fibrillation. The phenomenon of far-field oversensing of ventricular beats could be repeatedly observed during exercise testing and abolished by decreasing the atrial sensitivity.

[Acute myocarditis and cardiomyopathy in Lyme borreliosis]. / Akute Myokarditis und Kardiomyopathie bei der Lyme-Borreliose.

Heart involvement of Lyme disease occurs in about 4-10% of patients with Lyme borreliosis. The most common manifestation is acute, self-limiting Lyme carditis, which manifests mostly as transient conduction disorders of the heart, pericarditis and myocarditis. Laboratory tests (ELISA, immunoblotting and PCR) usually have limited sensitivity and specificity, and criteria of performance and interpretation have not yet been fully evaluated. Therefore the laboratory evidence should only be interpreted in conjunction with other clinical and diagnostic features. Recently there has been convincing evidence published that long standing dilated cardiomyopathy in many cases is associated with a chronic Borrelia burgdorferi (BB) infection. Several studies showed a higher prevalence of BB antibodies in patients with severe heart failure in endemic areas (e.g., 26% versus 8% in healthy individuals). The isolation of spirochetes from the myocardium gave further evidence that BB may cause chronic heart muscle disease. In several studies antimicrobial treatment showed an improvement of the left ventricular function in patients with dilated cardiomyopathy associated with BB. However the duration of dilated cardiomyopathy before treatment plays an important part in the clinical outcome of BB-associated chronic myocarditis.

[Rare complication of a heparin-induced thrombocytopenia type II]. / Seltene Komplikation einer Heparin-induzierten Thrombozytopenie Typ II (HIT II).

HISTORY AND CLINICAL FINDINGS: A 63-year-old man was admitted to a surgery department with fracture of the acetabulum and luxation of the hip joint. Eight days after intracondylar nail-extension during subcutaneous heparin prophylaxis he developed a dramatic deterioration of his condition with severe abdominal pain and fever and was admitted to our hospital. INVESTIGATIONS: White cell count was 12,000/microliter, C-reactive protein 7.90 mg/dl. CT-scan, abdominal ultrasound, mesenteric angiography and exploratory laparotomy revealed no pathological findings. At day 13 abdominal ultrasound showed adrenal haemorrhages on the right. Together with a drop in platelet count below 50,000/microliter, adrenal haemorrhage caused by heparin-induced thrombocytopenia (type II; immunological [HIT II]) was suggested. THERAPY: After discontinuation of heparin and starting therapy with recombinant hirudin and hydrocortisone, a dramatic clinical recovery followed within 24 hours. One year after the initial diagnosis the patient is in a good condition. CONCLUSION: When abdominal pain, hypotension and fever occurs with a drop in platelet count during heparin therapy HIT II should be considered. An early diagnosis is essential for treatment of this life-threatening complication at an early stage.