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In ischemia-reflow states of coronary artery disease, the activation of PMN precedes the initiation of tissue damage. Release of atrial natriuretic peptide (ANP) from myocytes occurs within minutes after the onset of myocardial ischemia, which suggests a possible role of ANP in PMN activation. To investigate this possibility, we tested the effects of ANP on functions of PMN in vitro. ANP is a potent signal for priming the PMN respiration burst to secrete superoxide anion. Phorbol 12-myristate 13-acetate, opsonized zymosan, or FMLP could all be used as triggering stimuli to demonstrate the priming of PMN activation by ANP. Only ANP fragments 1-28 and 7-28 enhanced respiration burst activity but identical preparations of ANP fragments 13-18 or 1-11 failed to do so. This structure-activity relationship is typical of receptors for ANP found in other tissues. In addition, ANP stimulated the release of beta-glucuronidase From PMN triggered by FMLP. The observed inhibition by ANP of FMLP-stimulated chemotaxis of PMN may be due to their enhanced adhesiveness. These data show that a classic cardiac hormone is involved in regulating important functional activities of PMN. These data support the possibility that ANP could act as a preinflammatory substance in ischemia-reperfusion states and myocardial necrosis.

SUMMARY The neuroendocrine potypeptide hormone beta-endorphin (β-END), which is released from various tissues including the anterior pituitary gland and cells of the immune system, has recently been implicated as having an immunoregulalory role. We used a radioimmunoassay to measure β-END levels in circulating mononuclear leucocytes from normal subjects and patients with various rheumatic diseases. Levels of β-END in leucocytes from patients were lower than in leucocytes from healthy subjects (P

As neutropenia is a common side effect of treatment with 2-chlorodeoxyadenosine (2-CdA), we investigated the myelosuppressive action of 2-CdA in Dexter-type human long-term bone marrow cultures (LTBMCs). LTBMCs were incubated with varying doses of 2-CdA (5 to 20 nM/L) during the first week. At 20 and 10 nM/L 2-CdA, we found a marked reduction in colony-forming unit-granulocyte/macrophage (CFU-GM) production throughout the culture period of 7 weeks (maximum reduction to 3.5% of untreated control cultures with 20 nM/L and to 27.2% with 10 nM/L, respectively). Even the lowest 2-CdA dose tested (5 nM/L) strongly reduced the number of CFU-GM progenitors during the first 3 weeks (maximum reduction to 52.4% of untreated controls), but this effect was transient, and values had recovered to normal within in 5 weeks. 2-CdA was also shown to cause a dose-dependent decrease in long-term culture-initiating cell (LTCIC) detections after 5 weeks in culture (49.6% of control cultures with 10 nM/L 2-CdA and 14% with 20 nM/L 2-CdA, respectively). When 2-CdA was added to LTBMCs initiated on preformed irradiated stromal feeder layers, similar results on CFU-GM production were obtained, indicating that the effects observed were not secondary to effects on the formation of a supportive layer. In addition, IL-6-concentrations in the supernatant of LTBMCs measured at various intervals after the addition of fresh medium with or without 2-CdA showed no significant decrease in cultures treated with 2-CdA. As neutropenia has been shown to be associated with a small but significant risk of fatal infection, we subsequently investigated the reversal potential of the 2-CdA effect by addition of recombinant human granulocyte colony-stimulating factor (rhG-CSF) or rh interleukin-3 (rhIL-3). The weekly addition of 100 ng/mL rhG-CSF counteracted the 2-CdA-mediated decrease in CFU-GM numbers during the entire period of 7 weeks, reaching statistical significance from weeks 3 to 7 (p0.05). Addition of rhIL-3 (100 ng/mL) showed an enhancement of CFU-GM output in 2-CdA-treated cultures that resulted in their numbers exceeding those in control cultures (without 2-CdA) from weeks 1 to 5 (p0.05) with a maximum increase of 5.1-fold over the parallel control value at week 3.(ABSTRACT TRUNCATED AT 400 WORDS)

The aim of the present study was to investigate prognosis and life expectancy in patients with primary biliary cirrhosis. We retrospectively analysed 59 patients from western Austria over 15 years (mean 6 years). The results of the present study were compared with the average life expectancy of the population of western Austria and with the results of the Mayo study published in 1989. The mean survival time in our study was 112.7 months, 25% were dead by 132 months. Kaplan-Meier analysis showed a 95% probability to survive 1 year and a 84% probability to be alive at 5 years. Asymptomatic patients had a significantly better prognosis than symptomatic patients. In comparison with the Mayo study the patients in our study had a better prognosis and in comparison with the normal population a significantly worse life expectancy.

In animal studies of myocardial ischemia/reperfusion l-arginine reduces necrotic injury by preservation of endothelial function and attenuation of neutrophil accumulation in ischemic cardiac tissue. Because release of oxygen radical species by circulating neutrophils is important in endothelial function and ischemia-reperfusion injury, this study investigated the effect of intravenous administration of L-arginine on the in vitro release of superoxide anion of neutrophils in healthy young adults. Neutrophils were obtained at various time points before, during, and after infusion of l-arginine (17 mg kg−1 min−1 for 30 min) and analyzed for superoxide dismutase inhibitable reduction of ferricytochrome c. The spontaneously occurring respiratory burst of polymorphonuclear leukocytes at basal conditions was compared with that after triggering by 1 μmol/l formylpeptide or 50 ng/ml phorbolester. Infusion of l-arginine inhibited both basal (P < 0.01) and formylpeptide-triggered (P < 0.05) release of superoxide anion did, but not affect release stimulated by phorbol 12-myristate 13-acetate. Pretreatment of neutrophils with 1 mmol/l l-arginine in vitro also significantly reduced formylpeptide-triggered (1 μmol/l) superoxide anion release, suggesting that the affects observed after in vivo pretreatment may be due to direct action of l-arginine on neutrophils. These findings demonstrate the ability of L-arginine to reduce release of oxygen radical species by circulating neutrophils in man.

Factors that affect leukocyte-endothelial cell interaction in high endothelial postcapillary venules and vascular sinuses of lymphatic tissues indirectly regulate immune function. Studies in sheep demonstrated that acute infusion of substance P (SP) into cannulated popliteal lymph node afferent lymphathics produced a marked and prolonged increase in the output of lymphocytes into nodal efferent lymph. The proposed mechanism is an influence of SP on lymph vascular systems. Such functional importance of the immunoregulatory properties of SP in man is unknown.The expression and distribution of SP receptors in human lymphoid tissue was investigated using slide-mounted fresh-frozen sections of lymph node, hyperplastic tonsillitis, and spleen for ligand binding and autoradiographic studies.Specific binding of radiolabeled SP to lymph node and tonsils reached a plateau within approximately 40 minutes, being half-maximal at 20 minutes. The specific binding was between 65 and 75% of total binding. In contrast, iodinated neurokinin A under identical incubation conditions, did not significantly associate with the tissues. Neither the SP nor the neurokinin A tracer specifically associated with spleen. Binding specificity of radiolabeled SP was analyzed in binding competition experiments. Synthetic SP, SP (3-11), a selective neurokinin-1 agonist and a neurokinin-1 antagonist competed with the specific binding of SP to lymph node and tonsil sections. The half-maximal inhibition of binding was obtained at a concentration of about 0.5 nmol/liter of SP. The fragment SP (1-4) and selective neurokinin-2 ligands did not compete with the specific binding of SP. Scatchard and nonlinear algorithm analyses revealed two binding sites for SP. For lymph node and tonsil, one site showed a high affinity of about 0.4 nmol/liter and 0.7 nmol/liter and a low capacity for SP, respectively. The second site exhibited a lower affinity of 100 nmol/liter and 50 nmol/liter and a higher capacity for SP in lymph node and tonsil, respectively. Autoradiographic localization of the binding sites shows a very high concentration of silver grains when compared with controls. The reaction occurred mainly over vascular sinuses and high endothelial venules with heterogenous density. Silver grain accumulation was also noticed over the marginal sinuses of the B cell follicles.The biochemical results indicate the presence of neurokinin-1 receptors in human lymph node and tonsil. We suggest that the neurokinin-1 receptors localized to vascular tissues of lymph node and tonsil mediate the affects of SP on lymphocyte traffic, and we propose that SP plays a regulatory role in lymphocyte homing in man.

The short- and long-term therapeutic results of transseptosphenoidal adenomectomy were studied retrospectively in 92 patients with pituitary tumors (42 nonsecreting adenomas, 21 GH-, 15 PRL-, 10 ACTH-, 2 TSH-, and 2 FSH-secreting adenomas). Severe surgically related complications were not observed. The early remission rate was 53.7% in nonsecreting, 57.1% in GH-secreting, 60% in PRL-secreting, 88.9% in ACTH-secreting, and 75% in TSH- or FSH-secreting adenomas. The recurrence rate in patients with nonsecreting adenomas was 47.1%, with GH-secreting adenomas 10%, with ACTH-secreting adenomas 25%, and with TSH- or FSH-secreting adenomas 66.7%, respectively. A long-term cure rate of 69.2% was observed in prolactinomas in combination with a facultative dopamine agonist therapy. More patients had normal pituitary function concerning TSH, ACTH, and LH/FSH post-operatively (48.9% versus 46.6% preoperatively). These data confirm that transseptosphenoidal surgery is a safe and selective treatment for pituitary adenomas with efficient preservation of the normal pituitary gland.

Orthotopic liver transplantation offers the only therapeutic option for many patients with end-stage liver disease. In adults, the overall five-year survival following transplantation has increased dramatically from approximately 30% a decade ago to nearly 70% currently. Cyclosporine A became available in the 1970s and substantially improved immunosuppressive therapy. It is now the mainstay of the therapeutic approach to prevent graft rejection. The postoperative care of liver transplant recipients is one of the most exciting challenges in clinical medicine. On the basis of the experience and results of the Innsbruck liver transplant programme the management of liver transplant recipients will be discussed with regard to the typical time frame of complications. We present data of 87 liver transplantations in 84 patients during a 10-year observation period. At present, intraoperative mortality is fortunately close to zero. Most of the deaths occur in the immediate postoperative period. Major complications are haemorrhage, hepatic artery or portal vein thrombosis, biliary leakage or graft dysfunction. In addition, side-effects resulting from high-dose immunosuppressive therapy or from antibiotic and antiviral therapy add to problems in this early period. Opportunistic infections, chronic graft failure, disease recurrence and nephrotoxicity related to Cyclosporine A therapy are complications seen during long-term management of liver transplant patients. The differential diagnosis and the adequate management of these complications are a great challenge to every hepatologist.

The effects on proliferation of Molt-4 lymphoblasts of cholecystokinin (CCK-8), somatostatin-14 (SS), vasoactive intestinal peptide (VIP) and substance P (SP) were investigated using different combinations of the peptides, peptide analogs and their antagonists. In vitro proliferation of the cells was measured by a colorimetric assay for cell growth and survival. Results indicate that SP and SP (3-11) stimulated, whereas CCK-8, VIP and SS inhibited, proliferation in a dose-dependent manner (P0.05). Unsulfated CCK-8 had no effect on growth of Molt-4 lymphoblasts, and a specific antagonist of CCK, at a concentration 10(-6) M, diminished the inhibitory effect of CCK-8 on Molt lymphoblasts (P0.05). This suggests that the inhibitory action of CCK-8 was mediated by peripheral-type CCK receptors. SS and VIP, at equimolar concentrations of 10(-6) M, significantly augmented the CCK-8-induced inhibition of Molt-4 lymphoblast proliferation. However, none of the inhibiting neuropeptides suppressed stimulation of Molt-4 lymphoblast proliferation in response to SP. These data suggest a role of sensory neuropeptides including CCK in modulating human T lymphoblast proliferation during neuroendocrine interactions with the immune system.

The case of a young female patient with homozygous alpha-1-antitrypsin deficiency (Pi-ZZ) associated chronic liver disease, who developed primary hepatic tuberculosis shortly after delivery of a healthy baby girl is reported. These findings emphasize that this rare disease should be considered even in patients with precirrhotic liver disease, while pointing out that the genetically determined deficiency of protease inhibitor alpha-1-antitrypsin (AAT) predisposes to hepatic infection.

Pulmonary infiltrations associated with renal failure demand several diagnostic procedures to exclude autoimmune disorders affecting both organ systems or to find an infectious cause of the disease. We report the case of a 60 year-old man with chronic renal failure and recurring pulmonary infiltrations. On admission to hospital all diagnostic parameters for systemic vasculitis, infectious or neoplastic disease were negative, including the histological report on transbronchial biopsies. Eventually, follow-up biopsies taken 3 months later showed vegetable fibres and necrosis due to intensive snuff abuse during the previous months. After the patient stopped taking snuff the pulmonary infiltrations improved quickly. Uraemic neuropathy, which may have facilitated aspiration, as well as the reduced pulmonary and systemic defence mechanisms due to chronic renal failure probably contributed to a considerable degree to the development of pulmonary infiltration.

Previous studies have shown that 2-chloro-2'-deoxyadenosine (CdA) is markedly toxic to normal and malignant human lymphocytes in vitro and in vivo. Recent clinical trials have shown that CdA is a very promising drug for the treatment of lymphoid malignancies. The present investigations were designed to test the effect of CdA on the in vitro clonal growth of both myeloid progenitors and T-lymphocyte colony-forming cells (CFU-TL) obtained from normal human bone marrow and peripheral blood. Cells were exposed to CdA in doses up to 1280 nmol/L. To reduce indirect effects of CdA mediated by accessory cells, monocyte- and T-lymphocyte-depleted bone marrow cells were used for our investigations. The results show a marked inhibition of myeloid progenitor and lymphocyte colony-forming cells in a dose-dependent manner, correlating with maturation stage in that the immature progenitor cells are more sensitive to this drug. Furthermore, our studies suggest that a sequence of metabolic events previously described for lymphocytes may be operative in myeloid progenitor cells because a minimal exposure time of 48 hours is required to obtain a marked inhibition. CdA toxicity was proposed to be linked with phosphorylation by deoxycytidine-kinase (E.C. 2.7.1.74), the levels of which have been found to be high in lymphocytes, but low in granulocytes. However, the marked inhibition of myeloid progenitor cells shown in these studies suggests that other factors such as modulation of the effect of CdA by the ambient levels of other deoxynucleosides might influence the apparent sensitivity of myeloid cells.

Four weeks after appendicectomy a 28-year-old man developed dragging pains in the left calf. Left popliteal, posterior tibial and dorsalis pedis arteries could not be palpated. Angiography revealed an embolic occlusion of the left superior femoral artery at the level of the adductor canal. Echocardiography demonstrated a pedunculated left ventricular thrombus, 3.5 x 2.0 cm, as a possible source of the embolus. After successful trifurcation embolectomy and saphenous vein patch-plasty acenocoumarol, 4 mg/d and heparin, 3 x 7500 IU/d were administered. Because the thrombus failed to shrink, systemic thrombolysis, initially 750,000 IU streptokinase and 3000 IU heparin i.v., was begun. After five days the thrombus diameter had decreased to 0.7 cm. But because thrombus movement had increased, streptokinase was replaced by 70 IU/d ancrod i.v. The thrombus completely disappeared within two weeks. The patient was symptom-free during the period of anticoagulation with acenocoumarol. Six months later echocardiography confirmed the absence of thrombus in the left ventricle.

During the last years several risk factors for cerebrovascular disease (CVI) could be identified by epidemiologic studies; the incidence of CVI, like that of coronary artery disease, seems to be closely related to high blood pressure, hyperlipidaemia, smoking and diabetes mellitus. The diagnostic difficulties in CVI, especially concerning the localization and size of vascular lesions, explain controversal results in the evaluation of different clinical studies. A comparison of these results is often hard to perform also out of the different statistical methods applied in the various trials. The development of improved diagnostic methods, especially ultrasonography, which allow a better definition of disease processes, offers an advantage for controlled screening and intervention trials. After all further improvements in disease prevention as well as in diagnostic and therapeutic procedures require an intensive co-operation between internal medicine and neurology.

Cytokines are mainly produced by monocytes and lymphocytes and influence a broad spectrum of physiological processes within the hematopoietic and the immune system. Clinical trials have mainly been initiated with a subgroup of cytokines namely the hematopoietic growth factors. Interleukin 3 (IL-3) was recently introduced into phase I and II trials. This factor was also termed "multipoietin" because of its ability to stimulate in vitro the hematopoietic stem cell and thus all three hematopoietic cell lines. The latest in vivo data, however, demonstrate that IL-3 stimulates leukopoiesis and megakaryopoieis with only marginal effects on erythropoiesis. In large clinical trials the therapeutic effect of this factor is investigated in patients with myelodysplastic syndromes. Further indications will be other primary bone marrow failures and aplasia caused by bone marrow transplantation, aggressive chemotherapy and radiation. Potential applications offered by combinations with other cytokines can hardly be foreseen.

Cardiovascular disease remains the major cause of death in the industrialized world with dyslipidemia, hypertension and cigarette smoking leading a long list of risk factors. Recently, controversy arose from some critical articles expressing concern about the evaluation and interpretation of statistical data of epidemiologic studies. One study using covariance analysis reported an absence of the widely accepted negative association between coronary heart disease (CHD) and high density lipoprotein (HDL) cholesterol. Also criticism was expressed regarding the cost-effectiveness of preventive measures such as the use of lipid lowering drugs on life expectancy. Because of such recent scientific controversy and discussions already taking place in the media, we have summarized in this article recent epidemiologic evidence including a meta-analysis of the major epidemiologic studies on HDL. We have directed particular attention to 3 large epidemiological studies, i.e., the Familial Atherosclerosis Treatment Study (FATS), the Program on the Surgical Control of the Hyperlipidemias (POSCH), and the Cholesterol Lowering Atherosclerosis Study (CLAS), all of which have clearly demonstrated a desirable effect of intensive lipid lowering therapy on coronary lesions.

Alpha-1-antitrypsin deficiency (A1ATD) is one of the most common lethal hereditary disorders. Approximately 5 to 10% of the general population carry an "at risk" gene for the development of liver disease or emphysema of the lung. Patients with A1ATD associated liver disease constitute a histologically and clinically heterogeneous group. The pathogenesis of the disease still remains to be elucidated. Recent experimental evidence produced in the transgenic mouse model is in favour of the engorgement hypothesis considering the deposition of amorphous A1AT in the hepatocytes the prime event causing liver disease. This theory, however, fails to explain the clinical observation of the presence of a number of other factors known to cause chronic liver disease in A1ATD patients. The latter observation is in support of the deficiency theory, which explains the pathogenesis of emphysema of the lung, and would point to A1ATD as a predisposition to acquire chronic disease. The meaning of the increased synthesis of stress proteins in patients with liver disease is still speculative.

Very low density lipoproteins (VLDL) have been isolated and subfractionated on the basis of their differing flotation rates. The procedure consists of a single 45-min zonal ultracentrifugation step using a linear density gradient of d = 1.00 to 1.15 g/ml. Appropriate fractions of the zonal rotor effluent containing the entire VLDL spectrum were characterized by analytical ultracentrifugation, gel filtration chromatography, and complete chemical analysis. Flotation rates of VLDL subspecies from hypertriglyceridemic and normolipemic plasmas correlated directly with their Stokes radii and triglyceride content and inversely with their proportion of cholesterol, cholesteryl esters, phospholipids, and total protein. There was also an inverse correlation of flotation rate with the fraction of tetramethylurea-insoluble protein. This procedure provides a reliable methodology for a rapid isolation of VLDL subfractions and the accurate determination of their flotation rates.

The lipoproteins of very low density, low density and intermediate density were isolated by zonal ultracentrifugation from the plasma of subjects with familial type III hyperlipoproteinaemia and studied by electron microscopy. Each of these lipoproteins exhibited a spherical shape when free-standing. The very low density, low density and intermediate density lipoproteins ranged in diameter from 31 - 80, 17 - 23, .and 21 - 35 nm, respectively. These results are consistent with our previous findings that the intermediate density lipoprotein particles characteristic of plasma from type III subjects exhibit properties which are intermediate between those of very low density and low density lipoproteins.

Human plasma proteins were isolated by zonal ultracentrifugation and the fractions obtained examined under the electron microscope. HDL2 had a high degree of uniformity in normal persons, characterised by numerous two-dimensional, hexagonal arrangements. Optical diffraction analysis of HDL2 gave a centre distance of 11.3 nm, individual HDL2 particles being spherical with a diameter of 9.8 nm. HDL3 represented a somewhat less uniform lipoprotein population with a particle diameter between 6.5 and 9.5 nm. LDL had a diameter of 20-25 nm. In patients with hyperlipoproteinaemia type III a third peak was isolated, in addition to the two normal lipoprotein peaks VLDL and LDL. It lies between them and has been called Lp III. VLDL from type III plasma consisted of spherical particles, diameter 31-81 nm, morphologically indistinguishable from normal VLDL. Lp III consisted of a relatively homogeneous spherical lipoprotein population with a diameter of 25-30 nm. LDL consisted of spherical particles whose size was highly homogeneous (18-23 nm diameter), indistinguishable from normal LDL.

The major lipoprotein density classes (chylomicrons-VLDL, LDL, HDL(2) and HDL(3)) were isolated from human plasma in a two-step ultracentrifugal procedure using the Ti-14 zonal rotor. The isolation of the two major high density lipoprotein subclasses (HDL(2) and HDL(3)) was achieved in a 24-hr run using a nonlinear NaBr gradient in the density range of 1.00-1.40. The lipoproteins with a density < 1.063 found in the rotor's center were isolated in a second run of 140 min duration using a continuous linear NaBr gradient in the density range of 1.00-1.30. The isolated lipoproteins were analyzed for chemical composition and for electrophoretic mobility; purity of isolated fractions was checked by immunochemistry. The lipoproteins exhibited flotation rates, chemical compositions, and molecular weights similar to those found with the common sequential procedures in angle-head rotors. The amount of lipoprotein lipids in the bottom fraction of the zonal rotor was comparable to that of the angle-head rotor. The described method yields the main lipoprotein density classes free from albumin in a very short running time; compared with the rate-zonal techniques already in use, this method allows the quantitative separation of an additional lipoprotein density class (HDL(2)) without increasing the running time. Furthermore, this procedure proved to be suitable for isolation of plasma lipoproteins from subjects with various types and varying degrees of hyperlipoproteinemia.

The immediate short-term effect on plasma renin activity of intravenous injection of propranolol was studied in 31 normal subjects and 166 hypertensive patients. In patients with essential hypertension and normal subjects plasma renin activity fell considerably within 15 minutes; the fall was directly proportional to initial plasma renin levels. In contrast, in patients with renal hypertension the fall was much less pronounced or totally absent. These differences in response to propranolol provide, though presently only on a group basis, a biochemical means of differentiating between patients with renal hypertension and those with essential hypertension. The observations also indicate that, unlike normal subjects and patients with essential hypertension, in patients with renal hypertension sympathetic activity plays no part in the control of basal plasma renin levels.

Wenige Stunden nach Frakturen kommt es im Plasma zu einem ausgepragten Absinken der Triglyceride sowie auch des Cholesterins und der Phospholipide. Ein Zusammenhang mit dem Auftreten von Fettembolien wird diskutiert.

Die 420–580 A grosen Partikeln, sowie die 1500–2400 A grosen Gebilde, die sich im Cytoplasma von Leberzellen bei H.e. und SH nachweisen lassen, werden an Hand eines groseren Patientenmaterials eingehend beschrieben und in ihrer Bedeutung diskutiert.