Positive rate-sensitive corticosteroid feedback mechanism of ACTH secretion in Cushing's disease.

To define the nature of the disturbance of the corticosteroid feedback mechanism in Cushing's disease, the dynamic aspects of the ACTH response to corticosteroid administration have been studied in patients with Cushing's disease after total adrenalectomy (C.d. post adx.). The results were compared with those obtained in patients with Addison's disease (control group). Different experimental designs for administration of cortisol were chosen to provide extreme variations in the input signal. The response of the system was evaluated by measuring plasma ACTH concentrations (radioimmunoassay) at short time intervals. Infusion of cortisol at constant rate (50 mg/h for 2 h) resulted in a transient, paradoxical rise in ACTH levels with a maximum at 15 min. (315+/-65%, mean+/-SEM). In contrast, in the control group there was an immediate and rapid decrease in ACTH levels with a significant inhibition after 15 min (80+/-6%, mean+/-SEM). Infusion of 50 mg cortisol for 5 and 15 min, respectively, produced an increase in ACTH levels, which was confined to the time when cortisol levels were rising (maximum: 137+/-30% and 139+/-10% at 5 and 15 min, respectively, mean+/-SEM). This increase corresponded in time to the first decrease in ACTH levels in the Addisonian patients. With bolus injections of 25 mg cortisol, ACTH levels remained unchanged during the first 15 min. The time-course in the patients with C.d. post adx. was essentially the same as in the Addisonian patients. From these results it is concluded that in the patients with C.d. post adx. the rapid, rate-sensitive feedback mechanism was converted into a positive one, whereas the delayed, dose-sensitive mechanism was completely undisturbed. The capacity of dexamethasone to activate rate-sensitive feedback elements was markedly diminished. Accordingly, there were only minor positive feedback effects upon ACTH secretion in the patients with C.d. post adx.

Differential and integral corticosteroid feedback effects on ACTH secretion in hypoadrenocorticism.

Recent work suggests the existence of a dual corticosteroid feedback mechanism of stress-induced ACTH secretion in the rat. This possibility led us to study the kinetics of suppression of ACTH levels by corticosteroid administration in patients with nonstress ACTH hypersecretion secondary to hypoadrenocorticism. Cortisol was administered according to different protocols, which were chosen to provide extreme variations of the input signal. By this means, two phases of suppression of ACTH levels could be differentiated. A first decrease occurred without latency whenever, and as long as, plasma cortisol levels were rising. There was a linear regression between the logarithm of the increments in cortisol concentrations and the decrease in ACTH levels per minute (r = 0.951) (differential or rate-sensitive feedback mechanism). Neither the absolute doses of cortisol, nor plasma cortisol concentrations were closely correlated with the degree of suppression of ACTH by this rapid mechanism. A second decrease in ACTH levels began congruent with30 min after corticosteroid administration. In this case there was a significant linear regression between the degree of inhibition of ACTH levels and the cortisol doses (r = 0.997) (integral or dose-sensitive feedback mechanism). The dose-sensitive feedback effects of dexamethasone were less than might have been predicted from its relative anti-inflammatory potency. No rate-sensitive effects were seen with dexamethasone doses of 1.0 or 1.25 mg.

Rapamycin antagonizes interleukin-6 mediated growth arrest and differentiation of myeloblastic M1 cells.

The immunosuppressant rapamycin is known to be a potent inhibitor of cytokine driven proliferation of T-lymphocytes and other cell types. Here we have examined the effect of rapamycin on the myeloblastic cell line M1 which responds to interleukin-6 (IL-6) with growth arrest and monocytoid differentiation. Single-agent rapamycin led to a retardation of M cell growth. In spite of this intrinsic antiproliferative effect, rapamycin was found to abrogate IL-6 induced growth arrest. Concomitant exposure to rapamycin and IL-6 also reduced the extent of monocytoid differentiation as compared to treatment with IL-6 alone. Excess levels of the FK-506 analogue ascomycin reversed the antagonistic effect of rapamycin on IL-6 mediated growth suppression, suggesting that this biological action of rapamycin is mediated by a rapamycin/immunophilin complex. The findings demonstrate that rapamycin can also act as an antagonist of cytokine induced growth arrest and differentiation.

Allogeneic CD34-enriched peripheral blood stem cell transplantation in a patient with paroxysmal nocturnal haemoglobinuria.

Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired clonal disorder of haematopoietic stem cells associated with a somatic mutation in the phosphatidylinositol glycan complementation class A (PIG-A) gene. The only curative option is an allogeneic stem cell transplant (SCT), although treatment is hazardous. A 46-year-old male patient with PNH and obvious signs of severe, progressive haemolysis was transplanted in July 2002 with highly purified CD34 T-cell depleted peripheral blood stem cells from his HLA-identical brother. Prior to transplantation, the PNH was resistant to immunosuppressive therapy. The patient received 6.1 x 10(6)/kg bodyweight CD34-positive cells with a proportion of CD3-positive cells of 0.81 x 10(4)/kg bodyweight. After engraftment, 12 days post transplant (neutrophils>1.0/nl) the patient's physical condition steadily improved and parameters of haemolysis decreased. No glycophosphatidylinositol-deficient cells in peripheral blood could be detected by flow cytometry 40 and 100 days after transplant. We conclude that PNH may be cured by allogeneic CD34-enriched SCT from a sibling donor attempting to avoid acute GVHD and to reduce cumulative organ toxicity by using this transplantation modality.

Transplantation of highly purified HLA-identical sibling donor peripheral blood CD34+ cells without prophylactic post-transplant immunosuppression in adult patients with first chronic phase chronic myeloid leukemia: results of a phase II study.

The feasibility of transplantation using highly purified G-CSF-mobilized peripheral blood CD34+ cells from HLA-identical sibling donors without prophylactic post-transplant immunosuppression was prospectively studied in 10 adult first chronic phase chronic myeloid leukemia (CML) patients with special reference to graft engineering performance and follow-up studies of minimal residual disease and immune reconstitution. CD34+ cells were enriched by clinical-scale magnetic-activated cell separation (MACS) using iron-dextran beads bound to monoclonal anti-CD34 antibody. Grafts contained a median of 9.7 (range 1.7-16.6) x 10(6) CD34+ cells per kilogram of recipient body weight with a purity between 94.5% and 98.3% (median 97.2%). The median number of transfused CD3+ T lymphocytes was 1.0 (range 0.5-8.5) x 10(4)/kg, corresponding to a log10 T lymphocyte depletion between 3.8 and 5.0 (median 4.6). All patients engrafted rapidly with a median duration to neutrophil counts >500/microl of 8 (range 8-19) days and to self-sustaining platelet counts >20,000/microl of 12 (range 9-25) days. Isolated skin acute graft-versus-host disease (GVHD) of stages I to II occurred in three patients. One patient developed secondary graft failure and was successfully salvaged by an unmanipulated blood stem cell graft from the same donor. All 10 patients are surviving in complete hematologic, cytogenetic and molecular remission (four patients after donor lymphocyte infusions) between 12 and 22 (median 16) months post transplant. In conclusion, transplantation of MACS-purified blood CD34+ cells from HLA-identical sibling donors in adult CML patients appears safe, effectively prevents acute GVHD without prophylactic post-transplant immunosuppression, and is capable of inducing complete cytogenetic and molecular remissions.

High-affinity binding of crustacean hyperglycemic hormone (CHH) to hepatopancreatic plasma membranes of the crab Carcinus maenas and the crayfish Orconectes limosus.

The binding properties of the crustacean hyperglycemic hormone (CHH) of two species, the shore crab, Carcinus maenas (Brachyura) and the crayfish, Orconectes limosus (Astacura), were investigated using purified plasma membranes of one of the main target organs, the hepatopancreas. Assays were performed under equilibrium binding conditions with 125I-CHH as labeled ligand and unlabeled CHH in increasing concentrations as displacing ligand. In both cases, comparable binding characteristics were observed for the homologous CHH to the respective hepatopancreatic membrane source, indicating saturable and displaceable binding with nonlinear dependence on monovalent cations and a dissociation constant (Kd) of 4 to 6 x 10(-10) M. Binding capacity was in the range of 200-400 fmol/mg membrane protein. In heterologous displacement studies a certain degree of species specificity was found, particularly with regard to selective binding by the Orconectes receptor, suggesting that the group specificity of biological activity of CHH reflects coevolution of both hormone and receptor.

Unique alterations of thyroid function parameters after i.v. administration of alkylating drugs (cyclophosphamide and ifosfamide).

Alkylating drugs (cyclophosphamide and ifosfamide) have been in clinical use for the treatment of malignant diseases in the past. They are most useful anticancer agents and cyclophosphamide is also widely used for its immunosuppressive properties. However the effect of alkylating drugs on thyroid hormone parameters have not been evaluated so far. Three groups of patients were prospectively evaluated: Group I: 15 patients with Wegener's granulomatosis and 4 patients with severe scleritis received a single dose cyclophosphamide (15 mg/kg bw/day) and 250 mg prednisone i.v. Group II: 9 patients with malignant lymphomas were treated according to the IMVP 16-protocol. Patients received daily ifosfamide 1000 mg/m2 from day 0 to 4 and vepesid from day 0 to 2. Patients did not receive corticosteroids additionally. Group III: 6 patients with a relapse of malignant lymphomas received ifosfamide 1.500 mg/m2/day from day 0 to 4 i.v. and dexamethasone 40 mg/m2 as well as ara-c and etoposid. All patients received mesna to prevent hemorrhagic cystitis and odansetran or metoclopramide as antiemetic drugs. Alkylating drugs were given as a one hour infusion. Thyroid hormone parameters were determined before and on day 1, 2, 3, 4 after drug administration. We observed a significant increase in T4 and fT4 concentrations and a concomitant fall in TSH in either group one day after the administration of alkylating drugs. The effect was most pronounced in group III: T4 increased from 113 +/- 8 nmol/L to 175 +/- 8 (normal: 58-154) and fT4 from 14.0 +/- 0.8 to 24.8 +/- 2.5 pmol/L (normal 10-25). TSH dropped from 1.27 +/- 0.16 to 0.33 +/- 0.07 mU/L (normal 0.3-4). All changes were significant: p < 0.001. Two of the six patients displayed biochemical hyperthyroidism. Also reverse T3 increased significantly. Two days after drug administration a gradual normalization occurred. However, T3, Tg, TBG, Transthyretin and albumin levels did not change throughout the study period. One patient with coexisting hypothyroidism, who received his last thyroxine substitution therapy one day before the administration of cyclophosphamide (as in group I), also demonstrated an increase in T4, fT4 and rT3 and a fall in TSH concentrations. I.v. administrations of cyclophosphamide and ifosfamide induce a transient increase in T4 and fT4 concentrations and a concomitant fall of TSH in the presence of normal Tg, T3 and thyroid binding protein concentrations. These data suggest, that the changes are not due to a release of thyroid hormones from the thyroid itself, but is likewise related to a release of thyroxine from cellular pools such as the liver.

Significant changes in thyroid hormone parameters after a four week recreation period at the North Sea without alterations of iodine intake.

UNLABELLED: Many studies have been carried out evaluating thyroid hormone parameters in patients suffering from various illnessess. However data on thyroid function after a recreation period are missing. Therefore we evaluated thyroid hormone parameters in 178 patients (mostly suffering from chronic obstructive lung disease) undergoing a four week recreation period in a health spa on the island Borkum at the North Sea. We observed a subtle, but significant increase in basal TSH concentrations from 1.20 mU/l (median) to 1.50 mU/l; (p<0. 001) and a fall in T4 values from 97.5 +/- 17.7 nmol/l (mean +/- SD) to 90.3 +/- 17.0 (p<0.001) and T3 from 2.21 +/- 0.33 nmol/l to 2.09 +/- 0.33 (p<0.001). However no increase in iodine intake occurred during the four weeks: median iodine excretion 61 microg iodine/g creatinine at the beginning vs 65 microg iodine/g creatinine at the end. IN CONCLUSION: a recreation period at the North Sea is associated with subtle but significant changes in thyroid hormone parameters. However no increase in iodine intake occurs during the four week observation period.

Phase IB study of sorafenib in combination with gemcitabine and cisplatin in patients with refractory solid tumors.

PURPOSE: Sorafenib (BAY 43-9006), a multikinase inhibitor, has been shown to inhibit tumor growth and tumor angiogenesis by targeting Raf kinase, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor. This study investigated the safety, pharmacokinetics, and preliminary efficacy of sorafenib in combination with gemcitabine and cisplatin. METHODS: Patients with advanced solid tumors were treated with 75 mg/m(2) cisplatin on day 1 and 1,250 mg/m(2) gemcitabine on days 1 and 8 of each 21-day cycle. On day 5 of cycle 1, sorafenib 400 mg twice daily was started and continued throughout the complete treatment cycles without interruption. RESULTS: Nineteen patients were valid for safety analysis. The most frequent toxicities related to the cytotoxic agents were hematological disorders. Sorafenib-related toxicities were skin-related, gastrointestinal, and constitutional symptoms. No clinically relevant pharmacokinetic drug-drug interaction between sorafenib, cisplatin, and gemcitabine was detected. AUC(0-72) and C (max) of total and unbound platinum were only marginally changed by concomitant sorafenib. Concomitant sorafenib increased mean AUC and C (max) of gemcitabine by 12 and 21%. CONCLUSIONS: Sorafenib as continuous oral treatment in combination with gemcitabine and cisplatin demonstrated an acceptable safety profile. No clinically relevant pharmacokinetic interaction was detected. Preliminary antitumor activity, pharmacokinetic, and safety data support the recommendation of 400 mg sorafenib twice daily in combination with cisplatin and gemcitabine to be further evaluated in clinical studies.

[An electronic data processing program for respiratory function diagnosis with the KRS 4201 computer]. / Ein EDV-Programm für die Atemfunktionsdiagnostik mit dem Rechner KRS 4201.

The computer program LSD 1 published in 1973 which was used for daily processing of lung function data in a number of hospitals is at present realized on the computer KRS 4 201. In the last years new reference values and new valuations of parameters lead to changed and more complete programs. The here presented new program is based consequently in magnetic files from data input with DEG 1 370 to output of the computed parameters. It concludes new reference values and SI-units also. With the computer KRS 4 201 parameters were corrected and computed, respectively, derivated diagnostic valuations were printed out and all data stored by magnetic files.

[Correlation between average pulmonary artery pressure under rest and stress conditions in relation to the stage of silicosis]. / Zusammenhang zwischen den Pulmonalarterienmitteldrucken unter Ruhe- und Belastungsbedingungen in Abhängigkeit vom Silikosestadium.

The value of measuring the median pressure of the pulmonary artery for the prognosis of silicosis remains undebatable since the development of pulmonary heart disease has multifactorial causes and extreme interindividual variations. On the other side, during the course of silicosis disease, the increase of pressure is relatively small or even absent during years. Thus, measuring of mean pulmonary artery pressure is only required at larger intervals.

[Evaluation of measurement accuracy in microcatheterization of the heart]. / Einschätzung der Messgenauigkeit des Mikroherzkatheterismus.

In 192 patients with silicosis the results of the cardiac micro-catheterisation under conditions of rest were compared with those ones of a secondary examination performed two years later. This allows conclusions to the behaviour of the pressure values measured in the period observed as well as to the evidence of an individual cardiac micro-catheterisation. No essential increase of the mean pressure of the pulmonary artery was observed. The dispersion of an individual measurement is 3 Torr. A pulmonary hypertension, which is given from 20 Torr upwards, consequently may be established with a 95% statistical certainty only from an individual measuring value of 26 Torr.

[Assessment of diagnostic lung function parameters in underground workers exposed to diesel gas]. / Untersuchungen zur Beurteilung lungenfunktionsdiagnostischer Parameter bei Dieselabgasexponierten unter Tage.

Evaluations of lung function parameters were carried out in underground miners with outstanding exposition to diesel exhaust by diesel-driven machines. Data obtained over a three year period were compared with the results of a non-exposed population. There were no differences between both groups following to the influence of diesel exhaust.

[Problems of early detection of latent pulmonary hypertension--the value of ergometric tests and the correlation between pulmonary circulation and parameters of lung function (author's transl)]. / Zur Problematik der Früherkennung einer latenten pulmonalen Hypertonie, die Bedeutung von Belastungsuntersuchungen und die Beziehungen von pulmonaler Hämodynamik und Lungenfunktionsparametern.

The possibility of early detection of pulmonary hypertension is rather late according to the large capacity of the lung vessels in the condition of rest. Consequently the parameters of the pulmonary circulation were measured in 89 healthy subjects and 261 men suffering from silicosis in rest and bicycle exercise by means of the microcatheter technique and statistically compared with other parameters of lung function. In conclusion it can be said there is a statistical correlation between pressure at rest and during exercise conditions, but this is not available in an individual case. Furthermore the pressure values of persons suffering from silicosis are higher than those of the healthy group at rest and the pressure rise is higher in the ill group during exercise. Statistically there is a slight correlation between the pressure behavior and the FEV1, Rtot, PO2, DCO and of minor importance to VC, RC and FRC.

[The influence of hypobaric hypoxia upon the hemodynamics of the pulmonary circulation (author's transl)]. / Der Einfluss der hypobaren Hypoxie auf die Hämodynamik des kleinen Kreislaufes.

The influence of hypobaric hypoxia at the pulmonary gaseous exchange and the hemodynamics of the pulmonary circulation was tested by 12 healthy subjects at the age from 33 to 47 years. They were submitted to a basis investigation with determination of VC, VE, VO2, VCO2, Hb, PO2A/a, pH, HR, ECG, PVd, PAp, HZV, RL. These investigations were followed by stress examination by means of the bicycle ergometry in four rectangular steps during conditions of normoxia and of hypobaric hypoxia in a low-pressure chambre at 66.5 kPa (500 Torr) each of 6 min duration. During the influence of hypoxia a PO2a-decrease in a sense of partial insufficiency could be already observed at rest during conditions of a decreased alveolar oxygen-partial-pressure. At the same time was found a significant increase of the systolic peripheral and the diastolic pulmonary arterial pressure. At the increasing step by step ergometric exercise during conditions of the hypoxia stress were growing significance evidence of different reactions of the pulmonary and cardiocirculatory parameters occurred.

[Results of an epidemiologic analysis on the pathogenesis of chronic obstructive bronchitis in miners]. / Ergebnisse einer epidemiologischen Analyse zur Pathogenese der chronisch obstruktiven Bronchitis des Bergmannes.

An epidemiological evaluation of chronic obstructive bronchitis in miners showed that smoking ranges in first place in the aetiopathogenesis. In addition, after prolonged underground exposure, the irritating nuisance of the respiratory tract must be considered as causal cofactor.

[Relationship of closing volume to other lung function tests]. / Beitrag über Beziehungen des Closing-Volume zu weiteren Lungenfunktionsprüfungen.

The closing volume method is suitably to be used in exposed groups of the population, the preliminary diagnostics of them is inconspicuous, in order to establish in time beginning and thus therapeutically influencible alterations of the small respiratory tract. In such a group of test persons only relatively slight connections with the other conventional lung standard methods are the result, by means of which its independence is emphasized. On the other hand less promising seems to be the application of the method in the verification of a "small airways obstruction" in smokers, whose vital capacity, forced expiratory volume and residual volume are within the normal.