Showing papers in "Journal of Molecular Medicine in 1990"

Cancer, cytokines, and cytotoxic cells: interleukin-2 in the immunotherapy of human neoplasms.

Abstract: Modern immunotherapy of human cancer has evolved as a rapidly expanding field of clinical and experimental research. Employing the systemic application of recombinant interleukin-2 (IL-2) in humans, Rosenberg and colleagues from the National Cancer Institute reported the regression of advanced metastatic tumors in approximately 10%–30% of patients treated. The additional adoptive transfer of autologous patient-derived activated lymphocytes was performed to enhance therapeutic efficacy. While the exact mechanisms of IL-2 based immunotherapy in cancer remain unclear, it has been hypothesized that both the IL-2 activated lymphocyte and its secretory products such as interferon-γ or tumor-necrosis factorβ may contribute to the lysis of tumor cells in vivo. Accordingly, research has been directed toward enhancing both the activation state and the specificity of IL-2 induced killer cells in humans. Based on in vitro and animal data, the retransfusion of tumor-infiltrating lymphocytes has been shown to mediate the regression of metastatic neoplasms in up to 50% of patients receiving systemic IL-2. Considerable toxicity from the use of high-dose IL-2 has prompted attempts to develop low-dose regimens which allow for the outpatient treatment of patients presenting poor prognosis. While in most clinical trials involving IL-2, patient follow-up has been short, and no or only limited data have become available from controlled prospective and randomized clinical studies, IL-2 has shown some promise in patients with metastatic renal cell cancer or malignant melanoma. Novel approaches toward the improvement of clinical efficacy of IL-2 include local (e.g., intracavitary) application or combinations with other cytokines such as interferon-α or cytostatic drugs.

Control of prolactin secretion

Abstract: 1. Prolactin is a 21,500 Dalton single-chain polypeptide hormone but may occur in 50 kDa and 150 kDa molecular variants. 2. These large PRL variants may be secreted predominantly; this condition is termed "macroprolactinemia". It is characterized by high immunological and normal biological serum levels of prolactin, and lack of clinical symptoms of hyperprolactinemia. 3. The information on PRL is encoded on chromosome 6. Transcription can be enhanced and suppressed by a variety of hormonal factors. 4. PRL is secreted in a pulsatile fashion; it displays a circadian rhythm (with a maximum during sleep) and is stimulated by some amino acids. PRL also responds to mechanical stimulation of the breast. 5. PRL rises during pregnancy, and maintainance of hyperprolactinemia (and, thereby, physiological infertility) is dependent on the frequency and duration of breast feedings. 6. Hypothalamic regulation of prolactin mainly involves tonic inhibition via portal dopamine. The physiological importance of various stimulating factors present in the hypothalamus is still incompletely understood. In particular, there is still no place for TRH in PRL physiology. 7. PRL is released in response to stress; this response may be mediated by opioids. The low-estrogen, low-gonadotropin amenorrhea of endurance-training women is not mediated by prolactin, however. 8. Estrogens stimulate PRL gene transcription via at least two independent mechanisms. There are many clinical examples of this estrogen effect on prolactin serum levels, and also on the growth of prolactinomas. 9. Mild hyperprolactinemia remains an enigma which cannot satisfactorily be resolved by biochemical or radiological testing. The border between "normal" and "elevated" prolactin is ill-defined. The possibility of macroprolactinemia complicates this matter even further. 10. The number of drugs which suppress prolactin by acting on pituitary D2 receptors, and which are useful in the treatment of hyperprolactinemia, continues to increase. In the field of ergot alkaloids, parenteral application appears to be a logical solution to the problem of the high first-pass effect; in addition, this form of treatment is frequently better tolerated than the oral route. 11. Prolactinoma development is presently being studied employing molecular biological techniques; the question of whether tumorigenesis can be attributed to specific defects of gene regulation remains to be answered.

[Results of a double-blind study of diclofenac + vitamin B1, B6, B12 versus diclofenac in patients with acute pain of the lumbar vertebrae. A multicenter study].

Abstract: Several clinical trials have shown that the duration of treatment of painful vertebral syndromes can be shortened by using a combination of vitamins B1, B6, B12 and diclofenac instead of diclofenac. In addition, a more efficient pain relief could be achieved by the combination therapy. In order to confirm these results, we compared the clinical efficacy of diclofenac (25 mg) and a combination preparation with diclofenac (25 mg) plus vitamins B1 (thiamine nitrate 50 mg), B6 (pyridoxine hydrochloride 50 mg) and B12 (cyanocobalamin 0.25 mg) in a multicentric randomized double-blind study including 418 patients. All patients received 3 x 2 capsules daily for a maximum of 2 weeks. In case of total pain relief, therapy should be discontinued after one week. Data of 376 patients could be evaluated. 53 out of 184 patients receiving the combination and 48 out of 192 patients treated with diclofenac alone could stop therapy due to sufficient pain relief after one week. The evaluation of the "Hoppe Pain Questionnaire" and the data concerning pain intensity also revealed better results for the combination preparation. The differences in favour of the B-vitamin-diclofenac-combination were statistically significant in patients with severe pain at the beginning of therapy. Considering undesirable side-effects (symptoms in 70 out of 418 patients) there were no significant differences between the two medications. This clinical trial provides further evidence that the combination therapy with diclofenac plus B-vitamins is more effective than diclofenac alone for the treatment of painful vertebral syndromes.

Endocrine activity of the "silent" adrenocortical adenoma is uncovered by response to corticotropin-releasing hormone.

Abstract: The purpose of this study was to ascertain whether the pituitary-adrenal responses to human corticotropin-releasing hormone (hCRH) in “non-functioning” adrenocortical adenoma would uncover a functional activity in these adrenal nodules. Eleven patients with incidentally discovered “silent” adrenocortical adenoma and eleven controls were studied. The initial clinical and laboratory examination, including an overnight 1 mg dexamethasone suppression test, revealed no abnormalities in any of the subjects. IR-ACTH and serum steroids (F, S, P, 17OHP, 18OHB, and aldosterone) were normal in both controls and patients. After pulse IV injection of 100 νg hCRH, the cortisol response was significantly exaggerated (P=0.01). Stimulated plasma ACTH levels were, however, significantly lower in patients than in controls (P=0.01), indicating counter-feedback regulation of cortisol. The peak cortisol/peak ACTH ratio (Fmax/ACTHmax) in the patients was significantly elevated (26.8±4.37 nmol/ng vs. 14.6±2.16 nmol/ ng,P=0.02). Two further patients with incidentally discovered “pre-Cushing's” adrenocortical adenoma displayed an even higher ratio (43.5 and 45.5 nmol/ng). In established Cushing's syndrome due to an autonomous adrenocortical adenoma, suppression of ACTH and of the ACTH response to hCRH occurs with a very high basal cortisol/ basal ACTH ratio. Our findings suggest some functional activity even in clinically “silent” adrenocortical adenoma. Response to hCRH uncovers a continuous spectrum between adrenocortical adenoma, “pre-Cushing's”, and Cushing's syndrome.

[Reduced diclofenac administration by B vitamins: results of a randomized double-blind study with reduced daily doses of diclofenac (75 mg diclofenac versus 75 mg diclofenac plus B vitamins) in acute lumbar vertebral syndromes].

Abstract: Pain syndromes of the lumbar spine are one of the main problems in orthopedic practice. The therapeutic effect of NSAIDs is not subject to doubt in this connection. But considering that the application of NSAIDs is frequently associated with side effects, a reduction of dosage would be to the patient's benefit. Clinical studies have shown that concomitant treatment with vitamins B1, B6, B12 and diclofenac leads to a more efficient pain relief than treatment using diclofenac alone and thus provides the possibility of saving NSAIDs. This clinical trial was carried out in order to determine whether these results can also be achieved when a reduced dosage of diclofenac (75 mg daily) is used. 123 patients with acute pain syndromes of the lumbar spine were treated with either B-vitamins and diclofenac or diclofenac alone for a maximum of 7 days. There was the option to terminate therapy in the trial after 3-4 days in the case of total pain relief. 45 patients could stop the treatment due to remission of symptoms. 30 patients belonged to the combination therapy group, the other 15 took diclofenac alone; this difference is statistically significant (p less than 0.05). All parameters concerning pain relief and movement of the vertebral column showed statistically significant differences in favour of the B-vitamin-diclofenac-combination, too. The results document the positive influence of B-vitamins on painful vertebral syndromes and indicate that B-vitamins contribute to saving of NSAIDs by shortening the treatment time and reducing daily NSAID-dosage.

Influence of B vitamins on binding properties of serotonin receptors in the CNS of rats.

Abstract: Treatment of normal adult rats with pyridoxine or a B-vitamin mixture resembling Neurobion® 1 led to an increase in serotonin content of various brain areas and to a decrease in the number of serotonin S2 receptors. The results indicate that the pyridoxal phosphate level in regions of the brain regulates the extent of decarboxylation of 5-hydroxytryptophan, the precursor of serotonin. The results also suggest a continuum from deficiency in pyridoxine to treatment of animals with a moderate excess of pyridoxine which is reflected in the synthesis and secretion into the synaptic cleft of the neurotransmitter serotonin.

Psychopathological and neuropsychological symptoms in patients with subclinical and remitted hyperthyroidism.

Abstract: To investigate relationships between hyperthyroidism and behavior, 45 formerly hyperthyroid patients (now euthyroid) and 51 control subjects were investigated by (a) a semi-structured psychiatric examination, (b) self-rating scales to assess mood states and personality, and (c) neuropsychological tests. Patients with “subclinical” or “remitted” hyperthyroidism showed more abnormalities than the controls in all dimensions investigated. Forty-three percent of patients (10% of controls) complained of “seriously reduced” well-being with feelings of fear, hostility, and inability to concentrate. While a fearful-agitated syndrome dominated in the initial phase of the illness, a mainly depressive syndrome was characteristic after a longer period of remission. More than 25% of the patients (2% of controls) showed “markedly impaired” neuropsychological functioning. Patients with a relapse within 2.5 years exhibited the most abnormal results. Even after a longer period of hormonal remission, there was no complete psychopathological and neuropsychological normalization. A thorough follow-up of hyperthyroid patients is recommended.

Value of urinary neopterin in the differential diagnosis of bacterial and viral infections

Abstract: Neopterin is released by stimulated macrophages. In this study we analyzed the diagnostic potential of urinary neopterin concentrations in patients with bacterial and viral infection. All but one of 17 patients with viral infection had increased urinary neopterin concentrations. Patients with bacterial urinary tract infection also showed increased neopterin concentrations, whereas patients with bacterial pneumonia had significantly lower neopterin levels. In addition, patients with acute bacterial pneumonia had lower neopterin levels than patients with protracted infection. A significant inverse correlation between urinary neopterin and hemoglobin concentrations was found. Neopterin concentrations could serve as a helpful additional marker of infectious diseases. Combined with other clinical and laboratory parameters it is a useful parameter for distinguishing between viral and bacterial origins of infection, as was shown by multivariate stepwise linear discriminant analysis.

Persistent atrioventricular block in Lyme borreliosis.

Abstract: Cardiac manifestations are reported in 0.3%–4.0% of European patients withBorrelia burgdorferi (B.b.) infection. Usually symptoms disappear within 6 weeks. We report a case with persistent impairment of atrioventricular (AV) conduction. Diagnosis was confirmed by demonstration of IgM antibodies and increase of IgG antibody titers against B.b. in serum, by isolation of the spirochete from skin biopsy material and by the typical clinical combination of erythema migrans, Bannwarth syndrome (meningoradiculitis), and complete heart block. Despite immediate antibiotic therapy with ceftriaxone, first degree AV block and second degree block Wenckebach with atrial pacing at 100 beats/minute persisted for 2 years. We conclude, that Lyme carditis can cause long-standing or irreversible AV conduction defects despite adequate and early antimicrobial therapy.

Reference Data for Ambulatory Blood Pressure Monitoring: What Results are Equivalent to the Established Limits of Office Blood Pressure ?

Abstract: In 1039 subjects ambulatory blood pressure monitoring was performed to define threshold values, which are equivalent to the established limits of the office blood pressure. Mean values and proportions of elevated single readings were correlated to office blood pressure by regression analyses. To avoid impact of varying sleeping periods on 24 h blood pressure, only daytime readings were considered. Correlations between average daytime blood pressure and office blood pressure were linear: Mean daytime values of 135 mmHg (systolic) and of 84 mmHg (diastolic) were equivalent to the casual blood pressure limits of 140 mmHg and 90 mmHg. Correlations between percentages of elevated single readings and office blood pressure were nonlinear: Proportions of 25% systolic readings > 140 mmHg and of 17% diastolic readings > 90 mmHg were equivalent to casual blood pressure limits of 140 mmHg and 90 mmHg. On the basis of the regression equations, any result of ambulatory blood pressure recording during daytime can now be evaluated in terms of the established standards of office blood pressure.

Mixed-chain phospholipids and interdigitated bilayer systems.

Abstract: The lipid bilayer is a fundamental structural component for all biological membranes. The function of lipid bilayers may be considered not only to serve as a permeability barrier preventing the free flows of ions and polar molecules between the cell interior and its external environment, but also to modulate the activity of bilayer-spanning proteins or glycoproteins in biological membranes. Based on the location of the terminal methyl groups of the two hydrocarbon chains in phospholipids or glycosphingolipids, two broad categories of lipid bilayers have been recognized: (1) the non-interdigitated and (2) the interdigitated bilayers. Depending on the chain-length difference between the two hydrocarbon chains, three different types of packing models for interdigitated bilayer systems have been identified. Among the three types, the mixed interdigitated bilayer is perhaps unique, since the hydrocarbon chains in the bilayer core are observed to be interdigitated in both the gel and the liquid-crystalline states. In this communication, various experimental data supporting the chain packing characteristics of the mixed interdigitated bilayer for a large number of mixed-chain phospholipid species are considered. In addition, two types of phase diagrams for binary phospholipid mixtures obtained with mixed-chain phospholipids are also presented. These studies may be of great importance in understanding the functional control of bilayer-spanning proteins in biological membranes, and for providing basic information explaining the dynamic regulation of membrane activities in general.

Serum erythropoietin level: relationships to blood hemoglobin concentration and erythrocytic activity of the bone marrow.

Abstract: The question as to whether the serum concentration of erythropoietin is relatively high for the degree of anemia in patients with erythrocytic hypoplasia has regained interest, since recombinant human-like erythropoietin has become available as a drug for replacement therapy. We have compared the concentration of serum immunoreactive erythropoietin in nonrenal anemic patients with erythrocytic hypoplasia (22 cases) or active erythropoiesis (82 cases). In both groups a negative correlation was determined between the blood hemoglobin concentration and the logarithm of the erythropoietin concentration. However, the two regression lines were not identical, and the serum erythropoietin concentration was significantly higher for the degree of anemia in the patients with erythrocytic hypoplasia. Additional measurements in four patients suffering from acute leukemia with marrow failure showed that the erythropoietin concentration decreased towards the values observed in anemic patients with active erythropoiesis when the erythron recovered in the early phase of complete remission. These data support the idea that, independent of the O2 offer, the proliferating erythrocytic progenitors by negative feedback lower the blood level of erythropoietin.

Dietary sodium restriction: adverse effect on plasma lipids.

Abstract: In order to examine the effect of dietary sodium intake on plasma lipids, 15 healthy male volunteers were given a low-salt diet (20 mmol/day) for 3 weeks, adding either placebo, sodium chloride (200 mmol/day), or a non-chloride sodium salt (sodium citrate, 200 mmol Na/day) for one week each, in a single-blind randomized crossover study. Plasma levels of total cholesterol and LDL cholesterol were significantly higher at the end of the placebo period than with either sodium chloride (by 8.7 and 11.9%, respectively) (P less than 0.005) or sodium citrate (by 11.3% and 16.8%, respectively) (P less than 0.005). Thus this effect was dependent on sodium but not on chloride intake. Triglyceride and HDL-cholesterol levels were not affected by the dietary regimens. We conclude that short-term dietary sodium restriction may lead to a rise in plasma total and LDL cholesterol, thereby possibly increasing the risk of atherosclerotic vascular disease. Our findings render it possible that diuretic-induced lipid disturbances may also be caused by sodium depletion.

Acute tubulo-interstitial nephritis with uveitis (TINU syndrome) in a patient with serologic evidence for Chlamydia infection.

Abstract: A 38-year-old female patient with acute tubulo-interstitial nephritis and uveitis (TINU syndrome) is described. The cause of this rare disease is unknown; most patients affected are adolescent females. Serologic investigations in the patient reported point to a possible etiologic role of Chlamydia infection in this disease.

Einsparung von Diclofenac durch B-Vitamine: Ergebnisse einer randomisierten Doppelblindprüfung mit reduzierten Tagesdosierungen von Diclofenac (75 mg Diclofenac versus 75 mg Diclofenac plus B-Vitamine) bei akuten Lendenwirbelsäulensyndromen

Abstract: Pain syndromes of the lumbar spine are one of the main problems in orthopedic practice. The therapeutic effect of NSAIDs is not subject to doubt in this connection. But considering that the application of NSAIDs is frequently associated with side effects, a reduction of dosage would be to the patient's benefit. Clinical studies have shown that concomitant treatment with vitamins B1, B6, B12 and diclofenac leads to a more efficient pain relief than treatment using diclofenac alone and thus provides the possibility of saving NSAIDs. This clinical trial was carried out in order to determine whether these results can also be achieved when a reduced dosage of diclofenac (75 mg daily) is used. 123 patients with acute pain syndromes of the lumbar spine were treated with either B-vitamins and diclofenac or diclofenac alone for a maximum of 7 days. There was the option to terminate therapy in the trial after 3–4 days in the case of total pain relief. 45 patients could stop the treatment due to remission of symptoms. 30 patients belonged to the combination therapy group, the other 15 took diclofenac alone; this difference is statistically significant (p< 0.05). All parameters concerning pain relief and movement of the vertebral column showed statistically significant differences in favour of the B-vitamin-diclofenac-combination, too. The results document the positive influence of B-vitamins on painful vertebral syndromes and indicate that B-vitamins contribute to saving of NSAIDs by shortening the treatment time and reducing daily NSAID-dosage.

Atrial natriuretic peptide in peripheral organs other than the heart.

Abstract: The heart atria represent the major site of synthesis of atrial natriuretic peptide (ANP) in mammals including man, and its function as a regulator of water and salt homeostasis has been repeatedly suggested. However, more recently ANP has been located in organs not intimately related to cardiovascular physiology, e.g. the adrenals, lungs, and gut, as well as tissues belonging to the lymphatic, reproductive or endocrine systems. Thus, ANP might serve many more physiological roles than originally thought, but the functional significance of ANP in these non-cardiac tissues is presently poorly understood.

Proteinases and the glomerulus: their role in glomerular diseases.

Abstract: Degradation of matrix in normal glomeruli occurs through the action of neutral metalloproteinases which are in turn regulated by specific inhibitors. Both of these proteins are secreted by mesangial cells. Macrophages and IL-1 enhance the secretion of the proteinase. Decreased production of the metalloproteinase and for increased secretion of its inhibitor may lead to matrix accumulation. Neutrophil serine paternases degrade glomerular basement membrane (GBM)in vitro. In both animal and human disease urine excretion of these enzymes is accompanied by proteinuria and the presence of GBM-fragments. Further knowledge of the processes involved in matrix degradation may lead to improved therapy of glomerular disease.

Ammonium and bicarbonate homeostasis in chronic liver disease.

Abstract: Whereas traditionally in acid-base physiology one considers just two organs (lungs and kidneys) to be involved in the regulation of systemic acid-base homeostasis, recent developments indicate that also the liver must be viewed as an important organ for pH regulation. This is because urea synthesis is a quantitatively important bicarbonate-consuming process, which in turn underlies a feedback control by the acid-base status at least in vitro. Consequently, renal ammoniagenesis, generally accepted to be a direct bicarbonate-generating process, can be viewed as a pH-controlled ammonium homeostatic response. In view of the controversies regarding the roles of ureogenesis and renal ammoniagenesis in acid-base regulation, their relationships were studied in 28 patients with normal renal functions, but varying degrees of a well-compensated chronic liver disease. Progressive loss of urea cycle capacity (as determined by in vitro incubations of human liver tissue) was parallelled by increasing in vivo plasma bicarbonate levels (and metabolic alkalosis) and an increasing NH4+ excretion into the urine. Accordingly, renal ammoniagenesis rose with the extent of metabolic alkalosis. Neither hypokalemia, hyperaldosteronism, diuretic treatment, or volume contraction were present, and a satisfactory explanation for this unusual behavior of renal ammoniagenesis in terms of traditional acid-base physiology cannot be given. Here, it seems that renal ammoniagenesis is governed rather by the need to eliminate ammonia than by the acid-base status.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-mistletoe lectin antibodies are produced in patients during therapy with an aqueous mistletoe extract derived from Viscum album L. and neutralize lectin-induced cytotoxicity in vitro.

Abstract: The humoral response components of an aqueous mistletoe extract (HM) was evaluated in 23 tumor patients who had been treated from 2 months up to 6 years with increasing dosages of HM. IgG antibodies against mistletoe lectin and other components of this extract were detected by ELISA, immunodiffusion, and blotting technique, using either the aqueous extract (HM) or a purified lectin preparation (ML). Their activity depended upon dosage of HM and length of therapy. No anti-HM/ML antibodies of the IgM type could be detected. Immunoblotting revealed lectin-specific antigens at 62 kD, 33k D, and 29 kD. In the presence of ML or HM, PHA-induced proliferation of normal lymphocytes was decreased in a dose-dependent manner; this effect was neutralized by adding the IgG fraction from pooled anti-HM-antibody-positive sera, indicating that the cytotoxic effect of lectins was eliminated by these specific antibodies. In view of these findings, it is questionable whether exposing tumor cells to mistletoe extracts in vivo exerts the same direct effect on tumor cells that is observed in vitro.

Circadian rhythm of interleukin-1 production of monocytes and the influence of endogenous and exogenous glucocorticoids in man.

Abstract: We found a dose-dependent inhibition of spontaneous and LPS-induced IL-1 production of isolated human monocytes by methylprednisolone (MP) in vitro. Kinetic studies of spontaneous and LPS-induced IL-1 production of isolated monocytes of 10 normal individuals showed a synchronous circadian rhythm, with its maximum at 4:00 p.m. and its minimum at 4:00 a.m., which is most probably independent of the physiological circadian rhythm of cortisol levels because the IL-1 production was of the same value at the times of maximum and minimum cortisol levels. In contrast, in a patient with hypercortisolism and a preserved circadian rhythm of cortisol levels, we found the minimum of IL-1 production at 4:00 p.m., 8 hours after the maximum cortisol level was reached. Furthermore, in 7 patients with sarcoidosis both spontaneous and LPS-induced IL-1 production of isolated monocytes were significantly decreased 8 hours after the first injection of MP (1 mg/kg bw i.v.) compared to the values before MP administration. Our findings suggest a physiological circadian rhythm of spontaneous and LPS-induced IL-1 production of monocytes, independent of physiological cortisol levels, whereas unphysiological amounts of endogenous and exogenous glucocorticoids cause a substantial inhibition of IL-1 production with a latency time of 8 hours.

Acute effects of vitamin B6 and fixed combinations of vitamin B1, B6 and B12 on nociceptive activity evoked in the rat thalamus: dose-response relationship and combinations with morphine and paracetamol.

Abstract: Nociceptive activity was elicited in neurones of the thalamus by supramaximal electrical stimulation of afferent C fibres in the sural nerve of rats under urethane anesthesia. The fixed combination of vitamin B1, B6, B12 (Neurobion®) as well as of vitamin B6 administered by i.p. injection dose-dependently reduced the evoked nociceptive activity. The ED50 of Neurobion® is 4.6 ml/kg (at 100 min after injection) and that of vitamin B6 is 189mg/kg (at 90 min after injection). The minimum effective doses of Neurobion® and vitamin B6 are 0.5 ml/kg and 40 mg/kg, respectively. When Neurobion® or vitamin B6 were given at their minimum effective doses, and the minimum effective doses of morphine (0.025 mg/kg) or paracetamol (5 mg/kg) were injected i.v. 80 min later, i.e., when the maximum effect of higher doses of Neurobion® or vitamin B6was about to develop, no supraadditive effect developed. It is concluded that the antinociceptive effect caused by a single injection of Neurobion® is largely due to vitamin B6. Vitamin B12 may contribute to this effect, whereas vitamin B1 alone exhibited only a slight effect on nociception. Moreover, it appears that Neurobion® produces its antinociceptive effect after a single injection and after repeated administration during several days by different mechanisms so that the effect of analgesic agents is not enhanced following a single injection of Neurobion® but may be enhanced after repeated administration of the compound.

Sequential psychological testing during the course of autoimmune hyperthyroidism

Abstract: Although the psychological disturbances accompanying Graves' disease are well known, the time required for normalisation of these disturbances during antithyroid drug treatment is not known. Therefore sequential psychological testing during the course of Graves' disease was done. There are also contradictory results concerning the possible correlation of neurophysiological and psychological test results during the course of Graves' disease with thyroid hormone values. Finally, psychological disturbances have been proposed as possible etiologic factors in Graves' disease. In our study, a significant decrease in anxiety and irritability could be observed at the time euthyroidism was achieved. Self-evaluations of depressivity, activity, exhaustion, well-being, extraversion, introversion, and the ability to concentrate changed 1 or 2 months after euthyroidism was induced. Similar test results could be observed after induction of euthyroidism by antithyroid drugs and subtotal thyroid resection. Therefore the mode of therapy does not seem to influence the course of normalisation of psychological parameters. In contrast to other investigations there was hardly any correlation between thyroid hormone values and psychological test results or the ability to concentrate. Nontheless, patients with Graves' disease showing high scores for depression and anxiety exhibit abnormal peripheral helper/suppressor T-lymphocyte relations. Furthermore, patients suffering from Graves' disease tend to be more anxious than controls. It remains to be determined whether an increased susceptibility to psychological disturbances has led to these alterations of lymphocyte subsets in Graves' disease patients with severe depression and anxiety.

[Plasma endothelin in normal probands and patients with nephrologic-rheumatologic and cardiovascular diseases].

Abstract: Plasma concentrations of the recently isolated potent vasoconstrictory peptide endothelin were measured in 382 patients. The investigations were performed by means of a sensitive radioimmunoassay specific for Endothelin-1, 2. The results from 110 healthy volunteers displayed a normal range of 44.67 +/- 3.51 pg/ml. Significantly raised levels were found in 33 patients with chronic end-stage renal failure both before and after hemodialysis. In contrast, 35 patients with compensated renal insufficiency did not differ from the normals. Sixty-five patients after kidney transplantation revealed significantly elevated levels, as did 27 patients with acute myocardial infarction, 8 after coronary bypass surgery, and 5 with liver cirrhosis. The mean values of 27 patients with untreated hypertension, 22 with secondary hypertension, of various causes and 16 with coronary artery disease were comparable to the normal population. The values were significantly decreased in 9 pregnant women with hypertension and proteinuria. A marked decline was found in 5 patients with systemic lupus erythematodes, while 20 patients with rheumatoid arthritis demonstrated only a slight decrease. The pathophysiological role of endothelin as a local or circulating hormone in regulating systemic blood pressure or release of other hormones remains to be determined.

Gemfibrozil absorption and elimination in kidney and liver disease.

Abstract: The disposition of the lipid-lowering drug gemfibrozil was studied in patients with either renal (n= 8) or hepatic disease (n= 8) and compared to those of healthy volunteers (n= 6). Gemfibrozil was determined in plasma and urine by means of a HPLC method. Urine was also analyzed for gemfibrozil conjugates. Following oral administration of 900 mg gemfibrozil, maximal plasma levels of the parent drug were 46.1±15.8 μg/ml, attained after 2.2±1.1 h. In chronic renal failure and in liver cirrhosis the plasma concentrations of gemfibrozil did not significantly differ from that of controls except in those patients who were comedicated with antacids. These patients had significantly lower Cmax and AUC values. The elimination half-life of the drug was 1.5 h in controls, 2.4 h in renal failure, and 2.1 h in liver disease. In healthy volunteers, only 0.02 to 0.15% of the given dose was recovered in the urine as parent gemfibrozil, while conjugates made up 7–14%. In patients with renal failure also, only traces of parent gemfibrozil could be detected, and conjugates accounted for 0.5–9.8%. In those with liver disease, however, about 0.1–0.2% were recovered in urine as parent gemfibrozil and up to 50% as conjugates. Strikingly, the amount of excreted conjugates in the urine was positively correlated to the direct bilirubin plasma concentration. It can be concluded that the elimination of gemfibrozil is not significantly influenced by renal failure. However, comedication with antacids markedly reduced plasma disposition of the drug. Patients with severe liver disease excreted more conjugated gemfibrozil via the kidney than did healthy controls. Thus, transfer across the canalicular cell membrane to the bile duct, rather than drug metabolization, is primarily disturbed in liver disease. Gemfibrozil accumulation is unlikely to occur in either kidney or liver disease.

[Therapy of hirsutism in females with adrenal enzyme defects of steroid hormone biosynthesis: comparison of dexamethasone with cyproterone acetate].

Abstract: In patients with adrenal hirsutism or enzyme deficiencies in steroidogenesis, elevated adrenal androgens could be normalized by dexamethasone. We were interested to see if dexamethasone would be as effective as cyproterone acetate in treating hirsutism in selected patients with adrenal pathogenesis. Therefore 28 patients with hirsutism of adrenal origin or enzyme deficiency were treated cyclically either with cyproterone acetate and ethinylestradiol (2 mg cyproterone acetate + 0.035 mg ethinyl-estradiol days 1-21, +10 mg cyproterone acetate days 1-15) (n = 15) or with 0.25-0.5 mg dexamethasone daily at 10 pm (n = 13). In the dexamethasone group there was a significant drop in dehydroepiandrosterone and dehydroepiandrosterone sulfate levels within 9 months, but there was a diminution in hirsutism in only four women (31%); in four out of seven menstrual irregularities decreased. In the cyproterone acetate group hirsutism diminished significantly in 66% (n = 10) without suppression of adrenal androgens. Weight gain occurred in a few cases in both groups; other side effects developed in 33% in the cyproterone acetate group. Preselection of patients with hirsutism is useful with respect to diagnosis; adrenal pathogenesis should not generally indicate dexamethasone treatment of hirsutism unless there is a desire for pregnancy, because cyproterone acetate is a more powerful agent in reducing hair growth.

Concordant dyslipidemia, hypertension and early coronary disease in Utah families.

Abstract: Platelet-derived growth factor (PDGF) is the principal mitogen for connective tissue-derived cells such as fibroblasts, smooth muscle cells, and glial cells. It is synthesized by a variety of cell types and the synthesis of PDGF and its receptors is tightly controlled. Accumulating evidence obtained in vitro and in vivo suggests that PDGF plays important roles in the pathogenesis of clinically important diseases such as atherogenesis and cancer. Moreover, PDGF is an important research tool to study the signal transmission pathway of growth factors and other hormones.

Duplexsonography in the diagnosis of renovascular hypertension

Abstract: Duplexsonography (DS) has become a well established method for diagnosing peripheral vascular diseases. Technical developments (higher resolution of transducer and deeper penetration) have made also abdominal and retroperitoneal vessels, including renal arteries, accessible for duplexsonography. This method provides the opportunity to recognize renal artery stenoses causing renovascular hypertension without invasive procedures. We therefore examined 86 hypertensive patients with a high likelihood of renovascular hypertension. Due to technical problems (bowel gas, adipositas) we excluded 7 patients. 79 patients (17–79 years) were included in our study. Flow patterns of several renal vascular areas were evaluated while the renal artery was demonstrated on a B-scan. A spectrumanalysis included the evaluation of the frequency pattern (widening of the frequency band and loss of a frequency free window below the systolic rise?), the sloping of the diastolic shoulder, and the calculation of different parameters like accelerationindex, decelerationindex, resistanceindex, accelerationtime, and systolic peak velocity. The accuracy of DS in diagnosing renal artery stenoses was compared with arterial digital substraction angiography (DSA).

Acromegaly and hypertension: prevalence and relationship to the renin-angiotensin-aldosterone system.

Abstract: The prevalence of arterial hypertension was evaluated in a retrospective study of 158 patients with acromegaly, and results were compared to control populations, namely, the Munich Blood Pressure Study (MBPS) and the Framingham Study. The prevalence of hypertension (defined according to WHO criteria) was significantly increased in female patients but not in men; hypertensive acromegalics were older and tended to have higher body weight compared to normotensive patients. Hypertension was not related to serum concentrations of growth hormone. After successful treatment of acromegaly, growth hormone levels and systolic and diastolic blood pressure fell only in female hypertensive acromegalics; this did not occur in normotensives. The rise in plasma renin activity in response to upright posture was diminished in 57.9% of acromegalic patients. The prevalence of low-renin hypertension in our group of patients was 31.6%, which is similar to figures reported for unselected non-acromegalic subjects with essential hypertension. Orthostatic renin activity was weakly and inversely related (r=− 0.3) to blood pressure. No relationship between plasma aldosterone concentration and blood pressure could be detected; however, in acromegalic women, aldosterone rose higher after ambulation than in men. In conclusion, hypertension is a common problem in acromegaly and at least in part related to similar risk factors in control populations. The association with abnormalities of the renin-angiotensine-aldosterone system is difficult to interpret and does not offer an explanation for the slight increase in the prevalence of hypertension.

Diabetic autonomic neuropathy: abnormal cardiovascular reactions under general anesthesia.

Abstract: The influence of diabetic autonomic neuropathy upon the behavior of the circulatory system was investigated in 56 patients who had undergone ophthalmological surgery. A standardized test combination (variability in heart rate during deep breathing, Valsalva ratio, 30∶15 ratio, change in blood pressure from lying to standing, sustained handgrip test) was used to study the patients' cardiovascular reflectory reactions. The patients were then divided into the following groups: Group I, non-diabetics Group II, diabetics without autonomic neuropathy Group III, diabetics with autonomic neuropathy The anesthetic (induction by barbiturates and conduction by inhalation agents) and the surgical procedure (pars plana vitrectomy) were standardized and always identical. During anesthesia patients in group III experienced hypotensive reactions (systolic blood pressure below 90 mm Hg) significantly more often (72.2%) than patients in group I (25%). In order to achieve stability in blood pressure the patients of group III had to be given vasoactive drugs much more often (77.8%) than the patients of group I (12.5%) and those of group II (35.7%). We found a significant correlation between the degree of autonomic dysfunction and the largest drop in blood pressure under narcosis (r=−0.60,P<0.001). However, marked variability in heart rate and cardiac rhythm disorders during anesthesia were seen only in patients of groups I and II. These results prove the atypical hemodynamic behavior and especially the extreme instability in blood pressure in diabetic autonomic neuropathy under general anesthesia. Therefore we consider it to be very helpful to check the cardiovascular reflectory status of diabetics preoperatively.

Cardiovascular effects of n-6 fatty acids.

Abstract: N-6 fatty acids comprise linoleic, dihomo-gamma-linolenic and arachidonic acid. Each of these polyunsaturated fatty acids display an individual pattern of cardiovascular effects. Moreover, the supplementation of the diet with one of these n-6 fatty acids results in a concomitant effect on the resorption, distribution and metabolism of the other n-6 fatty acids. While linoleic acid is abundant in our diet, the other n-6 fatty acids are only found in minute amounts. Accordingly, the effects with linoleic acid are less impressive, but more complex (e.g. lowering of plasma cholesterol, inhibition of renin) than with both other n-6 fatty acids. Linoleic acid, being no direct prostaglandin precursor, displays a variety of effects on the prostaglandin cascade, while dihomo-gamma-linolenic acid gives rise to 1-series prostaglandins and arachidonic acid to prostaglandins (eicosanoids) of the 2-series. The quality and quantity of prostaglandins formed, contribute essentially to the cardiovascular effects of the individual n-6 fatty acids.