[The effect of combination epidural anesthesia techniques in upper abdominal surgery on the stress reaction, pain control and respiratory mechanics]. / Der Einfluss epiduraler Kombinationsanaesthesieverfahren bei Oberbaucheingriffen auf Stressreaktion, Schmerzverhalten und Atemmechanik.

Twenty-eight patients undergoing upper abdominal operations (mainly selective proximal vagotomy [SPV]) were referred for assessment of the hormonal metabolic reaction (adrenocorticotropic hormone [ACTH], arginine vasopressin [AVP], cortisol, and glucose), the postoperative pain reaction, and respiration according to the method of anesthesia (group 1: neuroleptanesthesia [NLA], group 2: NLA in combination with epidural opiate analgesia, group 3: NLA in combination with local anesthesia). To alleviate postoperative pain piritramide was systematically administered in group 1, whereas in groups 2 and 3 a thoracic epidural catheter was injected with morphine or bupivacaine. Postoperative analgesia was better in patients with epidural administration than in those with systemic application. On the 1st and 2nd postoperative days the vital capacity was statistically significantly higher by 10%-15% in groups 2 and 3 than in group 1. As expected, the neurohormonal and metabolic stress response was highest in all patients in the intraoperative and immediate postoperative phases: ACTH, AVP, and glucose levels were in most cases significantly higher compared with the initial values. However, cortisol levels decreased intraoperatively, probably as a result of the generally used induction agent etomidate. Comparison of the three methods of anesthesia revealed that all mean hormone levels analyzed in group 2 patients were lower both intraoperatively and 2 h postoperatively, which implies that epidurally administered morphine reduces the stress reaction, probably indirectly through additional selective alleviation of pain at the spinal cord level. The various differences in hormonal reactions of patients in groups 1 and 3 gave no clear evidence, however, of possible mitigation of the stress reaction by epidural local anesthetics in upper abdominal operations.

Identification of cells responsible for the suppression of anti-beta-cell cytotoxicity in type I (insulin-dependent) diabetes mellitus.

Peripheral blood mononuclear cells (PBMC) from newly diagnosed type I diabetic patients induced a significantly higher cytotoxic insulin leakage from isolated rat islets during a 20-h incubation. compared with PBMC from healthy controls (13.9 +/- 7.7 versus 2.6 +/- 3.2 ng insulin/islet/20 h). The addition of PBMC from healthy subjects in a ratio of 1:4 suppressed the cytotoxic effect (13.9 +/- 7.7 to 6.7 +/- 4.4 ng insulin/islet/20 h). Depletion of CD8+ T lymphocytes from the PBMC of healthy subjects abolished their suppressive capacity, while depletion of CD4+ T lymphocytes and pre-incubation with CD3 monoclonal antibodies had no effect.

Lymphocyte transfusion in recent onset type I diabetes mellitus--a one-year follow-up of cell-mediated anti-islet cytotoxicity and C-peptide secretion.

In 19 patients with newly diagnosed Type I diabetes mellitus a single transfusion of 1.9 x 10(9) to 1.5 x 10(10) lymphocytes was performed. Fifteen Type I diabetic patients who did not receive a transfusion were used as controls. Anti-beta-cell cell-mediated cytotoxicity was measured using an insulin release assay. Stimulated C-peptide secretion (100 g glucose orally, 1 mg glucagon i.v.) was used to estimate residual beta-cell function. Both parameters were measured prior to transfusion and after 12 months. The transfusions were followed by a fall of cytotoxicity below the 95% confidence limit of the controls in 11 of the 19 patients ('responders') (15.7 +/- 1.7 ng insulin/islet/20 h vs 6.7 +/- 1.3 P less than 0.001), while the other eight transfused patients ('non-responders') (13.5 +/- 1.9 vs 17.1 +/- 2.9, ns) and the non-transfused control patients (11.6 +/- 1.1 vs 14.2 +/- 2.4, ns) displayed persistently high cytotoxicity levels. In the responder group a slight improvement in stimulated C-peptide secretion was observed (136 +/- 43 pmol/dl vs 148 +/- 38, ns) whereas in the non-responder (127 +/- 28 vs 106 +/- 25, ns) and in the control group (130 +/- 17 vs 97 +/- 19, P less than 0.05) the stimulated C-peptide responses declined during the 12-month follow-up. Thus, lymphocyte transfusion may have beneficial effects by suppressing anti-beta-cell cytotoxicity and preserving C-peptide secretion.

Clinical experience with a radioreceptor assay for TSH-binding inhibiting immunoglobulins (TBII).

The aim of the present study was to evaluate the clinical value of a commercial kit for determination of TBII. Forty-seven of 50 patients with untreated hyperthyroid Graves' disease were TBII positive (sensitivity 94%). TBII was in the normal range in all normal volunteers and in patients with simple goiter, thyroid cancer and in most cases of nonimmunogenic hyperthyroidism (19 of 22). After 12 months antithyroid drug therapy with methimazole of 21 patients the prevalence of positive TBII findings was 28%. In contrast to this, 50 percent of the patients had increased microsomal antibodies at the end of therapy. The determination of TBII by TRAK-assay proved to be a sensitive, specific and practical method. The assay can be used to differentiate between hyperthyroidism of autoimmune or nonimmunogenic origin. Even so this method seems to be helpful for the follow-up during medical treatment of patients with Graves' disease. The results indicate that persistence of increased TBII levels are markers of active Graves' disease and suggest that in this situation ablative measures should be performed. Normalization of TBII on the end of a longstanding antithyroid therapy does not exclude the possibility of relapse in the further course.

Electron microscopical investigations on lymphocyte cytotoxicity against beta-cells in recent onset IDDM.

The effect of lymphocytes from patients with newly diagnosed insulin dependent diabetes on isolated rat or human islets during a 20 h in vitro incubation was investigated by morphological and biochemical methods. All stages of target cell reaction of lymphocytes against beta-cells were observed. Cytoplasmic projections towards and contacts with beta-cells, circumscribed lysis of the outer cell membrane at the contact side and complete lysis of beta-cells were seen. Such findings could not be registered with alpha- or other non beta-cells and in control experiments using lymphocytes from healthy persons. In some cases the lymphocytes were phenotyped using monoclonal antibodies by the indirect immuno-gold technique. It could be demonstrated that lymphocytes in contact with necrotic beta-cells were of the CD8+ve subset. In addition the morphological investigations were supplemented by quantitative biochemical studies measuring the non-secretory insulin release ("cytotoxic" release) from islets into the culture medium and their ability to respond to a consecutive stimulation by arginin with insulin and glucagon secretion. The mean cytotoxic insulin release was 11.3 +/- 1.5 ng/islet/20 h (n = 25) in the diabetic group versus 0.56 +/- 0.15 ng/islet/20 h (n = 15) in the control subjects (alpha less than 0.001). Functional testing of the islets following incubation with lymphocytes from diabetic patients showed diminished insulin (58.6 +/- 5.1%, n = 18, alpha less than 0.001) and unchanged glucagon response (103.0 +/- 3.4%, n = 10, n.s.) when compared with untreated islets (= 100%).(ABSTRACT TRUNCATED AT 250 WORDS)

Defect of cellular suppressor function in the pathogenesis of type I diabetes mellitus.

In 29 out of 30 type I diabetic patients the peripheral blood lymphocytes induced an insulin release from isolated rat islets which was regarded as a cytotoxic effect, i.e. a model of beta cell destruction in diabetes mellitus. In 11 out of 12 cases, this effect was inhibited by the in-vitro addition of lymphocytes from healthy probands. Thus the activation of cytotoxic T-cells demonstrated by this observation might be the consequence of a defect in suppressor cell function. Consequently, the transfusion in vivo of lymphocytes from healthy probands strongly reduced the cytotoxic reaction of the lymphocytes from newly diagnosed diabetic recipients in vitro.

A follow-up study of cell-mediated cytotoxicity and beta cell function in type I diabetes.

In 20 patients with a newly diagnosed type I diabetes mellitus a cytotoxic effect of blood lymphocytes against beta cells of the pancreas of neonatal rats could be demonstrated. This effect remained nearly unchanged during the first 12 months of control. During the course up to 18 months, the cytotoxicity decreased significantly. After stimulation with glucose and glucagon, a C-peptide secretion was demonstrated in all patients during the first 12 months but it decreased thereafter. The follow-up study showed cell-mediated immune reactions against beta cells in type I diabetics as long as the existence of beta cells can be assumed on the basis of functional tests. Thus the immune process seems to depend on the presence of the specific antigen.

[Clinical relevance of the determination of TSH-binding inhibitory immunoglobulins (TBII) in patients with immunogenic hyperthyroidism in methimazole therapy]. / Klinische Relevanz der Bestimmung von TSH-Bindungs-inhibierenden Immunglobulinen (TBII) bei Patienten mit immunogener Hyperthyreose unter Methimazoltherapie.

In 38 patients with immunogenic hyperthyroidism a follow-up was performed to estimate the value of TBII before, during and after methimazole therapy. Before therapy increased TBII were detectable in 37 patients (94.4%). After 12 months methimazole therapy 25 patients had TSH-receptor antibodies (66%) within the normal range. In 13 patients positive antibody titres were found. In most cases persistence of increased TBII-values during drug treatment was an indicator of the persistence of active hyperthyroidism (10 of 13 patients). In the rule a disappearance of TBII-activity was combined with a functional remission (22 of 25 patients). Prolonged demonstration of TBII-activity in conjunction with persistence of hyperthyroidism should lead to ablative measures. In contrast to this medical therapy should be finished in patients with immunological and functional remission. Though in the further follow-up a recurrence of the immunological base of the disease with a functional and clinical relapse is possible.

[Insulin therapy of obese diabetic patients? Consequences for the evaluation of insulin secretion and metabolic behavior]. / Insulintherapie bei fettsüchtigen Diabetikern? Konsequenzen aus der Bewertung des Insulinsekretions- und Stoffwechselverhaltens.

UNLABELLED: In 83 diabetics insulin secretion was examined after a mean diabetes duration of 7.5 years, when an insufficient metabolic situation could be found. Insulin secretion was stimulated with 100 g glucose (orally) and 1.0 mg glucagon i.v. (60 min after glucose intake). We investigated additionally in a retrospective manner blood-glucose and urine glucose behaviour as well as the development of the body weight. In dependence of the actual body weight at the time of investigation of insulin secretion, two groups were formed: b. w. less than 120% acc. Broca index, group A, n = 38; b. w. greater than 120% acc. Broca index. group B, n = 45). Immediately after manifestation of the disease 71 diabetes were treated with pure dietetic measures. At the examination of insulin secretion all patients were treated with glibenclamide. After this examination in 20 patients of the group A and in 17 patients of the group B an insulinisation was started. In the others glibenclamide treatment was continued. The general characteristics of the whole group was a significant reduction of the maximum stimulability of insulin secretion, compared with the insulin secretion of n = 19 healthy probands (11 probands with normal body weight and 8 obese probands). A hyperinsulinism (maximum values higher than mean + 1 s of the health persons) could not be found in any case. The mean of the maximum insulin values was below mean - 1 s of the healthy persons. Insulinisation provoked an improvement of the metabolic situation. This was correlated with an additional improvement of the subjective behaviour. CONCLUSION: Evaluation of insulin secretion in obese diabetics with bad metabolic situation is necessary to find out those who are to be treated with insulin. We have no clinical or other possibilities to recognize patients with a hyperinsulinism or reduced insulin secretion than by evaluation of insulin secretion alone. But higher degrees of decompensated metabolism are nearly always explained by a significant reduction of insulin secretion.

Specific immunotherapy in insulin-dependent diabetes mellitus (preliminary report).

In 7 patients with newly diagnosed insulin-dependent diabetes mellitus a cytotoxic effect of blood lymphocytes against B-cells could be demonstrated by incubation of isolated rat islets with the lymphocytes. The addition of lymphocytes from healthy persons significantly reduced this effect in vitro. The transfusion of 1.9 X 10(9) - 1.5 X 10(10) lymphocytes from the parents to the patients produced a significant decrease of the cytotoxic effect of the lymphocytes from the patients. This effect could be demonstrated during the preliminary control period up to 12 weeks.

Cell-mediated immune reactions against B cells and defect of suppressor cell activity in type 1 (insulin-dependent) diabetes mellitus.

A cytotoxic effect of peripheral blood mononuclear cells from 22 out of 23 newly diagnosed Type 1 (insulin-dependent) diabetic patients against B cells of isolated rat islets was demonstrated. The addition of peripheral blood mononuclear cells from healthy subjects reduced the cytotoxic effect in 9 out of 10 patients. The addition of peripheral blood mononuclear cells from other diabetic patients was without significant effect in 14 out of 16 cases. The results indicate functional abnormalities of peripheral blood mononuclear cells in newly diagnosed Type 1 diabetes. Beside cytotoxic effects against B cells, a defect in the suppressor function seems to exist. The activation of T-lymphocytes might be a consequence of such a defect.

[Action of [3,14-L-selenocysteine, 8-D-tryptophan]-somatostatin on insulin and glucagon secretion of the isolated perfused pancrease of the Wistar rat]. / Zur Wirkung von [3,14-L-Selenozystein, 8-D-Tryptophan]-Somatostatin auf die Insulin- und Glukagonsekretion des isoliert perfundierten Pankreas der Wistar-Ratte.

By isolated perfused pancreas of Wistar rats the glucose (11 mmol/l) and arginine (10 mmol/l) stimulated insulin (IRI) and glucagon (IRG) secretion was measured in order to investigate the inhibitory activities of somatostatin-14 (SS 14) and the somatostatin analogue [3,14-L-seleno-cysteine, 8-D-tryptophan]-somatostatin (SeSS). SS-14 or SeSS (152.8 nmol/l) inhibit the glucose stimulated IRI secretion by 75 and 65%, respectively. Only the second phase of the biphasic arginine stimulated insulin secretion pattern by 40%. SeSS has under these conditions no effect, whereas 58 nmol/l SS-14 or SeSS show a suppressing effect on the first (20 and 55%, respectively) and second phase (65 and 85%, respectively) of the insulin secretion. Using 5.8 nmol/l SS-14 or SeSS the arginine stimulated IRG secretion was inhibited only in the second phase of the biphasic glucagon secretion pattern by about 40%. 58 nmol/l SS-14 or SeSS show an inhibiting effect on the first and on the second phase of secretion, in both cases about 50%. It is concluded that in the SS-14 molecule the sulfur of cysteine in position 3 and 14 can be exchanged by selenium without modifying the biological activities measured in the glucose or arginine stimulated IRI and IRG secretion in vitro. The D-Trp8 in the SeSS analogue does not show the typical better inhibitory action of D-Trp8-SS-14 on insulin and glucagon secretion compared with SS-14. Possibly the selenium in the SeSS analogue abolishes this effect.

[Clinical value of the determination of TSH-binding inhibitory immunoglobulins (TBII) by a radioreceptor assay]. / Klinische Wertigkeit der Bestimmung von TSH-Bindungs-inhibierenden Immunglobulinen (TBII) durch einen Radiorezeptorassay.

The aim of the present study was to evaluate the clinical value of a commercial kit for determination of TBII. The study consisted of 50 patients with untreated Graves' disease, 21 patients with Graves' disease before und during medical therapy, 18 patients after finishing medical therapy and 10 patients after surgical treatment. Besides these, 41 patients with other thyroid diseases and 36 patients without any thyroid disorder were included. In 47 (94%) of 50 patients with untreated Graves' disease TBII were detectable in serum using a TSH-standard-curve. Binding activities exceeding 10 U/l TSH equivalents were regarded as positive. In other thyroid diseases TBII were negative with the exception of 3 of 22 patient with autonomously functioning thyroid nodules. After 12 months of antithyroid drug treatment of 19 patients the incidence of positive antibody findings was 26%. During follow-up after medical therapy (1-9 years) 7 of 18 patients had increased TBII in correlation with clinical and functional findings. The determination of TBII by TRAK-Assay proved to be a sensitive and specific method. The assay can be used to differentiate between hyperthyroidism of autoimmune or non-immunogenic origin. Even so this method seems to be helpful for the follow-up under medical treatment of patients with Graves' disease.

[In vitro and in vivo effect of gold thioglucose on the insulin- and glucagon-secretion of the isolated perfused rat pancreas]. / In vitro- und in vivo-Wirkung von Goldthioglukose auf die Insulin- und Glukagonsekretion des isoliert perfundierten Rattenpankreas.

Effects of gold thioglucose on the insulin and glucagon secretion by the isolated perfused pancreas of Wistar rats in vivo and in vitro Gold thioglucose (GTG), hitherto administered predominantly to mice can also be used in rats in a non toxic dosage, if GTG is injected intravenously (i.v.) together with sodium hexobarbital. Wistar rats tolerate a single injection of GTG in doses ranging from 40 to 1200 mg/kg bw. GTG (10 mmol/l in the perfusion medium) has no in vitro effect--tested by the isolated perfused rat pancreas--on the basal (5.5 mmol/l glucose) or stimulated (11 mmol/l glucose) insulin (IRI)-secretion. This is valid also for glucagon (IRG)-secretion. After in vivo injection of GTG (600 mg/kg bw, together with sodium hexobarbital (10 mg/100 g bw, i.v.] extensive alterations of IRI- and IRG-secretion result as tested under in vitro conditions in the isolated perfused pancreas of the rat, Glucose stimulation (11 mmol/l) causes a hyperinsulinism and a hypersecretion of IRG, a so-called paradoxical glucagon secretion, lasting for 2 days while IRI secretion is already diminished. At the same time food intake is very low and the body weight decreases. Ten days later the body weight has reached the starting value again and the IRI secretion shows again signs of hyperinsulinism. Six months after a single injection of GTG (600 mg/kg bw, i.v.) the rats were obese and react after glucose stimulation with hyperinsulinism and again with a paradoxical glucagon secretion. The blood glucose levels were normoglycaemic, whereas serum IRI rose in parallel with development of the obesity. Also with histological methods we could distinguish an acute from a chronic phase of GTG toxicity visible in the tested organs (liver, kidney, thyroid gland). The endocrine pancreas reacts after a single injection of GTG with a lowered number of B cells. The remaining cells reveal variable amounts of degranulation. In the early phase the hypothalamus, in particular the ventromedial hypothalamic nucleus, shows most clearly signs of destruction and 6 months after a single injection of GTG the number of cells is still reduced in this region. We conclude that GTG reacts primarily on the hypothalamus and modulates the reactivity of the endocrine pancreas in a permanent manner via the vegetative nervous system, because we test the function of the pancreas in an in vitro system. As a consequence the threshold of the B and A cell against the stimulus glucose is altered in two ways.(ABSTRACT TRUNCATED AT 400 WORDS)

[Effect of subtotal small intestine resection on insulin and glucagon secretion by the isolated perfused rat pancreas following glucose stimulation]. / Zur Wirkung einer subtotalen Dünndarmresektion auf die Insulin- und Glukagonsekretion des isoliert perfundierten Pankreas der Wistar-Ratte nach Glukosestimulation.

An attempt has been made to investigate possible regulatory effects of gastrointestinal hormones on insulin and glucagon secretion in Wistar rats that had been subjected to partial resection of the duodenum and jejunum or the ileum. Release of insulin and glucagon was studied on perfused pancrease 4 weeks after the operation. Partial resection of both the duodenum and jejunum resulted in a significant decrease of glucose-induced insulin secretion and basal glucagon release when compared with the controls. Glucagon release was not further suppressed by increasing glucose concentration in the perfusion medium. Resection of the ileum only had no effects. Also, there was no difference to be observed in plasma insulin levels between the two groups. Resection of the ileum, however, provoked a drastical decrease of plasma insulin levels. Food intake was not significantly changed while body weight slightly decreased 1 week after operation but returned to normal after 4 weeks. The results suggest that the various parts of the small intestine seem to be involved in the regulation of glucose-stimulated insulin secretion as well as basal glucagon release. The alterations in glucose-stimulated insulin or glucose-suppressed glucagon secretion are likely due to the action of gastrointestinal hormones or hitherto unknown peptides.

Simultaneous biochemical and morphological investigations on the effect of leukocytes from type I diabetics on isolated rat islets.

The first morphological and biochemical findings on the effect of leukocytes from a newly diagnosed type I diabetic patient on isolated rat islets are presented. Leukocytes from venous blood were co-incubated with isolated neonatal rat islets for 22 h. According to the biochemical and electron-microscopical findings, beta cells localized in the periphery of the islets and a few single beta cells show lytic alterations (single cell necroses). The electron micrographs suggest that the beta cells were lysed after contact with lymphocytes or lymphoid cells from the diabetic patient (target cell reaction). The simultaneous biochemical and morphological investigations reveal that after beta cell lysis, insulin released in a granular state can be phagocytosed by granulocytes and thus escape the estimation of insulin concentration in the medium.

[Long-term course of type I-simulating type II-diabetes mellitus]. / Langjähriger Verlauf des Typ-I-unter dem klinischen Bild des Typ II-Diabetes mellitus.

In only few cases of primarily non- insulin-dependent diabetes mellitus after many years an absolute insulin dependency can develop. Within 5000 patients of a diabetic outpatient clinic in 2 years this happened in 21 patients. These patients offered a C-peptide-secretion after stimulation which was typical for an insulin dependent diabetes. The investigation of HLA-frequencies showed a marked increase of the DR 3 und DR 4 loci. These results demonstrate that obviously the genetically as type I characterized diabetes may appear clinically in the picture of type II-diabetes for many years. This must be taken in consideration in therapeutic or epidemiologic questions.

[Influence of alloxan-diabetes in pregnant sows on body composition, glucose tolerance and insulin reaction of newborn piglets]. / Einfluss eines Alloxan-Diabetes tragender Sauen auf Körperzusammensetzung, Glukosetoleranz und Insulinreaktion neugeborener Ferkel.

Diabetes was induced in 3 pregnant sows by administration of alloxan tetrahydrate (50 mg/kg body weight) at the 60th-70th day of gestation. Body weight, concentration of glycogen in liver, heart and skeletal muscle, weight of liver, heart, pancreas, thyroid gland and adrenal glands as well as plasma concentrations of glucose, fructose and insulin (IRI) were determined immediately after birth in the piglets of diabetic sows (4 litters). Furthermore, the plasma glucose and insulin reactions to and intravenous bolus injection of glucose (0.5 g/kg) were examined 4-8 hours and 6-7 days after birth. The results were compared with the values obtained from the offspring of 4 normal litters. Newborn piglets of diabetic sows showed a significantly increased absolute and relative weight of liver as well as a significant increase in the relative weight of heart, thyroid gland and pancreas. The concentration of glycogen in heart and skeletal muscle as well as the amount of glycogen in liver/kg body weight were significantly elevated. Furthermore, we found significantly higher plasma glucose values in the offspring of alloxan treated sows, while there were no differences in plasma insulin and fructose levels. When compared to normal piglets, the diabetic piglets displayed an impaired insulin response and glucose tolerance after a bolus injection of glucose. The results obtained suggest considerable differences in the fetal development and pancreatic function during a diabetic pregnancy in different species.