Genetic aspects of sarcoidosis. Class II histocompatibility antigens and a family study.

In a study designed to evaluate the concept of inherited susceptibility to sarcoidosis, 73 patients with histologically proved chronic disease of sarcoid lung fibrosis (group 1) underwent typing of HLA-A, -B, -C and -DR antigens. Tests on 156 antiserum samples comprising 52 antigens of A, B, and C loci and on 35 comprising seven DR antigens on the surface of B cells were performed by means of the microdoplet assay of human serum cytotoxins. Two race-matched control groups consisted of 37 patients with lung fibrosis due to chronic extrinsic allergic alveolitis (group 2) and 162 healthy volunteers (group 3). The study further included a kinship with progressive sarcoidosis. The frequency of HLA-DR5 was significantly increased only in group 1 (relative risk, 6.6). HLA-DR5 was found in 38 patients (52%) in group 1, compared with five (14%) in group 2 and 23 (14%) in group 3. In the one family studied, HLA-DR5 was present only in one member, who had sarcoidosis. This study supports the hypothesis that the role of an infectious agent triggering sarcoidosis cannot be envisaged without considering genetically linked cofactors.

Effect of intra-articular orgotein versus a corticosteroid on rheumatoid arthritis of the knees.

The effects of intra-articular injections of orgotein (4 mg a week for six weeks) and of methylprednisolone acetate (4 mg a week for six weeks) on the knee joints were compared in a random long-term trial. Twenty-eight patients with active, definitive rheumatoid arthritis were studied by double-blind comparison. The first control examination made after six weeks of therapy showed no differences between the joints treated with orgotein or with steroid. However, at the final control examination after 24 weeks, a disparity between both drug regimens became apparent. Clinical response was evaluated in the knees in terms of cumulative rheumatoid activity index based on morning stiffness, range of flexion, pain scores, and 25-foot walking time. After 24 weeks, orgotein was found to be superior to steroid in the major points of the clinical assessment index but equipotent in marked improvement of the rheumatoid activity index after six weeks of treatment. After intrasynovial orgotein injections, synovial fluid enzyme activity fell significantly, concurrently with reduced prostaglandin E2 formation. Synovial fluid leukocyte counts also decreased, but the percentage of polymorphonuclear cells increased simultaneously only in the orgotein-treated group. The results suggest that patients with rheumatoid arthritis of the knee joints who show good response to orgotein during a short course of treatment are likely to continue their positive response and possibly attain increased relief of symptoms over longer periods of treatment, in contrast to those patients receiving steroids.

Six-week study of torsemide in patients with congestive heart failure.

A double-blind, randomized, multicenter study compared treatment with 10 mg torsemide, 20 mg torsemide, and 40 mg furosemide, once daily, in 70 patients with congestive heart failure who had been maintained on 40 mg furosemide daily for at least 2 weeks. All three treatment groups showed statistically significant decreases in body weight, ranging from 1 to 3 kg at week 6. The decreases in body weight were significantly greater in the 20-mg torsemide group than in the furosemide group at weeks 4 and 6 and in the 10-mg torsemide group than in the furosemide group at week 4. The 20-mg torsemide group showed a statistically significant reduction in edema. Both the 10-mg and 20-mg torsemide groups showed statistically significant improvement in heart size. Pulmonary congestion decreased with treatment in each group. At week 6, both edema and pulmonary congestion were significantly less in the 20-mg torsemide group than in the 10-mg torsemide or 40-mg furosemide groups. Torsemide was well tolerated. Small, clinically insignificant decreases in serum potassium and increases in creatinine and uric acid were observed with both torsemide and furosemide. In conclusion, 20 mg torsemide was more effective than 40 mg furosemide in reducing body weight and improving symptoms of congestive heart failure.

[Glucocorticoid-induced effect of erythropoietin in haemolytic anaemia with uraemia and red cell enzyme deficiency (author's transl)]. / Glukokortikoid-induzierte Erythropoetinwikung bei urämischen und enzymopenischen Hämolysen.

The effect of 6-methylprednisolone (GCC) was studied on erythropoietin (ESF) levels and on the metabolic functions of erythrocytes (RBC). GCC (U mg/kg/day for 15 days) was administered to 6 patients with the haemolytic-uraemic syndrome (group B) and to 6 patients with non-spherocytic haemolytic anaemia due to hereditary pyruvate kinase enzyme deficiency (group C). 6 healthy persons served as control (group A). The metabolic functions of RBC were investigated by assaying HMPS activity, GSH/GSSG and lactate/pyruvate ratios, relevant glycolytic intermediates, 2,3-DPG, ATP, and key enzymes. A significant increase in ESF was observed in group B patients after GCC therapy, correlating with an improvement in the haemolytic state, and consequent rectification of the secondary disturbances of RBC metabolism. Group C patients already had raised ESF levels before GCC therapy; no further increase occured in response to treatment and no other clinical or haematological change was recorded. Hence, no harmonal influence of GCC on the disturbed RBC metabolic process was detectable in the cases.

[Disorders of erythropoiesis in alcoholic ketoacidosis in patients with chronic liver diseases]. / Erythropoiesestörungen alkoholtoxischer Ketoazidosen bei chronischen Lebererkrankungen.

To evaluate the toxic effect of ethanol on erythropoiesis in alcoholic ketoacidosis (AK), 6 male patients were studied in the acute and remittent phase of AK. Episodes of metabolic acidosis in nondiabetic chronic alcoholics were associated with protracted vomiting and prolonged intestinal symptoms. AK was associated with elevated beta-hydroxybutyrate, acetoacetate and lactate/pyruvate plasma levels. Analysis of plasma lipids showed raised HDL cholesterol, fatty acids and phospholipids resulting in a concomitant disorder of lipid metabolism in red cell ghosts. A red cell metabolic disorder with reduced ATP and glutathione levels was also observed in patients suffering from mild hemolytic anemia. On admission, miscellaneous toxic effects on erythropoiesis were detected when bone marrow was aspirated. This study lends further support to the hypothesis that there is a linkage of different factors producing serious but transient hematologic and oncologic implications of ethanol in patients with AK.

[Comparative double blind trial of pirprofen, indomethacin, and placebo in the treatment of rheumatoid arthritis]. / Essai comparatif en double insu du pirprofène, de l'indométacine et d'un placebo dans la polyarthrite rhumatoïde.

One hundred and thirty-four out-patients suffering from active rheumatoid arthritis were treated for 2 weeks by 1200 mg of Pirprofen (400 mg t.i.d.) 150 mg of Indomethacin (50 mg t.i.d.) or a placebo. On all criteria, the anti-inflammatories were more effective than the placebo (p less than 0.05). The overall therapeutic efficacy was satisfactory in 87% of patients on Pirprofen, 77% on Indomethacin and 26% on placebo.

Red cell metabolism in transient haemolytic anaemia associated with Zieve's syndrome.

Reversible haemolytic anaemia associated with decreased red cell half-life and reticulocytosis was studied in 10 patients with Zieve's syndrome. Since the underlying cause of the red cell destruction is as yet unknown, we determined the critical metabolic functions of the red cells in order to define the assumed intracorpuscular defect causing haemolysis. The glucose metabolizing enzymes had normal or raised values. - In view of the diminished ATP and raised 2,3-diphosphoglycerate (2.3 DPG) levels - a combination which suggests a pyruvate kinase (PK) deficiency - additional procedures were carried out in order to detect an abnormal activity of the red cell PK. Studies of biochemical properties of PK such as thermostability, Michaelis-Menten constants, and activation and inhibition tests brought results markedly deviating from the norm.-Fractions containing old cells particularly disclosed PK instability. A defective red cell matabolism resulted which was measurable through ATP-instability, altered glucose utilization and lactate production. - Experimental cell aging procedures led to a markedly decreased red cell metabolism. These assays revealed that mutations of PK-control mechanisms might be involved as factor triggering haemolytic anaemia of Zieve's syndrome.

Erythrocyte membrane fluidity, lipid peroxidation and lysis in alcoholic liver disease.

The still unexplained occurrence of hemolytic anemia in cases of alcoholic liver disease prompted us to study the toxic effect of ethanol on the membrane and metabolic properties of erythrocytes (RBC) in chronic alcoholics (n = 7). Raised susceptibility of RBC to hydrogen peroxide with significantly increased fluidity of membrane lipids were obtained signaling an oxidative metabolic stress. A twofold reduction of ATP and GSH initiated an oxidation of cellular sulfhydryl groups thus impairing enzyme kinetics of pyruvate kinase (PK). Yet heat stability of PK was markedly reduced only in those fractions containing older RBC. Further results indicate that ethanol-induced acquired PK instability may be triggered by a dialyzable and hence non-protein-bound compound, not detectable by experimental procedures owing to its low molecular weight. Thus it is conceivable that the hemolytic implication of ethanol in alcoholic liver disease may be due to abnormal membrane fluidity and metabolic disorder finally involving PK-control mechanism.

[Genetic and diagnostic significance of the HLA picture in sarcoidosis]. / Genetische und diagnostische Bedeutung der HLA-Merkmale bei der Sarkoidose.

67 patients with histologically proven sarcoidosis underwent typing of HLA-A, B, C and DR antigens to evaluate further the question of genetic susceptibility to the disease. A race-matched group of healthy volunteers (n = 42) served as controls. The frequency of the B-cell alloantigen specificity DR5 was significantly increased only in 49% of the patients with sarcoidosis compared to 21% of the race-matched control persons. This study supports the hypothesis that genetic factors may be associated with the etiopathogenesis of sarcoidosis. The result might serve also as an additional diagnostic pointer to the disease.

Biorheological and metabolic dysfunctions of density-fractionated erythrocytes in diabetics with peripheral vascular disease.

Preliminary communications are presented about a serial study of biorheological and metabolic dysfunctions of density-fractionated erythrocytes (RBC) in diabetics with vaso-occlusive disorders. The study aimed at evaluating the influence of metabolic disorder due to diabetes mellitus on RBC substrates, deformability and glycohaemoglobin (HbA1) levels. The peak HbA1 level served to confirm the duration of serum metabolic disorder due to diabetic crisis. The rheological and metabolic changes of RBC were compared with serial estimations repeated on the same patients when asymptomatic concerning diabetes after insulin therapy. RBC deformability was measured optoelectronically by microcomputer-assisted polymicroviscometry (filtrometry) following separation of RBC into old (dense) and young (buoyant) fractions by means of density-layer centrifugation. 15 adult patients with diabetes mellitus typ II associated with macroangiopathy Fontaine II underwent RBC investigations before and after diabetic therapy. Those RBC fractions containing older cells disclosed an impaired metabolism, increased HbA1 levels and markedly altered deformability which significantly differed from values obtained from young RBC. But after insulin-therapy old RBC fractions only revealed persistently an increase of HbA1 levels and metabolic disorder associated with a still altered deformability, in contrast to young RBC which in again showed normal values. The preliminary results suggest an adaptable alteration of RBC metabolism and function in diabetes, predominantly existing in old RBC, but after insulin-therapy still persisting only in old (dense) fractions. Thus, a prolonged pathologic effect of older RBC occurred in diabetes probably resulting in a further persistent maintenance of diabetic vascular disease.(ABSTRACT TRUNCATED AT 250 WORDS)

[Long-term tolerance of oral gold therapy in rheumatoid arthritis. Frequency and intensity of undesirable side effects]. / Langzeitverträglichkeit der oralen Goldtherapie bei rheumatoider Arthritis. Häufigkeit und Intensität unerwünschter Nebenwirkungen.

In view of encouraging results from various reliable multicenter studies, an interesting new oral agent, auranofin (triethylphosphine gold), is believed to be a major advance towards more effective treatment of rheumatoid arthritis with mild adverse reactions. The present study evaluates the long-term efficacy of auranofin in 46 patients with active rheumatoid arthritis and attempts to delineate further the results of drug monitoring concerning adverse reactions. Six patients withdrew due to untoward and partially serious events, e.g. thrombocytopenia, colitis or pancreatic disease. In view of the high frequency of side effects which required immediate withdrawal of auranofin in 13%, with a total of 37% of patients experiencing adverse reactions, it should be kept in mind that oral gold therapy may be a two-edged sword and requires further critical drug monitoring.

Class II MHC antigen (HLA-DR3) predisposes to sarcoid arthritis.

Recent studies indicate that the susceptibility to various inflammatory rheumatic diseases is an inherited trait determined by gene products of the class II histocompatibility complex (HLA-DR determinants). In a study designed to evaluate the concept of inherited susceptibility to sarcoid arthritis (SA), 42 patients with histologically proved acute disease underwent typing of HLA-A, -B, -C and -DR antigens. Using the microdroplet assay of human serum cytotoxins, we employed 156 antiserums to identify 52 antigens on A, B and C loci and 35 to identify 7 DR antigens on the surface of B cells. An ethnically matched control group consisted of 134 healthy volunteers. The frequency of B cell isoantigen DR3 specificity was significantly increased in patients with SA (relative risk, 4.8); HLA-DR3 was found in 25 (60%) of the patients, compared with 31 (23%) of the controls. This study lends further support to the hypothesis that the putative role of an infectious agent triggering SA cannot be judged without considering genetic cofactors.

Intrasynovial orgotein therapy in rheumatoid arthritis.

30 patients with active classical rheumatoid arthritis affecting the knee took part in a 12-week double-blind trial in which intra-articular injections of orgotein (4 mg/week for 6 weeks) were compared with intra-articular aspirin 4 mg/week for 6 weeks. After 12 weeks clinical and biochemical assessments showed that orgotein was superior to aspirin. Clinical response was measured in terms of the cumulative rheumatoid activity index (RAI) which was based on scores for morning stiffness, range of flexion, pain and 25-foot (7.5 m) walking time. Treatment with orgotein resulted in significant improvement of the RAI; the improvement correlated with findings on knee-joint scanning which showed reduced mean uptake of 99mTc-pyrophosphate. After intra-articular orgotein injections, synovial fluid IgM and IgG rheumatoid factor levels fell significantly; so did prostaglandin E2 formation and lactate dehydrogenase activity. The changes in the synovial fluid suggest that the anti-inflammatory properties of orgotein may lie in its effect on proliferating synovia.

[Rheology, metabolism and oxygen transport in old and young erythrocytes in arterial occlusive disease]. / Rheologic, Stoffwechsel und Sauerstoff-transport alter und junger Erythrozyten bei arterieller Verschlusskrankheit.

Red blood cell (RBC) rheological and metabolic functions were studied in 10 diabetics with peripheral vascular disease (PAD) following separation of RBC according to cell age by density layer centrifugation. Decreased levels of ADP, ATP, 2,3-DPG and GSH were observed in dense layers of RBC containing older cell fractions. Further, raised lactate/pyruvate ratios were obtained from the same RBC fractions. O2-function was markedly impaired in all patients with PAD. Thus, metabolic disorder of RBC associated with reduced red cell deformity by retarding blood flow through the microcirculation may be important factors in states of peripheral vascular insufficiency in diabetics.

Disparity between clinical and immune responses in a controlled trial of azathioprine in rheumatoid arthritis.

Drugs that interfere with the immune response in vitro, such as azathioprine (AZ), have been used extensively since 1964 in clinical therapeutic trials of autoimmune diseases. However, few adequately controlled studies are available concerning the concurrent effect of AZ on the immune and clinical responses to treatment of rheumatoid arthritis (RA). Thirty patients suffering from classical seropositive RA received AZ (1.5 - 2.0 mg/kg/day) and placebo in a controlled clinical cross-over study for two 12-week periods. Other treatments were kept constant throughout the entire 6 months. In terms of the clinical responses of joint count and grip strength patients receiving AZ improved markedly, in contrast to the placebo group. After 2 months, joint scanning revealed no progress of the disease in patients undergoing AZ treatment. Corresponding with the remarkably beneficial clinical effect of AZ, a significant drop in immunoglobulins was observed. However, since AZ failed to suppress in vivo specific antibody synthesis in RA, the question remains as to whether this drug actually does interfere with the autoimmunogenesis of the disease.

[Insulin and proinsulin secretion under contraceptive steroid administration (author's transl)]. / Insulin- und Proinsulin-Sekretion bei Anwendung antikonzeptioneller Steroide

An ivestigation has been performed in 49 women about the influence exerted on the glucose-tolerance, insulin and proinsulin secretion by hormonal contraceptives of different types and compositions. A disturbed dynamics of the insulin secretion with elevated values in the OGTT at two and three hours has been proven at a nearly equal degree using combined preparations (Anacyclin, Eugynon, Neogynon, Mikrogynon) or sequential preparations (Kombiquens, Ovanon). Though there has been interference with the glucose tolerance, the serum proinsulin in the OGTT showed increased levels too. When a combined preparation was applied, the proinsulin values were significantyl higher compared to a sequential type contraceptive. The observed disturbance of the insulin and proinsulin secretion is explained by a decreased sensitivity to insulin in the peripheral fat tissue. The actual dose of the estrogen-gestagen components has no influence on the described changes. Elevated insulin levels are demonstrable already during the first treatment cycle. The degree of the disturbance is independent of the duration of the medicamentous application during the first 6 contraceptive months. After withdrawal of the respective contraceptive steroid the insulin secretion showed nearly normal dynamics during the subseqeunt menstrual cycle.

PIP: An investigation has been performed in 49 women with the influence exerted on the glucose tolerance, insulin and proinsulin secretion by hormonal contraceptives of different types and compositions. Disturbed dynamics of the insulin secretion with elevated values in the OGTT at 2 and 3 hours was proven at a nearly equal degree using combined preparations (Anacyclin, Eugynon, Neogynon, Mikrogynon) or sequential preparations (Kombiquens, Ovanon). Though there was interference with the glucose tolerance, the serum proinsulin in the OGTT showed increased levels, too. When a combined preparation was used, the proinsulin values were significantly higher compared with a sequential type contraceptive. The observed disturbance of the insulin and proinsulin secretion is explained by a decreased sensitivity to insulin in the peripheral fat tissue. The actual dose of the estrogen-gestagen components has no influence on the described changes. Elevated insulin levels are demonstrable during the 1st treatment cycle. The degree of the disturbance is independent of the duration of treatment during the first 6 contraceptive months. After withdrawal of the respective contraceptive steroid the insulin secretion showed nearly normal dynamics during the subsequent menstrual cycle.

[Pathologic fluidity, glycohemoglobin and erythrocyte metabolism disorder in Fontaine II diabetic macroangiopathy]. / Pathologische Fluidität, Glykohämoglobin und Stoffwechselstörung der Erythrozyten bei diabetischer Makroangiopathie Fontaine II.

This pilot study set out to evaluate the influence of metabolic disorders due to diabetes mellitus on red blood cell (RBC) substrates, deformability and glycohaemoglobin (HbA1) levels. RBC deformability was measured optoelectronically by microcomputer-assisted polymicroviscometry (filtrometry) following separation of RBC into old (dense) and young (buoyant) fractions by means of density-layer centrifugation. 20 adult patients with type II diabetes mellitus associated with Fontaine II macroangiopathy underwent RBC investigations before and after diabetic therapy. Those RBC fractions containing older cells exhibited impaired metabolism, increased HbA1 levels and markedly altered deformability which significantly differed from values obtained from young RBC fractions. However, old RBC fractions only of patients treated for diabetes persistently displayed a slight increase in HbA1 levels associated with a still altered deformability, in contrast to the young RBC fractions which showed normal values again after diabetic treatment. The preliminary results suggest an adaptive alteration of RBC metabolism and function in diabetes, predominantly existing in old RBC, which still persists only in old RBC fractions after diabetic therapy. Thus, a prolonged pathologic effect of older RBC on the peripheral microcirculation may occur in diabetes, resulting in a further persistent maintenance of diabetic vascular disease.