Obscurin Rho GEF domains are phosphorylated by MST-family kinases but do not exhibit nucleotide exchange factor activity towards Rho GTPases in vitro.

Obscurin is a giant muscle protein (>800 kDa) featuring multiple signalling domains, including an SH3-DH-PH domain triplet from the Trio-subfamily of guanosine nucleotide exchange factors (GEFs). While previous research suggests that these domains can activate the small GTPases RhoA and RhoQ in cells, in vitro characterization of these interactions using biophysical techniques has been hampered by the intrinsic instability of obscurin GEF domains. To study substrate specificity, mechanism and regulation of obscurin GEF function by individual domains, we successfully optimized recombinant production of obscurin GEF domains and found that MST-family kinases phosphorylate the obscurin DH domain at Thr5798. Despite extensive testing of multiple GEF domain fragments, we did not detect any nucleotide exchange activity in vitro against 9 representative small GTPases. Bioinformatic analyses show that obscurin differs from other Trio-subfamily GEFs in several important aspects. While further research is necessary to evaluate obscurin GEF activity in vivo, our results indicate that obscurin has atypical GEF domains that, if catalytically active at all, are subject to complex regulation.

Some relations between light transmission changes and biochemical parameters of stored platelet packs.

In the present work a computerised method for continuous monitoring of light transmission through platelet packs was evaluated. On series (Series 1) of 50 platelet concentrates was studied over a 5-day period, and thereafter the pH, extracellular lactate dehydrogenase (LDH) and platelet factor 4 (PF4) in the concentrates were determined. A second series (Series 2) of 52 concentrates was also monitored over 5 days, and thereafter the pH, extracellular LDH and intracellular concentrations of ATP, ADP and AMP were determined. 11 and 14 of the concentrates of Series 1 and 2, respectively, demonstrated long lasting transmission increases (> or = 3.0 days). In the total of 102 platelet concentrates 34 were observed to have late (< 1.0 day) or no transmission increase. It is concluded, that the present optical method identifies both a group of platelet concentrates having long lasting transmission increases and a group consisting of platelet concentrates having late or no transmission increase. Compared to the latter concentrates preparations with long lasting transmission changes demonstrated significant biochemical alterations. These observations could be applicable in the quality control of platelet concentrates.

ADP-induced platelet aggregation as a function of age in healthy humans.

In 120 healthy humans (58 males and 62 females) possible differences in platelet aggregability were investigated with respect to age and sex. By using a narrow range of final ADP concentrations (0.2-1.0 microM) primary and secondary aggregation were evaluated. The rate of primary aggregation was shown to be significantly related to increasing age and this was true for both sexes. As regards secondary aggregation the same pattern was seen in the group of male subjects. Thus, among the youngest (less than 34 years) the frequency of secondary waves was only one third of that encountered among the oldest (greater than 50 years). No similar association was detectable among the female subjects. The present study calls attention to some important issues which should be considered in platelet aggregation studies; the interpretation of data obtained from such studies invariably requires a careful selection of appropriate age- as well as sex-matched control groups.

Naturally occurring IgG autoantibodies to platelet cytoskeleton tropomyosin.

We have observed that naturally occurring serum antibodies generated a 30 Kd band in a platelet immunoblot assay. The target protein had the same molecular weight (30 Kd) under nonreduced and reduced electrophoretic conditions, and could be immunoblotted from either autologous or homologous platelet lysates. Also, the 30 Kd reactive autoantibodies could be totally adsorbed by platelet cytoskeletons. From these data one likely candidate for the autoantibody target was the intracellular platelet protein tropomyosin. Indeed, a commercially available monoclonal anti-tropomyosin antibody reacted with proteins comigrating with this 30 Kd band; affinity purified human platelet tropomyosin was bound by the antibodies that recognized the 30 Kd protein. This body of evidence conclusively demonstrated that naturally occurring serum autoantibodies reacted with the platelet cyto-skeleton protein-tropomyosin. These tropomyosin specific antibodies were found in roughly the same percentage of sera from patients with chronic idiopathic thrombocytopenic purpura (ITP) as from normal individuals.

Cigarette smoking increases thromboxane A2 formation without affecting platelet survival in young healthy females.

Smoking is a risk factor for the development of atherosclerotic cardiovascular disease, in men as well as in women. An increased urinary excretion of the thromboxane metabolite 2,3-dinorthromboxane B2 (Tx-M) has been observed in smokers of both genders, suggesting that cigarette smoking may facilitate cardiovascular disease via an action on the platelets. The present study addressed the hypothesis that the increased Tx-M excretion in female smokers reflects a true facilitation of platelet reactivity in vivo, rather than an increased destruction of the platelets. In healthy female volunteers (aged 20-46 years, 18 smokers and 17 non-smokers) platelet life-span and indices of platelet activity were determined, together with plasma levels of plasminogen activator inhibitor-1 (PAI-1), fibrinogen, peripheral blood cell counts and hematocrit. The urinary excretion of Tx-M was higher in smokers than in non-smokers (361 vs. 204 pg/mg creatinine, respectively, p < 0.05), while plasma and urinary beta-thromboglobulin, plasma platelet factor 4, platelet mean life-span and platelet production rate did not differ between the groups. PAI-1 activity, white blood cell count and hematocrit were higher in smokers than in non-smokers (p < 0.05). These data indicate that smoking facilitates platelet formation of thromboxane A2 without affecting platelet survival; i.e. it increases the activity of platelets without affecting their viability to a measurable extent. Such an increase in platelet activity, operating in parallel to a reduced fibrinolytic activity and a higher hematocrit and white blood cell count, may play an etiological role in smoking-induced cardiovascular disease in women.

The relation between platelet reactivity and coronary angiographic findings in young female survivors of acute myocardial infarction.

In 31 women who had survived their first acute myocardial infarction (MI) studies of platelet reactivity were related to coronary angiographic findings. The results were compared to those obtained from 38 age-matched control women. According to the cardioangiographic findings the group of MI was subdivided into: 9 patients with 1-vessel disease (VD), 10 patients with 2-VD, and 5 patients with 3-VD; 7 subjects did not reveal significant coronary stenosis. When each of these 4 subgroups of MI-patients were compared with the control material significant difference with respect to PF4 was found only for subjects with 1-VD (20.0 +/- 4.8 vs. 10.3 +/- 0.6 ng/ml). As regards BTG the difference was significant for 1-VD and 2-VD patients (69 +/- 12 and 59 +/- 3, respectively vs. 40 +/- 2 ng/ml). The cumulative frequency for secondary aggregation differed only as regards 1-VD patients (78 vs 40%).

Peripheral and intrasplenic platelet kinetics and bone marrow megakaryopoiesis in alpha-2b-interferon treated hairy cell leukemia.

In eight patients with previously untreated hairy cell leukemia (HCL), by using 111In-labelled platelets and megakaryocyte quantitation, the splenic platelet pooling and the platelet production rate (P) were evaluated before and during alpha-2b-interferon (IFN) treatment. Both before and after 8 months of IFN therapy the spleen was shown to pool a sizeable amount of the total body platelet mass. The average splenic platelet pools, prior to and after 8 months of IFN, were 58 +/- 17 and 47 +/- 11%, respectively. At the time when treatment was initiated, the patients were heterogeneous as regards the spleen size, platelet kinetics, and the bone marrow morphology. Three patients had values for P below the 95th percentile for a group of healthy control subjects; following IFN therapy they displayed a substantial increase in P. In three other HCL patients, with the largest spleens, the pre-treatment P was normal, or slightly above the values seen for the control subjects. In these patients, changes in splenic platelet pool size, blood volume, and platelet mean life-span accounted for the increase in platelet count observed in response to IFN. The mean megakaryocyte number and volume per microliter bone marrow increased during IFN therapy, while the mean P remained slightly reduced. It is concluded that splenic platelet pooling would explain the previously described difference in platelet counts between splenectomized and non-splenectomized patients treated with IFN.

DNA content and nuclear size of megakaryocytes in thrombocythaemia.

Total nuclear DNA content and nuclear size of megakaryocytes were studied in biopsies of the iliac bone marrow of individuals with normal or increased platelet counts. The DNA content was determined using Feulgen cytophotometry of bone marrow smears and the nuclear area by morphometric analysis of megakaryocytes of bone marrow sections. The mean DNA content and the mean nuclear area were both significantly larger in megakaryocytes of patients with thrombocytosis as a result of myeloproliferative disease than in patients with secondary thrombocytosis as well as in two control groups of individuals with normal platelets counts, one comprising healthy volunteers, the other with various non-haematological disorders. There was a statistically significant correlation between the DNA content and nuclear area of the megakaryocytes (r = 0.92) in the entire group of bone marrows studied.

Dysplastic megakaryopoiesis with thrombocytopenia and chromosomal aberration.

A case of isolated thrombocytopenia with decreased platelet production and abnormal megakaryopoiesis is described. In the bone marrow, a chromosomally aberrant clone, 45,XX,-11,-18,+der (11;18)(11q13;18p11), was found. These findings indicate a myelodysplastic nature of the abnormal thrombocytopoiesis. The described case demonstrates the value of a bone marrow examination including histopathology with immunologic techniques to evaluate the megakaryopoiesis in thrombocytopenia and the interest of cytogenetic studies not only in instances with overt hematologic malignancies or complete myelodysplastic syndromes, but also when morphologic abnormalities occur in a single cell line.

Low megakaryocyte ploidy in Ph-positive chronic myelogenous leukemia measured by flow cytometry.

In chronic myeloproliferative disorders, the megakaryocytes differ in size and maturation compared with those of healthy individuals. In the present study, by using a 2-color flow cytometry technique, we determined the frequency of bone marrow megakaryocytes in different ploidy classes in 13 newly diagnosed and untreated patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) and in 12 healthy volunteers. The results showed a significant difference in megakaryocyte ploidy distributions between these 2 study groups. On the average, patients with CML had 59% of their megakaryocytes in ploidy classes 2N to 8N; in contrast, the healthy volunteers had only 22% of their megakaryocytes in classes 2N to 8N. Two patients with complex Ph translocation and 2 patients with a small clone with a chromosome abnormality in addition to Ph had the same ploidy distribution as those with only Ph translocation. The platelet count did not correlate with the megakaryocyte mean ploidy.

Assessment of a tissue transport-medium in preservation of tissue-fixed immunoglobulins and complement demonstrated by direct immunofluorescence. A pilot study with skin from SLE patients.

The present work was undertaken in order to test the value of a tissue transport-medium (Histocon) for direct immunofluorescence studies. For this purpose one skin biopsy was performed on each forearm of 26 patients with systemic lupus erythematosus. One of the specimens was left in ice-cold Histocon solution for 4, 8, or 20 hours, and the other was immediately quick-frozen. The results of the immunofluorescence tests with the two methods yielded similar results. It is concluded that the solution allows the preservation of tissue-fixed immunoglobulins and complement during short periods of transport.

No increased frequency of trisomies 8 and 9 by fluorescence in situ hybridization in untreated patients with essential thrombocythemia.

Essential thrombocythemia (ET) is one of the diseases included among the myeloproliferative disorders in which trisomies for chromosomes 8 and 9 commonly occur. In ET, only a few patients are known to show clonal abnormalities. With fluorescence in situ hybridization (FISH), interphase cells can be evaluated and clones can be detected even though not revealed by conventional cytogenetic methods. By using FISH for enumeration of chromosomes 8 and 9 in bone marrow cells, we studied 22 patients with ET; 20 of them were investigated at the time of diagnosis when they were still untreated with myelosuppressive agents. Only two patients had trisomy 8; one of them was also found to have +8 with conventional cytogenetics. None of the patients had trisomy 9; two patients had borderline values in comparison to a control group. Thus, in ET, no increased frequency of patients with trisomy for 8 or 9 at the time of diagnosis could be detected with FISH.

Diagnostic and differential criteria of essential thrombocythemia and reactive thrombocytosis.

Among the chronic myeloproliferative disorders essential thrombocythemia (ET) is known to be a distinct clinical entity in which an excessive number of morphologically and functionally abnormal platelets are produced. The clonal nature of the disease is well established. Based on a review of the literature the present authors propose the following novel criteria for the diagnosis of ET: A1. Platelet count in excess of 600 x 10(9)/L. A2. No increase in red-cell mass (RCM) in the presence of stainable iron in the bone marrow or failure of iron trial (RCM < 36 mL/kg in males and < 32 mL/kg in females; or RCM < 25% above mean normal predicted value*). A3. No Philadelphia chromosome. A4. Megakaryocytic hyperplasia (= increased megakaryocyte number and size) in histological sections of bone marrow and/or increased megakaryocytic ploidy (two-color flow cytometry); no collagen fibrosis. B1. Splenomegaly on isotopic scan or echogram. B2. Unstimulated growth of BFU-E and/or CFU-Meg present. B3. Normal ESR/fibrinogen. The diagnosis of ET is considered to be established if A1 + A2 + A3 + A4 or A1 + A2 + A3 + two B-criteria are fulfilled. (* Br J Haematol 1995; 89:748-756.)

Plasma erythropoietin in essential thrombocythaemia: at diagnosis and in response to myelosuppressive treatment.

Sixty-five patients with essential thrombocythaemia (ET) on different treatment regimens were studied with regard to EDTA-plasma erythropoietin (EPO) concentrations. In accordance with other studies we found that close to 50% of the untreated ET patients had subnormal (<3.7 IU/L) plasma EPO. The mean plasma EPO concentration for untreated ET patients was significantly lower compared to patients treated with hydroxyurea (HU), radiophosphorous, alpha-interferon or combinations of myelosuppressive agents. This was also true after correction for differences in haemoglobin concentrations had been introduced. An increase in plasma EPO was recorded in all 20 ET patients in whom plasma EPO was registered before and after initiation of myelosuppressive therapy. At the time of diagnosis plasma EPO concentration was available in 31 of the ET patients. In 13 of them the plasma EPO was subnormal whereas the EPO concentrations were > or =3.7 IU/L in the remaining 18 subjects. It was demonstrated that the time to initiation of myelosuppressive treatment was significantly shorter for the former group of patients; they also had more vascular events (11 out of 13) than the group of patients with plasma EPO concentrations > or =3.7 IU/L (9 out of 18). It therefore appears that a subnormal plasma EPO in newly diagnosed ET might be a risk factor for the development of vascular complications.

The relation between plasma thrombopoietin and erythropoietin concentrations in polycythaemia vera and essential thrombocythaemia.

Plasma thrombopoietin (TPO) was measured, by immunoenzymometric assay, in 39 patients with polycythaemia vera (PV), 33 patients with essential thrombocythaemia (ET) and 10 healthy volunteers. The mean TPO concentration was significantly higher in ET patients than in PV patients (p=0.04) and normals (p<0.001). The 6 untreated ET patients had a significantly lower mean TPO concentration compared to the 27 ET patients who were on myelosuppressive regimens (p=0.01). The mean plasma TPO for the 5 PV patients treated with phlebotomy only did not differ significantly from the corresponding mean for the 34 PV patients treated with myelosuppressive agents. Concomitantly, plasma EPO was measured in 25 of the PV patients and in 30 of the ET patients by an immunoradiometric assay with normal reference interval in adults 3.7-16 IU/L. In the 14 PV patients with EPO <3.7 IU/L mean plasma TPO did not differ significantly from the mean for the 11 PV patients with EPO >or=3.7 IU/L; neither of these two groups had plasma TPO concentrations significantly different from the mean for the control subjects. The 7 ET patients with subnormal plasma EPO had significantly lower mean plasma TPO compared to the ET patients with normal and high plasma EPO concentrations (p=0.03 and p=0.02, respectively). Also, the 16 ET patients with normal plasma EPO had significantly lower plasma TPO compared to the 8 patients with high plasma EPO (p=0.04). The mean plasma TPO for each of these three groups of ET patients was significantly higher than the corresponding mean for the controls (p<0.001 for each group). The results of the present study indicate that a relationship between plasma EPO and TPO concentrations may exist and that myelosuppressive treatment affects the TPO concentration in ET but not in PV patients.

Plasma erythropoietin concentrations in polycythaemia vera with special reference to myelosuppressive therapy.

In 80 patients with polycythaemia vera (PV) a total of 108 venous blood samples were obtained and analysed for EDTA-plasma erythropoietin (EPO) concentration. At the time of study 21 of the PV patients were newly diagnosed and had prior to blood sampling neither received phlebotomy treatment nor therapy with myelosuppressive agents; these subjects had a mean plasma EPO concentration of 0.5+/-0.9 IU/L. Thirty-seven patients treated with phlebotomy only had a mean plasma EPO concentration of 2.5+/-2.9 IU/L. The mean plasma EPO concentrations for 26 patients treated with hydroxyurea, 13 patients treated with radiophosphorous and 11 patients given a combination of myelosuppressive agents were 8.9+/-8.0, 10.9+/-12.6 and 7.2+/-7.4 IU/L, respectively. Untreated patients and patients on phlebotomy only had significantly lower values for plasma EPO than patients on therapy with myelosuppressive drugs. This finding persisted also after a correction for differences in haemoglobin levels had been introduced. Thereby, the present results would suggest a difference in the EPO feedback system in untreated and phlebotomised PV patients compared to PV patients treated with myelosuppressive agents.

Diagnosis and treatment of polycythemia vera and possible future study designs of the PVSG.

The present study describes clinicopathological criteria to distinguish the 5 sequential stages proposed by Wasserman et al in the natural history of newly diagnosed PV patients. The European Working Group on MPD (EWG.MPD) extended and modified the PVSG diagnostic criteria of PV by including bone marrow histopathology. From the results of prospective randomized studies in PV it became evident that new clinical trials in previously untreated PV patients should focus on comparing interferon-alpha, a non-leukemogenic approach, versus a potential leukemogenic myelosuppressive treatment modality. Hydroxyurea appears to be the least leukemogenic myelosuppressive agent in long-term prospective clinical PV-studies extending observation periods of more than 10 years. The rational for using IFN-alpha as a first-line treatment option in newly diagnosed PV-patient include its effectiveness to abate constitutional symptoms and to induce a complete remission thereby avoiding phlebotomy, iron deficiency, and macrocytosis associated with hydroxyurea. Moreover IFN-alpha may prevent or delay the development of postpolycythemic myelofibrosis if used early in the course of the disease. Clinicians will be reluctant to postpone the use of hydroxyurea in early stage PV as long as a conservative approach using phlebotomy aiming at a hematocrit below 0.45, plus low-dose aspirin for the control platelet function or anagrelide for the control platelet number is used to keep the patient healthy. Low-dose aspirin will prevent the microvascular thrombotic complications of thrombocythemia associated with PV in remission after phlebotomy, but lacks myelosuppressive activity. Control of megakaryocyte maturation and reduction of platelet production to normal (<400 x 10(9)/l) by relatively low doses of anagrelide will predict a significant reduction of vascular complications in the early stages of PV, may prevent progression to myelofibrosis during follow-up of PV and very probable will postpone the use of hydroxyurea treatment for controlling the platelet count in PV. Large scale randomized clinical trials in PV are proposed, which should aim not only for clinical and hematological response, safety, efficacy, but should also assess toxicity, the need for phlebotomy and whether the development of progressive disease such as splenomegaly, pruritus, myelofibrotic myeloid metaplasia, spent phase, myelodysplasia and acute leukemia can be delayed or prevented by IFN-alpha as compared to a conservative approach of phlebotomy plus low-dose aspirin or anagrelide followed by hydroxyurea when signs of myeloproliferative activity became evident.

Negligible clinical effects of thalidomide in patients with myelofibrosis with myeloid metaplasia.

We conducted a nonrandomized prospective phase II study of thalidomide in anemic patients with myelofibrosis with myeloid metaplasia (MMM), with or without preceding polycythemia vera or essential thrombocythemia, with a primary aim to improve anemia. Thalidomide was given in escalating doses with a target dose of 800 mg daily, but the median dose of thalidomide that was actually tolerated was 400 mg daily. Fifteen patients were entered into the study and 14 were evaluable for response. Five of 14 (36%) patients discontinued thalidomide before 3 mo because of side effects, and none of these five patients had a response at the time when thalidomide was stopped. When evaluated after 3 mo of therapy, none of the remaining nine patients exhibited a discernible clinical response. Three patients showed progressive disease defined as > 50% increase in the need for red cell transfusions. Treatment was poorly tolerated, with all patients reporting side effects of thalidomide, the most prominent being fatigue documented in 80% of patients. Two patients died while on study, one from acute myelogenous leukemia and one from pneumonia. We conclude that thalidomide given in doses employed in the treatment of multiple myeloma gives no clinically relevant hematological effects in advanced MMM and is hampered by a very high incidence of side effects.

Diagnosis, pathogenesis and treatment of the myeloproliferative disorders essential thrombocythemia, polycythemia vera and essential megakaryocytic granulocytic metaplasia and myelofibrosis.

According to strict clinical, hematological and morphological criteria, the Philadelphia (Ph) chromosome negative chronic myeloproliferative disorders essential thrombocythemia (ET), polycythemia vera (PV), and agnogenic myeloid (megakaryocytic/granulocytic) metaplasia (AMM) or idiopathic myelofibrosis (IMF) are three distinct disease entities with regard to clinical manifestations, natural history and outcome in terms of life expectancy. As clonality studies have clearly demonstrated that fibroblast proliferation in AMM, as well as in many other conditions such as advanced stages of Ph(+)-essential thrombocythemia, Ph(+)-granulocytic leukemia, and Ph(-)-polycythemia vera, is polyclonal indicating that myelofibrosis is secondary to the megakaryocytic granulocytic metaplasia in these various conditions, AMM is illogically labeled as IMF. As abnormal megakaryocytic granulocytic metaplasia is the essential feature preceding the early prefibrotic stage of AMM, the term essential megakaryocytic granulocytic metaplasia (EMGM) can readily be used to characterize this condition more appropriately at the biological level. Clinical, hematological and morphological characteristics, in particular megakaryocytopoiesis and bone marrow cellularity, reveal diagnostic features, which enable a clear-cut distinction between ET, PV and EMGM or classical IMF. The characteristic increase and clustering of enlarged megakaryocytes with mature cytoplasm and multilobulated nuclei and their tendency to cluster in a normal or only slightly increased cellular bone marrow represent the hallmark of ET. The characteristic increase and clustering of enlarged mature and pleiomorphic megakaryocytes with multilobulated nuclei and proliferation of erythropoiesis in a moderate to marked hypercellular bone marrow with hyperplasia of dilated sinuses are the specific diagnostic features of untreated PV. EMGM, including the early prefibrotic stages as well as the various myelofibrotic stages of classical IMF appear to be a distinct neoplastic dual proliferation of abnormal megakaryopoiesis and granulopoiesis. The histopathology of the bone marrow in prefibrotic EMGM and in classical IMF is dominated by atypical, enlarged and immature megakaryocytes with cloud-like immature nuclei, which are not seen in ET and PV at diagnosis and during follow-up. Myelofibrosis in ET, PV and EMGM is graded into: no reticulin fibrosis (MF0), early reticulin fibrosis (MF1), advanced reticulin sclerosis with minor or moderate collagen fibrosis (MF2) and advanced collagen fibrosis with osteosclerosis (MF3). Myelofibrosis is not a feature of ET at diagnosis and during long-term follow-up. Myelofibrosis may be present in a minority of PV-patients at diagnosis and usually becomes apparent during long-term follow-up in the majority of PV-patients. Myelofibrosis secondary to the abnormal megakaryocytic and granulocytic myeloproliferation constitutes a prominent feature in the majority of EMGM/IMF at time of diagnosis and usually progresses more or less rapidly during the natural history of the disease. Life expectancy is normal in ET, normal during the 1st ten years and compromised during the 2nd ten years follow-up in PV, but significantly shortened in the prefibrotic stage of EMGM as well as in the various myelosclerotic stages of classical IMF. First line treatment options in prospective randomized clinical trials of newly diagnosed MPD-patients are control of platelet function with low-dose aspirin versus reduction of platelet count with anagrelide, interferon or hydroxyurea in ET; control of platelet and erythrocyte counts by interferon alone versus bloodletting plus hydroxyurea on indication in PV; interferon versus no treatment in the early stages of EMGM; a wait and see strategy in the fibrotic stages of EMGM or classical IMF with favorable prognostic factors, and bone marrow transplantation in classical IMF with poor prognostic factors at presentation or during short-term follow-up.

[Were the severe adverse effects on several organs and the marked blood pressure increase caused by oral contraceptives?]. / Svåra biverkningar på flera organ och kraftig blodtrycksstegring orsakades av p-piller?

PIP: A 22-year old unmarried healthy woman was admitted to the Swedish department with low fever, tiredness, SR 75 mm, positive uricult, but no urinary tract symptoms. Urinary tract infection was suspected and treatment was started with norfloxacin. Nevertheless, the urine culture proved to be negative. A few weeks later she had increasing trouble with stiff knee and shoulder joints and the left foot became swollen. The subfebrile status continued, and tonsillitis was suspected and diagnosed. V-penicillin and cefaklor treatment was applied. She was transferred to the infectious diseases ware, where fever was confirmed with leukocytosis (19 x 1 billion/1), C-reactive protein at 66 (normal value 10) mcg/ml, pronounced blood pressure increase (160/130 mm Hg), anemic signs, and pathological liver status with increased transaminases (ASAT 6.3-10.4 and ALAT 8.,8-16 ukat/1). ALP increased slightly to 6 ukat/1. The symptoms of weight loss indisposition, and muscles and joints aches, especially in foot ache continued. Collagen disease was suspected, and she was transferred to the internal medicine department. She regularly had tachycardia and high blood pressure. She had to use crutches for mobility because of the pain. S-albumin was 32 (normal 36- 50) g/l and S-hepatoglobin was 2.7 (normal value .4-1.8) g.l. Various others tests were normal. Ulnaris neuropathy was suspected on the left hand. Intensive blood pressure reducing combination treatment was started with 200 mg x 1 of metoprolol, 10 mg x 2 nifedipin, and 20 mg x 1 enalapril. The Desolett oral contraceptive (containing 30 mcg of ethinyl estradiol and 150 mcg of desogestrel) she had been taking for a few months were discontinued. Quick improvement of clinical and laboratory parameters followed. SR and leukocytosis became normal. The values of ALP, ASAT, and ALAT became normal some days later. She was discharged shortly thereafter, and blood pressure medication was gradually discontinued. In the 1940s there were reports about the hepatotoxic effects of synthetic estrogens followed by carbohydrate, lipid, and protein metabolism alterations. Jaundice has also been reported, and the Swedes have an ethnic susceptibility to it. The global incidence rate is 1/10.000 vs. 1/100 and 1/4000 in Sweden induced by high-dose OCs containing more than 50 mcg ethinyl estradiol, but with low-dose OCs this rate is much lower. Both estrogens and gestagens can increase blood pressure. A 1969 study reported that 22 young women developed arthritis, arthralgia, and myalgia after taking pills for 3- 12 months. Rheumatic symptoms were also recorded with pill use. Thus, it is very likely that OCs were responsible for the patient's symptoms, especially since her status rapidly improved after discontinuing them.^ieng