Cancer risk in patients with monoclonal gammopathy of undetermined significance.

To assess the cancer risk of monoclonal gammopathy of undetermined significance (MGUS) we identified 1229 cases of MGUS in the period 1978 to 1993. Data on cancer occurrence in the MGUS cohort were obtained from the Danish Cancer Registry. The expected numbers of cancer cases were calculated from age-, sex-, county-, and period-specific cancer incidence rates. In the MGUS cohort 64 new cancers with a known association with M-components were diagnosed versus 5.0 expected giving a standardized incidence ratio (SIR) of 12.9 (95% confidence interval, 9.9-16.5). The relative risks of developing multiple myeloma (SIR 34.3), Waldenström's macroglobulinemia (SIR 63.8), and non-Hodgkin's lymphoma (SIR 5.9) were significantly increased and independent of time passed from detection of the M-component. The relative risk of chronic lymphocytic leukemia was not significantly increased, SIR 2.7 (0.5-7. 7). Among cancer sites without known association with M-components 141 cases were observed versus 94.6 expected giving a SIR of 1.5 (1. 3-1.8). This enhanced risk was seen for several non-hematological cancer sites but for most cancer sites the risk was dependent on time passed from detection of the M-component, indicating a bias rather than a causal role of MGUS.

Locus-specific suppression of ilv1 in Saccharomyces cerevisiae by deregulation of CHA1 transcription.

The ILV1 gene of Saccharomyces cerevisiae encodes the anabolic threonine deaminase, which catalyzes the first committed step in isoleucine biosynthesis. Strains devoid of a functional Ilv1p have a requirement for isoleucine. Threonine can also be deaminated by a second serine/threonine deaminase encoded by the CHA1 gene. CHA1 is regulated by transcriptional induction by serine and threonine, and enables yeast to utilize the hydroxyamino acids as sole nitrogen source. Phenotypic suppression of ilv1 can occur by inducer-mediated transcriptional activation of the CHA1 gene. To identify mutations in putative trnas-acting factors regulating CHA1 expression, we have isolated and characterized three extragenic suppressors of ilv1. A dominant mutation, SIL4 (suppressor of ilv1), is allelic to HOM3. It increases the size of the threonine pool, by 15- to 20-fold, which is sufficient to induce CHA1 transcription, thereby creating a metabolic bypass of ilv1. A second dominant mutation, SIL3, and a recessive mutation, sil2, both suppress ilv1 by causing inducer-independent, constitutive transcription of CHA1. Importantly, sil2 and SIL3 increase the expression of a CHA1p-lacZ translational gene fusion, demonstrating that they exert their action through the CHA1 promoter. Genetic analysis showed that both SIL3 and sil2 are alleles of CHA4, a positive regulator of CHA1, i.e., they convert Cha4p to a constitutive activator.

Impaired migration in vitro of neutrophils from patients with paroxysmal nocturnal haemoglobinuria.

Migration of neutrophils in patients with paroxysmal nocturnal haemoglobinuria (PNH) was studied using two different complement-free in vitro model systems, subagarose and transendothelial migration. In the subagarose migration assay the mean migration distance of PNH neutrophils was slightly, but significantly, reduced to 1236 microns (range 753-1586, n = 6) compared to a normal mean of 1476 microns (range 1076-1768, n = 6, P = 0.016). By immunocytochemical staining for the urokinase type plasminogen activator receptor (uPAR) which is a glycosyl-phosphatidyl-inositol (GPI) anchored protein expressed by normal, but not by PNH-affected, neutrophils, it was shown that the uPAR-positive subpopulation of normal neutrophils predominated among the faster migrating cells (60-80% normal cells at the front of migration) while uPAR-negative (i.e. PNH-affected neutrophils) were more numerous close to the application well (5-30% normal cells). When migration of neutrophils was tested across a monolayer of human umbilical vein endothelial cells (HUVEC) cultured on polycarbonate filters, there was a 3-4-fold impairment of the migration of the PNH-affected neutrophils both in the absence of stimulation and after stimulation with fMLP (P < 0.001 in both cases). After IL-1 stimulation of the endothelium the impairment was even more pronounced (8-fold difference, P < 0.001). When the endothelial cells were grown on collagen-coated filters the impairment of the migration of PNH neutrophils was less pronounced, but still significant after stimulation with fMLP and IL-1 (2-fold, P < 0.05 in both cases). These results demonstrate that there is a complement-independent impairment of migration of neutrophils from patients with PNH which may be related to their failure to express GPI-linked proteins involved in cell migration and/or adhesion such as the uPA receptor and the CD66b antigen.

[Treatment of acute myeloid leukemia in the elderly with low-dose cytosine arabinoside]. / Behandling af akut myeloid leukaemi hos aeldre med lavdosis-cytosinarabinosid.

We report the outcome of 95 patients older than 60 years with de novo acute non-lymphocytic leukaemia (ANLL), treated in two institutions during a 10 year period. Thirty-two patients, mean age 78 years, did not receive any chemotherapy, and their median survival was 38 days. Five patients in good clinical condition, aged 60-63 years, were treated conventionally with an anthracycline and cytarabine, and three patients obtained a complete remission (CR) lasting 73, 417, and 1050 days. Fifty-eight patients were treated with low-dose cytarabine (LDC) for remission-induction and maintenance. Eighteen patients obtained CR, yielding a remission rate of 31%. The median duration of remission was 380 days and median survival of the same group was 498 days. LDC is valuable in the treatment of ANLL in the elderly. Controlled studies are warranted to define the indications for LDC versus conventional therapy in the large grey zone of elderly patients.

[Short-term and long-term effects on glycosylated hemoglobin after transition from conventional insulin treatment to multiple insulin injection regime in a diabetic outpatient clinic]. / Kort- og langtidseffekten på glykosyleret haemoglobin ved overgang fra konventionel insulinbehandling til multipel insulininjektionsregi i et diabetesambulatorium.

In order to examine the short- and long term effects of basal/bolus insulin therapy on the metabolic regulation assessed by glycosylated haemoglobin (HbA1c) the first 201 patients in the diabetes out-patient clinic of the Section of Endocrinology, Department of Medicine, Aalborg Hospital, assigned for this treatment were prospectively studied. In all 201 patients a significant decrease in mean HbA1c value was observed after 21 months on multiple injection therapy (8.5% vs 8.1%; p < 0.001). The higher the HbA1c value on conventional therapy, the greater was the observed decrease in HbA1c following six months on basal/bolus therapy (r = 0.57, p < 0.001). According to an anonymous questionnaire completed by the first 140 patients six months after the start of multiple injection therapy, 97% of the patients preferred to continue with basal/bolus therapy with NovoPen, and 87% felt that they had achieved a better general condition and that the basal/bolus regime made their daily life easier. It is concluded that basal/bolus therapy with NovoPen may combine the attainment of improved metabolic control assessed by a decrease in mean HbA1c in many poorly regulated patients and the subjective experience of an improved quality of life.

Long-term supplementation with n-3 fatty acids, II: Effect on neutrophil and monocyte chemotaxis.

The effect of a daily supplement with 4 g of n-3 polyunsaturated fatty acids (PUFA) for 9 months to 24 healthy volunteers on neutrophil and monocyte chemotaxis was studied using the under-agarose technique. Autologous serum and n-formyl-methionyl-leucyl-phenylalanine were used as chemoattractants. The effect after 9 months of supplementation with n-3 PUFA was also compared to results after short-term supplementation with n-3 PUFA for 6 weeks. Monocyte chemotaxis was reduced after 9 months of supplementation with n-3 PUFA to the same extent as after 6 weeks supplement. Neutrophil-directed migration towards chemoattractants was reduced after 9 months on fish oil, and this decrease was significantly greater than the decrease obtained after 6 weeks of supplementation. The spontaneous migration of neutrophils was significantly attenuated after 9 months compared to baseline and to 6 weeks. These findings lend support to a role for n-3 PUFA in the management of chronic inflammatory and atherosclerotic vascular diseases.

Granulocyte chemotaxis before and after urography. Influence of four different radiographic contrast media.

Granulocytes isolated from whole blood of 10 volunteers with Hypaque/Ficoll or Percoll gradient centrifugation showed a significant inhibition of their chemotactic response when incubated with diatrizoate. The influence of 4 different i.v. injected radiographic contrast media (CM) on granulocyte chemotaxis was evaluated using the under agarose assay. Each CM was injected in 10 consecutive outpatients referred for urography. Cells and serum were obtained before and 20 min after the injection of CM. Autologous serum was used as chemoattractive agent, and the cell suspensions from both samples were tested against serum drawn both before and after the injection of CM. No significant changes in granulocyte chemotaxis or the chemotactic potential of serum were seen. Furthermore, there was no change in the chemotactic response towards homologous serum or N-fmlp after injection of diatrizoate or iohexol. In conclusion, the investigation did not unveil any change in granulocyte chemotaxis 20 min after the injection of CM in the 40 subjects studied.

n-3 fatty acids and leukocyte chemotaxis. Effects in hyperlipidemia and dose-response studies in healthy men.

Dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFAs) has been shown to inhibit neutrophil and monocyte chemotaxis in healthy subjects and, with respect to neutrophils, also in various patient groups. We studied the effect of dietary supplementation with n-3 PUFAs on monocyte and neutrophil chemotaxis in patients with hyperlipidemia. Chemotaxis was investigated with the under-agarose assay, using autologous serum and N-formyl-methionyl-leucyl-phenylalanine as chemoattractants. The patients were examined before and after 6 weeks of supplementation with 6 g n-3 PUFAs daily. Monocyte chemotaxis was reduced after n-3 PUFA supplementation in type IIa patients but was unaffected in patients with type IV hyperlipidemia. Furthermore, monocyte chemotaxis was increased in untreated type IIa patients compared with normocholesterolemic controls. We also studied the dose-response effects of n-3 PUFAs on monocyte and neutrophil chemotaxis in healthy men given 1.3, 4, and 9 g n-3 PUFAs daily for 6-week periods. Monocyte and neutrophil chemotaxis was reduced after n-3 PUFA supplements in a dose-dependent fashion, with the majority of the effect observed after the low dose. These results lend support to the notion of an antiatherosclerotic effect of n-3 PUFAs and may provide an explanation for the hitherto-unexplained effect of low doses of n-3 PUFAs in coronary heart disease.

Granulocyte chemotaxis. Influence of radiographic contrast media on the chemoattractive properties of serum.

One of the important functions of granulocytes is the ability to respond to a chemoattractive signal by migration. The influence of radiographic contrast media (CM) on the chemoattractive properties of serum was investigated by under agarose technique for chemotaxis. No chemotactic response was seen when serum was incubated with different concentrations of CM after heat inactivation. The CM did not generate the heat stable complement split product C5a-desarg which would have resulted in a chemotactic response. Without heat inactivation all complement available in the serum was activated by the agarose in the chemotaxis assay. Low concentrations of iohexol and iodixanol brought about an increased chemotactic response relative to a reference with saline instead of CM. This may be due to activation of heat labile chemoattractants from other sources than the complement cascade. At high concentrations of all five investigated CM, a decreased number of granulocytes migrated over a shorter distance when compared with the reference, and this may be due to interactions between the CM and chemoattractants or their precursors.

The effect of n-3 polyunsaturated fatty acids on lipids, platelet function, coagulation, fibrinolysis and monocyte chemotaxis in patients with hypertension.

We have studied the effect of dietary supplementation with 4 g of n-3 polyunsaturated fatty acids (n-3 PUFA) daily for 6 wk on plasma lipids, haemostasis and monocyte chemotaxis in 10 patients with untreated hypertension. Total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides did not change, but the ratio of total to HDL-cholesterol was significantly reduced after the fish oil supplement. Platelet function was unaltered by intake of n-3. Plasma fibrinogen and fibronectin decreased after supplementation with n-3 PUFA, while the effects on fibrinolysis were equivocal. Monocyte chemotaxis was reduced by the supplement. These data lend support to a role for an increased intake of n-3 PUFA in the management of patients with hypertension.

[Acute thrombocytopenic hemorrhage as the initial symptom of infectious mononucleosis]. / Akut trombocytopenisk blødning som debutsymptom ved infektiøs mononukleose.

A case of acute thrombocytopenic haemorrhage caused by infectious mononucleosis is presented. The differential diagnostic deliberations and the treatment are discussed.

Chromosome C-band polymorphism in relation to fertility in boars of the Duroc breed.

In a study of the variation of fertility in boars of the Duroc breed from Danish AI stations, chromosome investigation has been conducted on 11 boars with high and 11 with low fertility, respectively, out of a total of 98 boars having normal semen quality according to AI standards. All 22 boars had the normal chromosome number. C-band polymorphism at chromosome 16 and 17 was more frequent in the low fertility boars compared with high fertile ones (P less than 0.01), and on average a C-band polymorphic boar sired 0.99 piglet less per litter than a non-polymorphic. More investigations are warranted before application of the results can be brought into practical swine breeding.

The effect of n-3 fatty acids on lipids and haemostasis in patients with type IIa and type IV hyperlipidaemia.

Plasma lipids and haemostasis were investigated in 17 patients with hyperlipidaemia before and after 6 weeks supplementation with 6 g n-3 fatty acids. Nine of the patients had type IIa and 8 had type IV hyperlipidaemia. No effect on plasma cholesterol, LDL- or HDL-cholesterol were seen, but plasma triglycerides decreased after n-3 supplementation. Apolipoprotein B increased and apolipoprotein A1 decreased after the oil supplement. The bleeding time was prolonged, but platelet aggregation was unaltered by n-3 fatty acids. Protein C activity increased in type IIa and decreased in type IV after the supplement. Fibrinolysis was markedly depressed while von Willebrand factor antigen was reduced after intake of n-3 fatty acids.

Cod liver oil inhibits neutrophil and monocyte chemotaxis in healthy males.

Epidemiological evidence suggests a reduced rate of chronic inflammatory diseases and ischaemic heart disease in populations with a high consumption of fish. This has been ascribed to the high content in sea food of polyunsaturated fatty acids (PUFAs), belonging to the n - 3 family. We have studied neutrophil and monocyte chemotaxis in 12 healthy males before and after 6 weeks supplementation with cod liver oil, corresponding to 5.3 g n - 3 PUFAs daily. Neutrophil and monocyte chemotaxis were investigated using the under agarose technique with N-formyl-methionyl-leucyl-phenylalanine (N-FMLP) and autologous serum as chemoattractants. Neutrophil chemotaxis towards both chemoattractants and monocyte chemotaxis towards N-FMLP were significantly reduced after supplementation with cod liver oil.

Changes in PMN leukocyte migration activity and complement C3d levels in RA patients with high disease activity during steroid treatment.

We have investigated chemotaxis of polymorphonuclear granulocytes (PMN) from 7 well characterized RA patients with intense disease activity, before and after steroid treatment. Increased spontaneous and directed granulocyte migration was observed in 6 out of 7 patients before steroid treatment. In 5 patients these parameters were reduced after treatment. In contrast to this, decreased chemotaxis of polymorphonuclear granulocytes (PMN) from patients with Rheumatoid Arthritis (RA), have been reported earlier. This has been suggested as a partial explanation of the increased morbidity of these patients. Plasma levels of Complement C3d were initially increased in all patients and were slightly reduced following treatment. PMN migration in highly active RA cases is increased and responds markedly to steroid treatment, in contrast to the complement activation. The mainly unaffected, increased levels of plasma C3d might, in part, explain the early recurrence of symptoms often seen when steroid medication is withdrawn. Our results contrast with earlier findings and need to be confirmed in further studies.

Granulocyte chemotaxis. Chemoattractive properties of a synthetic tripeptide are inhibited by radiographic contrast media.

The under agarose method for evaluation of leucocyte chemotaxis was used to investigate the effect of radiographic contrast media (CM) on granulocyte locomotion. The CM tested had no chemoattractive properties. CM inhibited N-fmlp, a synthetic formylated Met-tripeptide, which is a strong chemotactic agent and an analogue to chemotatic peptides produced by bacteria. The inhibition of N-fmlp was most pronounced for diatrizoate. Equiosmolal saline was not so inhibitive. Therefore, some part of the inhibition was caused by factor(s) other than hyperosmolality inherent in the CM solution.

The effect of n-3 polyunsaturated fatty acids on lipids, haemostasis, neutrophil and monocyte chemotaxis in insulin-dependent diabetes mellitus.

Insulin-dependent diabetes mellitus (IDDM) is associated with an increased risk of coronary artery disease (CAD). There is some evidence that polyunsaturated fatty acids of the marine n-3 type (n-3 PUFA's) may offer protection against CAD. We have studied the effect of short-term dietary supplementation with n-3 PUFAs on lipids, haemostasis, neutrophil and monocyte chemotaxis in 10 patients with IDDM. The patients were given 4 g daily of n-3 PUFAs (fish oil) for 6 weeks and were investigated before and after the supplement. No significant effects on platelets or haemostasis were observed. High density lipoprotein (HDL)-cholesterol significantly increased, and triglycerides and the ratio of total cholesterol to HDL-cholesterol significantly decreased. Monocyte chemotaxis was unaltered, while neutrophil chemotaxis significantly increased after fish oil. The finding of an improvement in neutrophil chemotaxis after supplementation with n-3 PUFAs to patients with IDDM needs to be confirmed in future studies.