Restrictions among heavy and light chain determinants of granulocyte-specific antinuclear factors

In fifty-five rheumatoid arthritis sera with positive granulocyte-specific antinuclear factors (GS-ANF) tests were made to further characterize these antibodies. All sera contained GS-ANF of the IgG class and most of the sera also of the IgM and IgA classes, whereas only about 10 per cent of the sera contained GS-ANF of the IgD class. Most of the sera contained GS-ANF carrying both κ and λ light chain determinants, but in five cases only one of the light chain subclasses could be found.The distribution of the GS-ANF among the four subclasses of IgG showed marked variations. From one to three subclasses could be lacking or noticeably depressed. There was no predominance of any one or two subclasses. Complement (C₃) fixing properties correlated with GS-ANF of the IgG₁ and/or IgG₃ subclasses. These properties make the GS-ANF interesting as possible pathogenic factors in rheumatoid arthritis.Some evidence is presented that the GS-ANF may be directed against several different antigens in the polymorphonuclear granulocyte nuclei.     

Rheumatoid arthritis may be primarily associated with HLA-DR4 molecules sharing a particular sequence at residues 67–74

Genomic typing of in vitro amplified DNA with sequence-specific oligonucleotide (SSO) probes was performed for DRB1, DQA1, DQB1, DPA1 and DPB1 alleles in 54 random Norwegian rheumatoid arthritis (RA) patients and 181 healthy controls. DRB1 alleles encoding the serological specificity DR4 were found in 80% of the patients, compared to 34% of the controls (relative risk = 7.9, p less than 0.0001). All DR4-positive RA patients carried either DRB1*0401 (Dw4), 0404 (Dw14), or 0405 (Dw15), while no patients were found to carry DRB1*0402 (Dw10) or 0403 (Dw13). The frequency of the DRB1*0101 allele encoding DR1 was not increased, even among DR4-negative RA patients, and we were unable to detect any sharing of other class II alleles among DR4-negative patients. No contribution of any DQA1, DQB1, DPA1 or DPB1 alleles to RA susceptibility could be detected. The results suggest that in the Norwegian population RA is primarily associated with a shared sequence at residues 67-74 of the DR beta 1 chain, but only when this sequence is expressed on DR4 molecules.     

Alpha-adrenoceptors, 5-hydroxytryptamine receptors and the action of dihydroergotamine in human venous preparations obtained during saphenectomy procedures for varicose veins

Summary Changes in tension were monitored isometrically on spiral strips from human saphenous veins obtained during surgical removal of varicose veins. Concentration-response curves for noradrenaline and 5-hydroxytryptamine (5-HT) were established by cumulative administrations, curves for dihydroergotamine were constructed from the mean responses to single concentrations. The use of the antagonists prazosin, yohimbine and pizotifen provided evidence for the existence of both postjunctional ₁- and ₂-adrenoceptors and for the existence of 5-HT receptors. The venoconstrictor effects of dihydroergotamine were unchanged by prazosin. Yohimbine antagonized both dihydroergotamine and 5-HT at about 60 times higher concentrations than required against noradrenaline whereas pizotifen inhibited responses to both dihydroergotamine and 5-HT at about 100 times lower concentrations than those to noradrenaline.These new results are in contrast to conclusions drawn from animal studies and do not support the suggestion that in man the venoconstrictor activity of dihydroergotamine is mediated through stimulation of -adrenoceptors. The present results strongly suggest that in human saphenous veins the constrictor activity of dihydroergotamine is mediated at least in part through stimulation of 5-HT receptors.     

Tissue specific susceptibility of alpha-adrenoceptor mediated vasoconstriction to nifedipine

Summary The influence of the calcium antagonist nifedipine on ₁- and ₁-adrenoceptor vasoconstrictor effects was investigated in vitro. Changes in tension were monitored isometrically on helical strips of canine circumflex coronary and saphenous arteries suspended in 10 ml organ baths and of saphenous veins superfused with Krebs-Henseleit solution. Distinction between ₁- and ₂-adrenoceptor was made by using selective -adrenoceptor blocking drugs such as rauwolscine, yohimbine, corynanthine and prazosin, and the agonists noradrenaline, phenylephrine and guanfacine. In venous and both arterial vascular smooth muscles, the contractile process could be triggered by stimulation of both ₁- and ₂-like adrenoceptors. Nifedipine inhibited the venoconstrictor response to the ₂-agonist guanfacine, leaving that to the ₁-agonist phenylephrine unchanged. In saphenous arteries, nifedipine in addition to guanfacine also antagonized constrictor responses to phenylephrine, though to a significantly weaker extent. In circumflex coronary arteries, nifedipine was equally potent in antagonizing responses to both ₁- and ₂-adrenoceptor stimulation.It is suggested that the susceptibility of -adrenoceptormediated vasoconstrictor effects to blockade by calcium antagonists depends not only on the subtype of -adrenoceptor but, in addition, on the type and origin of vascular smooth muscle and may be a reflection of tissue variations in intracellular calcium stores.     

C3 activation products, C3 containing immune complexes, the terminal complement complex and native C9 in patients with rheumatoid arthritis

Complement activation products, C9 and C3-containing circulating immune complexes (CIC), were evaluated in plasma and synovial fluid (SF) from patients with rheumatoid arthritis (RA) and osteoarthritis. C3 activation products and the fluid phase terminal complement complex were considerably elevated in SF from RA patients reaching levels five- to eighttimes that in plasma, consistant with a local activation of the whole cascade in the joints. The results emphazise the importance of detecting C3 activation by neoepitope expression instead of single fragment determinations. The concentration of native C9 was lower in synovial fluid compared with plasma, consistant with the excessive local complement activation. Increased CIC levels which correlated with the degree of complement activation were also found in the SF from the RA patients.     

Kidney Function and Plasma Copeptin Levels in Healthy Kidney Donors and Autosomal Dominant Polycystic Kidney Disease Patients

Background and objectives

Plasma copeptin, a marker of arginine vasopressin, is elevated in patients with autosomal dominant polycystic kidney disease and predicts disease progression. It is unknown whether elevated copeptin levels result from decreased kidney clearance or as compensation for impaired concentrating capacity. Data from patients with autosomal dominant polycystic kidney disease and healthy kidney donors before and after donation were used, because after donation, overall GFR decreases with a functionally normal kidney.

Design, setting, participants, & measurements

Data were obtained between October of 2008 and January of 2012 from healthy kidney donors who visited the institution for routine measurements predonation and postdonation and patients with autosomal dominant polycystic kidney disease who visited the institution for kidney function measurement. Plasma copeptin levels were measured using a sandwich immunoassay, GFR was measured as ¹²⁵I-iothalamate clearance, and urine concentrating capacity was measured as urine-to-plasma ratio of urea. In patients with autosomal dominant polycystic kidney disease, total kidney volume was measured with magnetic resonance imaging.

Results

Patients with autosomal dominant polycystic kidney disease (n=122, age=40 years, men=56%) had significantly higher copeptin levels (median=6.8 pmol/L; interquartile range=3.4–15.7 pmol/L) compared with donors (n=134, age=52 years, men=49%) both predonation and postdonation (median=3.8 pmol/L; interquartile range=2.8–6.3 pmol/L; P<0.001; median=4.4 pmol/L; interquartile range=3.6–6.1 pmol/L; P<0.001). In donors, copeptin levels did not change after donation, despite a significant fall in GFR (from 105±17 to 66±10; P<0.001). Copeptin and GFR were significantly associated in patients with autosomal dominant polycystic kidney disease (β=−0.45, P<0.001) but not in donors. In patients with autosomal dominant polycystic kidney disease, GFR and total kidney volume were both associated significantly with urine-to-plasma ratio of urea (β=0.84, P<0.001; β=−0.51, P<0.001, respectively).

Conclusions

On the basis of the finding in donors that kidney clearance is not a main determinant of plasma copeptin levels, it was hypothesized that, in patients with autosomal dominant polycystic kidney disease, kidney damage and associated impaired urine concentration capacity determine copeptin levels.