VAV1 regulates experimental autoimmune arthritis and is associated with anti-CCP negative rheumatoid arthritis.

Rheumatoid arthritis (RA) patients can be stratified into two subgroups defined by the presence or absence of antibodies against citrullinated circular peptides (anti-CCP) with most of the genetic association found in anti-CCP positive RA. Here we addressed the role of VAV1, previously associated to multiple sclerosis (MS), in the pathogenesis of RA in experimental models and in a genetic association study. Experimental arthritis triggered by pristane or collagen type II was induced in DA rats and in the DA.BN-R25 congenic line that carries a polymorphism in Vav1. Difference in arthritis severity was observed only after immunization with pristane. In a case-control study, 34 SNPs from VAV1 locus were analyzed by Immunochip genotyping in 11475 RA patients (7573 anti-CCP positive and 3902 negative) and 15,870 controls in six cohorts of European Caucasians. A combination of the previous MS-associated haplotype and two additional SNPs was associated with anti-CCP negative RA (alleles G-G-A-A of rs682626-rs2546133-rs2617822-rs12979659, OR=1.13, P=1.27 × 10-5). The same markers also contributed to activity of RA at baseline with the strongest association in the anti-CCP negative group for the rs682626-rs12979659 G-A haplotype (ß=-0.283, P=0.0048). Our study suggests a role for VAV1 and T-cell signaling in the pathology of anti-CCP-negative RA.

Effect of liver enzymes on the mutagenicity of nitroheterocyclic compounds: activation of 3a,4,5,6,7,7a-hexahydro-3-(1-methyl-5-nitro-1H-imidazol-2-yl)- 1,2-benzisoxazole and deactivation of nitrofurans and nitroimidazoles in the Ames test.

The effect of liver enzymes (S9) on the mutagenic response of nitroimidazoles and nitrofurans in the Ames test was evaluated with strain TA100. A diminished response was observed with a 5-nitroimidazole and 5-nitrofurans when the S9 preparation was incorporated in the agar layer. Preincubation with S9 under anaerobic conditions prior to adding the bacteria resulted in a greater and sometimes complete loss of the mutagenic effect. The loss of mutagenic potency was dependent on both incubation time and quantity of the S9 preparation. These results suggest that metabolites formed after reductive metabolism are neither mutagenic (presumably due to the loss of the nitro group) nor capable of activation to mutagenic metabolites. One 5-nitroimidazole, 3a,4,5,6,7,7a-hexahydro-3-(1-methyl-5-nitro -1H-imidazol-2-yl)-1,2-benzisoxazole (MK-0436), gave an increased response in the presence of S9 in both the plate test and when preincubated under aerobic conditions. 7 metabolites were produced by the incubation. 4 monooxygenated metabolites were isolated and found to possess significant mutagenic activity. 2 synthetic dihydroxy analogs were more mutagenic than MK-0436. Similar results were obtained with S9 preparations from human liver and the livers of control, phenobarbital and Aroclor-1254 pretreated rats.

A comparison of budesonide nasal dry powder with fluticasone propionate aqueous nasal spray in patients with perennial allergic rhinitis.

There is circumstantial evidence that the incidence of allergic rhinitis is becoming increasingly common. There may also be a need for more potent drugs with minimal local and systemic side effects. This study has compared the efficacy and safety of budesonide delivered as nasal dry powder with fluticasone propionate aqueous nasal spray in the treatment of perennial allergic rhinitis. Ninety-eight patients participated in a randomized, parallel group and partly blinded study. Treatment consisted of budesonide dry powder (Rhinocort Turbuhaler) at once daily doses of 200 micrograms (n = 24) or 400 micrograms (n = 22), fluticasone propionate (200 micrograms) once daily (n = 25), and placebo for budesonide dry powder (n = 27). A six-week treatment period was preceded by a two-week baseline period without treatment. Efficacy was assessed by daily subjective scoring of nasal symptoms. Safety was assessed by rhinoscopy, analysis of urine cortisol, and questioning of adverse events. All active treatments were significantly superior to placebo in controlling nasal symptoms. No significant differences in efficacy were found between the two budesonide regimens and fluticasone propionate. Adverse events were few and minor, and non-significantly distributed between treatments. In conclusion, this study shows that budesonide dry powder administered from Turbuhaler (200 or 400 micrograms) and fluticasone propionate aqueous spray (200 micrograms) administered in once daily doses, are effective and safe treatments of perennial allergic rhinitis. These novel treatments may enhance the current available alternatives in clinical practice.

Colorimetric measurement of dermatan sulphate.

The periodate-Schiff reaction has been adapted for the measurement of dermatan sulphate. The method is specific for this glycosaminoglycan, provided that glycogen and glycoproteins are removed. Measurements of dermatan sulphate present in the urine of patients affected by various mucopolysaccharidoses indicate a good agreement between the values obtained with enzymic methods and those obtained with the colorimetric method described.

The efficacy of oxymetazoline administered with a nasal bellows container and combined with oral phenoxymethyl-penicillin in the treatment of acute maxillary sinusitis.

The efficacy of a new administration form of oxymetazoline, a nasal bellows container, was investigated in two separate studies by means of a combined treatment with phenoxymethyl-penicillin for acute maxillary sinusitis. In the first study (study 1), oxymetazoline administered with a bellows (OXBE) was compared both with a placebo belows (PLBE) as well as with oxymetazoline and placebo administered with a conventional nasal spray (OXSP respective PLSP) in 73 patients. In the second study (study 2), OXBE was compared only with PLBE in 48 patients. Objective evaluation was made by comparing the radiographical improvement in conventional plain sinus X-ray images. A scoring system corresponding to the outcome of antral irrigation was used for evaluating the X-ray pictures. Subjective symptoms; nasal stuffiness and pain, were assessed by registrations on visual analogue scales. Neither with regard to radiographical improvement nor to decrease in subjective symptoms could any significant differences be found between the different treatment modes. Oxymetazoline administered with a nasal bellows thus did not accelerate the rate of healing of acute maxillary sinusitis in these two studies. It is inferred from these results that decongestion of the sinus ostia is not of primary importance for the course of healing of a manifest acute sinusitis.

Induced degradation of glycosaminoglycans in Hurler's and Hunter's syndromes by plasma infusion.

The effects of the administration of normal human plasma to patients affected by mucopolysaccharidoses I and II (Hurler's and Hunter's syndromes) have been evaluated. The infusion was followed by a decreased urinary excretion of relatively large molecular weight glycosaminoglycans and by an increased excretion of their products of degradation. Among the latter, products of the degradation of dermatan sulfate and heparan sulfate could be demonstrated. The results indicate that normal human plasma may contain those "factors" that are involved in the normal degradation of dermatan sulfate and heparan sulfate, that are missing in the diseased states.