Analysis of impaired in vitro immunoglobulin synthesis in rheumatoid arthritis.

Decreased immunoglobulin production in pokeweed mitogen driven lymphocyte cultures has been reported in rheumatoid arthritis (RA). Here various activators and experimental designs have been used to determine the contribution of B cells, T cells, or monocytes to this low response. Sixty patients with RA and paired controls were studied at the onset of disease and again six months later. Concentrations of IgA, IgG, and IgM in cultures of RA peripheral blood mononuclear cells stimulated with thymus dependent activators were already decreased at the onset of the disease. Six months later RA mononuclear cells produced even lower concentrations of immunoglobulin. In contrast, stimulation with a T cell independent activator showed that RA B lymphocytes had retained normal potential to synthesise immunoglobulin. Poor helper function was indicated by costimulation experiments and cultures of mixed mononuclear cells from patients and controls. This notion was supported also by the fact that phytohaemagglutinin induced interleukin-2 production by RA mononuclear cells was less than half of the control values. Nonspecific suppressor activity was similar in RA and controls. Monocyte functions were normal when tested by addition of indomethacin or 2-mercaptoethanol to the mitogen activated cultures. The defect in mitogen stimulated immunoglobulin production in vitro of RA mononuclear cells thus was more pronounced with time and probably reflects impaired mediator associated help in the differentiation of B lymphocytes into immunoglobulin secreting cells.     

Costal cartilage fractures in blunt polytrauma patients — a prospective clinical and radiological follow-up study

Emergency Radiology - To assess the healing of costal cartilage fractures (CCFX) in patients with blunt polytrauma with follow-up imaging and clinical examination. Effect on physical performance...     

FGF-2 blocks TGF-beta1-mediated suppression of Bcl-2 in normal melanocytes

Normal melanocytes require growth support provided by the adjacent basement membrane. In contrast, nevus cells and melanoma cells survive in the dermis, and in vitro on a soft collagen gel. Transforming growth factor-beta1 (TGF-beta1) produced by melanocytes themselves induces apoptosis in normal melanocytes cultured on collagen gel, an effect that can be counteracted by fibroblast growth factor-2 (FGF-2). The purpose of this study was to investigate the mechanisms by which FGF-2 counteracts the apoptotic signals from TGF-beta1 in melanocytes cultured on collagen gel. We report that FGF-2 did not interfere with the signal transduction from the TGF-beta1 receptors to SMAD2/3 proteins. Instead, TGF-beta1 decreased the level of Bcl-2 in normal melanocytes cultured on collagen gel, and FGF-2 reversed the TGF-beta1-mediated reduction in the level of Bcl-2. In nevus and melanoma cells, TGF-beta1 was unable to induce a decrease in the level of Bcl-2, and treatment with FGF-2 did not cause an increase in the level of Bcl-2 in nevus or melanoma cells. In conclusion, our results suggest that a reduction in the level of the anti-apoptotic Bcl-2 is involved in the execution of apoptosis induced by TGF-beta1 in normal melanocytes cultured on collagen gel and that FGF-2 can prevent TGF-beta1 from causing this reduction.     

Effects of the common cold and intranasal fluticasone propionate treatment on mucosal host defense assessed by human saliva

OBJECTIVE: The purpose of this investigation was to study the effect of a potent topical steroid, fluticasone propionate, on patients with early signs and symptoms of the common cold. To characterize the mucosal inflammatory response, salivary defense factors and flow rate in these patients were analyzed. STUDY DESIGN: Forty patients with symptoms of the common cold were randomized into 2 groups to receive either high-dose fluticasone propionate (100 microg per nostril) or placebo 4 times daily for 6 days. Paraffin-stimulated whole saliva was collected on day 1 (before the onset of medication), day 7 (posttreatment), and day 21 (follow-up). RESULTS: Salivary flow rate, innate host defense factors, and total protein content were not affected by the common cold. IgA increased between day 7 and day 21 (P < or = .01; Student 2-tailed t test), and the relative proportions of salivary peroxidase and IgA increased on day 7 (P = .01) and day 21 (P= .05). In patients receiving fluticasone, saliva flow rate was lower on day 21 (P < or = .05) than on days 1 and 7. The innate salivary defense factors were not affected, but IgA increased both on day 7 (P < or = .001) and on day 21 (P < or = .001) in comparison with day 1. CONCLUSIONS: Of the oral mucosal defense factors, only IgA is activated during the common cold. Intranasally administrated fluticasone propionate does not have a suppressive effect on salivary antimicrobial capacity.     

The metabolism of iodine-123 labelled 3-(5-cyclopropyl-1,2,4-oxadiazo-3-yl)-7-iodo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine (NNC 13–8241) measured in human plasma is only minor

The imidazobenzodiazepine derivate ¹²³I-labelled 3-(5-cyclopropyl-1,2,4-oxadiazo-3-yl)-7-iodo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]-benzodiazepine (NNC 13–8241) is a partial benzodiazepine agonist and binds with a high affinity to the benzodiazepine receptor. The favourable kinetic properties indicate that [¹²³I]NNC 13–8241 is a promising SPET ligand. In the present study, an extensive examination of the metabolite pattern of [¹²³I]NNC 13–8241 in plasma and urine from seven healthy subjects was performed using gradient HPLC. After injection of [¹²³I]NNC 13–8241 into human beings, only one radioactive metabolite was found in plasma 3–300 min post injection. This polar metabolite eluted together with the solvent front fraction. The proportion of unchanged [¹²³I]NNC 13–8241 was 82–86 per cent during the entire study. In addition, two other radioactive metabolites were found in urine. The first metabolite was lipophilic and eluted slightly before the parent compound [¹²³I]NNC 13–8241. The second metabolite eluted slightly after solvent front peak. The amount of unchanged [¹²³I]NNC 13–8241 in human urine was 9 per cent and the solvent front fraction contained 72 per cent of total radioactivity. No detectable radioactivity appeared with the same retention time as synthetisized nor-NNC 13–8241 in plasma or urine, which excludes the possibility of in vivo demethylation of [¹²³I]NNC 13–8241. In conclusion, the [¹²³I]NNC 13–8241 was found to have only a minor metabolism, which favours its use as a SPET tracer for quantitation of the benzodiazepine receptor. © 1998 John Wiley & Sons, Ltd.     

Conserved region mutations of the p53 gene are concentrated in distal colorectal cancers

Distal colorectal cancers, especially those in the rectum, are more aggressive and more commonly recurrent than proximal cancers. We studied the possible relationship between p53-gene mutation type and location of the tumour, since mutations in the conserved areas of the p53 gene have been suggested to result in a poorer outcome of colorectal cancer than mutations outside these areas. Exons 5 to 8 of the p53 gene were studied in specimens from 72 colorectal-cancer patients. Polymerase-chain-reaction-amplified products of tumour DNA were analyzed by automated direct sequencing. Of the mutations detected in distal cancers, 71% were located in conserved regions of the gene, while only 42% of the mutations in proximal cancers were in these areas. In rectal cancers, 81% of the mutations were located in conserved regions. The tumours with mutations in the conserved regions were more often poorly differentiated (23%) than those with other mutations (0%). Our results indicate that mutations in the conserved regions of the p53 gene accumulate in distal but not in proximal tumours. This difference may be related to the more aggressive behaviour and to different aetiological factors associated with distal tumours. Int. J. Cancer 74:97–101. © 1997 Wiley-Liss, Inc.