Peripheral lymph node helper T-cell recovery after syngeneic bone marrow transplantation in mice prepared with either gamma-irradiation or busulfan

The optimum marrow ablative regimen for preparing recipients of bone marrow transplantation (BMT) has not been established. gamma- Irradiation, but not busulfan, produces a characteristic microvascular injury pattern which results in depressed capacity of normal lymphocytes to localize into the lymph nodes of syngeneic murine BMT recipients. Since peripheral lymph nodes are important sites for initiation and amplification of immune responses, the preparative regimen might delay recovery of regionally compartmentalized immune functions after BMT. We evaluated the effects of busulfan and gamma- irradiation on the phenotypic and functional reconstitution of helper T- cell function within the peripheral lymph nodes of BMT recipients. Both marrow ablative regimens caused a protracted delay in regeneration of peripheral lymph node CD4+ T cells. Specific helper T-cell functions, such as contact hypersensitivity and alloantigen responses, remained significantly depressed in the lymph nodes of irradiated mice for prolonged periods (up to 60 weeks). These responses recovered more rapidly in busulfan-treated BMT recipients. In contrast, the capacity of peripheral lymph node T cells to provide "help" for antigen-specific immunoglobulin production was only transiently depressed by either preparative regimen. Our experiments confirm the hypothesis that the marrow ablative regimen, particularly gamma-irradiation, may contribute to the period of immunodeficiency which follows BMT. The pattern of immune recovery observed suggests that preparative total body irradiation (TBI) may selectively depress the regional recovery of the TH1 [interleukin-2 (IL-2) and gamma-interferon (gamma-IFN) secreting] lymphocyte subset.     

Patients who develop inflammatory polyarthritis (IP) after immunization are clinically indistinguishable from other patients with IP

Musculoskeletal symptoms may occur following various types of immunization, and it has also been suggested that, like infection, immunization may act as a trigger for rheumatoid arthritis (RA). A total of 48 of 898 (5.3%) patients with early inflammatory polyarthritis (IP) referred to the Norfolk Arthritis Register reported an immunization in the 6 weeks prior to symptom onset. There were no important clinical or demographic differences between the 48 immunized patients and 185 consecutive patients who did not report prior immunization. In addition, the frequencies of HLA-DRB1*01. *04 and the shared epitope in 33 of the immunized patients were similar to those in the 185 non-immunized patients and to those in 136 healthy controls. Further results from a case-control study suggest that the rate of immunization is higher amongst cases (5.5%) than age- and sex-matched controls (2.8%). In a small number of susceptible individuals, immunization may thus act as a trigger for RA.      

Endotoxins of anaerobic gram-negative rods.

Endotoxic lipopolysaccharides (LPS) isolated from Fusobacterium are similar to those of Salmonella with respect to chemical composition, O-antigenic specificity and endotoxic activity. Bacteroides LPS are highly atypical with respect to the chemical composition, and their endotoxic activity is low. O-Antigenic specificity is present. B. fragilis LPS is chemotactic for polymorphonuclear leukocytes in vitro and in vivo. The chemotactic activity is brought about by activation of the alternative complement pathway.     

Recycling with nicotine patches in smoking cessation

The aim was to evaluate if recycling of failures from a smoking cessation study may be of value. The study comprised 126 smokers (50%) of 252 failures, from a double-blind smoking cessation trial with nicotine patch, who accepted recycling after 1 year. Subjects were allocated nicotine patches delivering 15, 20 or 25 mg of nicotine (over 16 hours) according to their base-line saliva cotinine concentrations in an open trial. The treatment period was 12 weeks followed by tapering over 6 weeks. The percentage of quitters after 3, 12, 26, and 52 weeks was 44, 20, 7 and 6%, respectively. After 26 weeks, all subjects had relapsed in the group previously treated with active nicotine patch compared with 12% abstainers in the previous placebo subjects. The sustained abstinence rate without slips after one year was 2%. Recycling does not seem to be of long-term clinical relevance in our set-up for subjects initially treated with nicotine, but of some value in subjects quitting without nicotine therapy initially.     

Compound heterozygosity for the shared epitope and the risk and severity of rheumatoid arthritis in extended pedigrees

The objective was to explore the role of HLA-DRB1 genes in determining disease severity in rheumatoid arthritis (RA). The population comprised extended pedigrees of 17 multicase RA families. Family members were genotyped for both HLA-DRB1 alleles using restriction fragment length polymorphism (RFLP). Identification of HLA-DRB1*04 variants was performed using the Multiplex ARMS-RFLP technique. Compound heterozygote individuals carrying two different alleles containing the shared epitope (SE) were at greatest risk of developing RA (odds ratio = 36, 95% CI 9.1-143). A synergistic or additive effect of these alleles is suggested. Individuals carrying no SE alleles expressed milder disease, as measured by the Spread Severity (SS) index, compared to compound heterozygotes (P = 0.045). Compound heterozygosity was not invariably associated with severe disease with six (50%) having clinically mild disease at a median age of 57.5 yr and median disease duration of 16 yr. Inheriting two different SE-bearing alleles results in an increased risk of RA and, on average, greater disease severity. This is not, however, invariably associated with severe disease, making it of limited use as a predictor of prognosis.      

A variant of von Willebrand's disease with abnormal expression of factor VIII procoagulant activity

Reports on variants of von Willebrand's disease are numerous, but many of these are based on tests that will show marked fluctuations with time and tests that might not be similar in affected family members. This report describes 8 patients with a new variant of von Willebrand';s disease in which there is a normal APTT, slightly reduced one-stage factor VIII:C assay (VIII:C-1), and a drastically reduced two- stage factor VIII:C assay (VIII:C-2). The VIII:C in this variant is more readily adsorbed to AI(OH)3. This variability in VIII:C assays and excessive adsorption to AI(OH)3 are corrected by the addition of either hemophilic plasma or hemophilic factor-VIII-related antigen. This variant is stable with restudy on multiple occasions and is inherited in a stable fashion in three generations of one family. The multimeric structure of the VIIIR:Ag appears normal, although the concentration is moderately reduced. The differences in functional activity, the adsorption to AI(OH)3, and the differences between functional and antigenic (VIII:C Ag) assays of VIII:C support that this is a functional abnormality of type I von Willebrand's disease.     

Direct evidence of monocyte recruitment to inflammatory bowel disease mucosa

Alterations in phenotype and function of intestinal macrophages occur in inflammatory bowel disease (IBD) but it is unclear whether these changes result from the recruitment of circulating monocytes to the intestine or from proliferation of resident intestinal macrophages. We sought to demonstrate the arrival of blood monocytes, the precursors of macrophages, in IBD mucosa. Peripheral blood mononuclear cells were isolated from 23 patients with clinically active intestinal inflammation (13 Crohn's disease, eight ulcerative colitis, two infective colitis), then radiolabelled with ^99mtechnetium (Tc)-stannous colloid (n=13) or ¹¹¹indium (In)-oxine (n=10) before re-injection and abdominal scanning. Four patients had demonstrable intestinal monocyte uptake using [^99mTc]-stannous colloid, while six [¹¹¹In]-oxine-labelled monocyte scans were positive. Uptake sites correlated with actively inflamed regions. Patients demonstrating monocyte uptake had been treated with corticosteroids for a significantly (P < 0.02) shorter duration (median 3 vs 20 days) than those with negative scans. There was no significant difference between positive and negative scans for disease category, clinical or histological disease activity, or radioisotope used. Biopsies of inflamed mucosa from two patients suffering ulcerative colitis who had positive scans showed a high proportion of CD14-positive macrophages, 4–9% of which contained autoradiographic grains. These results demonstrate that blood monocytes are recruited to the mucosa of actively inflamed bowel, and suggest that this process may be inhibited by corticosteroids. Moreover, the phenotype of the recently-arrived monocytes indicates their susceptibility to stimulation by lipopolysaccharide, and suggests a mechanism for the continuing inflammation in the bacterial product-rich milieu of IBD.     

Development of a group-based self-management programme for individuals with chronic fatigue syndrome: a pilot study

Objective: The aim of the study was to develop a group-based self-management programme for individuals with chronic fatigue syndrome (CFS) by using the participants’ experiences with the initial version of the programme, which intends to promote coping with the illness in a primary healthcare setting. Methods: An initial programme was developed, based on self-efficacy theory and the concepts of client-centred practice and empowerment. Subsequently, the programme was tested and further developed by drawing on the participants’ experiences with the programme. Focus-group interviews were applied. The interviews were analysed using thematic analysis. Results: The initial programme was found to be feasible, although several modifications regarding the content and practical organization of the programme were proposed. Conclusion: In line with the participants’ experiences, the final self-management programme was developed, which includes short presentations of eight topics, exchange of experiences among participants, goal-setting, construction of action plans, and relaxation exercises, in addition to a meeting for relatives. The programme will be provided in eight biweekly sessions and be led by juxtaposed peer counsellors and occupational therapists. The effects of the final programme will be evaluated in a randomized controlled trial.