Anti-CD4 treatment inhibits autoimmunity in scurfy mice through the attenuation of co-stimulatory signals.

A major concept in autoimmunity is that disruption of Foxp3(+) regulatory T cells (Tregs) predisposes to breach of tolerance. This is exemplified by the Foxp3-linked disorder termed IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X-linked) which affects newborn children. There has been considerable clinical interest in the role of non-depleting anti-CD4 antibodies as a means of upregulating the function of Foxp3(+) Tregs in order to control detrimental inflammatory responses such as transplant rejection. However, according to the paradigm of a Treg-dependent mechanism of action, the effectiveness of anti-CD4 antibodies as a therapy for human autoimmune diseases is unclear considering that Treg function might be intrinsically impaired. Specifically, anti-CD4 therapy is expected to fail in patients suffering from the IPEX syndrome due to the lack of functional Foxp3(+) Tregs. Taking advantage of natural Foxp3 mutant scurfy (sf) mice closely resembling the IPEX syndrome, and genetically engineered mice depleted of Foxp3(+) Tregs, we report here that anti-CD4 treatment induces tolerance independent of Foxp3(+) Tregs. This so far undefined mechanism is dependent on the recessive non-infectious tolerization of autoreactive T cells. Treg-independent tolerance alone is powerful enough to suppress both the onset and severity of autoimmunity and reduces clinically relevant autoantibody levels and liver fibrosis. Mechanistically, tolerance induction requires the concomitant activation of autoreactive T cells and is associated with the down-regulation of the co-stimulatory TNF-receptor superfamily members OX40 and CD30 sustaining CD4(+) T cell survival. In the light of ongoing clinical trials, our results highlight an unexpected potency of anti-CD4 antibodies for the treatment of autoimmune diseases. Particularly, CD4 blockade might represent a novel therapeutic option for the human IPEX syndrome.

An audit of the provision of environmental control systems in Northern Ireland, 1992-1997.

OBJECTIVE: To evaluate the provision of environmental control systems (ECS) in Northern Ireland with regard to assessment and prescription, installation and review and propose guidelines for future service delivery. DESIGN: Structured interview, physical examination, Barthel ADL Index, demonstration and assessment of suitability of ECS for patient. SUBJECTS: Prescriptions for ECS from April 1992 to 1997 were identified from centrally held records. Current users were assessed in their own homes. RESULTS: Forty-six out of 49 current users identified were assessed. All were severely disabled (Barthel 0-9); 24% were living alone; 7 (15%) were not utilizing the system; 96% were satisfied with their initial assessment. Prior to prescription 52% had information about ECS and 20% had a practical demonstration; 78% felt that this would have been useful; 52% of users were not under routine clinical review; 41% of ECS had been altered since installation. Repairs had taken longer than 7 days in 11% of cases. In 45 cases the ECS was essential and in 43 it was appropriate to the users' needs and abilities. CONCLUSIONS: ECS are a valuable tool for severely disabled persons and are appropriately prescribed in Northern Ireland. A multidisciplinary team should perform assessment and prescription. All patients should have a practical trial of the equipment to assist in prescriptions. Regular review by the team should be performed to identify changes in need and alter systems appropriately. Users who live alone should represent a priority for repairs.

B7h, a novel costimulatory homolog of B7.1 and B7.2, is induced by TNFalpha.

In a screen to identify genes induced by NF-kappaB/Rel transcription factors, we cloned a novel gene, b7h, that is a close homolog of B7 costimulatory ligands expressed on antigen-presenting cells. B7h can costimulate proliferation of purified T cells through a receptor on T cells distinct from CD28 or CTLA-4. Surprisingly, although B7h is expressed in unstimulated B cells, its expression is induced in both 3T3 cells and embryonic fibroblasts treated with TNFalpha, and it is upregulated in nonlymphoid tissues of mice treated with LPS, a potent activator of TNFalpha. These data define a novel costimulatory ligand for T cells and suggest that induction of B7h by TNFalpha may function as a mechanism to directly augment recognition of self during inflammation.

Detection of circulating tumor cells in patients with Ewing's sarcoma and peripheral primitive neuroectodermal tumor.

PURPOSE: To determine the feasibility of detecting Ewing's sarcoma (ES) or peripheral primitive neuroectodermal tumor (PNET) through a reverse-transcriptase polymerase chain reaction (RT-PCR) of the t(11;22)(q24;q12) fusion transcript in blood and bone marrow samples from patients with these neoplasms. PATIENTS AND METHODS: Peripheral-blood (PB) and/or bone marrow aspirate (BM) samples were obtained from 28 patients with ES or PNET at initial presentation or at relapse. Patients were divided into two groups: newly diagnosed patients with nonmetastatic disease and those with metastatic/relapsed disease. RNA was extracted from fractionated BM and PB samples, and RT-PCR was performed for the EWS/HumFLI1 fusion mRNA was transcribed across the t(11;22) breakpoint. RESULTS: Among the 16 patients with nonmetastatic disease, three of 16 were RT-PCR positive for EWS/HumFLI1 RNA in BM and three of 10 were positive in PB. The total number of nonmetastatic patients who were positive in either PB or BM was four of 16 (25%). Among patients with metastatic/relapsed disease, two of six were positive in BM and five of 10 were positive in PB. The total fraction of patients with metastatic/relapsed disease that was positive in either BM or PB was six of 12 (50%). CONCLUSION: In this study, we show that it is possible to amplify the EWS/HumFLI1 RNA by RT-PCR from the BM and PB of a subset of patients with both nonmetastatic and metastatic ES or PNET, which implies that occult tumor cells are present at these sites. The true biologic and clinical meaning of this information is unknown. However, it does suggest a possible application of RT-PCR for the monitoring of residual disease in patients who are undergoing therapy for ES or PNET. This approach may permit early identification of patients who may benefit from alternative therapy or who may be spared possible overtreatment.

Remodelling of the nuclear periphery during muscle cell differentiation in vitro.

We have examined the composition and ultrastructure of the nuclear periphery during in vitro myogenesis of the rat myoblast cell line, L6E9. Immunofluorescence labelling and immunoblotting showed that lamins A/C and B were all present in undifferentiated cells, but that they increased significantly before extensive cell fusion had occurred, with lamins A/C increasing proportionately more. Electron microscopic observations were consistent with these results, showing an increase in the prominence of the lamina during differentiation. On the other hand, immunofluorescence labelling suggested that the P1 antigen began to disappear from the nuclear periphery as the cells were fusing, after the increase in lamin quantity, and was no longer detectable in multinucleated cells. Unexpectedly, however, P1 was readily detected in isolated nuclei, whether prepared from myoblast or differentiated cultures, as well as in both myoblast and myotube nuclear matrices. It appears probable, therefore, that the fading of P1 labelling is due to masking of the epitope by a soluble factor recruited to the nuclear periphery as cell differentiate. These data, together with evidence that the genome is substantially rearranged during L6E9 myogenesis [Chaly and Munro, 1996], suggest that L6E9 cells are a useful model system in which to study the interrelationship of nuclear envelope organization, chromatin spatial order, and nuclear function.

Shared care between general practitioners and urologists in the management of benign prostatic hyperplasia: a survey of attitudes among clinicians.

Recent community-based population surveys have revealed a much greater prevalence of benign prostatic hyperplasia than previously suspected. From these data it has been projected that there may be more than 2 million men in the UK whose quality of life is to some extent impaired by this disorder. Since there are only 330 fully trained urologists in this country it will not be feasible for every individual presenting with prostatism to be assessed by a specialist. In an attempt to provide a more rational basis from which family practitioners can decide whether or not to refer a patient for a specialist opinion a 'shared care' flow diagram was developed and assumptions contained within field tested by means of a postal questionnaire which was sent to 2020 urologists, family practitioners and other interested clinicians. There was general agreement with most of the precepts set out in the flow diagram, the main exception was a rejection of the suggestion that every patient with prostatism should have a prostate-specific antigen level determined before referral. We conclude that there seems a consensus among respondents that a shared care approach to the management of BPH may both improve the standard of care provided in this area by family practitioners and allow hard pressed urologists to focus greater attention on those patients whose conditions require surgical expertise to resolve.

Subacute sclerosing panencephalitis in Northern Ireland: twenty years' experience.

Subacute sclerosing panencephalitis (SSPE) is a rare degenerative disease of the central nervous system that affects primarily children and adolescents. It is a late manifestation of measles virus infection. In a 20-year period (1965-85) there have been 26 cases of SSPE in Northern Ireland, a frequency of approximately one case per 1.2 million population per year. Males were affected more frequently than females. In other parts of the world the incidence of this disease has been dramatically reduced following effective measles immunisation programmes. The vaccination rate in Northern Ireland probably remains too low to have a similar effect.

Subsets of T lymphocytes in relation to T lymphocyte function in multiple sclerosis.

T lymphocyte control of Epstein-Barr virus (EBV) infection of autologous B lymphocytes was examined in parallel to the enumeration of subpopulations of mononuclear cells in 22 multiple sclerosis (MS) patients and in 22 healthy individuals. All were seropositive for EBV. The incidence of lack of T cell control was significantly higher in patients than in controls, confirming previous published work. In the present study, we have shown in addition a significantly reduced proportion of OKT8+ cells and a significantly increased ratio of OKT4/OKT8 cells in the group of patients with lack of control. The findings point to abnormal immunoregulation in MS.

Effects of smoking on oral fat tolerance and high density lipoprotein cholesterol.

Changes in serum triglyceride and high density lipoprotein (HDL) cholesterol after a fatty meal have been studied in smokers and nonsmokers. Average serum triglyceride during the study was higher in smokers than in non-smokers. In non-smokers there was a rise in the HDL2/HDL3 cholesterol ratio after oral fat, but not in smokers. These findings are compatible with the hypothesis that smoking interferes with the lipolysis of triglyceride rich lipoproteins and the conversion of HDL3 into HDL2.

Clinicopathological study of Refsum's disease with particular reference to fatal complications.

The clinical and pathological findings in two brothers with biochemically diagnosed Refsum's disease are given. The pathology, in general, was that already described in this condition. An unusual complication in one case was the development of renal failure. Death was caused in the other by heart failure.

Carotid artery thrombosis, encephalitis, myelitis and optic neuritis associated with rubella virus infections.

The clinical, virological and pathological findings in 5 patients with neurological complications associated with rubella virus infection are described. The neurological illnesses began four to ten days after the rubella illnesses. The patients were all males aged between 6 and 17 years and were diagnosed during one non-epidemic year in a population of 1-5 million people. All the patients had rubella specific IgM in their sera. Two patients had no rash. In one of the patients who died, left internal carotid artery thrombosis and cerebral infarction were found at post-mortem. Rubella virus antigen and particles resembling rubella virus were found in the brain together with IgG and IgM in the same areas. This patient also had extensive liver necrosis. The other patient had a severe meningomyelitis and radiculitis and he recovered completely after two years. His serum rubella antibody rose significantly and was shown to leak into CSF during the acute stage of his illness. Three patients had a rash. Two of these patients had encephalitis: one recovered completely and the other had residual disability. The third patient had bilateral optic neuritis from which he recovered completely. Rubella specific IgM was, however, present in his serum for the abnormally long time of twenty-eight weeks indicating possible persistence of rubella virus.