THE EFFECT OF INDOMETHACIN ON THE PSYCHOMOTOR FUNCTION OF PATIENTS WITH RHEUMATIC DISEASES

We have compared the effect of single and multiple doses ofindomethacin and placebo on objective measurements of psychomotorimpairment in patients. Following a single 50 mg dose (n = 8),indomethacin produced psychomotor disturbance in only thosepatients who had no recent history of NSAID exposure. Aftermultiple doses of indomethacin (25 and 50 mg tid for 5 days),no significant psychomotor impairment was observed. We concludethat other NSAIDs may induce cross-tolerance to the psychomotoreffects of indomethacin. Tachyphylaxis may develop to the psychomotordisturbance caused by indomethacin. KEY WORDS: Tachyphylaxis, Tolerance, NSAID, Central nervous system, Flicker fusion threshold, Choice reaction times     

Neurite outgrowth-regulating properties of GABA and the effect of serum on mouse spinal cord neurons in culture

Time-lapse photography was used to examine the effects of γ-aminobutyric acid (GABA) on the outgrowth and motility of neurites in cultures from mouse spinal cord. GABA at concentrations of 100, 10 and 1 μ m caused significant inhibition of neurite outgrowth and the motility of growth cones was significantly reduced by treatment with 100 and 10 μ m GABA. This effect was mimicked by the GABA_B receptor agonist baclofen, whereas the GABA_A receptor agonist muscimol had no effect. The effect of GABA on outgrowth and motility seems to be dependent on the type of serum employed. The results reported here were obtained only when heat-inactivated serum was used and not when non heat-inactivated serum was added to the culture medium. They suggest that GABA has a role in the regulation of process outgrowth within the embryonic mouse spinal cord.     

Human monoclonal antibodies against Plasmodium falciparum: production, stabilization and characterization

Nine human monoclonal antibodies (MoAbs) recognizing 7 different antigenic structures of blood-stages of the human malarial parasite P. falciparum (Pf) were produced by Epstein-Barr virus transformed B-cell lines (EBV-TCL) with or without fusion to the lymphoblastoid cell line KR4. The peripheral blood B-lymphocytes were obtained from 8 Gambian donors immune to Pf malaria. Two of the EBV-TCL could be expanded and maintained for more than 6 months but neither one could be cloned. Six additional EBV-TCL were stabilized after fusion with the KR4 lymphoblastoid cell line. All resulting hybridomas permitted easy cloning. Some of the MoAbs produced distinct fluorescent staining patterns of asexual Pf blood-stage parasites when using high-resolution digitized video-intensified fluorescence microscopy. Antigens on 195 kD and 155 kD proteins were recognized by 3 and 1 MoAb, respectively, using Western blotting and immunoprecipitation techniques.     

SULPHASALAZINE IN THE MANAGEMENT OF PSORIATIC ARTHRITIS

There are few ‘second-line’ drugs available forthe treatment of PSA and their use is often limited by toxicity.Thirty-nine patients with active PSA recruited from two rheumatologyunits were randomly allocated to either enteric-coated sulphasalazine(SASP) or placebo and followed for 24 wk. Six patients in theSASP group and 11 on placebo discontinued therapy before 24wk. Evaluation of effect of treatment revealed significant improvementsin articular index in both groups at 12 wk. By 24 wk the articularindex in placebo group was still showing benefit. In additionto articular index the SASP group improved significantly interms of visual analogue scale, duration of morning stiffnessand ESR. SASP is effective in PSA but the partial clinical response toplacebo indicates the importance of placebo-controlled studiesin this variable disease. KEY WORDS: Skin, Arthritis, Treatment     

SERUM BIOCHEMISTRY IN RHEUMATOID ARTHRITIS, SERONEGATIVE ARTHROPATHIES, OSTEOARTHRITIS, SLE AND NORMAL SUBJECTS

Most arthritic conditions are characterized by chronic inflammation,resulting in secondary changes in serum biochemistry. In anattempt to profile different mechanisms of inflammation whichmight account for the clinical diversity of rheumatic diseases,we have measured C-reactive protein (CRP), plasma viscosity,serum histidine and total serum sulphydryl in 259 patients withrheumatoid arthritis (RA), 84 with ankylosing spondylitis (AS),76 with osteoarthritis, 69 with psoriatic arthritis, 34 withsystemic lupus erythematosus (SLE), 36 with Reiter's syndromeand 121 normal controls. The most extreme abnormalities were seen in rheumatoid arthritisand the least in osteoarthritis. The seronegative spondarthritidesand SLE occupied a midway position, emphasizing a correlationbetween biochemical abnormality and severity of inflammation. A low serum histidine characterized both RA and SLE. The formerwas more likely to be associated with a raised CRP. Plasma viscositywas characteristically raised in psoriatic arthritis and CRPin AS. KEY WORDS: Serum biochemistry, Rheumatoid arthritis, Seronegative arthropathies     

THYROTROPHIN RESPONSE TO THYROTROPHIN-RELEASING HORMONE IN OPHTHALMIC GRAVES'' DISEASE: CORRELATION WITH OTHER ASPECTS OF THYROID FUNCTION, THYROID SUPPRESSIBILITY AND ACTIVITY OF EYE SIGNS

Thirty-four patients with ophthalmic Graves' disease were investigated by routine thyroid function tests, by measurement of the serum thyroid-stimulating hormone (TSH) response to thyrotrophin-releasing hormone (TRH) and by measurement of the serum triiodothyronine (T₃) levels. The patients could be divided into four groups according to their response to TRH—normal, impaired, absent and exaggerated. Those with normal responses had routine thyroid function tests and serum T₃ levels which in general did not differ from normal control values. Those with impaired and with absent responses showed routine thyroid function tests which approached the hyperthyroid range together with significant elevation of serum T₃ levels. It is suggested that they might represent examples of ‘subclinical T₃ thyrotoxicosis’. Patients with exaggerated responses had routine thyroid function tests near the lower end of the normal range and could be regarded as suffering from ‘subclinical hypothyroidism’. There was a good correlation between a normal TRH response and normal thyroid suppressibility by T₃, and between impaired and absent responses and impaired thyroid suppressibility. It is evident that the TRH test which is safer, shorter and more convenient, can replace the T₃ suppression test in routine clinical practice. The response to TRH also provided information on the activity of the eye signs, a normal response was associated with improving eye signs whereas impaired, absent or exaggerated responses were associated with static signs or actual deterioration. The TRH test is of value in the diagnosis of unilateral exophthalmos since about three-quarters of the patients in this series showed some abnormality. The wide range of TRH response and of circulating thyroid hormone levels is to be expected since the thyroid is not subject to the normal finely-balanced negative feed-back mechanism via TSH.     

SULPHASALAZINE ALONE OR IN COMBINATION WITH D-PENICILLAMINE IN RHEUMATOID ARTHRITIS

Thirty patients (22 women) with active rheumatoid arthritisparticipated in an open study of 6 months' treatment with eitherenteric-coated sulphasalazine (SASP) or SASP plus D-penicillamine(DPA). Patients were assessed at regular intervals using a numberof clinical and biochemical tests designed to detect specificantirheumatic activity. There were significant improvements in clinical and laboratoryvariables with both regimens consistent with second-line activity.Improvements were greater and more numerous with combinationtherapy. At the end of the trial period, there were nine ‘responders’in the SASP/DPA group but only six in the SASP group. Neitherefficacy nor toxicity could be related to patient acetylatorstatus. Nausea and dyspepsia were frequent problems with both treatmentregimens but dysgeusia and thrombocytopenia were confined tothe SASP/DPA group. Study withdrawals were twice as common withcombination therapy. These results suggest that a combination of SASP and DPA ismore potent than SASP alone but at the expense of poorer patienttolerance. KEY WORDS: Rheumatoid arthritis, Sulphasalazine, D-Penicillamine, Combination therapy     

Ki-ras MUTATIONS IN ADENOMAS: A CHARACTERISTIC OF CANCER-BEARING COLORECTAL MUCOSA

Activating mutations in the Ki- ras 2 oncogene are frequently observed in sporadic colorectal adenomas and their incidence is reported to rise in large and tubulovillous adenomas to values close to those in carcinomas. This study shows that this property is a feature of adenomas growing in large bowel that has already demonstrated its propensity to engender malignant tumours: i.e., bowel in which there is a synchronous carcinoma. Adenomas from cancer-free bowel do not share this high incidence of Ki- ras mutations. This difference in mutation incidence between adenomas from cancer-free and cancer-bearing patients does not appear to derive from sampling bias relative to adenoma size, site, or patient age, nor is it found in another gene (APC) known to be of importance in adenoma formation. Large, dysplastic adenomas from cancer-bearing bowel, however, are particularly liable to carry Ki- ras mutations when they arise in patients over 70 years old. The observations suggest that the role of Ki- ras mutations may be more subtle than merely enhancing adenoma growth. Adenoma cells of cancer-prone individuals may suffer more mutational events than those in persons selected as cancer-free.     

PHTHALYLSULPHATHIAZOLE IN RHEUMATOID ARTHRITIS

Sixteen patients with active rheumatoid arthritis were treatedwith phthalylsulphathiazole (4 g/day) over a period of 24 weeks.Although there was some statistically significant improvementin plasma viscosity, IgM, pain score, morning stiffness andsummated change score, this was either intermittent or not maintained.Five patients withdrew from the trial before completion, four(25%) with non-serious adverse reactions and one patient fromlack of efficacy; only one patient elected to remain on thedrug beyond the 24-week period. Low free and total sulphathiazoleserum concentrations were found, confirming that most of thedrug remained within the gut. This investigation suggests, certainlyat the dose used, that phthalylsulphathiazole does not havethe properties of a second-line agent. Higher doses of the drugwill not be ethically feasible. KEY WORDS: Sulphonamides, Second-line agent, Rheumatoid arthritis     

ARTHRITIS WITH SIGMOID VOLVULUS AND HL-A B27

A 43-year-old male developed seronegative polyarthritis aftera short attack of diarrhoea. For about two years before he hadexperienced intermittent abdominal pain, distension and constipation.Laparotomy showed a chronic sigmoid volvulus for which sigmoidcolectomy was performed. Post-operatively he had no furtherbowel symptoms, no further arthritis and there was radiologicalimprovement of involved joints. Tissue typing showed HL-A B27antigen.