Biomedical subjects
Publications and source records attributed to R J Griffiths.
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The diversity of breast pads available and absence of data on their effectiveness led the Breastfeeding Association of South Africa to design laboratory simulation experiments measuring fluid retention and evaporative properties as indicators of pad surface dryness. Questionnaires distributed at four breastfeeding clinics were used to obtain data on mothers' use of pads and incidence of breast problems. The majority of mothers surveyed used a new disposable breast pad made by Johnson & Johnson. The experimental studies showed that this pad allowed no leaking and kept the breast markedly drier than other disposables. Exclusive use of these pads or cotton towelling pads did not produce a detectable increase in nipple problems. A home-made disposable breast pad using a nappy (diaper) liner encasing toilet paper was most effective at keeping the breast dry and offered good protection against leaking. Since it is economical and easy to use, it is recommended as a good alternative to expensive disposables. Clinging materials, e.g. gauze, cottonwool or paper, and panty liners, maintain excessive surface dampness and are not recommended. If used, two layers of nappy liner on the inner surface may enhance nipple dryness.
The optimum conditions for the induction of antigen-induced arthritis in the rat have been studied. Two immunisations with methylated bovine serum albumin (mBSA) (0.5 mg) in Freund's complete adjuvant (FCA) containing 0.375 mg Mycobacterium tuberculosis followed by an intra-articular injection of mBSA (0.5 mg) led to the production of a chronic, erosive arthritis. The development of the arthritis was associated with the appearance of T lymphocytes and other inflammatory cells in the synovium. Male and female animals were equally susceptible to the disease. Prednisolone, indomethacin and methotrexate inhibited the development of the arthritis but ibuprofen and D-penicillamine were without any significant effect.
The conditions necessary for the passive transfer of antigen arthritis induced by methylated bovine serum albumin (mBSA) in the rat have been studied. Spleen cells from immunised rats were not capable of transferring disease unless they were first activated in culture with mBSA or concanavalin A. Cells from sham-immunised animals could not be activated to transfer the arthritis. The immunosuppressant drug FK 506 could inhibit the development of the arthritis when present during the activation period in culture or when dosed to the recipients of activated cells.
Intraperitoneal and intra-articular (knee joint) injection of zymosan in the rat caused two phases of increased vascular permeability, a rapid increase (0.25-0.5 h) and a secondary increase (2-3 h) which was temporally associated with the onset of leukocyte infiltration. Intraperitoneal injection of zymosan led to a single peak of eicosanoid production (LTB4, C4, D4, E4 and 6-oxo-PGF1 alpha) which was maximal at 0.125-0.25 h. Intra-articular injection led to an initial peak of LTB4 production (maximal at 0.25 h) and a secondary peak of LTB4 and PGE2 production (maximal at 3 h). Oral administration of the 5-lipoxygenase (5-LO) inhibitors phenidone, BW A4C (N-hydroxy-N-[3-(3-phenoxyphenyl)-2-propenyl] acetamide), A63162 (N-hydroxy-N-[1-(4-(phenylmethoxy) phenyl)ethyl] acetamide and ICI 207 968 (2-[3-pyridylmethyl]-indazolinone inhibited LTB4 production in A23187 stimulation blood ex vivo. The glucocorticosteroid dexamethasone had no effect in this model. The initial phase of increased vascular permeability in the peritoneal cavity and LTB4 production was dose dependently inhibited by the 5-LO inhibitors phenidone, BW A4C, A63162, and ICI 207 968 but not by dexamethasone or colchicine. The initial phase of increased permeability in the joint was unaffected by phenidone, BW A4C, dexamethasone or colchicine. However the latter two drugs inhibited the later phase of increased permeability and leukocyte infiltration in the joint and peritoneal cavity. These results demonstrate that zymosan induces eicosanoid production in vivo but the relative importance of these mediators varies depending on the inflammatory site.(ABSTRACT TRUNCATED AT 250 WORDS)
FK506 and cyclosporin A inhibited the development of antigen-induced arthritis in the rat and rabbit. FK506 was five times more potent than cyclosporin A in the rat and approximately 20 times more potent in the rabbit. FK506 was effective in both species if administered either from the day of intra-articular administration of antigen or when the arthritis was established. In the rabbit, arthritis returned when administration of FK506 was stopped. FK506 (10 mg/kg/day) caused renal damage which was not observed at a dose of 2.5 mg/kg/day. Both of these doses were equally effective at inhibiting the arthritis. The conclusion from these studies is that FK506 is a more effective anti-arthritic agent than cyclosporin A and that a pronounced therapeutic effect can be achieved at non-toxic doses of the drug.
FLP 62064 [N-(4-methoxyphenyl)-1-phenyl-1H-pyrazole-3-amine] is a dual inhibitor of prostaglandin synthetase and 5-lipoxygenase. The compound had anti-inflammatory activity in vivo in a number of models. It inhibited peritoneal inflammation induced by immune-complex when given locally. When applied to the skin, FPL 62064 inhibited UV irradiation-induced erythema and PGE2 formation in the guinea pig and also oedema formation and eicosanoid production in the mouse ear produced by arachidonic acid. Co-injected with arachidonic acid in rabbit skin, FPL 62064 inhibited oedema and eicosanoid formation.
Ciclosporin is clinically effective in a variety of inflammatory skin diseases. We have therefore studied the effects of the drug on cutaneous inflammation in mice. Ciclosporin inhibited the inflammatory response to 12-O-tetradecanoylphorbol-13-acetate (TPA) and to the contact sensitising agent oxazolone when applied topically to mouse skin. The drug had no effect on arachidonic acid-induced inflammation. The protein synthesis inhibitor cycloheximide showed a similar profile of activity. Ciclosporin, like actinomycin D but unlike cycloheximide, was only effective in inhibiting the inflammatory response to TPA if given 0.5 h before, but not 2 h, after TPA. These results suggest that the anti-inflammatory activity of ciclosporin in the skin is due to an effect on the production of proinflammatory proteins.
Topical application of TPA to mouse skin causes oedema (2-6 h) neutrophil influx (3-24 h) and epidermal cell proliferation (24-48 h). Topical application of a cyclooxygenase inhibitor (indomethacin) dual cyclooxygenase and lipoxygenase inhibitors (phenidone and BW755C) a selective lipoxygenase inhibitor (AA861), protein synthesis inhibitors (cycloheximide and actinomycin D) or a glucocorticosteroid (prednisolone) inhibited oedema and neutrophil influx. Systemic administration of an inhibitor of microtubule assembly (colchicine) also prevented neutrophil influx and oedema. These results suggest that the inflammatory response to TPA depends on an interaction between a protein and products of arachidonic acid metabolism to produce a neutrophil dependent oedema. Epidermal cell proliferation was inhibited by topical administration of prednisolone, indomethacin, BW755C and cycloheximide but not systemically administered methotrexate. This suggests that inhibition of the early inflammatory response to TPA prevents the subsequent epidermal proliferation.
1. Employing rat femoral head cartilage implanted in a 6 day old mouse air pouch, the effects of inflammatory stimuli (i.e. cotton pellets, carrageenan, zymosan) on the loss of proteoglycan and collagen and granuloma formation have been studied. 2. Wrapping of the cartilage in cotton resulted in granuloma formation with accelerated loss of proteoglycan and collagen over the 14 day implantation period. The amount of loss increased with increasing weight of cotton. 3. The effects of different classes of anti-rheumatic drugs on granuloma formation and proteoglycan and collagen loss from cotton wrapped femoral head cartilage in the mouse air pouch have been studied. 4. Non-steroidal anti-inflammatory drugs (NSAIDs) had no influence on granuloma formation, but in general accelerated the rates of proteoglycan and collagen loss. 5. Dexamethasone and prednisolone significantly reduced granuloma formation and had a marked protective effect on cartilage breakdown. 6. Of the slow acting anti-rheumatic drugs examined, only gold sodium thiomalate (GSTM) and dapsone significantly decreased cartilage loss, with an accompanying modest decrease in granuloma formation. 7. The immunosuppressants cyclophosphamide and methotrexate, but not azathioprine, reduced cartilage degradation, but had no effect on granuloma formation. 8. The results for the different classes of anti-inflammatory and anti-rheumatic drugs are discussed in relation to their effects in other animal models and their reported therapeutic activities in man. It is concluded that the mouse air pouch method as described offers advantages as an animal model over existing procedures to predict therapeutic efficacy in man.
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Serial measurements of the HbA1c levels were performed during pregnancy in 4 groups of patients attending Antenatal Clinics: 36 normal pregnancies; 16 pregnancies in established insulin-dependent diabetic patients; 9 patients with gestational diabetes diagnosed during that pregnancy; and 21 patients who had been diagnosed as having gestational diabetes in at least one previous pregnancy. In the normal pregnancy HbA1c levels showed a small but significant increase from the end of the first trimester to delivery despite blood glucose levels remaining constant throughout. In the insulin-dependent and gestational diabetic patients, blood glucose levels remained significantly higher than in the normal throughout pregnancy but only in insulin-dependent diabetic patients and the newly diagnosed untreated gestational diabetic patients were the HbA1c levels significantly higher than in the normal. In those patients who had previous pregnancies complicated by gestational diabetes, blood glucose levels were significantly higher than in the normal but HbA1c levels were not. This dissociation between blood glucose and HbA1c levels in gestational diabetic pregnancies in particular limits the value of HbA1c levels in monitoring antidiabetic treatment in such pregnancies.
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The spontaneous release of prostanoids from rat isolated perfused lungs was studied after acid/organic extraction of perfusates by bioassay, radioimmunoassay, thin layer and high performance liquid chromatographic methods and by gas chromatography-negative ion mass spectroscopy (g.c.n.i.m.s.). An acid/organic extractable anti-aggregatory vasodilator prostaglandin which inhibited the twitch response of the field-stimulated guinea-pig vas deferens was released from the Krebs-perfused rat lung in nanogram amounts similar to those of other detected prostanoids. Parallel biological assay suggested that this prostaglandin had very closely similar pharmacological activity to authentic 6-oxo-prostaglandin E1 (6-oxo-PGE1), a metabolite of prostacyclin (PGI2) generated by the action of the enzyme 9-hydroxyprostaglandin dehydrogenase (9-PGDH). 6-oxo-PGE1 was identified conclusively in extracts of rat lung perfusate by thin layer chromatography, high performance liquid chromatography and g.c./m.s. combined with bioassay (inhibition of platelet aggregation), and its covalent structure was defined by g.c. negative ion chemical ionization mass spectroscopy. The rank order of spontaneous release of prostanoids (measured by radioimmunoassay) from the perfused rat lung was 6-oxo-PGF1 alpha greater than thromboxane B2 (TXB2) greater than PGE2 greater than 6-oxo-PGE1 (measured biologically) greater than PGF2 alpha. Release of all five prostanoids was inhibited by indomethacin, but only that of 6-oxo-PGE1 was inhibited by naringenin. Rat lung 100,000 g cytosolic supernatants contained 9-PGDH activity capable of removing 9 beta-tritium from labelled prostacyclin and forming an acid/organic extractable 6-oxo-PGE1-like anti-aggregatory substance. This 9-PGDH activity was inhibited by naringenin (IC50 10.3 microM). 6 The relevance of these findings to the possible physiological role of 6-oxo-PGE1 in the lung is discussed, and we propose that 6-oxo-PGE, should be accorded the status ofa physiologically relevant, naturally occurring metabolite of arachidonic acid.
Two Caucasian patients with bovine tuberculous meningitis are described. Classical Mycobacterium bovis was isolated from the cerebrospinal fluid on both occasions. Despite the elimination of cattle tuberculosis in this country, reactivated primary disease due to the bovine tubercle bacillus may still occur.
During 1969-84 Mycobacterium bovis was isolated from 20 patients with pulmonary tuberculosis. This represented less than 1% of the total cases of respiratory tuberculosis confirmed bacteriologically at the Liverpool Public Health Laboratory during this period. All 20 patients were considered to have reactivated disease and all presented with the typical features of respiratory tuberculosis. During the same period four cases of pulmonary infection by Mycobacterium africanum were recognised. This organism is difficult to differentiate from M bovis and failure to distinguish the two mycobacteria could lead to a misleading epidemiological picture of bovine tuberculosis in man.
Between 1969 and 1983 inclusive, the bovine variants of Mycobacterium tuberculosis (M. bovis and M. africanum) were isolated from 75 patients with tuberculosis. This represented 2.9 per cent of all significant mycobacteria identified at the Liverpool Public Health Laboratory during this period. The clinical and radiological features of infection did not differ from those found with M. tuberculosis. There was an association between M. bovis infection, extrapulmonary disease and lifelong United Kingdom residency, and between M. africanum infection, pulmonary disease and immigrant status. Correlations between the present incidence of reactivated M. bovis disease and past prevalence of bovine tuberculosis in man and cattle, and between the isolation rate of M. africanum and the size of the immigrant community served by the laboratory, were also demonstrated. All the patients with M. bovis infection were considered to have a reactivated or slowly progressive primary infection. It is proposed that M. bovis only accounts for a small proportion of isolates from adults with tuberculosis because the organism displays a low tendency to reactivate.
Synthesis and catabolism of 6 oxo PGE1 was assessed in 100,000 g cell-free supernatant fractions of kidneys obtained from rats aged 20, 34 and 70 days. In addition the release of PGI2, TxA2 (measured as 6 oxo PGF1 alpha and TxB2, respectively), PGE2 and PGF2 alpha from kidney slices prepared from these three groups of rats was determined using specific radioimmunoassays. The conversion of PGI2 to 6 oxo PGE1 (but not 13,14 dihydro 15 oxo PGF2 alpha to 13,14 dihydro 15 oxo PGE2) was detected in supernatant fractions of kidneys from 20 day rats. Slices prepared from the kidneys of these animals spontaneously released significant amounts of three prostanoids (6 oxo PGF1 alpha greater than PGE2 greater than PGF2 alpha greater than TxB2 = 0). No formation of 6 oxo PGE1 from exogenous PGI2 was demonstrated in renal 100,000 g supernates from 34 and 70 day rats even though these supernates avidly oxidised 13,14 dihydro 15 oxo PGF2 alpha to 13,14 dihydro 15 oxo PGE2. In these animals the rank order of prostanoid release from kidney slices was PGE2 greater than 6 oxo PGF1 alpha greater than PGF2 alpha greater than TxB2 = 0. The catabolism of 6 oxo PGE1 is also age-dependent. In 20 and 34 day old rats 6 oxo PGE1 and PGE1 incubated with renal 100,000 g supernates undergo loss of biological activity as determined by the ability to inhibit ADP induced human platelet aggregation. In contrast, kidney 100,000 g supernates prepared from 70 day rats convert 6 oxo PGE1 to an unidentified metabolite with more potent anti-aggregatory activity. The possibility that 6 oxo PGE1 has a biological role in the developing rat kidney is discussed.