==================================BSR34================================== 34. Spontaneous arthritis in rats or mice. I am particularly interested in reports of such in nude rats, but not limited to this strain. Also, arthritic rats as models of chronic pain. 1 UI - 87102962 AU - Johnson WJ ; DiMartino MJ ; Hanna N TI - Macrophage activation in rat models of inflammation and arthritis: determination of markers of stages of activation. AB - Disease-associated alterations in macrophage functions were assessed by investigating the stages of activation of peritoneal macrophages obtained from adjuvant-induced arthritic rats. The stages of activation were established by defining several functional parameters in macrophages obtained from normal, sterile-irritant injected and Propionibacterium acnes injected animals. Peritoneal macrophages taken from arthritic rats 17 days post adjuvant injection displayed parameters characteristic of activated, but not elicited or resident macrophages. Specifically, an increased number of macrophages was recovered from arthritic rats which spread readily in culture, exhibited enhanced Fc receptor-mediated phagocytosis, increased leucine aminopeptidase ectoenzyme activity, enhanced secretion of prostaglandin E2 and interleukin 1, and ability to lyse tumor cells spontaneously. In addition, these macrophages were impaired in their ability to secrete superoxide anion. These data demonstrate distinct differences in parameters of peritoneal macrophage activation in rats compared to mice and that macrophage activation is associated with disease progression in adjuvant-induced arthritic rats. MH - Animal ; Arthritis/*IMMUNOLOGY ; Arthritis, Adjuvant/*IMMUNOLOGY/ PATHOLOGY ; Cytotoxicity, Immunologic ; Inflammation ; Interferon Type II/ PHARMACODYNAMICS ; Interleukin 1/SECRETION ; Lipopolysaccharides/ PHARMACODYNAMICS ; *Macrophage Activation/DRUG EFFECTS ; Macrophages/ *IMMUNOLOGY/SECRETION ; Male ; Phagocytosis ; Prostaglandins E/SECRETION ; Rats ; Rats, Inbred LEW ; Superoxide/SECRETION ; Tetradecanoylphorbol Acetate/PHARMACODYNAMICS SO - Cell Immunol 1986 Nov;103(1):54-64 2 UI - 87085745 AU - Levine JD ; Dardick SJ ; Roizen MF ; Helms C ; Basbaum AI TI - Contribution of sensory afferents and sympathetic efferents to joint injury in experimental arthritis. AB - We used pharmacological and surgical methods to determine the contribution of several neural components to joint injury in rats with adjuvant-induced arthritis. Both neonatal administration of capsaicin, which eliminates small-diameter afferents, and peripheral sympathectomy, which depletes catecholamines, attenuated joint injury. In contrast, the arthritis was more severe in spontaneously hypertensive rats, which have increased sympathetic tone. To address the contribution of the central vs peripheral afferent terminal selectively, a group of rats underwent unilateral dorsal rhizotomy. These rats developed a more severe arthritis in the deafferented limb. The increase in arthritis severity produced by dorsal rhizotomy could be reduced by prior sympathectomy or, less effectively, by prior treatment with capsaicin. The latter observation suggests that large-diameter afferents that are cut during dorsal rhizotomy also influence inflammation. Finally, intracerebroventricular injection of morphine attenuated the severity of arthritis, possibly through activation of bulbospinal sympathoinhibitory circuits. Taken together, these data indicate that no one class of nerve fiber is wholly responsible for the neurogenic component of inflammation in experimental arthritis but that large- and small-diameter afferents, sympathetic efferents, and CNS circuits that modulate those fiber systems all influence the severity of joint injury in arthritic rats. MH - Animal ; Arthritis/*PATHOLOGY ; Arthritis, Adjuvant/COMPLICATIONS/ *PATHOLOGY ; Capsaicin/PHARMACODYNAMICS ; Ganglia, Spinal/PHYSIOLOGY ; Hypertension/COMPLICATIONS/PATHOLOGY ; Male ; Morphine/PHARMACODYNAMICS ; Neurons, Afferent/DRUG EFFECTS/*PHYSIOLOGY ; Neurons, Efferent/DRUG EFFECTS/*PHYSIOLOGY ; Rats ; Rats, Inbred Strains ; Rats, Inbred WKY ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. ; Sympathectomy ; Sympathetic Nervous System/*PHYSIOPATHOLOGY SO - J Neurosci 1986 Dec;6(12):3423-9 3 UI - 87040362 AU - Guilbaud G ; Peschanski M ; Briand A ; Gautron M TI - The organization of spinal pathways to ventrobasal thalamus in an experimental model of pain (the arthritic rat). An electrophysiological study. AB - The spinal ascending pathways responsible for neuronal ventrobasal (VB) thalamic responses elicited by joint stimulation of the posterior paw were determined in arthritic rats used as a model of experimental pain. Responses of a same neurone to mechanical (movement--pressure--brushing) or thermal stimulation (50 degrees C) were analysed before and after discrete lesions in the white matter of the spinal cord. For 6 neurones responding exclusively to brushing applied on a small receptive field (RF) strictly contralateral to the recording site, responses were not altered as long as the contralateral dorsal column was intact. Twenty neurones exhibited bilateral symmetrical RF located on the posterior paws including the ankles and for some units the digits. They were driven by moderate pressure and/or mild sustained joint movement and by immersion in a hot water bath at 50 degrees C. Their responses were not significantly modified when the lesions destroyed most of the dorsal and the dorsolateral parts of the spinal cord. In 16/20 cases effect of one hemisection of the cord was studied: when the hemisection was contralateral to the recording site (n = 8) VB neuronal responses elicited from the paw ipsilateral to this side were eliminated in 6/8 cases; when the 1/2 section was ipsilateral to the recording site (n = 8) the lesion induced the elimination of the responses elicited from the paw opposite to the recorded VB for one unit only. The involvement of the spino-reticular pathways which have not only a crossed but also a non-crossed component is suggested. This hypothesis is discussed by comparison to data previously obtained, showing that by contrast in healthy rats the spino-thalamic tract is essential for VB neuronal responses to noxious stimuli. MH - Afferent Pathways/PHYSIOPATHOLOGY ; Animal ; Arthritis, Adjuvant/ PHYSIOPATHOLOGY ; Disease Models, Animal ; Electrophysiology ; Neurons/ PHYSIOPATHOLOGY ; Pain/*PHYSIOPATHOLOGY ; Rats ; Spinal Cord/ *PHYSIOPATHOLOGY ; Thalamus/*PHYSIOPATHOLOGY SO - Pain 1986 Sep;26(3):301-12 4 UI - 87039681 AU - Braga PC ; Biella G ; Tiengo M ; Fraschini F TI - Depressant effects of suprofen, a new non-steroidal anti-inflammatory drug on thalamic evoked neuronal firing in arthritic rats. AB - The effects of suprofen, a new non-steroidal anti-inflammatory drug, (NSAID), the activity of which is mainly antinociceptive, were compared with those of aspirin (as a reference drug) in a study of spontaneous and evoked firing of thalamic neurons (nucleus lateralis and ventrobasalis) in rats rendered arthritic by injection of Freund's adjuvant into the paw. Suprofen (3.7 mg/kg, i.v.) induced a marked decrease in the firing evoked in arthritic rats by ankle mobilization. This effect, after a rapid onset, lasted on the average for 60 min. A similar effect was obtained with aspirin, but with 54 mg/kg (i.v.) (14 times more than suprofen). With increasing doses of suprofen, it was possible to obtain an increased long-lasting inhibition of the evoked activity, with a significant dose-effect linear regression. The possibility that there are both CNS and peripheral effects of suprofen is discussed in relation to the possible role of aspirin (the reference standard for NSAIDs) in enhancing presynaptic inhibition, thus reducing the effectiveness of incoming sensory stimuli. MH - Animal ; Anti-Inflammatory Agents, Non-Steroidal/*THERAPEUTIC USE ; Arthritis/*DRUG THERAPY ; Arthritis, Adjuvant/*DRUG THERAPY ; Aspirin/ THERAPEUTIC USE ; Depression, Chemical ; Drug Screening ; Electrophysiology ; Evoked Potentials/DRUG EFFECTS ; Male ; Neurons/*DRUG EFFECTS ; Phenylpropionates/*THERAPEUTIC USE ; Rats ; Rats, Inbred Strains ; Support, Non-U.S. Gov't ; Suprofen/*THERAPEUTIC USE ; Thalamus/ *DRUG EFFECTS SO - Neuropharmacology 1986 Sep;25(9):1055-62 5 UI - 87027511 AU - Kayser V ; Neil A ; Guilbaud G TI - Repeated low doses of morphine induce a rapid tolerance in arthritic rats but a potentiation of opiate analgesia in normal animals. AB - The effect of repeated low doses of morphine (0.3-3 mg/kg s.c., twice daily for 4 days) on subsequent sensitivity to the antinociceptive effect of morphine was tested in arthritic and normal rats. Chronic morphine induces tolerance in arthritic rats. This tolerance develops rapidly since it is clearly present after one day of treatment. By contrast, in normal animals similarly treated, a potentiation of morphine analgesia was observed. MH - Animal ; Arthritis/*THERAPY ; Arthritis, Adjuvant/*THERAPY ; Drug Tolerance ; Male ; Morphine/ADMINISTRATION & DOSAGE/*THERAPEUTIC USE ; Pain/*DRUG THERAPY ; Rats ; Rats, Inbred Strains ; Sensory Thresholds/ DRUG EFFECTS ; Support, Non-U.S. Gov't SO - Brain Res 1986 Sep 24;383(1-2):392-6 6 UI - 86295948 AU - Dardick SJ ; Basbaum AI ; Levine JD TI - The contribution of pain to disability in experimentally induced arthritis. AB - We examined the differential effects of disease severity and pain on morbidity (as measured by weight loss and decrease in activity) in rats with adjuvant-induced arthritis. We found that eliminating nociceptive messages from affected extremities, although not significantly affecting the course of the disease, attenuated the morbidity observed in arthritic rats. When pain was factored out, the severity of the arthritis had no significant effect on the same measures of morbidity. These findings suggest that treatment of pain may reduce morbidity, and thereby may have significant benefits beyond that provided by slowing of the disease process. MH - Animal ; Arthritis/*PHYSIOPATHOLOGY ; Body Weight ; Disease Models, Animal ; Male ; Motor Activity ; Nociceptors/PHYSIOPATHOLOGY ; Pain/ *PHYSIOPATHOLOGY ; Rats ; Rats, Inbred Strains ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. SO - Arthritis Rheum 1986 Aug;29(8):1017-22 7 UI - 86258709 AU - Godefroy F ; Butler SH ; Weil-Fugazza J ; Besson JM TI - Do acute or chronic tricyclic antidepressants modify morphine antinociception in arthritic rats? AB - In a chronic pain model, the arthritic rat, tricyclic antidepressants (TCAs) have been shown to clearly reduce behavioural signs of nociception. In the present work, using a test of acute nociception (vocalization threshold to graded foot pressure) in the same model, we evaluated the possible potentiation of morphine analgesia by 2 TCAs: amitriptyline (AMIT) and imipramine (IMIP). Using this test of acute nociception, we failed to demonstrate any analgesic effect of AMIT or IMIP given either acutely or chronically. We also failed to demonstrate any potentiation of morphine by these compounds. On the contrary, we found a significant decrease of morphine antinociception after acute AMIT administration and a tendency towards diminution with both TCAs given chronically. These results appear to temper enthusiasm for human application of this combination. They also indicate that careful further studies in a chronic pain model using behaviour evaluations are necessary before definite conclusions can be drawn concerning TCAs/opiate interaction. MH - Amitriptyline/THERAPEUTIC USE ; Animal ; Antidepressive Agents, Tricyclic/ *THERAPEUTIC USE ; Arthritis/*PHYSIOPATHOLOGY ; Arthritis, Adjuvant/ *PHYSIOPATHOLOGY ; Drug Synergism ; Drug Therapy, Combination ; Imipramine/THERAPEUTIC USE ; Male ; Morphine/THERAPEUTIC USE ; Nociceptors/DRUG EFFECTS ; Pain/*DRUG THERAPY/PHYSIOPATHOLOGY ; Rats ; Rats, Inbred Strains ; Sensory Thresholds/DRUG EFFECTS ; Support, Non-U.S. Gov't ; Vocalization, Animal SO - Pain 1986 May;25(2):233-44 8 UI - 86242404 AU - Tanaka I ; Yoshizumi H ; Tanaka Y ; Takeda S ; Kamei C ; Nakaya N ; Kitazumi K ; Tagami H ; Tasaka K TI - Pharmacological profiles of 2-carboxyphenyl-1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetate and 2-[(2-carboxyphenoxy)-carbonyl]phenyl-1-(4-chlorobenzoyl)-5-meth oxy-2- methylindole-3-acetate, new antiinflammatory agents. AB - When the effects of new antiinflammatory drugs, 2-carboxyphenyl-1-(4-chlorobenzoyl)-5-methoxy-2-methyl-indole-3-acetate (TB 219) and 2-[(2-carboxyphenoxy)carbonyl]phenyl-1-(4-chlorobenzoyl)-5- methoxy-2-methylindole-3-acetate (TB 220), were investigated in various experiments, the following results were obtained: 1. TB 219 and TB 220 showed remarkable inhibitory effects on carrageenin edema, ultraviolet erythema and adjuvant arthritis. Although TB 219 displayed almost equipotent or slightly more potent effect than those of indometacin and acemetacin, TB 220 was slightly less effective than these two reference drugs except for the therapeutic effect on adjuvant arthritis. 2. TB 219 and TB 220 inhibited the writhing syndrome induced by acetic acid and inflammatory hyperesthesia, and they provided a significant antipyretic activity. 3. Both drugs elicited almost negligible side effects in the gastrointestinal tract even after the repeated administrations. Especially, ulcerogenic activity of TB 220 was extremely weak. LD50's of both drugs are higher than that of indometacin in rats. 4. Both drugs elicited no appreciable changes in general behavior in mice and rats after oral administration. After intraperitoneal or intravenous injection of these two drugs, no marked changes in spontaneous EEG pattern and the spinal reflex were observed. MH - Analgesics, Anti-Inflammatory ; Animal ; Anti-Inflammatory Agents/ *PHARMACODYNAMICS ; Arthritis, Adjuvant/PREVENTION & CONTROL ; Capillary Permeability/DRUG EFFECTS ; Edema/PREVENTION & CONTROL ; Emotions/DRUG EFFECTS ; Erythema/PREVENTION & CONTROL ; Erythrocyte Membrane/DRUG EFFECTS ; Exploratory Behavior/DRUG EFFECTS ; Female ; Gastrointestinal System/DRUG EFFECTS ; Guinea Pigs ; Human ; In Vitro ; Indomethacin/ *ANALOGS & DERIVATIVES/BLOOD/PHARMACODYNAMICS ; Male ; Mice ; Rats ; Rats, Inbred Strains SO - Arzneimittelforschung 1986 Apr;36(4):703-9 9 UI - 86217185 AU - Kayser V ; Besson JM ; Guilbaud G TI - Analgesia produced by low doses of the opiate antagonist naloxone in arthritic rats is reduced in morphine-tolerant animals. AB - In a model of experimental chronic pain (adjuvant-induced arthritic rats), low doses of the opiate antagonist naloxone produced a profound analgesia. Maximum analgesia was seen with 3 micrograms/kg (i.v.). In contrast, hyperalgesia was obtained with much higher doses (1-3 mg/kg, i.v.). The hyperalgesic effects were not affected in arthritic animals rendered tolerant to morphine, but the paradoxical analgesic effects were significantly reduced. This decrease suggests that naloxone analgesia involves interaction with opiate receptors and that the operation of endorphinergic systems differs in normal animals and animals which experience persistent pain. MH - Animal ; Arthritis, Adjuvant/THERAPY ; Drug Tolerance ; Endorphins/ PHYSIOLOGY ; Male ; Morphine/*PHARMACODYNAMICS ; Naloxone/*THERAPEUTIC USE ; Pain/*DRUG THERAPY/PHYSIOPATHOLOGY ; Rats ; Rats, Inbred Strains ; Receptors, Endorphin/*DRUG EFFECTS ; Sensory Thresholds/DRUG EFFECTS ; Support, Non-U.S. Gov't SO - Brain Res 1986 Apr 16;371(1):37-41 10 UI - 86217123 AU - Calvino B ; Le Bars D TI - The response to viscero-peritoneal nociceptive stimuli is reduced in experimental arthritic rats. AB - Reciprocal inhibitory influences of heterotopic nociceptive stimuli have been known for centuries (counter-irritation phenomena). To assess whether such phenomena could be measured objectively in a chronic pain model, we have investigated the writhing behaviour induced by a viscero-peritoneal nociceptive stimulus (i.p. acetic acid) in arthritic rats. The latter was induced by s.c. injection of mycobacterium butyricum suspended in oil into the base of the tail and experiments carried out at various (1-9 weeks) post-inoculation periods. To assess the arthritis-induced hyperaesthesia, the threshold for struggle triggered by a calibrated pressure applied on an inflamed hindpaw (Randall-Selitto test) was measured before each experiment. A clear relationship was observed between the two parameters during the evolution of the disease. In the most severe phase (2nd to 5th week post-inoculation), when arthritis-induced hyperaesthesia was most pronounced (50% reduction of the threshold for struggle), writhing behaviour was strongly reduced (80%). At that time, writhing behaviour was enhanced by naloxone (0.4 mg/kg i.v.). In the following period (5-9 weeks), the progressive decrease of hyperaesthesia was correlated with a recovery of the writhing behaviour. We conclude that in this chronic pain model, the behavioral reaction to a viscero-peritoneal nociceptive stimulus is impaired. Endogenous opioid systems could be involved in this phenomenon. Such heterotopic inhibitory processes could be relevant to some paradoxical clinical observations such as the masking of a pain by the experience of pain at another locus. MH - *Abdomen ; Animal ; Arthritis/*PHYSIOPATHOLOGY ; Arthritis, Adjuvant/ *PHYSIOPATHOLOGY ; Central Nervous System/*PHYSIOPATHOLOGY ; Endorphins/ *PHYSIOLOGY ; Male ; Naloxone/DIAGNOSTIC USE ; Neural Transmission ; Pain/ *PHYSIOPATHOLOGY ; Rats ; Rats, Inbred Strains ; Sensory Thresholds SO - Brain Res 1986 Apr 2;370(1):191-5 11 UI - 86198883 AU - Millan MJ ; Millan MH ; Cz:onkowski A ; H:ollt V ; Pilcher CW ; Herz A ; Colpaert FC TI - A model of chronic pain in the rat: response of multiple opioid systems to adjuvant-induced arthritis. AB - Chronic arthritic pain was induced by intradermally inoculating rats at the tail-base with Mycobacterium butyricum, which results in swelling, inflammation, and hyperalgesia of the joints. These symptoms peak at 3 weeks after inoculation and disappear by 10 weeks. The following changes were seen at 3 weeks. Immunoreactive dynorphin (ir-Dyn) and ir-alpha-neo-endorphin (alpha-NE) manifested comparable patterns of change. Their levels were increased in the anterior, but not neurointermediate, pituitary. The thalamus showed a rise in ir-Dyn and ir-alpha-NE, but no alterations were seen in other brain regions. In each case, cervical, thoracic, and lumbosacral sections of the spinal cord showed a rise in ir-Dyn and ir-alpha-NE: This was most pronounced in the lumbosacral region, where the magnitude of these shifts correlated with the intensity of arthritic symptoms. In addition, a moderate elevation in ir-methionine-enkephalin (ME) was seen in lumbosacral spinal cord. In brain, ir was not changed. The level of ir-beta-endorphin (beta-EP) was elevated both in the plasma and the anterior, but not the neurointermediate, pituitary. In addition, the content of messenger RNA encoding the beta-EP precursor, proopiomelanocortin (POMC), was enhanced in the anterior lobe. Thus, there was a selective activation of synthesis of beta-EP in, and its secretion from, the anterior lobe. In no brain tissue did levels of ir-beta-EP change. At 10 weeks postinoculation, the above changes were no longer apparent, indicating their reversibility.(ABSTRACT TRUNCATED AT 250 WORDS) MH - Animal ; Arthritis/*METABOLISM ; Arthritis, Adjuvant/*METABOLISM ; Brain/ *METABOLISM ; Brain Chemistry ; Chronic Disease ; Diprenorphine/ METABOLISM ; Disease Models, Animal ; Dynorphin/ANALYSIS/METABOLISM ; Endorphins/ANALYSIS/*METABOLISM/PHYSIOLOGY ; Hypothalamus/ANALYSIS/ METABOLISM ; Male ; Mesencephalon/ANALYSIS/METABOLISM ; Pain/*METABOLISM/ PHYSIOPATHOLOGY ; Rats ; Rats, Inbred Strains ; Receptors, Endorphin/ ANALYSIS/METABOLISM/PHYSIOLOGY ; Spinal Cord/*METABOLISM ; Support, Non-U.S. Gov't ; Thalamus/ANALYSIS/METABOLISM SO - J Neurosci 1986 Apr;6(4):899-906 12 UI - 86190652 AU - Tarkowski A ; Holmdahl R ; Rubin K ; Klareskog L ; Nilsson LA ; Gunnarsson K TI - Patterns of autoreactivity to collagen type II in autoimmune MRL/l mice. AB - The kinetics and mechanisms for secretion of antibodies against native and denatured collagen type II have been studied in spontaneously arthritic MRL/l mice. Circulating antibodies were quantified by an ELISA assay and frequencies of specific antibody secreting spleen cells by an ELISPOT assay. The degree of humoral immunity to collagen type II increased at late stages of the disease (6 months of age) whereas severe synovitis was seen earlier (5 months of age). Both the appearance of anti-collagen II producing cells and development of synovitis was preceded by and not correlated with a general state of polyclonal B cell activation. In MRL/l mice, collagen II specific antibodies appeared spontaneously and titres were largely unaffected by collagen II immunization. The levels of circulating anti-collagen II antibodies in MRL/l mice were lower, and the antibodies displayed lower avidities and different specificities as compared with the antibodies generated in collagen II high responder DBA/l mice after immunization with collagen II. It is suggested that the antibody response in MRL/l mice against collagen type II does not need MHC-restricted T cell help and that induction of antibody production to collagen II in MRL/l mice is triggered by joint cartilage destruction and subsequent collagen II release. MH - Aging ; Animal ; Antibody Affinity ; Antibody-Producing Cells/IMMUNOLOGY ; Arthritis/*IMMUNOLOGY ; Autoantibodies/*BIOSYNTHESIS ; Autoimmune Diseases/*IMMUNOLOGY ; Collagen/*IMMUNOLOGY ; Female ; IgG/BIOSYNTHESIS ; Immunoenzyme Technics ; Male ; Mice ; Mice, Inbred Strains ; Support, Non-U.S. Gov't SO - Clin Exp Immunol 1986 Feb;63(2):441-9 13 UI - 86185210 AU - Harris JP ; Woolf NK ; Ryan AF TI - A reexamination of experimental type II collagen autoimmunity: middle and inner ear morphology and function. AB - Type II collagen autoimmunity has been reported to result in a number of middle and inner ear morphological and functional abnormalities. We investigated the immunological, electrophysiological, and anatomical effects of this autoimmune state in well-established Wistar-Furth rat models of type II collagen autoimmune arthritis. Seventeen animals immunized with bovine type II collagen were divided into short term (1-3 months postimmunization) and long term (9-11 months) groups. Thirty-three experimental ears were tested electrophysiologically and were compared to nine ears of unimmunized Wistar-Furth rats. No hearing loss was found in the immunized animals, except for four animals that showed middle ear abscess formation consistent with spontaneous, purulent otitis media. All immunized animals showed very significant serum and perilymph antibody titers to type II collagen. No morphological abnormalities of the external, middle, or inner ears could be identified in the noninfected experimental animals. These findings do not support previously reported observations that type II collagen autoimmunity results in ear disease. MH - Animal ; Antibodies/ANALYSIS ; Arthritis/*IMMUNOLOGY/PATHOLOGY/ PHYSIOPATHOLOGY ; Autoimmune Diseases/*IMMUNOLOGY/PATHOLOGY/ PHYSIOPATHOLOGY ; Cochlear Microphonic Potentials ; Collagen/*IMMUNOLOGY ; Ear, Middle/PATHOLOGY ; Evoked Potentials, Auditory ; Labyrinth/ PATHOLOGY ; Otitis Media with Effusion/PHYSIOPATHOLOGY ; Rats ; Rats, Inbred WF ; Support, U.S. Gov't, Non-P.H.S. ; Support, U.S. Gov't, P.H.S. ; Temporal Bone/PATHOLOGY SO - Ann Otol Rhinol Laryngol 1986 Mar-Apr;95(2 Pt 1):176-80