Release of algesic substances in human experimental muscle pain.

OBJECTIVE: We employed the 'delayed onset of muscle soreness' (DOMS) and the 'hypertonic saline' muscle pain models in combination with muscle microdialysis to evaluate the role of potentially algesic substances (lactate, glutamate, prostaglandin E2 (PGE2), nitric oxide (NO) and substance P (SP)) in the development of human muscle pain. METHODS: DOMS was induced by 2 sets of 50 concentric/eccentric contractions of the calf muscles 24 h before the start of microdialysis. During microdialysis pain was stimulated through calf muscle contractions (dorsal and plantar flexions of the foot). Hypertonic saline was injected into the biceps muscle (5 x 200 microl 5.8% NaCl, 2 min interval) during dialysis. The calf (no treatment) and biceps (normal saline) of the other side was used as control. RESULTS: Both models reliably induced muscle pain with similar intensities as assessed by visual analog scale. The DOMS exercise caused an increase of lactate in serum and the calf muscles of the DOMS leg. In addition, glutamate, PGE2 and substance P dialysate concentrations increased following contraction-induced pain stimulation (peak concentrations 125 +/- 20 microM, 239 +/- 45 pg/ml and 60 +/- 11 pg/ml for glutamate, PGE2 and SP, respectively). This increase did not occur in the control leg (peak concentrations 97 +/- 12 microM, 114 +/- 26 pg/ml and 46 +/- 9 pg/ml for glutamate, PGE2 and SP, respectively). Concentrations of nitric oxide were lower in the DOMS than control leg, particularly during the first 4h of microdialysis. Injection of hypertonic saline into the biceps muscle caused a significant increase of dialysate glutamate concentrations (peak 50 +/- 3 microM) whereas glutamate remained constant after injection of normal saline (mean 26 +/- 1 microM). Injection of hypertonic saline had no effect on lactate, PGE2 or NO levels. CONCLUSION: Our data support the notion that an inflammatory reaction may be involved in muscle soreness following eccentric exercise, whereas the injection of hypertonic saline into the muscle probably directly stimulates muscle nociceptors and causes glutamate release.

Vertebral compression fractures in acute lymphoblastic leukaemia and remodelling after treatment.

Three children, aged 7-10 years, with acute lymphoblastic leukaemia presented with back pain, along with a mild kyphosis. Collapse of the vertebral bodies at multiple levels was shown on imaging. Chemotherapy resulted in pain resolution and spontaneous remodelling of the vertebrae.

Jejunal or portal vein infusions of lipids increase hepatic vagal afferent activity.

Jejunal infusions of linoleic acid, corn oil, or caprylic acid significantly increased hepatic vagal afferent activity, whereas saline infusions were ineffective. The magnitude of response was greatest with either linoleic acid or corn oil. Hepatic portal infusions of linoleic acid, Liposyn II, or caprylic acid significantly increased hepatic vagal afferent activity, whereas 5% albumin/phosphate buffer vehicle was ineffective. The magnitude of response was greatest with either linoleic acid or Liposyn II. These data show that either jejunal or portal infusions of lipids increase activity of hepatic vagal afferents and could potentially serve as a complementary and/or alternative substrate to celiac vagal afferents in mediating the effects of jejunal infusions of lipids in suppressing food intake.

Comparison of tissue concentrations after intramuscular and topical administration of ketoprofen.

PURPOSE: To assess whether topical ketoprofen, which has been reported to provide analgesic effects in clinical studies, reaches predictable tissue concentrations high enough to account for the reported analgesia. Intramuscular ketoprofen was used as positive control. METHODS: Muscle and subcutaneous tissue concentrations were assessed by microdialysis. Plasma and tissue concentrations after intramuscular injection were described using a three-compartment population pharmacokinetic model. The prediction performance of the model was assessed by superimposing tissue concentrations of 12 subjects that did not participate in the present study. RESULTS: Most dialysate concentrations after topical dosing of ketoprofen (100 mg) were below the quantification limit of 0.47 ng/ml. Plasma concentrations increased slowly and reached an apparent plateau of 7-40 ng/ml at 10-12h. No decline was observed up to 16 h. Tissue concentrations after intramuscular injection (100 mg) were about 10 times higher than those after topical dosing. Tissue concentrations measured in the majority of the 12 subjects that did not participate in the present study were found within the range of two-thirds of the predicted concentrations. CONCLUSION: Predictable and cyclooxygenase-inhibiting concentrations of ketoprofen were achieved in subcutaneous and muscle tissue after intramuscular but not after topical dosing. Thus, the tissue concentrations of ketoprofen after topical administration can hardly explain the reported clinical efficacy of topical ketoprofen.

Celiac vagotomy reduces suppression of feeding by jejunal fatty acid infusions.

We investigated the role of the celiac branch of the vagus nerve in suppression of food intake produced by jejunal fatty acids infusions. Following selective celiac vagotomy or sham surgery, adult, male Sprague-Dawley rats received 7 h infusions of linoleic acid or saline through indwelling jejunal catheters on four consecutive days. Although linoleic acid still produced significant suppression of intake in rats with celiac vagotomy, it was less effective in these animals than in controls. The temporal pattern of results suggested that celiac afferent fibers are involved in mediating both pre- and postabsorptive effects of infused fatty acids.

Autologous bone marrow transplantation for childhood acute lymphoblastic leukaemia in second remission - long-term follow-up.

From 1984 to 1996, 31 consecutive children without sibling donors, aged 5-19 years (median 8) with acute lymphoblastic leukaemia (ALL) in second complete remission (CR), received unpurged autologous bone marrow transplantation (ABMT) after melphalan and single fraction total body irradiation (TBI). ABMT was performed using fresh unmanipulated marrow harvested after standard reinduction and consolidation therapy 2-11 months (median 5) after relapse. With a median survival of 2.9 years the probability of survival for all patients in continuing second CR was 45.1% (95% CI, 24%-62%) after 5 years. Regimen-related and non-leukaemia mortality was 7% (95% CI, 2%-26%). The longest time to second relapse from ABMT was 3.1 years. Pituitary and gonadal dysfunction requiring hormonal replacement therapy occurred in the majority of long-term survivors. Twelve patients developed cataracts. ABMT with melphalan/single fraction TBI has proved an effective anti-leukaemia treatment with low regimen-related mortality but significant long-term morbidity. The current approach of allogeneic BMT from an unrelated donor when no sibling donor is available, following conditioning with cyclophosphamide/ fractionated TBI has resulted in a reduced relapse rate and improved short-term overall survival in the treatment of relapsed childhood ALL. However, long-term results are awaited.

Suppression of food intake, body weight, and body fat by jejunal fatty acid infusions.

Three experiments investigated effects of jejunal lipid infusions given on 4 or 21 consecutive days in adult, male Sprague-Dawley rats. In experiment 1, 7-h infusions of linoleic or oleic acid (0.2 ml/h for 7 h; total load = 11.5 kcal) on 4 consecutive days reduced total intake (ad libitum consumption of the liquid diet Boost, Mead Johnson, plus load) by approximately 15% and decreased weight gain compared with 4-day tests with saline administration. In experiment 2, linoleic acid at 0.1 ml/h for 7 h (5.7 kcal) was ineffective, whereas the same load delivered in 3.5 h produced effects similar in magnitude to those in the first experiment. In experiment 3, jejunal infusions of linoleic acid (0.2 ml/h for 7 h) on 21 consecutive days reduced mean total intake by 16%, body weight by 10%, and carcass fat by 48% compared with controls receiving saline. The net decrease in caloric intake may reflect the combined activation of pre- and postabsorptive mechanisms, and it suggests a possible treatment for obesity.

Responses of celiac and cervical vagal afferents to infusions of lipids in the jejunum or ileum of the rat.

Multiunit celiac and single-unit cervical recordings of vagal afferents were performed before and during infusions of fatty acids, triglycerides, or saline into either the ileum or jejunum of the rat. In multiunit recordings, lipids increased activity of vagal afferents to a greater extent than saline. The greatest increases in vagal afferent activity resulted from infusions of linoleic acid, conjugated linoleic acid, or oleic acid. The triglycerides, corn oil or Intralipid, were less effective than the fatty acids in affecting vagal afferent activity. Ileal pretreatment with the hydrophobic surfactant Pluronic L-81 significantly attenuated the response of celiac vagal afferents to ileal infusion of linoleic acid. Single-unit recordings of cervical vagal afferents supported the multiunit data in showing lipid-induced increased vagal afferent activity in approximately 50% of ileal units sampled and 100% of a limited number of jejunal units sampled. These data demonstrate that free fatty acids can activate ileal and jejunal vagal afferents in the rat, and this effect can be attenuated by pretreatment with a chylomicron inhibitor. These data are consistent with the view that lipid-induced activation of vagal afferents could be a potential substrate for the inhibitory effects of intestinal lipids on gastrointestinal function, food intake, and body weight gain.

Sexually dimorphic and radiation dose dependent effect of cranial irradiation on body mass index.

OBJECTIVES: To investigate the relation between cranial irradiation received during treatment for childhood leukaemia and obesity at final height. DESIGN: Retrospective cross sectional study. SETTING: Paediatric oncology centres at Great Ormond Street Hospital for Children and the Royal Marsden Hospital. SUBJECTS: Survivors of childhood leukaemia who received cranial irradiation, were in continuous first remission, and had reached final height. An unirradiated group of patients from the United Kingdom acute lymphoblastic leukaemia XI trial was also included; these patients were in continuous first remission and had been followed for at least four years from diagnosis. MAIN OUTCOME MEASURES: Body mass index standard deviation score (BMI z score) at final height for irradiated patients and at most recent follow up for unirradiated patients. Regression analysis was used to examine the effect on BMI z score of sex, age at diagnosis, and the dose of radiation received. RESULTS: For cranially irradiated patients, an increase in the BMI z score at final height was associated with female sex and lower radiation dose, but not with age at diagnosis. Severe obesity, defined as a BMI z score of > 3 at final height, was only present in girls who received 18-20 Gy irradiation and had a prevalence of 8%. Both male and female unirradiated patients had raised BMI z scores at latest follow up and there was no association with age at diagnosis. CONCLUSIONS: These data are further evidence for a sexually dimorphic and dose dependent effect of radiation on the human brain.

Localization and changes in NADPH-diaphorase reactivity and nitric oxide synthase immunoreactivity in rat pulp following tooth preparation.

Inflammatory changes in the dental pulp are accompanied by release of a wide variety of chemical mediators. Nitric oxide, an oxidative free radical produced by the enzyme nitric oxide synthase (NOS), has been implicated in multiple inflammatory processes, which makes it a suitable marker for changes which likely occur following tooth pulp insult. Since limited information on nitric oxide in the pulp is available, it is necessary first to examine relative distributions of NOS in uninflamed and inflamed rat pulp. We accomplished this by characterizing regions of nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) activity and the distribution of both macrophage NOS (macNOS) and neuronal NOS (nNOS) immunoreactivity in normal and inflamed rat molar pulp at multiple time points. The results showed that: (1) deep cavity preparation on the mesial surface of the molar produced a time-dependent inflammation, with acute inflammation early progressing to chronic, granulomatous inflammation with necrosis later that spread preferentially down the mesial root; (2) control (non-prepared) teeth showed a relatively faint and homogeneous distribution of NADPH-d and macNOS reactivity but no discernible nNOS reactivity; (3) inflamed teeth displayed localized increased intensity of NADPH-d and macNOS reactivity surrounding the inflamed area of pulp, but no increased nNOS activity; (4) pulp vessels supplying the inflamed area showed increased NADPH-d reactivity, but no increased macNOS or nNOS reactivity; and (5) neither NADPH-d, macNOS, nor nNOS reactivity was observed in pulpal nerves. Therefore, nitric oxide may mediate the pulpal inflammatory response through its effects on the paralesional pulp tissue and surrounding endothelial/vascular structures.

The antitussive effect of dextromethorphan in relation to CYP2D6 activity.

AIMS: To test the hypothesis that inhibition of cytochrome P450 2D6 (CYP2D6) by quinidine increases the antitussive effect of dextromethorphan (DEX) in an induced cough model. METHODS: Twenty-two healthy extensive metaboliser phenotypes for CYP2D6 were studied according to a double-blind, randomised cross-over design after administration of: (1) Placebo antitussive preceded at 1 h by placebo inhibitor; (2) 30 mg oral DEX preceded at 1 h by placebo inhibitor (DEX30); (3) 60 mg oral DEX preceded at 1 h by placebo inhibitor (DEX60); (4) 30 mg oral DEX preceded at 1 h by 50 mg oral quinidine sulphate (QDEX30). Cough frequency following inhalation of 10% citric acid was measured at baseline and at intervals up to 12 h. Plasma concentrations of DEX and its metabolites were measured up to 96 h by h.p.l.c. RESULTS: Inhibition of CYP2D6 by quinidine caused a significant increase in the mean ratio of DEX to dextrorphan (DEX:DOR) plasma AUC(96) (0.04 vs 1.81, P<0.001). The mean (+/-s.d.) decrements in cough frequency below baseline over 12 h (AUEC) were: 8% (11), 17% (14.5), 25% (16.2) and 25% (16.9) for placebo, DEX30, DEX60 and QDEX30 treatments, respectively. Statistically significant differences in antitussive effect were detected for the contrasts between DEX60/placebo (P<0.001; 95% CI of difference +80, +327) and QDEX30/placebo (P<0.001, +88, +336), but not for DEX30/placebo, DEX30/DEX60 or DEX30/QDEX30 (P=0.071, -7, +241; P=0.254, -37, +211; P=0.187, -29, +219, respectively). CONCLUSIONS: A significant antitussive effect was demonstrated after 60 mg dextromethorphan and 30 mg dextromethorphan preceded by 50 mg quinidine using an induced cough model. However, although the study was powered to detect a 10% difference in cough response, the observed differences for other contrasts were less than 10%, such that it was possible only to imply a dose effect (30 vs 60 mg) in the antitussive activity of DEX and enhancement of this effect by CYP2D6 inhibition.

Successful treatment of Aspergillus fungaemia in two children with acute lymphoblastic leukaemia.

Aspergillus species can cause life-threatening infection in immunocompromised children. Pulmonary infections are the most common, and are usually acquired through inhalations of aspergillus spores in unfiltered air. Some patients acquire invasive aspergillus infection from endogenous spread of colonized para-nasal sinuses.

Conservative management of follicular non-Hodgkin's lymphoma in childhood.

Among 447 children with non-Hodgkin's lymphoma (NHL) on the childhood U.K. registry, seven children with follicular (NHL) were identified. Four were male and their age ranged from 4.25 to 13.5 years (median 7.5); all had localized disease, Murphy's stage I (n = 4) and II (n = 3). Sites involved at presentation were cervical lymph nodes and tonsils (n = 5), ileum (n = 1) and parotid gland (n = 1). Three had complete surgical excision only and four had complete (n = 1) or incomplete excision (n= 3) followed by a short multi-agent chemotherapy regimen (UKCCSG 9001 protocol). With a median follow-up of 1.5 years (range 0.25-5 years) from diagnosis, six are alive in complete remission (CR) including three who had no chemotherapy. These results confirm previous reports that follicular lymphomas in children are rare (1.5%) and tend to be localized at presentation. Their rarity makes it difficult to produce guidelines about treatment, but in localized cases a period of non-intervention may be justified.

The role of steroids and their effects on phospholipase A2. An animal model of radiculopathy.

STUDY DESIGN: The possible role of phospholipase A2 in an animal model for lumbar radiculopathy and mechanisms of epidural steroid injections were studied. OBJECTIVES: To clarify the pathophysiologic mechanism of the recently proved animal model for lumbar radiculopathy and to characterize further the mechanisms of action of steroids. SUMMARY OF BACKGROUND DATA: There have been several reported animal models of peripheral neuropathy. Recently an animal model that shows reliable behavioral and neurochemical changes was proposed, and epidural steroid injections in this model were effective in the reduction of thermal hyperalgesia and allodynia. METHOD: In a behavioral study, 24 rats were divided into 4 groups: Group I, loose ligature of the left L4 and L5 nerve roots with 4-0 chromic gut sutures and an epidural injection of 0.1 mL of saline at 3 days after surgery; Group II, same as Group I but with an epidural injection of 0.1 mL of betamethasone on the day before the operation; Group II, same as Group II except injection at 1 day after surgery; Group IV, same as Group II except injection at 3 days after surgery. To test the phospholipase A2 activity in the nerve roots and dorsal root ganglia after the operation, eight rats were killed at given intervals. Analysis of variance techniques were used to test behavioral pattern changes and phospholipase A2 activity across time in each group. RESULTS: Thermal hyperalgesia reached its maximal point at 3 weeks after surgery in Group I, but in steroid injection groups, the recovery from hyperalgesia was faster than in Group I. However, there was no significant difference in recovery time among steroid injection groups. The level of phospholipase A2 activity was at its maximum at 1 week after surgery in Groups I and IV. It showed a steady reduction in the steroid group, whereas it remained relatively high and dropped rapidly after 3 weeks in the saline-treated group, and returned to the level of a normal nerve root at 6 weeks after surgery. CONCLUSION: These results suggest that the behavioral pattern changes observed in the irritated nerve root model are caused in part by a high level of phospholipase A2 activity initiated by inflammation, and that the mechanism of action of epidural steroid injection in this model is inhibition of phospholipase A2 activity.

The effect of epidural injection of betamethasone or bupivacaine in a rat model of lumbar radiculopathy.

STUDY DESIGN: The effect of epidural injection of betamethasone or bupivacaine was investigated in an animal model of lumbar radiculopathy. OBJECTIVE: To investigate the effects of an epidural steroid (betamethasone) or a local anesthetic (bupivacaine) in an animal model of radiculopathy produced by nerve root irritation. SUMMARY OF BACKGROUND DATA: Epidural injections are commonly used for the treatment of low back pain and sciatica. However, efficacy remains controversial, and there is a paucity of basic information to support clinical use or the injections. METHODS: Fifty-one rats were used. The left L4 and L5 nerve roots were loosely ligated with chromic gut, and either betamethasone, bupivacaine, betamethasone in combination with bupivacaine, or saline was injected using an epidurally placed catheter. The effects of epidural injection were evaluated using response to noxious stimuli and immunohistochemical methods. RESULTS: In betamethasone-treated rats (either alone or in combination with bupivacaine), thermal hyperalgesia was significantly less (P < 0.010 after surgery than that in saline- or bupivacaine-treated groups, in which the hyperalgesia was maximum at 2-3 postoperative weeks before resolving 5 weeks after surgery. Immunohistochemical analysis did not correlate with these results. CONCLUSIONS: Epidural steroid injection has a significant effect on the thermal hyperalgesia produced in a model of radiculopathy, which may provide clinical support for advocates of epidural steroids.

Responses of primary afferents and spinal dorsal horn neurons to thermal and mechanical stimuli before and during zymosan-induced inflammation of the rat hindpaw.

Intraplantar administration of zymosan produces inflammation and results in behavioral evidence of hyperalgesia to mechanical and thermal stimuli in the rat. In the present studies, responses of primary afferents and spinal dorsal horn neurons to mechanical and thermal stimuli were examined before and during zymosan-induced inflammation of the hindpaw. In tests of responses of primary afferents to mechanical stimuli, group mean mechanical response thresholds of C-mechanonociceptor (CMN) units significantly decreased after zymosan administration. The group mean mechanical response thresholds of low threshold mechanoreceptor (LTM) units, A-mechanoheat (AMH) units, high threshold mechanoreceptor (HTM) units, and C-mechanoheat (CMH) units showed either no change or were increased significantly by intraplantar administration of zymosan. The group mean total discharges evoked during the 10 s mechanical stimulus were significantly increased after zymosan administration in CMN units. The group mean total discharges were either significantly decreased or unchanged in LTM, AMH, HTM, and CMH units. In tests of responses of spinal dorsal horn neurons to mechanical stimuli, the group mean mechanical response threshold of nociceptive specific (NS) units decreased significantly 1 h following administration of zymosan, whereas no significant changes occurred in the mechanical response thresholds of wide dynamic range (WDR) neurons in zymosan-injected rats, WDR neurons in saline-injected rats, or NS neurons in saline-injected rats. The group mean total discharges of only NS neurons were significantly increased during the 10 s mechanical stimulus 3 and 4 h after zymosan administration. In tests of responses of primary afferents to thermal stimuli, intraplantar administration of zymosan resulted in significant decreases in group mean response thresholds of CMH units and significant increases in group mean response thresholds of AMH units. The group mean total discharges of CMH units was either unchanged or significantly increased during thermal stimuli depending on both the time of testing and the temperature of the test stimulus. The group mean total number of discharges of AMH units was significantly decreased during tests of all thermal stimuli. In tests of responses of spinal dorsal horn neurons to thermal stimuli, intraplantar administration of zymosan resulted in significant decreases in thermal response thresholds of both WDR and NS units of zymosan-injected rats, but no changes in WDR and NS units of saline-injected rats. The group mean total discharges evoked by the 15 s thermal stimuli also increased significantly in both WDR and NS units after zymosan administration. Zymosan administration resulted in increased background activity only in CMH units. These increases occurred immediately following the injection and dissipated by the first hourly test period. Significant changes in background discharges of both WDR and NS units occurred at some hourly test intervals following administration of zymosan, but these changes were not consistent with respect to either unit type or modality of the test stimulus. These data suggest that the zymosan-induced hyperalgesia to mechanical stimuli observed in behavioral studies reflects decreases in response thresholds of peripheral CMN units and spinal NS neurons. Hyperalgesia to thermal stimuli reflects decreases in response thresholds of peripheral CMH units, spinal WDR neurons, and spinal NS neurons. These data support the view that different physiological substrates mediate hyperalgesia to either thermal or mechanical stimuli following intraplantar administration of zymosan.

Responses of T2-4 spinal cord neurons to irritation of the lower airways in the rat.

The aim of the study was to investigate the information processing in the thoracic spinal cord (T2-4) after chemical irritation of the lower airways. Experiments were performed in pentobarbital sodium-anesthetized and pancuronium-paralyzed male Sprague-Dawley rats. Balloon distension of the esophagus was used as the search stimulus. Ammonia and smoke were applied by means of a tracheal cannula; they produced excitatory, inhibitory, and biphasic responses in a concentration-related manner (ammonia 39/39; smoke 23/ 39). Inhaled irritant-responsive neurons exhibited a number of similarities that have been described for neurons responding to stimulation of other thoracic viscera. These similarities relate to the distribution of neurons in the deeper laminae of the thoracic spinal cord, the relatively small number of neurons receiving input from the lower airways, the extensive convergent input from the skin and other thoracic viscera, and the pattern of responses. In addition, both stimulus-induced responses and spontaneous activity are subject to modulation from supraspinal sites. On the basis of responses to inhaled irritants after either spinal cord or vagus nerve block/transection, these T2-4 spinal neurons are likely to receive spinal afferent input that is modulated by vagal-brain stem input.

The role of phospholipase A2 and nitric oxide in pain-related behavior produced by an allograft of intervertebral disc material to the sciatic nerve of the rat.

STUDY DESIGN: To elucidate the pathomechanisms of radicular pain secondary to lumbar disc herniation. OBJECTIVES: To evaluate whether intervertebral disc material applied to the sciatic nerve produces hyperalgesia, and if the hyperalgesia in influenced by inhibitors of phospholipase A2 and nitric oxide synthase. SUMMARY OF BACKGROUND DATA: Previously, the authors reported that application of nucleus pulposus and anulus fibrosus material to the lumbar epidural space produces different forms of hyperalgesia (mechanical versus thermal), with different and distinct histologic changes. Additional pharmacologic studies showed that phospholipase A2 and nitric oxide are involved in the mechanisms that produce the mechanical and thermal hyperalgesia, respectively, N omega-nitro-L-arginine methyl ester and mepacrine are relatively selective inhibitors of nitric oxide synthase and phospholipase A2, respectively. However, it is not known what the relation is between the hyperalgesia produced and the activation and involvement of phospholipase A2 and production of nitric oxide, or why the application of nucleus pulposus and nucleus pulposus with anulus fibrosus produces different types of hyperalgesia. METHODS: Experiments were performed in five groups of rats: The control group (no treatment), the sham group (exposure of the sciatic nerve only), the fat group (allografted fat on the sciatic nerve), the nucleus pulposus group (allografted nucleus pulposus) and the nucleus pulposus + anulus fibrosus group (allografted nucleus pulposus and anulus fibrosus). Withdrawal threshold and latency from mechanical pressure and a radiant heat to hind paws were measured preoperatively and postoperatively. After local sciatic nerve administration of N theta-nitro-L-arginine methyl ester or mepacrine into the operated site, sensitivities to noxious stimuli were reevaluated after treatment. RESULTS: Only rats in the nucleus pulposus group showed evidence of mechanical hyperalgesia. However, injection of N theta-nitro-L-arginine methyl ester resulted in evidence of mechanical hyperalgesia in the nucleus pulposus + anulus fibrosus group. Mechanical hyperalgesia was produced in the nucleus pulposus group and after injection of N theta-nitro-L-arginine methyl ester in the nucleus pulposus+anulus fibrosus group, both of which returned to normal after mepacrine injection. There were no significant changes in sensitivity to thermal stimuli in any of the experimental groups. CONCLUSION: It appears that phospholipase A2 and nitric oxide play important but different roles in pathomechanisms of radicular pain in lumbar disc herniation.

Donor lymphocyte infusion for childhood acute lymphoblastic leukaemia relapsing after bone marrow transplantation.

Four children with acute lymphoblastic leukaemia (ALL) who relapsed after allogeneic bone marrow transplantation (BMT) were treated with donor lymphocyte infusion (DLI) without prior conditioning. Three patients had previously received a non-T-cell-depleted matched sibling BMT and the fourth had a T-cell-depleted matched unrelated BMT. Two patients developed grade III-IV acute graft-versus-host-disease (GVHD) of the skin, which required intervention. Both are alive in complete haematological remission 7 and 10 months from DLI with chronic GVHD of the skin requiring immunosuppressive therapy. A third patient went into haematological remission 6 weeks after DLI, but with no clinical evidence of GVHD. His bone marrow remained in remission 11 months post-DLI despite the disease (ALL) relapsing in extramedullary sites. The fourth patient showed no clinical or haematological response to three consecutive doses of DLI given at 4-weekly intervals and died from progressive disease 11 months after relapse. These preliminary observations indicate that in constrast to experience in adult ALL, DLI may be effective in inducing sustained remission in children with ALL relapsing after BMT, and a response may occur even in the absence of clinical evidence of GVHD.

Intraplantar zymosan as a reliable, quantifiable model of thermal and mechanical hyperalgesia in the rat.

The study of the mechanisms of thermal and mechanical hyperalgesia produced in human inflammatory conditions is dependent on a reliable, consistent model. The present investigation shows that the intraplantar administration of zymosan in the rat hindpaw produces a reliable and quantifiable thermal and mechanical hyperalgesia accompanied by oedema that closely mimics the symptoms of inflammation in man. Prior to the intraplantar injection of zymosan, there was no significant difference in withdrawal latencies, mechanical withdrawal thresholds or paw thickness between the left and right hindpaws. The intraplantar injection of zymosan (0.313-6.25 mg), an extract from yeast, produced a dose- and time-dependent thermal and mechanical hyperalgesia, a robust oedema and, at the greatest doses, produced evidence of spontaneous pain. At the least dose of zymosan tested (0.313 mg), there was a slight oedema; oedema was greatest at dosages > or =2.5 mg and was always maximal by 30 min postinjection, irrespective of the dose. On the other hand, thermal and mechanical hyperalgesia showed a more complex dose- and time-dependence. Mechanical hyperalgesia did not appear until dosages > or =1.25 mg and was maximal by 5 mg. In addition, mechanical hyperalgesia showed a time-dependent progressive onset so that hyperalgesia was maximal by the 4-h testing time-point. In contrast, thermal hyperalgesia showed a biphasic nature with two apparent maximal time-points (30 min and 4 h). There was an early-phase thermal hyperalgesia (maximal by 30 min) that was dose-dependent at dosages > or =2.5 mg (not apparent at lower dosages) and a late-phase (maximal by 4 h) that was dose-dependent at dosages > or =0.0625 mg. At the greatest doses administered (5 and 6.25 mg), there was evidence of spontaneous pain from the time of injection for up to 4 h that was characterized by occasional spontaneous flicking of the hindpaw, but more usually by holding the paw in an elevated position for extended periods of time. In addition, at the greatest dose tested (6.25 mg), all rats showed evidence of licking, biting and shaking of the injected hindpaw for up to 30-45 min after injection. These data demonstrate that the intraplantar injection of zymosan is a reliable and quantifiable model of tonic pain characterized by a dose- and time-dependent thermal and mechanical hyperalgesia accompanied by a robust oedema. This model is likely to be a useful, reliable model in which to study further the central and peripheral mechanisms of hyperalgesia.