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Abstract Background In recent years inhibitors directed against the epidermal growth factor receptor (EGFR) have evolved as effective targeting cancer drugs. Characteristic papulopustular exanthemas, often described as acneiform rashes, are the most frequent adverse effect associated with this class of novel cancer drugs and develop in > 90% of patients. Notably, the rash may significantly compromise the patients' quality of life, thereby potentially leading to incompliance as well as dose reduction or even termination of the anti-EGFR therapy. Yet, an effective dermatologic management of cutaneous adverse effects can be achieved. Whereas various case reports, case series or expert opinions on the management of EGFR-inhibitor (EGFRI) induced rashes have been published, data on systematic management studies are sparse. Methods Here, we present a retrospective, uncontrolled, comparative study in 49 patients on three established regimens for the management of EGFRI-associated rashes. Results Strikingly, patients' rash severity improved significantly over three weeks of treatment with topical mometason furoate cream, topical prednicarbate cream plus nadifloxacin cream, as well as topical prednicarbate cream plus nadifloxacin cream plus systemic isotretinoin. Conclusions In summary our results demonstrate that EGFRI-associated rashes can be effectively managed by specific dermatologic interventions. Whereas mild to moderate rashes should be treated with basic measures in combination with topical glucocorticosteroids or combined regiments using glucocorticosteroids and antiseptics/antibiotics, more severe or therapy-resistant rashes are likely to respond with the addition of systemic retinoids.

Mining activities generate large quantities of wastes that significantly alter the biogeochemistry and ecological structure of entire river basins. Microbial communities that develop in these areas present a variety of survival and adaptation mechanisms. Knowing this diversity at the molecular level is strategic both for understanding adaptive processes and for identifying genomes with potential use in bioremediation and bioprospecting. In this work, prokaryotic and eukaryotic communities were evaluated by meta-taxonomics (16S and 18S amplicons) in sediments and water bodies impacted by acid mine drainage in an important coal mining area in southern Brazil. Five sampling stations were defined on a gradient of impacts (pH 2.7-4.25). Taxon diversity was directly proportional to pH, being greater in sediments than in water. The dominant prokaryotic phyla in the samples were Proteobacteria, Actinobacteria, Acidobacteria, OD1, Nitrospirae, and Euryarchaeota, and among the eukaryotes, algae (Ochrophyta, Chlorophyta, Cryptophyceae), fungi (Basidiomycota, Ascomycota, and Cryptomycota), and protists (Ciliophora, Heterolobosea, Cercozoa). The prokaryotic genera Leptospirillum, Acidithiobacillus, Acidiphilium, Thiomonas, Thermogymnomonas, and Acidobacterium, and the eukaryotic genera Pterocystis and Poteriospumella were associated with more acidic conditions and higher metal concentrations, while the prokaryotic genera Sediminibacterium, Gallionella Geothrix, and Geobacter were more abundant in transitional environments., (© 2023. The Author(s), under exclusive licence to Springer Nature Japan KK, part of Springer Nature.)

Objective: Iodine-131-labelled meta-iodobenzylguanidine (I-mIBG) therapy is an established treatment modality for relapsed/refractory neuroblastoma, most frequently administered according to fixed or weight-based criteria. We evaluate response and toxicity following a dosimetry-based, individualized approach., Materials and Methods: A review of 44 treatments in 25 patients treated with I-mIBG therapy was performed. Patients received I-mIBG therapy following relapse (n=9), in refractory disease (n=12), or with surgically unresectable disease despite conventional treatment (n=4). Treatment schedule (including mIBG dose and number of administrations) was individualized according to the clinical status of the patient and dosimetry data from either a tracer study or previous administrations. Three-dimensional tumour dosimetry was also performed for eight patients., Results: The mean administered activity was 11089±7222 MBq and the mean whole-body dose for a single administration was 1.79±0.57 Gy. Tumour-absorbed doses varied considerably (3.70±3.37 mGy/MBq). CTCAE grade 3/4 neutropenia was documented following 82% treatments and grade 3/4 thrombocytopenia following 71% treatments. Further acute toxicity was found in 49% of patients. All acute toxicities resolved with appropriate therapy. The overall response rate was 58% (complete or partial response), with a further 29% of patients having stable disease., Conclusion: A highly personalized approach combining patient-specific dosimetry and clinical judgement enables delivery of high activities that can be tolerated by patients, particularly with stem cell support. We report excellent response rates and acceptable toxicity following individualized I-mIBG therapy.

Unlabelled: The aims of this study were to examine the relationship between whole-body absorbed dose and hematologic toxicity and to assess the most accurate method of delivering a prescribed whole-body absorbed dose in (131)I-metaiodobenzylguanidine ((131)I-MIBG) therapy for neuroblastoma., Methods: A total of 20 children (1-12 y), 5 adolescents (13-17 y), and 1 adult (20 y) with stage 3 or 4 neuroblastoma were treated to a prescribed whole-body absorbed dose, which in most cases was 2 Gy. Forty-eight administrations of (131)I-MIBG were given to the 26 patients, ranging in activity from 1,759 to 32,871 MBq. For 30 administrations, sufficient data were available to assess the effect of whole-body absorbed dose on hematologic toxicity. Comparisons were made between the accuracy with which a whole-body absorbed dose could be predicted using a pretherapy tracer study and the patient's most recent previous therapy. The whole-body absorbed dose that would have been delivered if the administered activity was fixed (7,400 MBq) or determined using a weight-based formula (444 MBq.kg(-1)) was also estimated., Results: The mean whole-body absorbed dose for patients with grade 4 Common Terminology Criteria for Adverse Events (CTCAE) neutropenia after therapy was significantly higher than for those with grade 1 CTCAE neutropenia (1.63 vs. 0.90 Gy; P = 0.05). There was no correlation between administered activity and hematologic toxicity. Absorbed whole-body doses predicted from previous therapies were within +/-10% for 70% of the cases. Fixed-activity administrations gave the largest range in whole-body absorbed dose (0.30-3.11 Gy)., Conclusion: The results indicate that even in a highly heterogeneous and heavily pretreated patient population, a whole-body absorbed dose can be prescribed accurately and is a more accurate predictor of hematologic toxicity than is administered activity. Therefore, a whole-body absorbed dose can be used to deliver accurate and reproducible (131)I-MIBG therapy on a patient-specific basis.

Previous studies have shown that administration of the fatty acids, linoleic and oleic acid, either by intragastric or intraintestinal infusion, suppresses food intake and body weight in rats. While still not fully understood, gut-mediated satiety mechanisms likely are potential effectors of this robust response to gastrointestinal fatty acid infusions. The objective of this study was to assess the effects of voluntary access to an oleic acid derivative, ethyl oleate (EO), on subsequent food intake and body weight in rats. Animals were randomized either to a 12.5% EO diet or a soybean oil diet as a "breakfast," followed either by two one-hour or one five-hour access periods to standard rodent diet, and food intake and body weights were collected. Across 14 days access, rats consuming EO on both feeding schedules gained less weight and consumed less total kilocalories than rats consuming the SO diet. Further, plasma levels of glucose and insulin were comparable in both EO and SO diet groups. In summary, EO was found to increase weight loss in rats maintained on a 75% food-restriction regimen, and attenuate weight-gain upon resumption of an ad-libitum feeding regimen. These data indicate that voluntary access to EO promoted short-term satiety, compared to SO diet, and that these effects contributed to an important and novel attenuated weight gain in EO-fed animals.

Introduction: (131)I-meta iodobenzylguanidine ((131)I-mIBG) therapy is established palliation for relapsed neuroblastoma. The topoisomerase-1 inhibitor, topotecan, has direct activity against neuroblastoma and acts as a radiation sensitiser. These 2 treatments are synergistic in laboratory studies. Theoretically, the benefit of (131)I-mIBG treatment could be enhanced by dose escalation and combination with topotecan. Haematological support would be necessary to overcome the myelosuppression, which is the dose-limiting toxicity., Aims: Firstly, one aim of this study was to establish whether in vivo dosimetry could be used to guide the delivery of a precise total whole-body radiation-absorbed dose of 4 Gy accurately from 2 (131)I-mIBG treatments. Secondly, the other aim of this study was to determine whether it is feasible to combine this treatment with the topotecan in children with metastatic neuroblastoma., Material and Methods: An activity of (131)I-mIBG (12 mCi/kg, 444 MBq/kg), estimated to give a whole-body absorbed-radiation dose of approximately 2 Gy, was administered on day 1, with topotecan 0.7 mg/m(2) administered daily from days 1-5. In vivo dosimetry was used to calculate a 2nd activity of (131)I-mIBG, to be given on day 15 which would give a total whole-body dose of 4 Gy. A further 5 doses of topotecan were given from days 15-19. The myeloablative effect of this regimen was circumvented by peripheral blood stem cell or bone marrow support., Results: Eight children with relapsed stage IV neuroblastoma were treated. The treatment was delivered according to protocol in all patients. There were no unanticipated side-effects. Satisfactory haematological reconstitution occurred in all patients. The measured total whole-body radiation-absorbed dose ranged from 3.7 Gy to 4.7 Gy (mean, 4.2 Gy)., Conclusions: In vivo dosimetry allows for a specified total whole-body radiation dose to be delivered accurately. This schedule of intensification of (131)I-mIBG therapy by dose escalation and radiosensitization with topotecan with a haemopoietic autograft is safe and practicable. This approach should now be tested for efficacy in a phase II clinical trial.

We have found that jejunal infusions of long-chain fatty acids, linoleic acid (LA) and oleic acid (OA), and gastric infusions of a fatty acid ethyl ester, ethyl oleate (EO), produce long-lasting suppression of total caloric intake. This effect is not seen in response to jejunal infusions of medium-chain fatty acids or medium- or long-chain triglycerides. Multiunit recordings have shown that intestinal infusions of LA or OA strongly activate celiac vagal afferents. Truncal vagotomy (TVX) and selective celiac-branch vagotomy (CVX) are equally effective in attenuating, but not eliminating, suppression of food intake by LA and EO. These outcomes suggest that intraintestinal fatty acids reduce intake by activation of vagal mechanisms, critically involving afferent fibers within the celiac branches, as well as unidentified nonvagal mechanisms. The role of cholecystokinin (CCK) in mediating the activation of celiac vagal afferents is suggested by studies showing that (1) inhibition of food intake by CCK-8 administration is attenuated after CVX but robust after celiac-spared vagotomy (CSV), (2) multiunit activity of celiac vagal afferents is increased by CCK-8 administration, and (3) activation of celiac fibers by intestinal LA infusion is severely attenuated by the CCK(A) antagonist lorglumide.

Two experiments investigated mechanisms underlying the decrease in food intake produced by lipid infusions into the jejunum. In Experiment 1, male Sprague-Dawley rats with truncal abdominal vagotomy (TVx), selective hepatic-branch vagotomy (HVx), or sham vagotomy received repeated 7 h infusions of linoleic acid (LA), corn oil (CO), or saline through indwelling jejunal catheters. Cumulative food intake was measured at 1, 3, 6, and 23 h. LA and, to a lesser extent, CO suppressed food intake in excess of the caloric value of the load. This effect was eliminated by TVx, which significantly attenuated the suppression of intake produced by both lipids at 3 and 6 h and also at 23 h when LA was infused. HVx attenuated suppression at 23 h on tests with LA and at 3 and 6 h on CO tests. Experiment 2 showed that jejunal infusion of LA had no effect on multi-unit activity of afferent fibers in the left splanchnic nerve in anesthetized rats. Thus, these results provide further evidence that satiating effects of intestinal lipid infusions are mediated by the vagal fibers, some of which lie within the hepatic branch. However, because significant suppression of food intake remained after TVx, and because of the negative results of Experiment 2, these lipid infusions engage as yet unidentified mechanisms independent of the vagus.

The present experiment examined whether neurons located in the paraventricular nucleus of the hypothalamus (PVN) respond to intestinal infusions of long-chain fatty acids. Single-unit recordings were made of neurons located in and adjacent to the PVN during jejunal administration of linoleic acid. Jejunal administration of linoleic acid increased single-unit activity of neurons located in the PVN but did not affect activity of neurons located in adjacent tissue outside the PVN. The largest increases in neuronal activity were observed in the anterior PVN (0.9-1.3 mm posterior to bregma) compared with the posterior PVN (1.8-2.1 mm posterior to bregma). Jejunal administration of saline failed to affect activity of neurons located either inside or outside the PVN. When the same neurons were subsequently tested for their response to intravenous administration of 2 microg/kg of CCK-8, excitatory responses were more frequently observed than inhibitory responses, but both types of responses were observed regardless of whether neurons were located inside or outside the PVN. In addition, there was no strong correlation between the magnitude of the neuronal response evoked by jejunal administration of linoleic acid compared with intravenous CCK-8. These data suggest that neurons located in the anterior PVN may play a role in the mediation of suppression of food intake produced by intestinal administration of lipids.

Patients undergoing targeted radionuclide therapy (TRT) may receive a series of two or more treatment administrations at varying intervals. However, the level of activity administered and the frequency of administration can vary widely from centre to centre for the same therapy. Tumour dosimetry is seldom employed to determine the optimum treatment plan mainly due to the potential inaccuracies of image quantification. In this work 3D dose distributions obtained from repeated therapies have been registered to enable the dose ratios to be determined. These ratios are independent of errors in image quantification and, since the same target volume can be transferred from one distribution to the next, independent of inconsistencies in outlining these volumes. These techniques have initially been applied to ten sets of I-131 mIBG therapy scan data from five patients, each undergoing two therapies. It was found that where a similar level of activity was administered for the second therapy, a similar tumour dose was delivered, and in two cases where a higher level of activity was administered for the second treatment, a correspondingly higher absorbed dose was delivered. This justifies an approach of administering activities based on individual patient kinetics rather than administering standard activities to all patients.

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.

Responses of either hepatic or celiac vagal afferents to intraportal hepatic vein administration of 2-mercaptoacetate (MA) were examined in rats maintained on either a high-fat or low-fat diet. Afferent activity in both hepatic and celiac vagal afferents significantly increased after administration of MA, but the magnitude of these increases did not differ as a function of either diet. Responses of hepatic vagal afferents were highly variable across individual rats, whereas those of celiac vagal afferents were remarkably consistent across individual rats. These data suggest that MA-induced enhanced feeding in rats given a fat-enriched diet does not depend on a stronger hepatic and/or celiac vagal afferent response than that of rats given a low-fat diet.

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 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.

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.

Topical analgesics are widely marketed for treatment of muscle and joint pain. We have recently developed a model of muscle pain and have used this model to evaluate the efficacy of commercially available topical and peroral ketoprofen in order to evaluate the time- and dose-dependence of analgesia. In the present study, we examined the dose- (0, 50, and 100 mg) and time-dependence (hourly to 8 h) of commercially available peroral and topical ketoprofen. In order to achieve infusion times of 8 h (and thus study the time course of analgesic action), we adapted the model of low pH-induced muscle pain in humans to these requirements by applying the infusions continuously for 10 min every hour for 8 h. We found that the 10 min infusion produced reliable and consistent pain levels that were reproducible over the 8 h of the study. The study was performed double-blind, randomized, and with a 1-week interval between each of five different sessions (cross-over). Altogether six volunteers underwent intramuscular infusions of isotonic phosphate-buffered saline solution of pH 5.2; during each 8 h session the infusion was switched on eight times with a duration of 10 min at 50 min intervals (there was no infusion during the 50 min interval). The intramuscular infusion of low pH phosphate buffer induced a localized dull-aching or stinging muscle pain sensation; the flow rate of the pH infusion was individually adjusted to induce pain of a magnitude of 20% on a visual analogue scale (ranging from "no pain" (0%) to "unbearable pain" (100%)). Twenty minutes after starting the infusion the volunteers received a capsule with either a placebo or 50 or 100 mg ketoprofen perorally and, in addition, either placebo gel or 50 or 100 mg of a 2.5% commercial ketoprofen gel was applied topically to the skin. One of the sessions included a placebo gel and an oral placebo. The intensity of the recurrent pain stimulus was significantly reduced by 59% following administration of 100 mg peroral ketoprofen within the first 3 h (P<0.03, Wilcoxon test); this analgesia lasted up to the sixth hour of the experimental protocol. Oral ketoprofen (50 mg) was less effective and reduced the pain intensity by 45% (P<0.05) from only the second to the third hour. In contrast, pain reduction after topical ketoprofen application was not of the same magnitude but appeared to be faster to develop (with a maximum effect within 1 h) on average. The maximum pain suppression with 100 mg topical 2.5% ketoprofen gel was by 51% (significant with P<0.03), while 50 mg topical ketoprofen produced a non-significant reduction of 29%. The apparent analgesia was rapid to develop but transient and pain ratings increased back to baseline values within 3 h for the 100 mg dose and within 2 h for the 50 mg dose. This data suggests that topical application of commercial gel-based systems does not provide long-lasting analgesia in the muscle when compared to perorally-dosed ketoprofen. In addition, the data show that even doses of 100 mg peroral ketoprofen do not provide complete relief of muscle pain.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

The present study examined the effects of colonic inflammation on reflex responses to colorectal distension (CRD) in awake rats. Visceromotor responses (VMR) to CRD were recorded in rats that received either no treatment or intracolonic saline or zymosan. Three hours following zymosan treatment (25 mg/ml; 1 ml) VMR response magnitudes were significantly increased at all intensities of CRD tested (10-80 mmHg). The enhanced responses to CRD were attenuated in a dose-dependent fashion by intrathecal administration of the non-competitive N-methyl-D-aspartate (NMDA) receptor channel blocker MK-801 to 60% of control and by the non-NMDA receptor antagonist DNQX to less than 20% of control. The metabotropic receptor antagonist AP-3 was without effect. Signs of multi-focal colonic inflammation were clearly present 3 h after zymosan treatment, characterized by an ingress of inflammatory cells and damaged crypts in and around these foci. Taken together these findings suggest that tissue inflammation increases the sensitivity of the colon to mechanical stimuli, leading to enhanced responses to CRD. This enhancement involves the activation of spinal NMDA as well as non-NMDA receptors, but not metabotropic receptors.

Study Design: This study was designed to evaluate whether allografts of intervertebral disc materials produce hyperalgesia in the rat and whether an immune response, pH, or chemicals correlate with the induced hyperalgesia., Objective: To elucidate the pathomechanisms of radicular pain secondary to lumbar disc herniation., Summary of Background Data: It has been reported that a low pH, an autoimmune reaction, or chemical radiculitis is likely responsible for radicular pain associated with lumbar disc herniation. In animal studies, it has been shown that hyperalgesia (an increased sensitivity to painful stimuli) involves activation of phospholipase A2 and nitric oxide synthase., Methods: Fat, nucleus pulposus, and anulus fibrosus were allografted into the epidural space at L6 in the rat. Withdrawal response thresholds to mechanical stimuli and withdrawal response latencies to thermal stimuli on the tail and pH in the applied tissues were measured after surgery. Interleukin-1, phospholipase A2, and nitric oxide synthase were examined in the applied tissues using immunohistochemistry, nicotineamide adenine dinucleotide phosphate-diaphorase histochemistry, and in situ hybridization., Results: Allografted fat did not produce hyperalgesia. Allografts of nucleus pulposus and nucleus pulposus plus anulus fibrosis showed evidence of mechanical and thermal hyperalgesia, respectively. There were no observed changes in pH over time. Although interleukin-1 was demonstrated in all applied tissues, phospholipase A2 was only observed around the applied nucleus A2 was only observed around the applied nucleus pulposus and nucleus pulposus plus anulus fibrosus. Nitric oxide synthase was only markedly increased around the applied tissues., Conclusion: The nucleus pulposus and anulus fibrosus produce different forms of hyperalgesia (mechanical vs. thermal) associated with different and distinct immunohistochemical changes. It is possible that radicular pain of a lumbar disc herniation results from chemicals, such as phospholipase A2 and nitric oxide.

There is general agreement that activation of the N-methyl-D-aspartate receptor is involved in thermal hyperalgesia. However, there is less agreement on the specific intracellular events subsequent to receptor activation and the involvement of other excitatory amino acid receptors in thermal hyperalgesia. In the present study, we found that the intrathecal administration of N-methyl-D-aspartate produced a dose- (1 fmol-1 pmol) and time-dependent thermal hyperalgesia. In contrast, over the dose range tested, intrathecal administration of either alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA; 10 fmol-100 pmol), 1,3-trans-1-aminocyclopentyl-1,3-dicarboxylate (10 fmol-100 pmol), quisqualate (10 pmol-5 nmol) or a 1:1 combination of AMPA and 1,3-trans-1-aminocyclopentyl-1,3-dicarboxylate (total dose 20 fmol-200 pmol) did not produce any evidence of thermal hyperalgesia; greater doses produced a caudally-directed biting and scratching behavior that precluded testing in the paradigm used. A fixed dose of 1,3-trans-1-aminocyclopentyl-1,3-dicarboxylate (100 pmol) did, however, potentiate the effects of N-methyl-D-aspartate (1-100 fmol). Thermal hyperalgesia produced by N-methyl-D-aspartate (1 pmol) was attenuated by intrathecal administration of the N-methyl-D-aspartate receptor-selective antagonist 2-amino-5-phosphonopentanoate (100 pmol), but not by the AMPA receptor-selective antagonist 6,7-dinitroquinoxaline-2,3-dione (1 nmol) or the metabotropic receptor antagonist 2-amino-3-phosphonoproprionate (10 nmol). In a second series of experiments, we examined the role of different signal transduction systems in acute N-methyl-D-aspartate-produced thermal hyperalgesia. N-Methyl-D-aspartate-produced thermal hyperalgesia (1 pmol) was attenuated by intrathecal hemoglobin (1-100 pmol) and dose-dependently by intrathecal N(G)-nitro-L-arginine methyl ester (10 pmol-l nmol), Methylene Blue (10 pmol-l nmol) and chelerythrine (1-100 pmol), suggesting that acute N-methyl-D-aspartate-mediated thermal hyperalgesia involves activation of nitric oxide synthase and protein kinase C. In contrast, N-methyl-D-aspartate-produced thermal hyperalgesia was unaffected by intrathecal administration of the phospholipase A2 inhibitor mepacrine (10 nmol) or the phospholipase C inhibitor neomycin (10 nmol). While prostaglandins and leukotrienes have been suggested to play a role in hyperalgesia, N-methyl-D-aspartate-produced thermal hyperalgesia (1 pmol) was unaffected by the non-selective eicosanoid inhibitor nordihydroguaiarate (1 nmol), the cyclo-oxygenase selective inhibitor indomethacin (10 nmol) or the lipoxygenase selective inhibitor baicalein (1 nmol). The results of the present study suggest that acute thermal hyperalgesia can be produced by activation of N-methyl-D-aspartate receptors. Activation of AMPA, metabotropic or co-activation of AMPA and metabotropic glutamate receptors, at the doses tested, did not produce an acute thermal hyperalgesia. The thermal hyperalgesia produced by N-methyl-D-aspartate is mediated by activation of nitric oxide synthase and protein kinase C, but not by phospholipase C, phospholipase A2, cyclo-oxygenase or lipoxygenase. Collectively, the results are consistent with a role for spinal N-methyl-D-aspartate receptors, nitric oxide and protein kinase C in thermal hyperalgesia.

The serotonin (5HT3) antagonist ondansetron was compared in a randomised study with metoclopramide and dexamethasone for the prevention of chemotherapy induced emesis. Thirty children aged 1-15 years with acute lymphoblastic leukaemia received 'intensification modules' according to the MRC United Kingdom acute lymphoblastic leukaemia regimen UKALL XI. This contains the moderately emetogenic drugs daunorubicin, etoposide, and cytarabine. Fifteen children received an intravenous loading dose of ondansetron followed by intravenous or oral doses 12 hourly for five days. Fifteen children received intravenous metoclopramide every six hours for three days with a loading dose of dexamethasone, repeated every eight hours for three days intravenously or orally. Efficacy was assessed by a diary card documenting the incidence of nausea, retching, or vomiting. In the 24 hour period after starting chemotherapy, ondansetron was more effective, with a complete or major response rate of 93%, compared with 33% using metoclopramide/dexamethasone.

Recent observations using both clinical and animal models have suggested that acidosis may initiate pain and sensitization. In the present study, we examined if changing the acidic environment around the rat sciatic nerve resulted in thermal hyperalgesia. Fresh solutions of preservative-free saline (PFS) and unbuffered PFS acidified to pH 3.5 were continuously infused around the left rat sciatic nerve for 7 days. Rats receiving unbuffered, acidified PFS developed a progressive thermal hyperalgesia that was maximal on infusion day 6. Unbuffered, acidified PFS significantly decreased the perineural pH (pH 6.9 +/- 0.15, P < 0.05), and decreasing perineural pH values were significantly correlated with increasing thermal hyperalgesia (r = 0.91) for individual rats. While it is likely that multiple factors play a role in the development of neuropathic pain, these data demonstrate that an acidic environment around the sciatic nerve will produce thermal hyperalgesia.

Absolute 99Tcm-dimercaptosuccinic acid (DMSA) uptake was measured in 160 children ranging in age from 3 months to 15 years. In total, 108 pairs of kidneys were normal and the mean uptake for the left and right kidneys was 24.0 and 23.4%, respectively. The mean summed uptake for the left and right kidneys was 47.3%. A method of calculation based on the geometric mean of the anterior and posterior views was used to allow for radiation attenuation. DMSA uptake did not vary significantly with the age of the child. The value of the method in the assessment of abnormal kidneys is presented. The effect of using a supine or prone position for the anterior view was also investigated.

Absolute renal uptake was measured at 2, 4 and 6 h in 27 patients in order to determine a more convenient time for uptake compared with the 6-h measurement proposed by other authors. Measurements made at 2 and 4 h would need to be increased by 20 and 6%, respectively, to convert to the value at 6 h. Measurements at 4 h are a reasonable compromise to achieve a high-count/low-background image in a reasonable time and to obtain a good estimate of the predicted 6 h uptake at a single scanning session. The percent renal uptake at 6 h, U(6), can be derived from the percent uptake measured at t hours after injection, U(t), using the following formula: U(6) = U(t) x CF(t), where CF(t) = 1.0 + 0.03 (6 - t) for 4 < or = t < or = 6.

Objective and Methods: Epicardial application of pharmacologic agonists has been used to study nociceptive and reflex responses to agents such as bradykinin. We utilized a model where intrapericardial bradykinin was administered in a closed-chest rat. The procedure allows for reproducible administration of microliter doses of pharmacologic agonists in both conscious and anesthetized animals., Results: Bradykinin (BK) has been shown to produce sympathoexcitatory reflexes when applied to the heart. BK typically produced a dose-dependent (0.001-10 micrograms) decrease in arterial blood pressure and tachycardia in pentobarbital-anesthetized rats. In contrast, in alpha-chloralose-anesthetized or awake rats, pericardial administration of BK produced a dose-dependent (0.001-10 micrograms) increase in arterial blood pressure and tachycardia. Maximal cardiovascular changes were produced by 1 microgram BK. The maximum change in arterial pressure was +33.6 +/- 9% in awake, +38.9 +/- 6% in chloralose-anesthetized, and -20 +/- 7% in pentobarbital-anesthetized rats. In alpha-chloralose-anesthetized rats, tachyphylaxis to pericardial administration of 1 microgram BK occurred at 5 and 15, but not at 30 min dosing intervals. Administration of the receptor selective B2-antagonist D-Arg,[Hyp3,Thi5,8 D-Phe7]-BK (200 micrograms) or the mixed B2/B1 antagonist [Thi5,8,D-Phe7]-BK (200 micrograms), produced similar attenuation of the pressor and tachycardia responses to BK. Bilateral transection of the cervical vagus nerve, bilateral removal of the stellate ganglion or ganglion blockade (hexamethonium), but not administration of indomethacin, reduced the magnitude of the tachycardia to BK. Only ganglionic blockade significantly reduced the pressor response to BK., Conclusions: These results demonstrate that pericardial administration of BK produces a tachycardia and pressor effect in awake and alpha-chloralose-anesthetized rats and a tachycardia and depressor effect in pentobarbital-anesthetized rats. These responses appear to be mediated through activation of BK (presumably B2) receptors on cardiac vagal and sympathetic afferents, and may include a direct action of BK on the heart. This model of pericardial administration of pharmacologic agonists may be useful in studies of cardiac pain and reflex responses.

Study Design: This study analyzed hypersensitization in sensory systems after mechanical irritation of the dorsal root ganglion., Objectives: To develop a reliable and reproducible animal model of hyperalgesia arising from the dorsal root ganglion and to understand the unique contributions of the dorsal root ganglion to clinical manifestations of sciatica., Summary of Background Data: The dorsal root ganglion likely plays an important role in disorders of sciatica. However, no previous study has analyzed sciatica after irritation of the dorsal root ganglion. Thermal hyperalgesia indicates a decrease in thermal nociceptive threshold and hypersensitization in sensory systems., Methods: The left L4 and L5 dorsal root ganglia in rats (n = 22) were exposed circumferentially. Other rats (n = 22) also had the left L4 and L5 dorsal root ganglia ligated loosely with two 4-0 chromic gut sutures. Changes in thermal withdrawal latency were examined in the hindpaws across time. Substance P and vasoactive intestinal polypeptide contents were quantified in the dorsal root ganglion and spinal cord. Substance P, calcitonin gene-related peptide, and c-fos expression also were examined in the spinal cord by immunohistochemistry. In addition, histologic changes in myelinated nerve content were examined in the dorsal root ganglion., Results: Thermal hyperalgesia occurred in rats with exposure of the dorsal root ganglion and in rats with loose ligation of the dorsal root ganglion, and was accompanied by an increase in c-fos expression and spontaneous pain-related behaviors., Conclusions: This experimental model reliably produced a disorder resembling an acute phase sciatica and should help further advance the understanding of pathomechanisms of spinal pain after irritation of the dorsal root ganglion in humans.

Recent reports suggest that NADPH-diaphorase (NADPH-d) may be a histochemical marker for neuronal nitric oxide synthase (nNOS) in the central nervous system. Carrageenan-produced unilateral hindpaw inflammation in the rat results in a bilateral increase in NADPH-d in spinal cord neurons. This suggests there would be a bilateral increase in NO, which mediates thermal hyperalgesia. However, carrageenan-produced unilateral hindpaw inflammation results in hyperalgesia of the inflamed hindpaw only. This study determined (1) if neurons that labeled for NADPH-d following carrageenan-produced unilateral hindpaw inflammation colocalized nNOS, and (2) whether there was an increase in nNOS-ir neurons following inflammation. Following unilateral hindpaw inflammation, double labeling of tissue sections and single labeling of alternate serial sections revealed a lack of colocalization or mismatch between NADPH-d histochemical activity and nNOS-like immunoreactivity in neurons in lamina I, the dorsolateral funiculus and lamina X. Quantitative analysis showed no difference in the number of nNOS-ir neurons and NADPH-d labeled neurons in the superficial laminae of the spinal cord in non-inflamed animals. Following unilateral hindpaw inflammation, there was a 34% increase in the number of NADPH-d labeled neurons but no increase in the number of nNOS-ir neurons. These results indicate that nNOS-immunoreactive neurons and NADPH-diaphorase stained neurons are not identical and that nNOS does not increase as a result of hindpaw inflammation, leaving the source of NO involved in thermal hyperalgesia following injury in question.

Six cases of fatal pneumococcal sepsis are described, occurring in the post-allograft setting, between 3 and 39 months after transplantation. Five of the six patients were suffering from chronic graft-versus-host disease and were receiving immunosuppressive therapy. Most were receiving prophylactic antibiotic therapy. This represents approximately 2% of the allograft population treated during the study period who survived for > 3 months after transplant. Pneumococcal sepsis is thus still a significant cause of death after allogeneic BMT and approaches to minimise its occurrence are discussed.