MR Imaging Features of Middle Cranial Fossa Encephaloceles and Their Associations with Epilepsy.

BACKGROUND AND PURPOSE: Middle cranial fossa encephaloceles are an increasingly recognized cause of epilepsy; however, they are also often encountered on neuroimaging in patients with no history of seizure. We characterized the MR imaging features of middle cranial fossa encephaloceles in seizure and nonseizure groups with the hope of uncovering features predictive of epileptogenicity. MATERIALS AND METHODS: Seventy-seven patients with middle cranial fossa encephaloceles were prospectively identified during routine clinical practice of neuroradiology at a tertiary care hospital during an 18-month period. Thirty-five of 77 (45%) had a history of seizure, 20/77 (26%) had temporal lobe epilepsy, and 42/77 (55%) had no history of seizures. Middle cranial fossa encephalocele features on MR imaging were characterized, including depth, area, number, location, presence of adjacent encephalomalacia, and degree of associated parenchymal morphologic distortion. MR imaging features were compared between the seizure and nonseizure groups. RESULTS: No significant difference in MR imaging features of middle cranial fossa encephaloceles was seen when comparing the seizure and nonseizure groups. Comparison of just those patients with temporal lobe epilepsy (n = 20) with those with no history of seizure (n = 42) also found no significant difference in MR imaging features. CONCLUSIONS: Anatomic MR imaging features of middle cranial fossa encephaloceles such as size, number, adjacent encephalomalacia, and the degree of adjacent parenchymal morphologic distortion may not be useful in predicting likelihood of epileptogenicity.

Bone loss from high repetitive high force loading is prevented by ibuprofen treatment.

We examined roles of loading and inflammation on forearm bones in a rat model of upper extremity overuse. Trabecular structure in distal radius and ulna was examined in three groups of young adult rats: 1) 5% food-restricted that underwent an initial training period of 10 min/day for 5 weeks to learn the repetitive task (TRHF); 2) rats that underwent the same training before performing a high repetition high force task, 2 hours/day for 12 weeks (HRHF); and 3) food-restricted only (FRC). Subsets were treated with oral ibuprofen (IBU). TRHF rats had increased trabecular bone volume and numbers, osteoblasts, and serum osteocalcin, indicative of bone adaptation. HRHF rats had constant muscle pulling forces, showed limited signs of bone adaptation, but many signs of bone resorption, including decreased trabecular bone volume and bone mineral density, increased osteoclasts and bone inflammatory cytokines, and reduced median nerve conduction velocity (15%). HRHF+IBU rats showed no trabecular resorptive changes, no increased osteoclasts or bone inflammatory cytokines, no nerve inflammation, preserved nerve conduction, and increased muscle voluntary pulling forces. Ibuprofen treatment preserved trabecular bone quality by reducing osteoclasts and bone inflammatory cytokines, and improving muscle pulling forces on bones as a result of reduced nerve inflammation.

Performance of a repetitive task by aged rats leads to median neuropathy and spinal cord inflammation with associated sensorimotor declines.

Epidemiological studies have demonstrated a relationship between advancing age and susceptibility to risk factors for median neuropathies and musculoskeletal disorders. In this study, we determined if performance of a voluntary reaching task by aged rats induced sensorimotor declines, median nerve dysfunction and increased inflammatory cytokines in peripheral nerves, muscle and spinal cord neurons. Aged (14 mon) rats were trained for 15 min/day for 4 weeks to learn a high repetition, low force (HRLF) task (19 reaches/min; 15% maximum pulling force). Aged task rats performed the task for 2 h/day, 3 days/wk, for 12 weeks (until they were 18 mon of age). No behavioral changes were detected in normal controls (NC) or food-restricted controls (FR C) as they aged. However, grip strength declined in HRLF rats in weeks 6-12 (P<0.01 each) and 12-week trained-only rats (TR; P<0.05), compared to NC. Mechanical hypersensitivity was present in weeks 9 and 12 HRLF reach limb forepaws (P<0.01 and P<0.05, respectively), and 12-week HRLF support limb forepaws (P<0.01) and hindpaws (P=0.03), compared to NC. By week 12, median nerve conduction velocity declined 23%, bilaterally, in HRLF (P<0.001 each), and 13% in TR (P<0.05), compared to NC. Tumor necrosis factor alpha (TNFα) increased in 12-week HRLF muscle (P=0.005), median nerve (P<0.01), and neurons in superficial lamina of HRLF cervical spinal cords (P<0.01), compared to NC. interleukin 1 beta (IL1ß) also increased in superficial lamina neurons (P<0.01). Loss of grip strength was correlated with median nerve conduction slowing (r=0.70) as well as increased nerve and muscle TNFα (r=-0.38 and r=-0.41, respectively); decrease in forepaw withdrawal thresholds was correlated with median nerve conduction slowing (r=0.81), increased nerve TNFα (r=-0.59), and increased TNFα and IL1ß in neurons in spinal cord dorsal horns (r=-0.52 and r=-0.47, respectively). Thus, aged rats performing a repetitive task exhibited sensorimotor declines that were associated with decreased median nerve conduction, and increased pro-inflammatory cytokines in the median nerve and cervical spinal cord neurons.

High force reaching task induces widespread inflammation, increased spinal cord neurochemicals and neuropathic pain.

Repetitive strain injuries (RSI), which include several musculoskeletal disorders and nerve compression injuries, are associated with performance of repetitive and forceful tasks. In this study, we examined in young, adult Sprague-Dawley rats, the effects of performing a voluntary, moderate repetition, high force (MRHF; nine reaches/min; 60% maximum pulling force) task for 12 weeks on motor behavior and nerve function, inflammatory responses in forearm musculoskeletal and nerve tissues and serum, and neurochemical immunoexpression in cervical spinal cord dorsal horns. We observed no change in reach rate, but reduced voluntary participation and grip strength in week 12, and increased cutaneous sensitivity in weeks 6 and 12, the latter indicative of mechanical allodynia. Nerve conduction velocity (NCV) decreased 15% in the median nerve in week 12, indicative of low-grade nerve compression. ED-1 cells increased in distal radius and ulna in week 12, and in the median nerve and forearm muscles and tendons in weeks 6 and 12. Cytokines IL-1alpha, IL-1beta, TNF-alpha, and IL-10 increased in distal forearm bones in week 12, while IL-6 increased in tendon in week 12. However, serum analysis revealed only increased TNF-alpha in week 6 and macrophage inflammatory protein 3a (MIP3a) in weeks 6 and 12. Lastly, Substance P and neurokinin-1 were both increased in weeks 6 and 12 in the dorsal horns of cervical spinal cord segments. These results show that a high force, but moderate repetition task, induced declines in motor and nerve function as well as peripheral and systemic inflammatory responses (albeit the latter was mild). The peripheral inflammatory responses were associated with signs of central sensitization (mechanical allodynia and increased neurochemicals in spinal cord dorsal horns).

Massive hepatic artery atherosclerosis of an otherwise suitable donor liver: a case report.

Most of the few reports about hepatic artery disease found in the literature describe hepatic artery aneurysms or hepatic artery calcifications. Atherosclerosis of the hepatic artery is not commonly evaluated during deceased donor liver procurement. Herein we present a case of a stable 47-year-old Caucasian female donor whose liver function tests were within normal limits and a liver biopsy showed less than 5% steatosis. The liver when received at our center appeared grossly unremarkable. Back-table evaluation showed a complete occlusion of the trunk of the proper hepatic artery. The pathology report revealed hepatic occlusion due to arterial atherosclerosis. Transplantation was canceled, and the liver was used for isolated hepatocyte perfusion, revealing < 25% hepatocyte viability. Hepatic artery atherosclerosis and patency need to be evaluated at the time of procurement to prevent recipient morbidity due to anesthetic induction, or initiation of a recipient abdominal incision prior to declining the liver graft for this rare finding.

Local modification of benthic flow environments by suspension-feeding stream insects.

Larval black flies often exhibit spatially aggregated distributions, and individuals within patches can potentially reduce the supply of suspended food particles to downstream neighbors by modifying local flow characteristics. We used hot-film anemometry to quantify the magnitude and spatial extent of flow modifications downstream from feeding Simulium vittatum larvae in a laboratory flume, and to determine whether temporal patterns of flow variation are related to movements of the larval feeding appendages. Mean velocity 1 mm downstream from feeding larvae was reduced by 75%, and the percent reduction in velocity diminished asymptotically with downstream distance. Reduced velocities were evident as much as 60 mm downstream from, and 3 mm to either side of, larvae. Turbulence intensity (i.e., the SD of the velocity time series) was generally higher in this region relative to control flow conditions. Three results demonstrate the major contribution of the larval feeding appendages (i.e., labral fans) to such flow modification. First, there was a minimal reduction in mean velocity 5 mm downstream from non-feeding larvae (i.e., with closed labral fans), whereas mean velocity at the same location was reduced markedly when larvae were feeding. Second, the power spectrum of the velocity time series exhibited greatest power at frequencies that corresponded to the frequency of labral fan motions. Third, fan flick times accounted for most of the variance in the velocity power spectrum. The large local flow modifications that we documented have potentially important consequences for the feeding performance and growth of individuals located within larval aggregations, and are likely to influence behavioral interactions and spacing patterns.

Firing rate modulation of motoneurons activated by cutaneous and muscle receptor afferents in the decerebrate cat.

The aim of this study was to investigate whether activation of spinal motoneurons by sensory afferents of the caudal cutaneous sural (CCS) nerve evokes an atypical motor control scheme. In this scheme, motor units that contract fast and forcefully are driven by CCS afferents to fire faster than motor units that contract more slowly and weakly. This is the opposite of the scheme described by the size principle. Earlier studies from this lab do not support the atypical scheme and instead demonstrate that both CCS and muscle stretch recruit motor units according to the size principle. The latter finding may indicate that CCS and muscle-stretch inputs have similar functional organizations or that comparison of recruitment sequence was simply unable to resolve a difference. In the present experiments, we examine this issue using rate modulation as a more sensitive index of motoneuron activation than recruitment. Quantification of the firing output generated by these two inputs in the same pairs of motoneurons enabled direct comparison of the functional arrangements of CCS versus muscle-stretch inputs across the pool of medial gastrocnemius (MG) motoneurons. No systematic difference was observed in the rate modulation produced by CCS versus muscle-stretch inputs for 35 pairs of MG motoneurons. For the subset of 24 motoneuron pairs exhibiting linear co-modulation of firing rate (r > 0.5) in response to both CCS and muscle inputs, the slopes of the regression lines were statistically indistinguishable between the two inputs. For individual motoneuron pairs, small differences in slope between inputs were not related to differences in conduction velocity (CV), recruitment order, or, for a small sample, differences in motor unit force. We conclude that an atypical motor control scheme involving selective activation of typically less excitable motoneurons, if it does occur during normal movement, is not an obligatory consequence of activation by sural nerve afferents. On average and for both muscle-stretch and skin-pinch inputs, the motoneuron with the faster CV in the pair tended to be driven to fire at slightly but significantly faster firing rates. Computer simulations based in part on frequency-current relations measured directly from motoneurons revealed that properties intrinsic to motoneurons are sufficient to account for the higher firing rates of the faster CV motoneuron in a pair.

Comparison of quality of care by specialist and generalist physicians as usual source of asthma care for children.

OBJECTIVE: To determine whether care for children was more consistent with national asthma guidelines when a specialist rather than a generalist was the usual source of asthma care. DESIGN: Cross-sectional survey. SETTING: Two large managed care organizations in the United States. PARTICIPANTS: A total of 260 parents of children with asthma. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Parent reports of the physician primarily responsible for asthma care (specialist, generalist, or both equally) and whom they would call (specialist or generalist) for questions about asthma care were used to define usual source of care. We assessed consistency of care with 1997 National Asthma Education and Prevention Program guidelines using 11 indicators in 4 domains of asthma care: patient education, control of factors contributing to asthma symptoms, periodic physiologic assessment and monitoring, and proper use of medications. RESULTS: In all 4 domains, care was more likely to be consistent with guidelines when specialists were the usual source of care. These differences remained after adjustment for symptom severity, recent care encounters, and parent demographics. Greatest differences for specialist versus generalist management were for use of controller medications (odds ratio [OR] 6.7; 95% confidence interval [CI]: 1.5-30.4), ever having a pulmonary function test (OR 6.5; 95% CI: 2.4-18.1), and having been told about asthma triggers and how to avoid them (OR 5.9; 95% CI: 1.3-26.2). CONCLUSIONS: In these managed care organizations, asthma care in children was more likely to be consistent with national guidelines when a specialist was the primary provider. Greater use of specialists or altering generalist physicians' care may improve the degree to which the care of children with asthma is consistent with national guidelines.

Race and sex differences in consistency of care with national asthma guidelines in managed care organizations.

BACKGROUND: In the United States, morbidity from asthma disproportionately affects African Americans and women. Although inadequate care contributes to overall asthma morbidity, less is known about differences in asthma care by race and sex. SUBJECTS AND METHODS: To examine the relationships of race and sex with asthma care, we analyzed responses to questionnaires administered to adults enrolled in 16 managed care organizations participating in the Outcomes Management System Asthma Study between September and December 1993. Indicators of care consistent with National Asthma Education and Prevention Program (1991) recommendations were assessed. Of a random sample of 8640 patients asked to participate, 6612 (77%) completed the survey. This study focused on 5062 (14% African American, 72% women) patients with at least moderate asthma symptom severity. RESULTS: Fewer African Americans than whites reported care consistent with recommendations for medication use (eg, daily inhaled corticosteroid use, 34.9% vs 54.4%; P =.001), self-management education (eg, action plan, 42.0% vs 53.8%; P =.001), avoiding triggers (37.6% vs 53.6%; P =.001), and specialist care (28.3% vs 41.0%; P =.001). Differences in asthma care by sex were smaller and tended to favor women except for daily inhaled corticosteroid use (women vs men: 49.6% vs 58.3%; P =.001) and having specialist care (37.7% vs 43.1%; P =.001). Similar race and sex differences were observed after adjusting for age, education, employment, and symptom frequency. CONCLUSIONS: Even among patients with health insurance, disparities in asthma care for African Americans compared with whites exist and may contribute to race disparities in outcomes. Women generally reported better asthma care but may benefit from greater use of inhaled corticosteroids.

Breast implants and cancer: causation, delayed detection, and survival.

Concern for many women with breast implants has been focused on three topics: cancer (both breast and other cancers), delayed detection of breast cancer, and increased breast cancer recurrence or decreased length of survival. In this study, a qualitative review of the literature on these subjects was conducted, coupled with a meta-analysis of the risk for breast cancer or other cancers (excluding that of the breast). Researchers have consistently found no persuasive evidence of a causal association between breast implants and any type of cancer. The meta-analysis results obtained by combining the epidemiology studies support the overall conclusion that breast implants do not pose any additional risk for breast cancer (relative risk, 0.72; 95% confidence interval, 0.61 to 0.85) or for other cancers (relative risk, 1.03; 95% confidence interval, 0.87 to 1.24). This analysis suggests that breast implants may confer a protective effect against breast cancer. Women with implants should be reassured by the consistency of scientific studies which have uniformly determined that, compared with women without implants, they are not at increased risk for cancer, are not diagnosed with later-stage breast malignancies, are not at increased risk for breast cancer recurrence, and do not have a decreased length of survival.

Selecting donors of platelets for refractory patients on the basis of HLA antibody specificity.

BACKGROUND: Patients who are refractory to platelet transfusion as a result of HLA alloimmunization are generally given HLA-matched or crossmatched platelets. However, HLA-matched platelets that are matched at HLA-A and -B loci (A-matched) or those without any mismatched or cross-reactive antigens (BU-matched) are frequently unavailable. A disadvantage of crossmatching is that crossmatched platelets have a shelf life of only 5 days, so that crossmatch tests must be performed frequently for patients requiring long-term platelet transfusions. An alternative method is the selection of platelets according to the patient's HLA antibody specificity, called the antibody specificity prediction (ASP) method. STUDY DESIGN AND METHODS: An anti-human globulin-enhanced microlymphocytotoxicity test modified by a double addition of serum and a computer program were used to determine the specificity of patients' HLA antibodies. Platelet crossmatching was performed with a solid-phase adherence assay. The percentage of platelet recovery (PPR) was determined in 1621 platelet transfusions in an observational study in 114 patients, and the PPR of platelets selected by the ASP method was compared with the PPR of those that were HLA-matched, crossmatched, or randomly selected. The numbers of potential donors in files of HLA-typed donors as identified by HLA matching vs. the ASP method were determined. RESULTS: After adjustments for covariates, the mean +/- SEM PPR was similar for HLA-matched (21 +/-4%), cross-matched (23+/-4%), and ASP-selected (24+/-3%) platelets and was significantly lower for randomly selected (15+/-1.4%) platelets. For 29 alloimmunized HLA-typed patients, the mean number of potential donors found in a file of 7247 HLA-typed donors was 6 who were an HLA-A match (median = 1), 33 who were an HLA-BU match (median = 20), and 1426 who were identified by the ASP method (median = 1365). CONCLUSION: The ASP method of donor selection for refractory alloimmunized patients appears as effective as HLA matching or crossmatching. Far more donors are identified in a file of HLA-typed donors by the ASP method than by HLA matching, and this indicates that the ASP method provides important advantages regarding the availability of compatible platelet components.

Frequency-dependent synaptic depression modifies postsynaptic firing probability in cats.

1. The influence of stimulus trains applied to single I a axons on the firing behaviour of single motoneurones was assessed in anaesthetized cats. The change in motoneurone firing probability associated with a single I a afferent spike was measured from short-latency peaks in peristimulus time histograms or cross-correlograms. Some synapses showed frequency-dependent depression of the short-latency peak, which is consonant with the frequency-dependent depression reported for the I a-motoneurone excitatory postsynaptic potential (EPSP). 2. Where they could be measured, EPSPs superimposed on the depolarizing ramps of potential recorded from motoneurones as they fired repetitively showed frequency-dependent changes in amplitude that parallelled those of the simultaneously recorded histograms. 3. Thus it appears that at synapses with small EPSPs, which are typical in the mammalian CNS, modulation of the EPSP should result in similar modulation of cell firing.

Both C3a and C3a(desArg) regulate interleukin-6 synthesis in human peripheral blood mononuclear cells.

Synthesis of complement components is part of the acute-phase response. Interleukin-6 (IL-6) is a critical mediator of the acute-phase response during infections and injuries. Plasma levels of C3a and IL-6 have been proposed as prognostic indicators in sepsis and trauma. The effects of C3a and C3a(des)Arg on IL-6 gene expression and protein production in human peripheral blood mononuclear cells (PBMC) were investigated. Neither C3a nor C3a(des)Arg alone induced detectable IL-6 protein or mRNA levels. However, C3a and C3a(des)Arg affected endotoxin-induced IL-6 synthesis in a dose-dependent manner. In nonadherent PBMC, C3a or C3a(des)Arg suppressed, while in adherent PBMC, C3a or C3a(des)Arg enhanced IL-6 protein and mRNA levels. These results suggest that C3a and C3a(des)Arg may provide a control mechanism of acute-phase responses by enhancing IL-6 synthesis in adherent monocytes at local inflammatory sites and by inhibiting IL-6 synthesis in circulating monocytes.

Treatment of chronic inflammatory demyelinating polyneuropathy with interferon-alpha 2a.

We performed an open-label, prospective, pilot study of interferon (IFN)-alpha 2a treatment for 6 weeks in 16 patients with chronic inflammatory demyelinating polyneuropathy (CIDP). All patients had failed to improve or relapsed after treatment with at least one conventional therapy (steroids, IV gamma globulin, or plasma exchange). Assessment included MRC strength score, leg sensory score, grip dynanometry, Rankin disability score, electrodiagnostic studies, and serum concentration of tumor necrosis factor-alpha. Nine (56%) improved after IFN-alpha therapy. Mean MRC score increased by 4.2 points (p = 0.01), and mean sensory score improved by 2.3 points (p = 0.02). Five patients improved five or more points on the MRC score, nine had slight improvement or were unchanged, and two worsened. We conclude that IFN-alpha may be effective in some patients with CIDP who relapse or fail to respond to conventional immunomodulating therapy.

Relationship of tissue and cellular interleukin-1 and lipopolysaccharide after endotoxemia and bacteremia.

Distributions of immunoreactive interleukin-1 (IL-1) and lipopolysaccharide (LPS) were studied in the tissues of rats after intravenous injection of purified LPS or live Escherichia coli bacteria. IL-1 staining in the spleen peaked at 4-8 h, colocalized with LPS in marginal zone macrophages, and was undetectable 24 h after injection, whereas LPS staining peaked at 24 h and was detectable for 4 weeks. The tissue IL-1 response was similar for LPS and live bacteria. Thus, tissue IL-1 is down-regulated within hours despite maintenance of LPS in the same cells for weeks. Macrophages in liver and lung had only slight IL-1 staining despite intense staining for LPS. Tissue IL-1 production appears to be differentially regulated after gram-negative bacteremia; LPS cleared by liver and lung macrophages elicit minimal IL-1, whereas there is high local IL-1 production in the marginal zone of the spleen that may increase immune responses to bacterial wall antigens.

Anti-interleukin-8 monoclonal antibody reduces free radical production and improves hemodynamics and survival rate in endotoxic shock in rabbits.

BACKGROUND: Although high levels of interleukin-8 (IL-8) have been found in patients with sepsis and a monoclonal antibody (MoAb) against IL-8 has been successfully used in some animal models of inflammation, no specific therapeutic agent against IL-8 has been tested for the treatment of sepsis. We studied the effects of a MoAb against IL-8 in the treatment of endotoxic shock with a prospective randomized rabbit endotoxic shock model. METHODS: Twenty New Zealand white rabbits were anesthetized and divided into four groups: normal, anti-IL-8, control-Ab, and lipopolysaccharide (LPS). Anti-IL-8 and control-Ab groups received a MoAb (immunoglobulin G, 3 mg/kg) 5 minutes before the LPS injection. All groups, except the normal group, received a continuous 20-minute infusion of LPS (500 micrograms/kg). The normal group received NaCl (0.9%) rather than LPS. RESULTS: The 7-day survival rates were 100% for normal group, 80% for anti-IL-8 group, 40% for control-Ab group, and 0% for LPS group. Compared with the LPS group, anti-IL-8 rabbits had a smaller decrease in mean arterial blood pressure (p < 0.05) and increased urinary volume (p < 0.05). Anti-IL-8 rabbits had lower plasmatic levels of IL-1 beta, less free radical production (p < 0.05), and a higher survival rate (p < 0.01). CONCLUSIONS: IL-8 plays a significant role in endotoxic shock, and IL-8 blockage results in attenuation of the hypotensive and tachypneic effects of LPS, reduced free radical production, and an increased survival rate after lethal endotoxic shock.

Interaction with autologous platelets multiplies interleukin-1 and tumor necrosis factor production in mononuclear cells.

The effect of activated platelets on cytokine production by human peripheral blood mononuclear cells (PBMC) was investigated. When PBMC were coincubated with activated autologous platelets amid lipopolysaccharide (LPS, 50-100 pg/mL) for 8 h, the production of interleukin (IL)-1alpha increased 11- to 18-fold and tumor necrosis factor (TNF)-alpha 3- to 5-fold compared with PBMC without platelets. Activated platelets in a dual-chamber well that prevented platelet-PBMC contact but permitted passage of soluble factors enhanced IL-1alpha production (P < .01). Platelet-PBMC contact in the chamber resulted in a further enhancement of IL-1alpha production. These data suggest that platelet-PBMC interaction, both directly and with platelet-derived factors, enhances production of shock-producing IL-1alpha and TNF-alpha, albeit differently. The interaction of platelets with monocytes may play an important role in the pathophysiology of sepsis and disseminated intravascular coagulation.

An antibody to a 17 amino acid synthetic peptide of the type I interleukin-1 receptor preferentially blocks interleukin-1 beta binding.

On the basis of their relative hydropathy and alpha-helical structure, we prepared antibodies to four synthetic peptides with amino acid sequences homolgous to four hydrophilic, extracellular regions of the murine 80 kDa type I interleukin-1 receptor (IL-1RI). Antibodies to each of the four peptides recognized their specific immunogen. Human [125I]-IL-1 alpha or -beta was crosslinked to murine EL4 and D10S cells. Antiserum to peptide 150-166 precipitated the IL-1/IL-1R complex, whereas antibodies to peptide 66-84, 190-200, or 266-285 did not. Antibody to peptide 150-166 did not precipitate the type II IL-1R. Anti-IL-1RI150-166 blocked 71% of the binding of radiolabeled human IL-1 beta to EL4 cells and 50% of the binding to D10S cells. Using affinity-purified anti-IL-1RI150-166, we compared the ability of this antibody to inhibit the binding of murine or human IL-1 alpha to that of murine or human IL-1 beta. At a concentration of 20 ng/ml, affinity-purified anti-IL-1RI150-166 blocked 50% binding of murine IL-1 beta. At 1 microgram/ml, 90% blockage was observed. In contrast, no significant blockade of IL-1 alpha binding was observed at concentrations as high as 3 micrograms/ml of anti-IL-1RI150-166. The selective blockade of IL-1 beta forms was not due to differences in the affinities of these ligands for receptors on these cells. The antibody also blocked the binding of human IL-1 beta but not human IL-1 alpha to EL4 cells. The biologic activity of murine IL-1 beta but not IL-1 alpha on EL4 cells was also inhibited by this antibody. These data suggest (1) that antibody to a specific epitope on the extracellular domain interferes with the binding of IL-1 beta but not IL-1 alpha, (2) the differential inhibition of binding of IL-1 beta but not IL-1 alpha by anti-IL-1RI150-166 also blocks biologic activity, and (3) IL-1 alpha and IL-1 beta may transduce different signals by binding to separate loci on the IL-1RI.

Three distinct promoters direct transcription of different 5' untranslated regions of the human interleukin 1 type I receptor: a possible mechanism for control of translation.

The 5' untranslated regions (UTR) of the human interleukin 1 (IL-1) type I receptor (IL-1RI) are encoded by one common exon (exon 2) but one of three distinct exons 1 (termed exon 1A, 1B, and 1C). These exons span approximately 50 Kb of genomic DNA. Exons 1A and 1B have multiple transcriptional initiation sites, whereas the promoter for exon 1C uses a single start site. There are no "TATA' or "CAAT' boxes, indicating that these promoters belong to the family of housekeeping gene promoters. Computer sequence analysis of exons 1A, 1B, and 1C predicts the potential to form stable secondary structures (delta G degrees 1A = -72.2 Kcal/mol, delta G degrees 1B = -125.8 Kcal/mol, delta G degrees 1C = -255.4 Kcal/mol). Exon 1C appears to be the most stable whereas exon 1A would yield a mRNA species more likely to be translated than those derived from exon 1B or 1C. The 5' UTR of exon 1C is also rich (75%) in GC which might inhibit expression. Therefore, we studied the effect of exon 1C on chloramphenicol acetyltransferase (CAT) activity. Deletion of 183 or 296 base pairs from this GC rich region was shown to increase CAT activity. In addition, insertion of a GC-rich fragment of exon 1C inhibited CAT activity driven by SV40 promoter. These results suggest that the 5' UTR exon 1C of the human IL-1RI may exert a suppressive effect on the translation of IL-1RI transcripts.

A new biologic role for C3a and C3a desArg: regulation of TNF-alpha and IL-1 beta synthesis.

The complement activation products C3a and C3a desArg are generated in the course of trauma, infection, tissue injury, and ischemia. We have investigated the effects of C3a and C3a desArg on gene expression and protein synthesis of TNF-alpha and IL-1 beta in PBMC. Neither C3a nor C3a desArg alone induced detectable protein or mRNA levels for TNF-alpha and IL-1 beta. C3a modulated LPS-induced TNF-alpha and IL-1 beta synthesis. In nonadherent PBMC, C3a suppressed LPS-induced synthesis of TNF-alpha (20-71% decrease by 0.2-10 microgram/ml of C3a, p less than 0.01) and IL-1 beta (19-57% decrease by 0.5-10 microgram/ml of C3a, p less than 0.01), independently of endogenous production of PGE2. C3a also suppressed LPS-induced mRNA levels for TNF-alpha and IL-1 beta. In contrast, in adherent PBMC, C3a at 5 to 20 microgram/ml enhanced LPS-induced TNF-alpha (75-188% increase, p less than 0.001) and IL-1 beta (119-274% increase, p less than 0.001) synthesis. C3a enhanced TNF-alpha and IL-1 beta mRNA levels in LPS-stimulated adherent cells. Furthermore, C3a desArg shared with C3a the ability to modulate LPS-induced mRNA and protein synthesis for TNF-alpha and IL-1 beta. These results suggest that C3a, thought to be proinflammatory, and C3a desArg, thought to be biologically inactive, are modulators of inflammation. Both C3a and C3a desArg may enhance cytokine synthesis by adherent monocytes at local inflammatory sites, while inhibiting the systemic synthesis of proinflammatory cytokines by circulating cells.