Persistent Severe Cerebral Edema with Neutrophil Infiltration Following Listeria Meningitis.

A 51-year-old man was admitted to the hospital with a diagnosis of Listeria monocytogenes meningitis. Diffuse cerebral edema appeared after improvement of meningitis with appropriate treatment and worsened for two months. Due to brain herniation, brain tissue leaked through the incision made during the drain insertion in a hydrocephalus surgery. We found pathological evidence of significant neutrophil infiltration with a few lymphocytes without bacterial detection in the degraded brain tissue. The present case indicates that fatal cerebral edema with significant neutrophil infiltration may develop even after appropriate treatment for L. monocytogenes meningitis.

Phase I Randomized Trial of 17 O-Labeled Water: Safety and Feasibility Study of Indirect Proton MRI for the Evaluation of Cerebral Water Dynamics.

BACKGROUND: 17 O-labeled water (PSO17) is a contrast agent developed to measure brain water dynamics and cerebral blood flow. PURPOSE: To evaluate the safety and feasibility of PSO17. STUDY TYPE: Prospective study. SUBJECTS: A total of 12 male healthy volunteers (23.1 ± 1.9 years) were assigned to three groups of four subjects: placebo (normal saline), PSO17 10%, and PSO17 20%. FIELD STRENGTH/SEQUENCE: Dynamic 3D fluid attenuated inversion recovery (FLAIR, fast spin echo with variable refocusing flip angle) scans of the brain were performed with 3-T MRI. ASSESSMENT: Contrast agents were injected 5 minutes after the start of a 10-minute scan. Any symptoms, vital signs, and blood and urine tests were evaluated at five timepoints from preinjection to 4 days after. Blood samples for pharmacokinetic analysis, including half-life (T1/2), maximum fraction (Cmax ), time-to-maximum fraction (Tmax ), and area under the curve (AUC), were collected at 13 timepoints from preinjection to 168 hours after. Regions of interest were set in the cerebral cortex (CC), basal ganglia/thalamus (BG/TM), and white matter (WM), and 17 O concentrations were calculated from signal changes and evaluated using Cmax . STATISTICAL TESTS: All items were compared among the three groups using Tukey-Kramer's honestly significant difference test. Statistical significance was defined as P < 0.5. RESULTS: No safety issues were noted with the intravenous administration of PSO17. The T1/2 was approximately 160 hours, and the AUCs were 1.77 ± 0.10 and 3.75 ± 0.36 in the PSO17 10% and 20% groups, respectively. 17 O fractions calculated from MRI signals were higher in the PSO17 20% group than in the 10% and placebo groups. Significant differences were noted between all pairs of groups in the CC and BG/TM, and between PSO17 20% and both placebo and 10% groups in the WM. DATA CONCLUSION: PSO17 might be considered safe as a contrast medium. Dynamic 3D-FLAIR might detect dose-dependent signal changes and estimate 17 O. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.

A case of longitudinally extensive transverse myelitis with an isolated pontine lesion following epidural and spinal anesthesia for cesarean section.

Severe neurologic complications following epidural and spinal anesthesia rarely occur. Transverse myelitis has been reported as a rare complication of epidural or spinal anesthesia. We report a case of longitudinally extensive transverse myelitis and an isolated pontine lesion, which responded to immunotherapy. The patient was a 31-year-old pregnant woman who underwent elective cesarean section under epidural and spinal anesthesia. Though the insertions of the epidural and spinal catheters were smooth, she experienced back pain and transient hearing loss during epidural anesthesia. Postoperatively, she exhibited severe motor weakness in both lower extremities, neuralgia below the level of Th10 dermatome, and urinary retention. Magnetic resonance imaging showed longitudinally extensive transverse myelitis from T6 to T10 with a ring-shaped enhanced lesion and an isolated pontine lesion. These findings on magnetic resonance imaging were suggestive of autoimmune diseases such as neuromyelitis optica. The patient was diagnosed with an immunoreactive disease triggered by epidural or spinal anesthesia and was administered high-dose methylprednisolone, which led to the improvement in clinical symptoms. Clinicians should be aware of the possibility of the development of longitudinally extensive transverse myelitis and isolated pontine lesions after cesarean section under epidural and spinal anesthesia.

[Spinal dural arteriovenous fistula presented with rapidly progressive myelopathy, longitudinally extensive spinal cord lesion, pleocytosis with polymorphonuclear predominance, and decreased cerebrospinal fluid glucose levels: a case report].

A 75-year-old woman developed low back pain, weakness of the lower extremities, and urinary retention. On day 7 after the onset of symptoms, she was brought to the emergency department of our hospital by an ambulance because of progressive weakness of both lower extremities. Spine MRI showed longitudinally extensive spinal cord lesion (LESCL) at the Th8-Th11 spinal cord level and flow voids around the lesions. Lumbar puncture revealed a normal opening pressure, yellowish appearance, pleocytosis with polymorphonuclear predominance, and decreased cerebrospinal fluid (CSF) glucose levels. Based on the rapidly progressing myelopathy, LESCL, and CSF findings, we initially diagnosed the patient with myelitis and administered acyclovir and high-dose intravenous immunoglobulin on day 7. Spine MRI with gadolinium-enhancement showed longitudinally extending flow voids of the thoracic cord, and digital subtraction arteriogram (DSA) revealed arteriovenous shunt on the dura with dilated and tortuous intradural veins. We finally diagnosed her with spinal dural arteriovenous fistula (SDAVF). Cases of SDAVF might be initially misdiagnosed as myelitis because of showing rapid progressive myelopathy, pleocytosis with polymorphonuclear predominance, and decreased CSF glucose levels. Lumbar puncture and steroid administration for the cases of SDAVF could aggravate the patient's neurological symptoms. Therefore, lumbar puncture and initiation of immunotherapy should be avoided until SDAVF is completely excluded in patients with suspected myelitis on spine MRI without gadolinium-enhancement, even if their neurological symptoms progress rapidly.

Quantitative evaluation of image recognition performance of fiducial markers in real-time tumor-tracking radiation therapy.

PURPOSE: To quantitatively evaluate and compare the image recognition performance of multiple fiducial markers available in real-time tumor-tracking radiation therapy (RTRT). METHODS: Clinically available markers including sphere shape, coil shape, cylinder shape, line shape, and ball shape (folded line shape) were evaluated in liver and lung models of RTRT. Maximum thickness of the polymethyl metacrylate (PMMA) phantom that could automatically recognize the marker was determined by template-pattern matching. Image registration accuracy of the fiducial marker was determined using liver RTRT model. Lung RTRT was mimicked with an anthropomorphic chest phantom and a one-dimensional motion stage in order to simulate marker motion in heterogeneous fluoroscopic images. The success or failure of marker tracking and image registration accuracy for the lung model were evaluated in the same manner as that for the liver model. RESULTS: All fiducial markers except for line shape and coil shape of thinner diameter were recognized by the PMMA phantom, which is assumed to have the typical thickness of an abdomen, with two-dimensional image registration accuracy of <2 pixels. Three-dimensional calculation error with the use of real-time stereoscopic fluoroscopy in RTRT was thought to be within 1 mm. In the evaluation using the lung model, the fiducial markers were recognized stably with sufficient accuracy for clinical application. The same was true for the evaluation using the liver model. CONCLUSIONS: The image recognition performance of fiducial markers was quantified and compared. The results presented here may be useful for the selection of fiducial markers.

Three-dimensional depth sensor imaging to identify adolescent idiopathic scoliosis: a prospective multicenter cohort study.

Adolescent idiopathic scoliosis is the most ordinary pediatric spinal disease that causes a three-dimensional deformity. Early detection of this potentially progressive deformity is considered crucial. The purpose of the present study was to report the potential for accurately diagnosis of adolescent idiopathic scoliosis using a newly developed, automated, noninvasive asymmetry-recognition system for the surface of the human back using a three-dimensional depth sensor. We included 170 subjects with suspected adolescent idiopathic scoliosis in this study. Outcomes measured included patient demographics, Cobbe angles from radiographic measurements, and asymmetry indexes. The coefficient of correlation between the asymmetry index and the Cobb angle was 0.85. For the prediction of scoliosis >10°, the area under the curve was 0.98, sensitivity was 0.97, specificity was 0.93, positive predictive value was 0.99, negative predictive value was 0.72, accuracy was 0.97, positive likelihood ratio was 13.55, and negative likelihood ratio was 0.04. The posterior test probability for the positive screen >10° was 98.9% if the asymmetry index was >1.268, three times in a row. This novel system automatically evaluated the back asymmetry. Therefore, this study demonstrates the outstanding discriminative ability of this newly developed system for deciding whether an examinee should undergo additional radiography to define scoliosis. This system can be used as an alternative to the forward bend test and scoliometer measurement in clinics. Future studies should seek to confirm these findings in a larger group and involve mass school scoliosis screening programs within the context of a multicenter trial.

A Nucleoside Anticancer Drug, 1-(3-C-Ethynyl-ß-D-Ribo-Pentofuranosyl)Cytosine, Induces Depth-Dependent Enhancement of Tumor Cell Death in Spread-Out Bragg Peak (SOBP) of Proton Beam.

The effect of 1-(3-C-ethynyl-ß-D-ribo-pentofuranosyl)cytosine (ECyd) on proton-induced cell death was evaluated in human lung carcinoma cell line A549 and Chinese hamster fibroblast cell line V79 to enhance relative biological effectiveness (RBE) within the spread-out Bragg peak (SOBP) of proton beams. Treatment with ECyd significantly enhanced the proton-induced loss of clonogenicity and increased senescence at the center, but not at the distal edge of SOBP. The p53-binding protein 1 foci formation assay showed that ECyd decelerated the rate of DNA double-strand break (DSB) repair at the center, but not the distal region of SOBP, suggesting that the ECyd-induced enhancement of proton-induced cell death is partially associated with the inhibition of DSB repair. This study demonstrated that ECyd enhances proton-induced cell killing at all positions of SOBP, except for the distal region and minimizes the site-dependent differences in RBE within SOBP. Thus, ECyd is a unique radiosensitizer for proton therapy that may be useful because it levels the biological dose within SOBP, which improves tumor control and reduces the risk of adverse effects at the distal edge of SOBP.

Evaluation of the relative biological effectiveness of spot-scanning proton irradiation in vitro.

Variations in relative biological effectiveness (RBE) from a fixed value of 1.1 are critical in proton beam therapy. To date, studies estimating RBE at multiple positions relative to the spread-out Bragg peak (SOBP) have been predominantly performed using passive scattering methods, and limited data are available for spot-scanning beams. Thus, to investigate the RBE of spot-scanning beams, Chinese hamster fibroblast V79 cells were irradiated using the beam line at the Hokkaido University Hospital Proton Therapy Center. Cells were placed at six different depths, including the entrance of the proton beam and the proximal and distal part of the SOBP. Surviving cell fractions were analyzed using colony formation assay, and cell survival curves were obtained by the curve fitted using a linear-quadratic model. RBE10 and RBE37 were 1.15 and 1.21 at the center of the SOBP, respectively. In contrast, the distal region showed higher RBE values (1.50 for RBE10 and 1.85 for RBE37). These results are in line with those of previous studies conducted using passive scattering proton beams. Taken together, these data strongly suggest that variations in RBE should be considered during treatment planning for spot-scanning beams as well as for passive scattering proton beams.

Integration of a real-time tumor monitoring system into gated proton spot-scanning beam therapy: an initial phantom study using patient tumor trajectory data.

PURPOSE: In spot-scanning proton therapy, the interplay effect between tumor motion and beam delivery leads to deterioration of the dose distribution. To mitigate the impact of tumor motion, gating in combination with repainting is one of the most promising methods that have been proposed. This study focused on a synchrotron-based spot-scanning proton therapy system integrated with real-time tumor monitoring. The authors investigated the effectiveness of gating in terms of both the delivered dose distribution and irradiation time by conducting simulations with patients' motion data. The clinically acceptable range of adjustable irradiation control parameters was explored. Also, the relation between the dose error and the characteristics of tumor motion was investigated. METHODS: A simulation study was performed using a water phantom. A gated proton beam was irradiated to a clinical target volume (CTV) of 5 × 5 × 5 cm(3), in synchronization with lung cancer patients' tumor trajectory data. With varying parameters of gate width, spot spacing, and delivered dose per spot at one time, both dose uniformity and irradiation time were calculated for 397 tumor trajectory data from 78 patients. In addition, the authors placed an energy absorber upstream of the phantom and varied the thickness to examine the effect of changing the size of the Bragg peak and the number of required energy layers. The parameters with which 95% of the tumor trajectory data fulfill our defined criteria were accepted. Next, correlation coefficients were calculated between the maximum dose error and the tumor motion characteristics that were extracted from the tumor trajectory data. RESULTS: With the assumed CTV, the largest percentage of the data fulfilled the criteria when the gate width was ± 2 mm. Larger spot spacing was preferred because it increased the number of paintings. With a prescribed dose of 2 Gy, it was difficult to fulfill the criteria for the target with a very small effective depth (the sum of an assumed energy absorber's thickness and the target depth in the phantom) because of the sharpness of the Bragg peak. However, even shallow targets could be successfully irradiated by employing an adequate number of paintings and by placing an energy absorber of sufficient thickness to make the effective target depth more than 12 cm. The authors also observed that motion in the beam direction was the main cause of dose distortion, followed by motion in the lateral plane perpendicular to the scan direction. CONCLUSIONS: The results suggested that by properly adjusting irradiation control parameters, gated proton spot-scanning beam therapy can be robust to target motion. This is an important first step toward establishing treatment plans in real patient geometry.

Biological effect of dose distortion by fiducial markers in spot-scanning proton therapy with a limited number of fields: a simulation study.

PURPOSE: In accurate proton spot-scanning therapy, continuous target tracking by fluoroscopic x ray during irradiation is beneficial not only for respiratory moving tumors of lung and liver but also for relatively stationary tumors of prostate. Implanted gold markers have been used with great effect for positioning the target volume by a fluoroscopy, especially for the cases of liver and prostate with the targets surrounded by water-equivalent tissues. However, recent studies have revealed that gold markers can cause a significant underdose in proton therapy. This paper focuses on prostate cancer and explores the possibility that multiple-field irradiation improves the underdose effect by markers on tumor-control probability (TCP). METHODS: A Monte Carlo simulation was performed to evaluate the dose distortion effect. A spherical gold marker was placed at several characteristic points in a water phantom. The markers were with two different diameters of 2 and 1.5 mm, both visible on fluoroscopy. Three beam arrangements of single-field uniform dose (SFUD) were examined: one lateral field, two opposite lateral fields, and three fields (two opposite lateral fields + anterior field). The relative biological effectiveness (RBE) was set to 1.1 and a dose of 74 Gy (RBE) was delivered to the target of a typical prostate size in 37 fractions. The ratios of TCP to that without the marker (TCP(r)) were compared with the parameters of the marker sizes, number of fields, and marker positions. To take into account the dependence of biological parameters in TCP model, α∕ß values of 1.5, 3, and 10 Gy (RBE) were considered. RESULTS: It was found that the marker of 1.5 mm diameter does not affect the TCPs with all α∕ß values when two or more fields are used. On the other hand, if the marker diameter is 2 mm, more than two irradiation fields are required to suppress the decrease in TCP from TCP(r) by less than 3%. This is especially true when multiple (two or three) markers are used for alignment of a patient. CONCLUSIONS: It is recommended that 1.5-mm markers be used to avoid the reduction of TCP as well as to spare the surrounding critical organs, as long as the markers are visible on x-ray fluoroscopy. When 2-mm markers are implanted, more than two fields should be used and the markers should not be placed close to the distal edge of any of the beams.

Aldehyde oxidase 1 gene is regulated by Nrf2 pathway.

Aldehyde oxidase is a member of the molybd-flavo enzyme family that catalyzes the hydroxylation of heterocycles and the oxidation of aldehydes into corresponding carboxylic acids. Aldehyde oxidase-1 (AOX1) is highly expressed in liver and is involved in the oxidation of a variety of aldehydes and nitrogenous heterocyclic compounds, including anti-cancer and immunosuppressive drugs. However, the physiological substrates of AOX1 have not been identified, and it was unknown how the expression of AOX1 is regulated. Here, we found that the AOX1 gene is regulated by the Nrf2 pathway. Two Nrf2 binding consensus elements (antioxidant responsive element, ARE) are located in the 5' upstream region of the rat AOX1 gene. Molecular analyses using reporter transfection analysis, EMSA, and ChIP analysis show that Nrf2 binds to and strongly activates the rat AOX1 gene.

CD73-generated adenosine promotes osteoblast differentiation.

CD731 is a GPI-anchored cell surface protein with ecto-5'-nucleotidase enzyme activity that plays a crucial role in adenosine production. While the roles of adenosine receptors (AR) on osteoblasts and osteoclasts have been unveiled to some extent, the roles of CD73 and CD73-generated adenosine in bone tissue are largely unknown. To address this issue, we first analyzed the bone phenotype of CD73-deficient (cd73(-/-)) mice. The mutant male mice showed osteopenia, with significant decreases of osteoblastic markers. Levels of osteoclastic markers were, however, comparable to those of wild-type mice. A series of in vitro studies revealed that CD73 deficiency resulted in impairment in osteoblast differentiation but not in the number of osteoblast progenitors. In addition, over expression of CD73 on MC3T3-E1 cells resulted in enhanced osteoblastic differentiation. Moreover, MC3T3-E1 cells expressed adenosine A(2A) receptors (A(2A)AR) and A(2B) receptors (A(2B)AR) and expression of these receptors increased with osteoblastic differentiation. Enhanced expression of osteocalcin (OC) and bone sialoprotein (BSP) observed in MC3T3-E1 cells over expressing CD73 were suppressed by treatment with an A(2B)AR antagonist but not with an A(2A) AR antagonist. Collectively, our results indicate that CD73 generated adenosine positively regulates osteoblast differentiation via A(2B)AR signaling.

Fibroblast growth factor-2 stimulates directed migration of periodontal ligament cells via PI3K/AKT signaling and CD44/hyaluronan interaction.

Fibroblast growth factor-2 (FGF-2) regulates a variety of functions of the periodontal ligament (PDL) cell, which is a key player during tissue regeneration following periodontal tissue breakdown by periodontal disease. In this study, we investigated the effects of FGF-2 on the cell migration and related signaling pathways of MPDL22, a mouse PDL cell clone. FGF-2 activated the migration of MPDL22 cells and phosphorylation of phosphatidylinositol 3-kinase (PI3K) and akt. The P13K inhibitors, Wortmannin and LY294002, suppressed both cell migration and akt activation in MPDL22, suggesting that the PI3K/akt pathway is involved in FGF-2-stimulated migration of MPDL22 cells. Moreover, in response to FGF-2, MPDL22 showed increased CD44 expression, avidity to hyaluronan (HA) partly via CD44, HA production and mRNA expression of HA synthase (Has)-1, 2, and 3. However, the distribution of HA molecular mass produced by MPDL22 was not altered by FGF-2 stimulation. Treatment of transwell membrane with HA facilitated the migration of MPDL22 cells and an anti-CD44 neutralizing antibody inhibited it. Interestingly, the expression of CD44 was colocalized with HA on the migrating cells when stimulated with FGF-2. Furthermore, an anti-CD44 antibody and small interfering RNA for CD44 significantly decreased the FGF-2-induced migration of MPDL22 cells. Taken together, PI3K/akt and CD44/HA signaling pathways are responsible for FGF-2-mediated cell motility of PDL cells, suggesting that FGF-2 accelerates periodontal regeneration by regulating the cellular functions including migration, proliferation and modulation of extracellular matrix production.

E-selectin engages PSGL-1 and CD44 through a common signaling pathway to induce integrin alphaLbeta2-mediated slow leukocyte rolling.

In inflamed venules, neutrophils rolling on E-selectin induce integrin alpha(L)beta(2)-dependent slow rolling on intercellular adhesion molecule-1 by activating Src family kinases (SFKs), DAP12 and Fc receptor-gamma (FcRgamma), spleen tyrosine kinase (Syk), and p38. E-selectin signaling cooperates with chemokine signaling to recruit neutrophils into tissues. Previous studies identified P-selectin glycoprotein ligand-1 (PSGL-1) as the essential E-selectin ligand and Fgr as the only SFK that initiate signaling to slow rolling. In contrast, we found that E-selectin engagement of PSGL-1 or CD44 triggered slow rolling through a common, lipid raft-dependent pathway that used the SFKs Hck and Lyn as well as Fgr. We identified the Tec kinase Bruton tyrosine kinase as a key signaling intermediate between Syk and p38. E-selectin engagement of PSGL-1 was dependent on its cytoplasmic domain to activate SFKs and slow rolling. Although recruiting phosphoinositide-3-kinase to the PSGL-1 cytoplasmic domain was reported to activate integrins, E-selectin-mediated slow rolling did not require phosphoinositide-3-kinase. Studies in mice confirmed the physiologic significance of these events for neutrophil slow rolling and recruitment during inflammation. Thus, E-selectin triggers common signals through distinct neutrophil glycoproteins to induce alpha(L)beta(2)-dependent slow rolling.

IL-6 increases B-cell IgG production in a feed-forward proinflammatory mechanism to skew hematopoiesis and elevate myeloid production.

Src homology 2 domain-containing inositol 5-phosphatase (SHIP(-/-)) animals display an age-related increase in interleukin-6 (IL-6), a decrease in B lymphopoiesis, and an elevation in myelopoiesis. We investigated the origin of the IL-6 production and show that it is largely produced by peritoneal and splenic macrophages. IL-6 production by these macrophages is not a direct result of the loss of SHIP: IL-6 production is not spontaneous, is absent from bone marrow-derived macrophages, declines with prolonged culture of macrophages, and requires a stimulus present in vivo. The IL-6-rich peritoneal cavity of SHIP(-/-) mice shows more than 700-fold more immunoglobulin G (IgG) than wild-type, approximately 20% of which is aggregated or in an immune complex and contains B220(+) cells that secrete IgG. The SHIP-deficient peritoneal macrophages show evidence of IgG receptor stimulation. Animals lacking both the signal-transducing gamma-chain of IgG receptors and SHIP or Ig and SHIP produce less IL-6. The data indicate a feed-forward process in which peripheral macrophages, responding through IgG receptors to secreted IgG, produce IL-6, to support further B-cell production of IgG. Because of the proinflammatory phenotype of SHIP(-/-) animals, these findings emphasize the importance of IL-6-neutralizing strategies in autoimmune and proinflammatory diseases.

Interleukin-6 aborts lymphopoiesis and elevates production of myeloid cells in systemic lupus erythematosus-prone B6.Sle1.Yaa animals.

We previously reported the inhibitory action of interleukin-6 (IL-6) on B lymphopoiesis with SHIP(-/-) mice and showed that IL-6 biases lineage commitment toward myeloid cell fates in vitro and in vivo. Because elevated IL-6 is a feature of chronic inflammatory diseases, we applied an animal model of systemic lupus erythematosus (SLE) to determine whether IL-6 has similar effects on hematopoiesis. We found that IL-6 levels were elevated in the B6.Sle1.Yaa mice, and the increase was accompanied by losses of CD19(+) B cells and more primitive B-lymphoid progenitors in bone marrow. Both the CD19(+) B-cell population and their progenitors recovered in an IL-6(-/-) background. The uncommitted progenitors, containing precursors for both lymphoid and myeloid fates, expressed IL-6 receptor-alpha chain and responded to IL-6 by phosphorylation of STAT3. IL-6 stimulation caused uncommitted progenitors to express the Id1 transcription factor, which is known to inhibit lymphopoiesis and elevate myelopoiesis, and its expression was MAPK dependent. We conclude that chronic inflammatory conditions accompanied by increased IL-6 production bias uncommitted progenitors to a myeloid fate by inducing Id1 expression.

Bacillus anthracis peptidoglycan stimulates an inflammatory response in monocytes through the p38 mitogen-activated protein kinase pathway.

We hypothesized that the peptidoglycan component of B. anthracis may play a critical role in morbidity and mortality associated with inhalation anthrax. To explore this issue, we purified the peptidoglycan component of the bacterial cell wall and studied the response of human peripheral blood cells. The purified B. anthracis peptidoglycan was free of non-covalently bound protein but contained a complex set of amino acids probably arising from the stem peptide. The peptidoglycan contained a polysaccharide that was removed by mild acid treatment, and the biological activity remained with the peptidoglycan and not the polysaccharide. The biological activity of the peptidoglycan was sensitive to lysozyme but not other hydrolytic enzymes, showing that the activity resides in the peptidoglycan component and not bacterial DNA, RNA or protein. B. anthracis peptidoglycan stimulated monocytes to produce primarily TNFalpha; neutrophils and lymphocytes did not respond. Peptidoglycan stimulated monocyte p38 mitogen-activated protein kinase and p38 activity was required for TNFalpha production by the cells. We conclude that peptidoglycan in B. anthracis is biologically active, that it stimulates a proinflammatory response in monocytes, and uses the p38 kinase signal transduction pathway to do so. Given the high bacterial burden in pulmonary anthrax, these findings suggest that the inflammatory events associated with peptidoglycan may play an important role in anthrax pathogenesis.