Cerebral Spinal Fluid Concentrations Research Articles

Disruption of the blood–brain barrier after generalized tonic-clonic seizures correlates with cerebrospinal fluid MMP-9 levels

BackgroundIncreasing evidence suggests seizures cause blood–brain barrier (BBB) dysfunction including decreased seizure threshold and higher onset potential of future seizures. However, the mechanisms underlying BBB damage in seizures remains poorly understood. Evidence in human and animal models shows BBB disruption is associated with activation of matrix metalloproteinase-9 (MMP-9) after cerebral ischemia and inflammation. The objective of this study was to determine whether MMP-9 concentrations in cerebral spinal fluid (CSF) are associated with BBB disruption in patients after epileptic seizures.MethodsThirty-one patients with generalized tonic-clonic (GTC) seizures were included in the study: 20 had recurrent GTC seizures (RS), and 11 had a single GTC seizure (SS) episode. Twenty-five adult non-seizure patients were used as controls. CSF samples were collected by lumbar puncture within 24 h after seizure cessation (range: 3–15 h, mean 6.2 h). CSF MMP-9 levels were determined by an enzyme-linked immunosorbent assay (ELISA). MMP enzyme activity was measured by gelatin zymography. The CSF/serum albumin ratio (albumin quotient, QAlb) was used as a measure of blood–brain barrier permeability.ResultsWe found significantly higher CSF MMP-9 concentrations in seizure patients compared with controls (P < 0.001). CSF MMP-9 levels and QAlb values were higher in RS patients compared with SS and controls. Moreover, CSF MMP-9 concentration showed strong correlation between QAlb values (r = 0.76, P < 0.0001) and between CSF leukocyte counts (r = 0.77, P < 0.0001) in patients after seizures. Gelatin zymography showed MMP-9 proteolytic activity only in GTC seizure patients.ConclusionsOur results suggest MMP-9 plays a role in BBB dysfunction, characterized by invasion of leukocytes into the CSF during seizures.

The NRTIs Lamivudine, Stavudine and Zidovudine Have Reduced HIV-1 Inhibitory Activity in Astrocytes

HIV-1 establishes infection in astrocytes and macroage-lineage cells of the central nervous system (CNS). Certain antiretroviral drugs (ARVs) can penetrate the CNS, and are therefore often used in neurologically active combined antiretroviral therapy (Neuro-cART) regimens, but their relative activity in the different susceptible CNS cell populations is unknown. Here, we determined the HIV-1 inhibitory activity of CNS-penetrating ARVs in astrocytes and macrophage-lineage cells. Primary human fetal astrocytes (PFA) and the SVG human astrocyte cell line were used as in vitro models for astrocyte infection, and monocyte-derived macrophages (MDM) were used as an in vitro model for infection of macrophage-lineage cells. The CNS-penetrating ARVs tested were the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir (ABC), lamivudine (3TC), stavudine (d4T) and zidovudine (ZDV), the non-NRTIs efavirenz (EFV), etravirine (ETR) and nevirapine (NVP), and the integrase inhibitor raltegravir (RAL). Drug inhibition assays were performed using single-round HIV-1 entry assays with luciferase viruses pseudotyped with HIV-1 YU-2 envelope or vesicular stomatitis virus G protein (VSV-G). All the ARVs tested could effectively inhibit HIV-1 infection in macrophages, with EC90s below concentrations known to be achievable in the cerebral spinal fluid (CSF). Most of the ARVs had similar potency in astrocytes, however the NRTIs 3TC, d4T and ZDV had insufficient HIV-1 inhibitory activity in astrocytes, with EC90s 12-, 187- and 110-fold greater than achievable CSF concentrations, respectively. Our data suggest that 3TC, d4T and ZDV may not adequately target astrocyte infection in vivo, which has potential implications for their inclusion in Neuro-cART regimens.

Lumbar denervation attenuates the sympathetic‐cardiovascular response to acute increases in cerebrospinal fluid sodium concentration

Increased concentration of sodium in cerebral spinal fluid elevates sympathetic nerve activity (SNA), heart rate (BPM), and mean arterial pressure (MAP). The present study aims to identify the contribution of the sympathetic nervous system to this response. In anaesthetized male Sprague Dawley rats, infusion of 1M NaCl (5μL/10min) into the lateral ventricle increased MAP (Δ 7±1 mmHg), heart rate (Δ 14±4 BPM), lumbar SNA (Δ 115±3%), splanchnic SNA (Δ117±4%) and adrenal SNA(Δ111±3%) but decreased renal SNA (Δ 89±3%). Pretreatment with the ganglionic blocker chlorisondamine (5mg/kg, IV) prevented the rise in MAP(Δ1±1mmHg) and heart rate (Δ4±3BPM). In a final set of experiments, the increase in MAP was significantly attenuated by lumbar denervation (area under the curve: control 5.3±0.8; lumbar 3.1±1.0) but unaffected by renal denervation (area under the curve: 5.6±1.5) or celiac ganglionectomy (area under the curve: 7.1±2.0). These findings indicate that an increase in sodium concentration in cerebral spinal fluid activates the lumbar nerve, at least partly, to increase MAP and heart rate.

Use of therapeutic drug monitoring to treat Elizabethkingia meningoseptica meningitis and bacteraemia in an adult

Use of therapeutic drug monitoring to treat Elizabethkingia meningoseptica meningitis and bacteraemia in an adult

Cerebrospinal fluid levels of CXCL13 are elevated in neuromyelitis optica

BackgroundB cells are believed to play an important role in the pathogenesis of NMO. Chemokine (C-X-C motif) ligand 13 (CXCL13), the most potent B-cell chemoattractant, is a chemokine which is critical for secondary lymphoid tissue development and for B-cell migration. Concentration of CXCL13 in cerebral spinal fluid (CSF) is elevated in patients with multiple sclerosis (MS). However, whether levels of CSF CXCL13 are elevated in NMO patients still remain unknown. ObjectiveTo measure the CSF concentration of CXCL13 in NMO patients, and to determine its relationship with NMO disease activity. MethodsCSF CXCL13 was measured by an enzyme-linked immunosorbent assay (ELISA) in NMO (n=22), MS (n=18) patients and controls (CTLs) (n=12). ResultsCSF CXCL13 levels in NMO were notable higher than MS (p=0.015) and CTLs (p<0.001), and were related to the NMO disease activity indicated by relapse rate and Expanded Disability Status Scale (EDSS) scores. NMO Patients with the higher relapse rates exhibited the higher CXCL13 concentrations in their CSF; and a trend of increased disease disability with increased CSF CXCL13 level was revealed. The CSF CXCL13 concentrations seemed to associate with CSF white blood cell counting, total protein concentration in NMO subgroup, thought did not quite reach statistical significance (WBC, p=0.473; TP, p=0.276). ConclusionsThe concentration of CSF CXCL13 was elevated in NMO patients, and correlated with NMO activity.

Pharmacokinetics and distribution of minocycline in mature horses after oral administration of multiple doses and comparison with minimum inhibitory concentrations

Minocycline holds great potential for use in horses not only for its antimicrobial effects but also for its anti-inflammatory and neuroprotective properties. However, there are no pharmacokinetic or safety data available regarding the use of oral minocycline in horses. To determine pharmacokinetics, safety and penetration into plasma, synovial fluid, aqueous humour (AH) and cerebral spinal fluid (CSF) of minocycline after oral administration of multiple doses in horses and to determine the minimum inhibitory concentrations (MIC) of minocycline for equine pathogenic bacteria. Six horses received minocycline (4 mg/kg bwt q. 12 h for 5 doses). Thirty-three blood and 9 synovial fluid samples were collected over 96 h. Aqueous humour and CSF samples were collected 1 h after the final dose. Minocycline concentrations were measured using high pressure liquid chromatography. The MIC values of minocycline for equine bacterial isolates were determined. At steady state, the mean ± s.d. peak concentration of minocycline in the plasma was 0.67 ± 0.26 µg/ml and the mean half-life was 11.48 ± 3.23 h. The highest trough synovial fluid minocycline concentration was 0.33 ± 0.12 µg/ml. The AH concentration of minocycline was 0.09 ± 0.03 µg/ml in normal eyes and 0.11 ± 0.04 µg/ml in blood aqueous barrier-disrupted eyes. The mean CSF concentration of minocycline was 0.38 ± 0.09 µg/ml. The MIC values were determined for 301 isolates. Minocycline concentrations were above the MIC(50) and MIC(90) for many gram-positive equine pathogens. This study supports the use of orally administered minocycline at a dose of 4 mg/kg bwt every 12 h for the treatment of nonocular infections caused by susceptible (MIC ≤ 0.25 µg/ml) organisms in horses. Further studies are required to determine the dose that would be effective for the treatment of ocular infections.

Effects of Exercise Therapy on Endogenous Pain-relieving Peptides in Musculoskeletal Pain

To review the literature regarding the effects of exercise in patients with musculoskeletal pain on modifying: (1) the plasma or cerebral spinal fluid concentrations of pain-relieving peptides and (2) changing the cerebral activity of areas linked with pain processing and modulation systematically. An extensive search of bibliographic databases including MEDLINE, EMBASE, EBM Reviews-Cochrane Central Register of Controlled Trials, ISI Web of Science, Scopus, PeDro, AMED, and CINAHL was made. Two independent investigators screened the titles of publications and completed quality assessment of the selected studies. The search of the literature resulted in a total of 1819 published studies. Of these only 1 study of low methodological quality was considered to be relevant. The agreement between reviewers to select the articles was κ=1. The agreement for the methodological quality evaluation was κ=0.9. Given the small number of studies identified and the low quality of research, no firm conclusions could be reached about the impact of therapeutic exercise on modifying concentrations of pain-relieving peptides or its effect on changing the cerebral activity of areas linked with pain processing in patients with musculoskeletal pain. There is a clear need for well-designed trials examining exercise therapy interventions and their effect on both pain-relieving peptides and cerebral activity in patients with musculoskeletal pain.

IL-6 and IL-8 in cerebrospinal fluid from patients with aseptic meningitis and bacterial meningitis: their potential role as a marker for differential diagnosis

Cytokines are molecules that act as mediators of immune response; cerebral spinal fluid (CSF) IL-6 is found in all meningeal inflammatory diseases, but IL-8 is associated with acute bacterial meningitis (ABM). A case control study was done to ascertain the discriminatory power of these cytokines in differentiating ABM from aseptic meningitis (AM); IL-6 and IL-8 CSF concentrations were tested through ELISA in samples collected from patients who underwent investigation for meningitis. Sixty patients, 18 with AM, nine with bacteriologic confirmed ABM and 33 controls, assisted in 2005 (MA and controls) and 2007 (ABM) were included. Differently from controls, IL-6 concentrations were increased both in MA and ABM patients (p < 0.05). CSF IL-8 levels were higher in ABM than in AM and controls (p < 0.05). Discriminatory power in ABM as assessed by the area under receiver operator (ROC) curve was 0.951 for IL-8, using a cut-off of 1.685 ng/dL (100% of sensitivity and 94% of specificity). The CSF concentration of both IL-6 and IL-8 are increased in the presence of meningeal inflammation, IL-8 could be an important tool to differentiate ABM from AM.

IL-6 and IL-8 in cerebrospinal fluid from patients with aseptic meningitis and bacterial meningitis: their potential role as a marker for differential diagnosis

Cytokines are molecules that act as mediators of immune response; cerebral spinal fluid (CSF) IL-6 is found in all meningeal inflammatory diseases, but IL-8 is associated with acute bacterial meningitis (ABM). A case control study was done to ascertain the discriminatory power of these cytokines in differentiating ABM from aseptic meningitis (AM); IL-6 and IL-8 CSF concentrations were tested through ELISA in samples collected from patients who underwent investigation for meningitis. Sixty patients, 18 with AM, nine with bacteriologic confirmed ABM and 33 controls, assisted in 2005 (MA and controls) and 2007 (ABM) were included. Differently from controls, IL-6 concentrations were increased both in MA and ABM patients (p<0.05). CSF IL-8 levels were higher in ABM than in AM and controls (p<0.05). Discriminatory power in ABM as assessed by the area under receiver operator (ROC) curve was 0.951 for IL-8, using a cut-off of 1.685ng/dL (100% of sensitivity and 94% of specificity). The CSF concentration of both IL-6 and IL-8 are increased in the presence of meningeal inflammation, IL-8 could be an important tool to differentiate ABM from AM.

Plasma and cerebral spinal fluid tranexamic acid quantitation in cardiopulmonary bypass patients

A method for the determination of tranexamic acid (TXA) in human plasma and cerebral spinal fluid (CSF) was developed. Analyses were performed by ultra performance liquid chromatography with tandem mass spectrometry detection (UPLC–MS/MS) using ɛ-aminocaproic acid (ACA) as an internal standard. TXA and ACA were extracted from a 50 μL sample of plasma or CSF using a methanol protein crash protocol, and chromatographic separation was performed on an ACQUITY™ TQD mass spectrometer using a UPLC C18 BEH 1.7 μm column with a water and methanol gradient containing 0.1% formic acid. The detection and quantitation was performed by positive ion electrospray ionization using the multiple reaction monitoring (MRM) mode. The method was linear over the concentration range of 0.1–10.0 μg/mL, with lower limit of quantitation of 0.1 μg/mL for TXA. The intra- and inter-assay precision was less than 12% and 13% respectively at the plasma and CSF TXA concentrations tested. The present method provides a relatively simple and sensitive assay with short turn-around-time. The method has been successfully applied to assess the plasma and CSF concentrations of tranexamic acid achieved with only one dosing regimen of tranexamic acid in patients undergoing cardiopulmonary bypass surgery (CPB).

Delayed Etiologic Diagnosis of Meningitis in an Extremely Low Birth Weight Newborn

Delayed Etiologic Diagnosis of Meningitis in an Extremely Low Birth Weight Newborn

Cerebral Spinal Fluid Penetration of Tigecycline in a Patient with Acinetobacter baumannii Cerebritis

To describe cerebral spinal fluid (CSF) penetration of tigecycline. A 38-year-old woman experienced a right internal carotid artery dissection and right anterior and middle cerebral artery strokes due to unknown causes and subsequently developed vasogenic edema requiring right hemi-craniectomy. Her postoperative course was complicated by multiple infections, and she developed multidrug, carbapenem-resistant Acinetobacter baumannii cerebritis. She was treated with a prolonged course of multiple antibiotics, including 18 days of therapy with tigecycline. Time-paired serum and CSF samples were obtained, and tigecycline concentrations were analyzed by high-performance liquid chromatography. We report serial, steady-state, serum, and CSF concentrations of tigecycline when administered in the Food and Drug Administration-approved dose of 50 mg every 12 hours. CSF concentrations remained relatively stable, suggesting that tigecycline did not accumulate in the CSF, at least in our patient. Tigecycline concentrations in the CSF were between 0.035 and 0.048 mg/L, while corresponding serum concentrations were 0.097-0.566 mg/L. The calculated tigecycline penetration ratio in this patient ranged from 0% to 52%, depending on the calculation methodology utilized. Concentrations, regardless of sample timing relative to dose, remained relatively stable in the CSF of our patient. The pharmacodynamic profile of tigecycline is not completely elucidated; however, it is presumed that the drug must be at the site of infection for efficacy. Our patient never obtained tigecycline concentrations in excess of the minimum inhibitory concentration for A. baumannii in either the serum or the CSF. Our patient experienced low CSF tigecycline concentrations and failed to achieve a clinical response while on therapy. CSF drug disposition of tigecycline requires further systematic study to fully elucidate the pharmacokinetic profile. Reduced CSF concentrations urge caution in the treatment of cerebritis with standard dosing of tigecycline.

Fatal Outcome of Disseminated Strongyloidiasis despite Detectable Plasma and Cerebrospinal Levels of Orally Administered Ivermectin

Strongyloides stercoralis affects over 100 million people worldwide. Those people most susceptible to infection are those with an immunocompromising condition, such as cancer or human immunodeficiency virus (HIV). Local disease may spread throughout the body of the host, causing a condition termed disseminated strongyloidiasis. Standard treatment for Strongyloides stercoralis infection is oral ivermectin. We describe a patient with chronic lymphocytic leukemia diagnosed with disseminated strongyloidiasis two weeks after initial presentation. After repeated dosing of oral ivermectin with no clinical response, serum and cerebral spinal fluid (CSF) concentrations of ivermectin were measured to assess absorption. The peak serum concentration of 49.3 ng/mL correlated with a CSF concentration of 0.14 ng/mL. Despite these concentrations, the patient eventually succumbed to multi-system organ failure. We discuss the reasons for treatment failure and explore the utility of measuring ivermectin concentrations.

Unbound Drug Concentration in Brain Homogenate and Cerebral Spinal Fluid at Steady State as a Surrogate for Unbound Concentration in Brain Interstitial Fluid

The objective of the present study was to examine the accuracy of using unbound brain concentration determined by a brain homogenate method (C(ub)), cerebral spinal fluid concentration (C(CSF)), and unbound plasma concentration (C(up)) as a surrogate for brain interstitial fluid concentration determined by brain microdialysis (C(m)). Nine compounds-carbamazepine, citalopram, ganciclovir, metoclopramide, N-desmethylclozapine, quinidine, risperidone, 9-hydroxyrisperidone, and thiopental-were selected, and each was administered as an intravenous bolus (up to 5 mg/kg) followed by a constant intravenous infusion (1-9 mg/kg/h) for 6 h in rats. For eight of the nine compounds, the C(ub)s were within 3-fold of their C(m); thiopental had a C(m) 4-fold of its C(ub). The C(CSF)s of eight of the nine compounds were within 3-fold of their corresponding C(m); 9-hydroxyrisperidone showed a C(CSF) 5-fold of its C(m). The C(up)s of five of the nine compounds were within 3-fold of their C(m); four compounds (ganciclovir, metoclopramide, quinidine, and 9-hydroxyrisperidone) had C(up)s 6- to 14-fold of their C(m). In conclusion, the C(ub) and C(CSF) were within 3-fold of the C(m) for the majority of the compounds tested. The C(up)s were within 3-fold of C(m) for lipophilic non-P-glycoprotein (-P-gp) substrates and greater than 3-fold of C(m) for hydrophilic or P-gp substrates. The present study indicates that the brain homogenate and cerebral spinal fluid methods may be used as surrogate methods to predict brain interstitial fluid concentrations within 3-fold of error in drug discovery and development settings.

Guillain-Barre Syndrome Complicating Multiple Myeloma

Background: Although neuropathies complicating multiple myeloma (MM) are common as a result of medications and spinal cord compression, neuropathy as a consequence of cross reactivity between the paraprotein and neural tissues is rare. In CANOMAD syndrome (chronic ataxic neuropathy, ophthalmoplegia, M-protein, agglutination, anti-disialosyl antibodies) IgM paraproteins with shared reactivity between Campylocacter jejuni lipopolysaccharides and human peripheral nerve disialylated gangliosides including GQ1b have been described. In POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) cerebral spinal fluid concentrations of vascular endothelial growth factor (VEGF) may be markedly elevated, similar to other inflammatory polyneuropathies. Guillain-Barre syndrome (GBS) is an acute inflammatory demyelinating polyradiculopathy yielding flaccid areflexic paralysis that, to our knowledge, has only been reported once as a complication of MM.Case reports: At Hackensack University Medical Center we have observed 5 cases of GBS complicating MM since 2002 (approximate incidence <0.5%). Details are described below. In all five cases, blood and cerebrospinal fluid cultures, anti-GQb1, anti-GM1, and anti-MAG antibodies were negative and radiographic imaging including computerized axial tomographic scan (CT) of the head and magnetic resonance imaging (MRI) of the brain were unrevealing. In four patients cerebrospinal fluid examination showed albumin/cytologic dissociation.Conclusions: Our observation represents the first series of patients with GBS complicating MM, and suggests that GBS, although rare, should be considered as part of the neurologic complications of plasma cell dyscrasias.CaseAgeSexType of MyelomaMM TherapyPresenting symptoms168MIIIB IgD lambdaVAD, Mel 200 PBSC, month 9, recurringCN VI palsy, areflexia upper extremities, hyporeflexia lower extremities, paresthesias feet & side face263MIIIA IgA kappaDex-Thal, Mel 200 PBSC, week 2Parasthesias hands, legs, and feet. Motor weakness lower extremities ascending.368MIIIA IgG kappaDex-Thal, CDEP, Mel 200 PSCT, wk 3Bilateral facial, sternocleidomastoid, neck muscle weakness with sluggish gag reflex. Upper and lower muscles weak and hyporeflexic.481FIII A IgA kappa + urineDex-LenolidomideLower extremity weakness, with areflexia and severely ataxic gait. Sensory defects in LE.525MIgA lambda plasma-cytomasNone (GBS presenting feature)Marked LE weaknessCSF proteinMotor Nerve ConductionsSensory Nerve ConductionsTreatment & Response1126 mg/dlProlonged median F wave latencyProlonged DSL superficial peronealPlasmapheresis, dex, thalidomide (improved)277 mg/dlSeverely prolonged DML, Reduced CMAP amplitudes, Slow CV, Conduction blockAbsent SNAPsPlasmapheresis (no response), IVIG (improved)376 mg/dlProlonged F wave latencies, Slow CV, Reduced CMAP amplitudesAbsent SNAPsIVIG (minimal response), plasmapheresis (slow improvement)4202 mg/dlProlonged distal motor latencies, Reduced amplitudes of CMAPS in lower extremities, Prolonged F wave latencies, Slow CV in lower extremitiesAbsent or reduced amplitudes of SNAPsIVIG (no response), plamapheresis (improved)559 mg/dlProlonged DML, Prolonged F wave latencies or absent F waves, Mild slowing CV, Mild reduction of CMAP amplitudesNormalIVIG and plasmapheresis (no response, paraplegia), Mel 200 PBSC X2 (improved)

Biotin accounts for less than half of all biotin and biotin metabolites in the cerebrospinal fluid of children

Background:Biotin is likely transported into cerebral spinal fluid (CSF) via one or more specific transporters. Concentrations of biotin in CSF measured by using modern analytic techniques that are specific for biotin and biotin metabolites have not previously been reported. Objectives:We aimed to accurately measure the concentration of biotin and major biotin metabolites, biotin sulfoxide (BSO) and bisnorbiotin (BNB), in the CSF of children. Design:Concentrations of biotin were determined initially as total avidin-binding substances (TABS) in CSF obtained by lumbar puncture from 55 children. Biotin, BSO, and BNB were quantitated by HPLC and an avidin-binding assay in CSF samples from a subset of 11 children. Results:Concentrations of TABS in CSF averaged 1.6 nmol/L with substantial variability (SD = 1.3 nmol/L). CSF concentrations of biotin and biotin analogs varied widely, but substantial amounts of BSO were detected in every sample. Biotin accounted for 42 ± 16%, BSO for 41 ± 12%, and BNB for 8 ± 14% of the total. It was surprising that the molar sum of biotin, BSO, and BNB on average was >200-fold the TABS concentrations from the same CSF sample. Using several analytic approaches, we found no masking of detection, nor did we find degradation of biotin or BSO. Gel electrophoresis and streptavidin Western blot detected several biotinylated proteins in CSF. Conclusions:Biotin appears to be bound to protein covalently, reversibly, or both, and this binding likely accounts for the increase in detectable biotin after HPLC. Protein-bound biotin may play an important role in biotin nutriture of the brain.

Method Validation for Cerebral Spinal Fluid Human Chorionic Gonadotropin Measurement with the Advia Centaur®2

Intracranial germ cell tumors account for 0.4%–3.4% of all brain tumors (1). These tumors can be divided into 2 groups, germinomas and nongerminomatous germ cell tumors. Germinomas, which are fairly treatable, arise from primordial germ cells that fail to migrate correctly in embryogenesis. Nongerminomatous germ cell tumors (including choriocarcinomas), which are more refractory to treatment, are differentiated tumors. Measurement of human chorionic gonadotropin (hCG)1 is an important adjunct method in the diagnosis of germ cell tumors. At high concentrations hCG can be detected in serum, but measurement of hCG concentrations in cerebral spinal fluid (CSF) is a more sensitive and reliable indicator of tumor presence (1). Pure germinomas are associated with very low concentrations of hCG in both serum and CSF. A subset of nongerminomatous germ cell tumors contains syncytiotrophoblastic giant cells. These tumors are associated with moderately increased concentrations of hCG (<1000 IU/L) in the serum, CSF, or both, and the survival rate in patients suffering these tumors is poorer than that for patients with pure germinomas …

Expression and significance of TNF-α and proteins in cerebral tissue of rats with acute necrotizing pancreatitis

Objective To investigate the expression of TNF-α messenger RNA(mRNA)and peptide in the brain of rats with acute pancreatitis(AP)and explore its significance in the pathogenesis of pancreatic encephalopathy(PE).Methods Modds of acute necrotizing pancreatitis(ANP,n=16)and acute edematous pancreatitis(AEP,n=16)were induced by injecting sodium taurocholate into the pancreatic duct of male Sprague Dawley rats.Another 16 normal rats were employed to serve as controls.Twelve hours after the induction of AP,the rats in each group were sacrificed and the blood and cerebral spinal fluid(CSF)samples were taken for determining the level of TNF-α by ELISA.TNF-α mRNA and peptide expression in the cerebral tissues was assessed by semiquantitative RT-PCR,Western blotting and immunohistochemistry,respectively.Results TNFF-α concentration in blood and CSF of rats with ANP showed significant elevation as compared with AEP and control grouP(P＜0.05).TNF-α concentration in blood of ANP,AEP and control group were 1065.6pg/ml,577.5pg/ml and 543.8pg/ml,respectively.The concentration in CSF was 820.9pg/ml,307.4pg/ml and 481.6Pg/ml,respectively.TNF-α mRNA expression and its protein level in the cerebra of rats with ANP were significantly greater than that in the other two groups respectively(P＜0.05).Double-labeling and immunohistochemical studies revealed that the protein was located in the microglial cells and neurons in the cerebrum.Conclusion The cerebrum might be one of the organs releasing cytokines during AP.TNF-α is overproduced by both microglial cells and neurons in the cerebrunl and might play an important role in the demyelinization of brain during the early stage of ANP. Key words: Pancreatitis; Tumor necrosis factor; Encephalopathy

Poor Central Nervous System Penetration of Tigecycline in a Patient with Sepsis and Ventriculitis Caused by Multidrug-Resistant Klebsiella Pneumoniae

Objective: To report the use of tigecycline in a case of ventriculitis and concurrent bacteremia. Case Summary: A 57-year-old African American male with a ruptured brain aneurysm was admitted to the intensive care unit after surgical intervention and external ventricular drainage placement. His hospital course was complicated by myocardial infarction, ventilator-associated pneumonia, ventriculitis, and sepsis, with multidrug-resistant (MDR) Klebsiella pneumoniae isolated from multiple sites, including blood and cerebral spinal fluid (CSF). The patient was treated with high doses of intravenous tigecycline and gentamicin along with intrathecal gentamicin. This combination eradicated infections outside the central nervous system (CNS) within 48 hours, but it took approximately 8 days for the CSF culture to become negative. Timed serum and CSF fluid samples were collected to determine CSF penetration of tigecycline on day 12 of therapy. CSF concentrations obtained 30 minutes after the dose and at the end of the dosing interval remained below the detectable limit of 0.05 μg/mL. Discussion: Although CSF tigecycline concentrations may not represent actual CNS tissue concentrations at the site of infection, the low CSF concentrations observed in our case may be responsible for the slow CSF clearance of infection. It was not clear whether gentamicin therapy alone, administered both intravenously and intrathecally, would have achieved the same outcome and cleared the infection from the CNS in this patient. Conclusions: Until additional clinical data are available, tigecycline should not be used for the management of MDR infections associated with the CNS.

Treatment of Serratia marcescens Meningitis with Prolonged Infusion of Meropenem

To describe the use of and cerebral spinal fluid (CSF) penetration of a prolonged infusion meropenem regimen in a patient with Serratia marcescens meningitis. A 54-year-old female was diagnosed with S. marcescens meningitis associated with an epidural abscess 57 days after surgery for a herniated spinal disk. Meropenem 2000 mg every 8 hours was administered as a prolonged (3 h) infusion for the purpose of optimizing pharmacodynamic exposure. Meropenem concentrations were measured from the patient's blood and CSF (via a lumbar drain). The prolonged infusion regimen resulted in concentrations in both serum and CSF above the meropenem minimum inhibitory concentration (MIC) of 0.047 microg/mL for 100% of the dosing interval. After 6 days of therapy, the patient showed no further signs of infection and was subsequently discharged to a rehabilitation facility. At follow-up, she had completed a 4 week course of the prolonged infused therapy without relapse or adverse events. Gram-negative infections of the central nervous system result in high morbidity and mortality. These infections are often difficult to treat because of poor antibiotic penetration coupled with increasing antibiotic resistance. Although there are 2 other case reports that describe the use of prolonged infusion of meropenem, our patient had a lumbar drain in place, thereby allowing us to collect multiple CSF samples and more accurately assess meropenem exposure at the site of infection. CSF penetration was 6.4% in this patient, resulting in 100% time above the MIC throughout the dosing interval. In this patient with meropenem-susceptible S. marcescens meningitis, the use of a high-dose prolonged infusion of meropenem resulted in adequate exposure at the site of infection and a successful clinical response.