Gram-negative bacillary community acquired meningitis is not a rare entity in last two decades

The aim of this short note is to assess gram-negative bacillary community acquired meningitis (CBM) and nosocomial meningitis (NM) within 17 years nationwide survey. All cases of gram-negative bacillary CBM within 1990-2007 were assessed in national database of 372 patients with bacterial meningitis: 69 of gram-negative cases were nosocomial and 24 of gram-negative meningitis cases were CBM. Those 24 cases were compared with all CBM (201 cases) for risk factors and outcome. Among nosocomial gram-negative pathogens, A. baumannii in 23 cases, Ps. aeruginosa in 15 cases and Enterobacteriaceae in 31 cases were isolated. Among CBM, in 13 cases Enterobacteriaceae (Escherichia coli 6, Klebsiella pneumoniae 3, Proteus mirabilis 2, Enterobacter cloacae 2), in 5 cases Ps. aeruginosa and in 6 cases Acinetobacter baumannii were isolated from cerebrospinal fluid (CSF). The only significant risk factor for CBM due to gram-negative bacilli was neonatal age (12.5% vs. 3.5%, p=0.04) as underlying disease. However, mortality among gram-negative bacillary meningitis was significantly higher (12.4% vs. 37.5%, p=0.001) in comparison to other meningitis.     

Chronic meningitis and Lyme disease in Sweden.

We studied 35 patients with chronic meningitis. The neurological abnormalities included aseptic meningitis, cranial neuropathy (mostly facial palsy), motor and sensory peripheral radiculoneuropathy, and myelitis. Neurological symptoms were sometimes preceded by erythema chronicum migrans or an insect bite and were often accompanied by fever, malaise, profound fatigue, and weight loss. The cerebrospinal fluid (CSF) abnormalities consisted of a predominantly mononuclear pleocytosis, an elevated CSF protein (mean 2.3 g/l), intrathecal synthesis of oligoclonal immunoglobulin G, and, in half of the patients, a fall in the CSF/blood glucose ratio. High antibody titers to the Lyme spirochete and the Swedish Ixodes ricinus spirochete were demonstrated by immunofluorescence in 26 of the 35 patients. By imprint immunofixation of electrofocused samples of serum and CSF, intrathecal production of oligoclonal Lyme-spirochete-specific IgG was demonstrated in one patient with chronic meningitis. Four sequential paired samples of serum and CSF from this patient showed local synthesis of spirochete-specific antibodies in CSF. The 35 patients improved or recovered, sometimes dramatically, during a two-week course of intravenous penicillin G.     

Pharmacokinetics and Bioavailability of a Therapeutic Enzyme (Idursulfase) in Cynomolgus Monkeys after Intrathecal and Intravenous Administration

Intravenous enzyme replacement therapy with iduronate-2-sulfatase is an approved treatment for Hunter syndrome, however, conventional intravenous delivery cannot treat the neurologic manifestations of the disease due to its limited central nervous system penetration. Intrathecal administration of iduronate-2-sulfatase for delivery to the central nervous system is currently under investigation. The objective of this study was to evaluate the pharmacokinetics of idursulfase in the central nervous system of cynomolgus monkeys (Macaca fasicularis) after intravenous and intrathecal administration. Twenty-seven monkeys, treatment-naïve to enzyme replacement therapy, were placed into 4 groups according to body weight: Group 1 was administered 0.5 mg/kg idursulfase intravenously, Groups 2–4 were administered an intrathecal formulation (1-, 10-, and 30-mg doses). Blood samples and cerebrospinal fluid (sampled at the cisterna magna or lumbar level) were collected at the same time points for 72 hours post dosing. Following intravenous administration, a high maximum serum concentration and rapid distribution of iduronate-2-sulfatase out of the central compartment were observed (elimination half-life: 4.3 hours). Iduronate-2-sulfatase exposure in the cerebrospinal fluid was limited, suggesting intravenous administration provided minimal penetration of the blood–brain barrier. Following intrathecal administration, a high maximum observed concentration was immediately noted and elimination half-life ranged between 7.8–10 hours and 5.9–6.7 hours (cisterna magna and lumbar sampling, respectively). Cerebrospinal fluid pharmacokinetic profiles at different doses of iduronate-2-sulfatase were similar and the dose/exposure relationship was proportional. After intrathecal administration, movement of iduronate-2-sulfatase from cerebrospinal fluid to serum was observed (systemic bioavailability was 40–83%). The clear penetration of iduronate-2-sulfatase into the cerebrospinal fluid and the dose response suggest that intrathecal delivery of iduronate-2-sulfatase may be suitable for treating the central nervous system manifestations associated with Hunter syndrome.     

Interleukin-2 and blood brain barrier in cats: pharmacokinetics and tolerance following intrathecal and intravenous administration.

Single bolus doses of glycosylated human interleukin-2 (n IL-2) in the range of 2.8 x 10(3) to 2.0 x 10(6) IU/kg were administered to anesthesized cats via the cephalic vein (n = 10) or using suboccipital puncture (n = 8). CSF (cerebrospinal fluid) and blood samples were collected by repeated puncture. The n IL-2 concentration in four cats was determined on the basis of its biologic activity using 3H-thymidine incorporation into human ConA-blasts and by radioimmunoassay. In additional experiments radioactivity was determined in cerebrospinal fluid and serum after intravenous and intrathecal (i.th.) application of 5.8 x 10(3) - 3.2 x 10(3) IU/kg of 14C-acetyl-n IL-2 in regular time intervals. CSF and serum concentration time-profiles show a biexponential decline in the plasma elimination phase with half-lives of 4 min (alpha-phase) and 90 min (beta-phase) after intravenous and 20-120 min (alpha-phase) and 2-16 hours (beta-phase) after intrathecal application. There is a trend towards longer terminal elimination half-lives with increasing doses. Interleukin-2 is able to penetrate the blood brain barrier from the circulation into the cerebrospinal fluid and vice versa. Due to a slow rate of penetration and rapid elimination from blood only traces of n IL-2 (2-8 IU/ml) are detected in CSF after i.v. injection of 2 x 10(6) IU/kg, whereas concentrations between 400 and 1600 IU/ml are maintained in CSF for several hours following i.th. administration of 2-10 x 10(5) IU/kg.(ABSTRACT TRUNCATED AT 250 WORDS)     

Compartmentalization of TNF and IL-6 in meningitis and septic shock

We examined the compartmentalization of bioactive tumour necrosis factor (TNF) and interleukin 6 (IL-6) to the subarachnoid space and systemic circulation in patients with meningococcal meningitis and septic shock/bacteraemia. In patients with meningitis, median levels of TNF in 31 paired samples of cerebrospinal fluid (CSF) and serum were respectively 783 pg/ml and below detection limit (p < 0.001) and median levels of IL-6 were 150 ng/ml and 0.3 ng/ml (p < 0.0001). In patients with septic shock without meningitis, median levels in paired samples of CSF and serum were respectively below detection limit and 65 pg/ml (not significant, (ns)) (TNF, eleven patients) and 1.3 ng/ml-3 ng/ml (ns) (IL-6, nine patients). The data show that TNF and IL-6 are localized to the subarachnoid space in patients with meningitis although the blood-brain barrier is penetrable to serum proteins. On the other hand, patients with septic shock tend to have cytokines in both serum and CSF.     

结核性脑膜炎与化脓性脑膜炎脑脊液与血浆生化指标比值的比较研究

目的:比较结核性脑膜炎与化脓性脑膜炎脑脊液与血浆生化指标比值。方法:选择2010年2月~2014年12月我院结核性脑膜炎患者82例,化脓性脑膜炎98例,检测脑脊液与血浆中的蛋白、糖及氯化物含量,并计算比值。结果:两组患者脑脊液蛋白、糖含量的差异无统计学意义(P0.05),化脓性脑膜炎组的氯化物含量高于结核性脑膜炎组(P0.05);两组血浆糖含量的差异无统计学意义(P0.05),化脓性脑膜炎组蛋白和氯化物含量明显高于结核性脑膜炎组(P0.05);化脓性脑膜炎组蛋白比值低于结核性脑膜炎组,氯化物比值则高于化脓性脑膜炎组,差异均有统计学意义(P0.05);两组间糖比值比较,差异无统计学意义(P0.05)。结论:脑脊液与血浆生化指标比值对鉴别诊断结核性脑膜炎与化脓性脑膜炎有重要意义。     

A new antibiotic combination for frozen bovine semen. 2. Evaluation of seminal quality

Amikacin, clindamycin, gentamicin, Linco-Spectin, minocin and tylosin were added individually and in combinations at various concentrations to bovine neat semen and to egg-yolk citrate, egg yolk-tris or heated whole milk extenders (nonglycerol fractions) prior to final processing for freezing to -196 degrees C. After thawing samples, seminal quality was measured by progressive motility and acrosomal integrity evaluations. Studies were performed in parallel with microbiological efficacy studies of Shin et al. (7). The antibiotic combination including gentamicin, tylosin and Linco-Spectin at 500 ug/ml, 100 ug/ml and 300/600 ug/ml, respectively, was not detrimental to seminal quality and, in the parallel studies, was most efficacious in controlling microorganisms potentially present in bovine semen.     

脑脊液腺苷脱氨酶和干扰素-r水平在结核性脑膜炎中的诊断价值

目的：探讨脑脊液腺苷脱氨酶和干扰素-酌水平在结核性脑膜炎中的诊断价值。方法：选取2012 年6 月-2014 年6 月期间于 我院进行治疗的结核性脑膜炎患者50 例作为研究组,同期健康体检者50 例作为对照组1,50 例非结核性脑膜炎者作为对照组 2。检测脑脊液中腺苷脱氨酶和干扰素-酌水平,并进行比较。结果：研究组患者脑脊液中腺苷脱氨酶和干扰素-r水平分别为 （22.45± 4.23）U/L和（36.45± 13.56）ng/L;对照组1 患者脑脊液中腺苷脱氨酶和干扰素-r水平分别为（16.32± 3.24）U/L 和 （12.78± 2.67）ng/L,对照组2 患者脑脊液中腺苷脱氨酶和干扰素-r水平分别为（7.48± 4.01）U/L 和（13.25± 2.89）ng/L,三组比较 差异有统计学意义（P＜0.05）,其中研究组患者脑脊液中腺苷脱氨酶和干扰素-r水平显著高于对照组1 和对照组2,两两比较差 异均有统计学意义（均P＜0.05）。结论：脑脊液腺苷脱氨酶和干扰素-r在结核性脑膜炎患者中具有诊断价值,值得推广应用。     

Intrathecal administration of Y-27632, a specific rho-associated kinase inhibitor, for rat neoplastic meningitis

The small GTP-binding protein Rho and its target Rho-associated kinase trigger an intracellular signaling cascade that controls actin cytoskeleton and plays an essential role in cell motility and adhesion. A specific Rho-associated kinase inhibitor, Y-27632, has been reported to inhibit cancer invasion. Clinically, disseminated tumor cells in the cerebrospinal fluid invade the intraparenchymal region, damaging the brain and nerves, resulting in fatal brain stem dysfunction, despite intrathecal chemotherapy. To expand therapeutic options for this devastating neoplastic meningitis, we evaluated the potential use of intrathecal Y-27632 administration by employing Walker 256 cells, a rat mammary cancer cell line. Y-27632 dose-dependently inhibited chemotactic and invasive activity of Walker 256 cells. Y-27632 also inhibited the phosphorylation level of regulatory myosin light chain in vitro, but the effect was temporary and was considerably diminished within 16 hours. Y-27632 induced striking morphologic changes in Walker 256 cells, as evidenced by decreased cell-matrix adhesion in culture dishes and three-dimensional collagen I gels, and slightly inhibited colony formation in soft agar. Nevertheless, this drug treatment did not affect Walker 256 cell growth rate. We were able to administer continuous delivery of this inhibitor using an osmotic pump and maintaining drug concentration of 10 mumol/L within the brain. Importantly, this concentration of Y-27632 showed minimal neurotoxicity both in vitro and in vivo. We found that an intrathecal therapy, combining 5-fluoro-2'-deoxyuridine with Y-27632, significantly increased the survival time of rats bearing meningeal carcinomatosis in comparison with animals treated with 5-fluoro-2'-deoxyuridine alone. Taken together, our findings indicate that continuous intrathecal administration of Y-27632 could be a promising therapeutic method when combined with chemotherapy for treating human neoplastic meningitis.     

CNS penetration of intrathecal-lumbar idursulfase in the monkey, dog and mouse: implications for neurological outcomes of lysosomal storage disorder

A major challenge for the treatment of many central nervous system (CNS) disorders is the lack of convenient and effective methods for delivering biological agents to the brain. Mucopolysaccharidosis II (Hunter syndrome) is a rare inherited lysosomal storage disorder resulting from a deficiency of iduronate-2-sulfatase (I2S). I2S is a large, highly glycosylated enzyme. Intravenous administration is not likely to be an effective therapy for disease-related neurological outcomes that require enzyme access to the brain cells, in particular neurons and oligodendrocytes. We demonstrate that intracerebroventricular and lumbar intrathecal administration of recombinant I2S in dogs and nonhuman primates resulted in widespread enzyme distribution in the brain parenchyma, including remarkable deposition in the lysosomes of both neurons and oligodendrocytes. Lumbar intrathecal administration also resulted in enzyme delivery to the spinal cord, whereas little enzyme was detected there after intraventricular administration. Mucopolysaccharidosis II model is available in mice. Lumbar administration of recombinant I2S to enzyme deficient animals reduced the storage of glycosaminoglycans in both superficial and deep brain tissues, with concurrent morphological improvements. The observed patterns of enzyme transport from cerebrospinal fluid to the CNS tissues and the resultant biological activity (a) warrant further investigation of intrathecal delivery of I2S via lumbar catheter as an experimental treatment for the neurological symptoms of Hunter syndrome and (b) may have broader implications for CNS treatment with biopharmaceuticals.     

儿童隐球菌性脑膜炎临床分析

目的分析并讨论儿童隐球菌性脑膜炎的临床特点、诊断及治疗方法等。方法回顾性分析上海长征医院皮肤科在1993年3月至2008年6月间16例经病原学确诊的隐球菌性脑膜炎患儿临床资料。结果患儿平均年龄7．25岁（2～15岁）,男女比例2．2：1,主要症状包括头痛（87．5％）、发热（81．25％）、恶心呕吐（75％）等,10例颅内压升高。确诊依据脑脊液真菌涂片、培养或隐球菌抗原检查。治疗采用两性霉素B和（或）两性霉素B脂质体静滴,5一氟胞嘧啶口服,辅以两性霉素B鞘内注射,联合氟康唑、伊曲康唑等药物治疗。16例患儿痊愈9例,病情明显好转5例,死亡2例。结论儿童隐球菌性脑膜炎起病缓慢,临床症状缺乏特异性,对疑有中枢神经系统感染性疾病时,应及早行脑脊液检查,并反复多次检查、联合检查以确定诊断,减少误诊、漏诊。早期诊断和及时、系统、足量、长程的抗真菌治疗是提高治愈率和患儿生存质量的关键。     

Effects of cerebral ventricular, systemic, and local administration of prostaglandin F2a on canine cerebral hemodynamics

The effects of Prostaglandin F_2a (PGF_2a) on cerebral blood flow, cerebral vascular resistance, and cerebrospinal and systemic arterial pressures were determined in anesthetized dogs. Flow was measured from the cannulated sinus confluens after occlusion of the transverse canals. Infusion of 1 to 100 ug/ml of PGF_2a into the cerebral ventricular system did not affect cerebral venous outflow but increased cerebral vascular resistance, arterial blood pressure, and cerebrospinal fluid pressure at the higher concentrations. Systemic, intra-aortic arch infusion of PGF_2a from 50 to 200 ug/min decreased cerebral venous outflow and increased cerebral vascular resistance slightly. Bilateral, intra-carotid artery infusion of PGF_2a at 20 to 80 ug/min produced effects similar in magnitude and direction to systemic, intra-aortic infusion. PGF_2a appears to increase cerebral vascular resistance by active vasomotion, dependent upon the route of administration. However, the magnitude of this constriction is not great considering the dose used. Also, PGF_2a can increase systemic arterial blood pressure via a central effect.     

Neurotensin-like immunoreactivity (NTLI) concentration in the cerebrospinal fluid of children and its alteration in a febrile aseptic meningitis

Neurotensin-like immunoreactivity (NTLI) concentrations in the cerebrospinal fluid (CSF) of normal children and patients with febrile aseptic meningitis, aged 7 months to 15 years, were studied. The NTLI concentrations in CSF of 27 children with normal CSF findings were 160.1 +/- 54.6 pg/ml (mean +/- S.D.). The NTLI concentration in CSF of 26 patients in an acute phase of aseptic meningitis was 110.6 +/- 51.1 pg/ml which was significantly (P less than 0.01) lower than the controls. These patients had a mean temperature of 101.4 +/- 1.5 degrees F which remained elevated for an average of 3.5 days. The NTLI concentrations in CSF of 23 patients in a recovery phase (after blood and CSF findings became normal with no fever) were 166.5 +/- 57.8 pg/ml, which did not differ significantly from the normal. There were no statistical correlations between the NTLI concentration in CSF and the protein concentration or total cell count in CSF. These results suggest that NTLI concentration changes during a febrile aseptic meningitis and that it may be associated with thermoregulation.     

Serum procalcitonin and cerebrospinal fluid cytokines level in children with meningitis

AIMS: To determine the level of serum procalcitonin and cerebrospinal fluid cytokines in children with bacterial or viral meningitis and to document the use of these parameters in differential diagnosis. RESULTS: Before the start of antibiotic treatment, serum procalcitonin and tumor necrosis factor alpha levels were found to be higher in acute bacterial meningitis compared with viral meningitis and with the control group. Similarly, cerebrospinal fluid interleukin-6 levels were found to be significantly higher in children with acute bacterial meningitis compared with viral meningitis. However, no significant difference was determined between groups in respect to the cerebrospinal fluid interleukin-8 level. CONCLUSION: Serum procalcitonin and cerebrospinal fluid tumor necrosis factor alpha levels can be used in the early diagnosis of bacterial meningitis. Similarly, they may be useful adjuncts in differential diagnosis of bacterial and viral meningitis.     

伏立康唑联合小剂量糖皮质激素治疗儿童隐球菌性脑膜炎:2例报道并文献复习

目的探讨伏立康唑联合小剂量糖皮质激素对儿童隐球菌性脑膜炎的疗效。方法分析2例采用伏立康唑联合小剂量糖皮质激素治疗的儿童隐球菌性脑膜炎病例并进行相关文献复习。结果患儿经治疗后头痛等症状消失,颅内压逐渐下降至正常水平,脑脊液蛋白水平明显下降并稳定。结论伏立康唑联合小剂量糖皮质激素能迅速有效地控制临床症状,使用方便、副作用小,可作为儿童隐球菌性脑膜炎诱导治疗的一种选择。     

Concentrations of hepatocyte growth factor in cerebrospinal fluid under normal and different pathological conditions

Hepatocyte growth factor (HGF) and its specific receptor, MET, are expressed in the developing and adult mammalian brain. Recent studies have shown a neurotrophic activity of HGF in the nervous system. The present study focused on HGF concentrations in the cerebrospinal fluid (CSF) and serum in normal persons and in different central nervous system (CNS) diseases considering blood-CSF barrier (BCB) function. Concentrations of HGF were analyzed using an enzyme-linked immunosorbent assay (ELISA). HGF was present in normal human CSF (346+/-126 pg/ml) representing approximately half of the HGF serum concentrations. The CSF HGF levels were not significantly changed in chronic CNS disease and in aseptic meningitis (419+/-71 pg/ml), but significantly increased in patients with bacterial meningitis (6101+/- 5200 pg/ml). The HGF levels in CSF were not influenced by increased serum concentrations in patients with normal or mildly affected BCB function. The results show that HGF is present in normal CSF and does not appear to cross the CSF barrier significantly unless it is severely disrupted. So far, strong increases of HGF concentration in CSF are only present in acute bacterial meningitis.     

Usefulness of Yeast Cell Counting and Lack of Clinical Correlation of the Antifungal Susceptibility Testing Results in Management of Aids-associated Cryptococcal Meningitis

Cryptococcal meningitis is one of the most seriously opportunistic infections in people living with HIV. We evaluated clinical and laboratorial features (minimum inhibitory concentrations for fluconazole, initial fungal burden in cerebrospinal fluid) and risk factors associated with in-hospital mortality. There is no good evidence for the use of minimum inhibitory concentrations for fluconazole in routine practice for the management of cryptococcosis patients. Counting yeast cells at cerebrospinal fluid can predict positive culture by not death. Data from 46 cryptococcal meningitis patients were reviewed, retrospectively. Patients who presented yeast cell count greater than 400 yeast cells/μ in their initial cerebrospinal fluid sample were associated with higher mortality (p = 0.014); moreover, the yeast cell count is an easy and cheap assay, with high values possibly associated to poor prognosis. Additionally, we verified no significant differences between fluconazole susceptibility profile, molecular type, clinical presentation, cytological analyses, time to sterilize the cerebrospinal fluid, agent recovering out of central nervous system, previous diagnosis of cryptococcal meningitis or usage of fluconazole, and overall mortality.     

A new antibiotic combination for frozen bovine semen, 3. Evaluation of fertility

Field fertility (nonreturn rate) studies were performed independently by three artificial insemination organizations to evaluate bovine semen processed for freezing using the antibiotics gentamicin, tylosin and Linco-Spectin at concentrations of 500 ug, 100 ug, and 300/600 ug, respectively, per milliliter of neat semen and per milliliter of nonglycerol portion of the extender. The antibiotic combination including penicillin, dihydrostreptomycin, polymyxin B sulfate, with/without Linco-Spectin (500 units/ml, 2000 ug/ml, 1000 units/ml and 300/600 ug/ml, respectively) was used as the control treatment. Results indicated no significant effect on seminal quality as measured by field fertility under the conditions of these experiments using heated whole milk or egg yolk-sodium citrate seminal extenders. Use of the new antibiotic combination has been adopted by Certified Semen Services.     

IN VIVO RELEASE OF ENDOGENOUSLY SYNTHESIZED CATECHOLAMINES FROM THE CAT BRAIN EVOKED BY ELECTRICAL STIMULATION AND BY d-AMPHETAMINE

Abstract— The cerebral ventricles of spinal-sectioned cats were perfused with artificial cerebrospinal fluid after the intraventricular administration of [³H]DOPA or [³H]tyrosine. Endogenously synthesized [³H]dopamine or [³H]norepinephrine were identified in the perfusate. Electrical stimulation of catecholaminergic nerve tracts in the hypothalamus increased the efflux of both catecholamines. The addition of d -amphetamine to the perfusing cerebrospinal fluid caused a large increase in [³H]dopamine and a small increase in [³H]norepinephrine appearing in the perfusate. Most of the endogenously synthesized [³H]catecholamines detected in the perfusate following stimuli originated from structures bordering the lateral cerebral ventricle. Thus, norepinephrine and dopamine can be synthesized in and released from catecholaminergic nerve terminals in structures bordering the cerebral ventricles.