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Concept: Meningitis

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Neisseria meningitidis is one of the leading causes of bacterial meningitis globally and can also cause sepsis, pneumonia, and other manifestations. In countries with high endemic rates, the disease burden places an immense strain on the public health system. The worldwide epidemiology of invasive meningococcal disease (IMD) varies markedly by region and over time. This review summarizes the burden of IMD in different countries and identifies the highest-incidence countries where routine preventive programs against Neisseria meningitidis would be most beneficial in providing protection. Available epidemiological data from the past 20 years in World Health Organization and European Centre for Disease Prevention and Control collections and published articles are included in this review, as well as direct communications with leading experts in the field. Countries were grouped into high-, moderate-, and low-incidence countries. The majority of countries in the high-incidence group are found in the African meningitis belt; many moderate-incidence countries are found in the European and African regions, and Australia, while low-incidence countries include many from Europe and the Americas. Priority countries for vaccine intervention are high- and moderate-incidence countries where vaccine-preventable serogroups predominate. Epidemiological data on burden of IMD are needed in countries where this is not known, particularly in South- East Asia and Eastern Mediterranean regions, so evidence-based decisions about the use of meningococcal vaccines can be made.

Concepts: Public health, Epidemiology, Bacteria, Meningitis, World Health Organization, Neisseria meningitidis, Meningococcal disease, Preventive medicine

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Enterovirus 71 (EV71) is a group of viruses that belongs to the Picornaviridae family, which also includes viruses such as polioviruses. EV71, together with coxsackieviruses, is widely known for its association with Hand Foot Mouth Disease (HFMD), which generally affects children age five and below. Besides HFMD, EV71 can also trigger more severe and life-threatening neurological conditions such as encephalitis. Considering the lack of a vaccine and antiviral drug against EV71, together with the increasing spread of these viruses, the development of such drugs and vaccines becomes the top priority in protecting our younger generations. This article, hence, reviews some of the recent progress in the formulations of anti-therapeutics and vaccine generation for EV71, covering (i) inactivated vaccines; (ii) baculovirus-expressed vaccines against EV71; (iii) human intravenous immunoglobulin (IVIg) treatment; and (iv) the use of monoclonal antibody therapy as a prevention and treatment for EV71 infections.

Concepts: Immune system, Enterovirus, Monoclonal antibodies, Immunology, Influenza, Meningitis

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Background Tuberculous meningitis is often lethal. Early antituberculosis treatment and adjunctive treatment with glucocorticoids improve survival, but nearly one third of patients with the condition still die. We hypothesized that intensified antituberculosis treatment would enhance the killing of intracerebral Mycobacterium tuberculosis organisms and decrease the rate of death among patients. Methods We performed a randomized, double-blind, placebo-controlled trial involving human immunodeficiency virus (HIV)-infected adults and HIV-uninfected adults with a clinical diagnosis of tuberculous meningitis who were admitted to one of two Vietnamese hospitals. We compared a standard, 9-month antituberculosis regimen (which included 10 mg of rifampin per kilogram of body weight per day) with an intensified regimen that included higher-dose rifampin (15 mg per kilogram per day) and levofloxacin (20 mg per kilogram per day) for the first 8 weeks of treatment. The primary outcome was death by 9 months after randomization. Results A total of 817 patients (349 of whom were HIV-infected) were enrolled; 409 were randomly assigned to receive the standard regimen, and 408 were assigned to receive intensified treatment. During the 9 months of follow-up, 113 patients in the intensified-treatment group and 114 patients in the standard-treatment group died (hazard ratio, 0.94; 95% confidence interval, 0.73 to 1.22; P=0.66). There was no evidence of a significant differential effect of intensified treatment in the overall population or in any of the subgroups, with the possible exception of patients infected with isoniazid-resistant M. tuberculosis. There were also no significant differences in secondary outcomes between the treatment groups. The overall number of adverse events leading to treatment interruption did not differ significantly between the treatment groups (64 events in the standard-treatment group and 95 events in the intensified-treatment group, P=0.08). Conclusions Intensified antituberculosis treatment was not associated with a higher rate of survival among patients with tuberculous meningitis than standard treatment. (Funded by the Wellcome Trust and the Li Ka Shing Foundation; Current Controlled Trials number, ISRCTN61649292 .).

Concepts: HIV, AIDS, Tuberculosis, Mycobacterium, Mycobacterium tuberculosis, Randomness, Meningitis, Robert Koch

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Vestibular schwannomas (VSs) are the most common tumours of the cerebellopontine angle. Ninety-five percent of people with VS present with sensorineural hearing loss (SNHL); the mechanism of this SNHL is currently unknown. To establish the first model to study the role of VS-secreted factors in causing SNHL, murine cochlear explant cultures were treated with human tumour secretions from thirteen different unilateral, sporadic VSs of subjects demonstrating varied degrees of ipsilateral SNHL. The extent of cochlear explant damage due to secretion application roughly correlated with the subjects' degree of SNHL. Secretions from tumours associated with most substantial SNHL resulted in most significant hair cell loss and neuronal fibre disorganization. Secretions from VSs associated with good hearing or from healthy human nerves led to either no effect or solely fibre disorganization. Our results are the first to demonstrate that secreted factors from VSs can lead to cochlear damage. Further, we identified tumour necrosis factor alpha (TNFα) as an ototoxic molecule and fibroblast growth factor 2 (FGF2) as an otoprotective molecule in VS secretions. Antibody-mediated TNFα neutralization in VS secretions partially prevented hair cell loss due to the secretions. Taken together, we have identified a new mechanism responsible for SNHL due to VSs.

Concepts: Cell, Secretion, Cochlear implant, Ototoxicity, Ear, Tinnitus, Sensorineural hearing loss, Meningitis

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A 39-year-old white man presented with intractable headaches and papilledema. The initial workup, with normal MRI and MRV but elevated cerebrospinal fluid protein raised concerns about the putative diagnosis of idiopathic intracranial hypertension, and his condition remained refractory to maximum medical treatment. Angiography revealed cerebral venous sinus stenosis, thought to represent chronic thrombosis. The diagnosis and treatment of cerebral venous sinus stenosis and thrombosis are discussed.

Concepts: Intracranial pressure, Neurology, Cerebrospinal fluid, Hydrocephalus, Meningitis, Headache, Cerebral venous sinus thrombosis, Dural venous sinuses

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BACKGROUND: Human enterovirus 71 (HEV71) is a common cause of severe outbreaks of hand-foot- and mouth disease, aseptic meningitis and encephalitis in Asian populations but has not caused such epidemics in all populations. OBJECTIVES: To analyze the frequency of HEV71 in the background childhood population in Finland by screening in stool and serum samples and by measuring neutralizing antibodies against HEV71 in serum and to compare the genetic relationship of virus strains detected in asymptomatic children and those causing severe illness in Finland to the strains found in other countries. STUDY DESIGN: 4185 stool samples and 5686 serum samples were collected and clinical symptoms recorded from children who were observed from birth. Additional stool samples were available from four children hospitalized due to EV71 infection. Samples were screened for the presence of RNA of human enteroviruses using RT-PCR and HEV71 amplicons were identified by sequencing. Phylogenetic analyses were carried out to study genetic relationships between different virus strains. Neutralizing antibodies against HEV71 were screened from 522 children. RESULTS: A total of 0.3% of stool samples and two serum samples from healthy children were positive for HEV71 genome. 1.6% of the children had neutralizing antibodies against HEV71. Most infections were asymptomatic or mild in contrast to the clear symptoms in the children hospitalized due to HEV71. All viruses were C strains. CONCLUSIONS: HEV71 is circulating in Finland but it is rare. No clear difference was seen between strains circulating in the Finnish background population and those found in hospitalized patients or those causing severe outbreaks worldwide.

Concepts: Enterovirus, Bacteria, Virus, Genome, Infection, Meningitis, Aseptic meningitis, Computer virus

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PURPOSE: To study the incidence and clinical characteristics of delayed cerebral thrombosis in bacterial meningitis patients. METHODS: We assessed the incidence and clinical characteristics of delayed cerebral thrombosis in adults with cerebrospinal fluid (CSF) culture-proven community-acquired bacterial meningitis included in a prospective nationwide study in The Netherlands performed from 2006 to 2012. RESULTS: Delayed cerebral thrombosis occurred in 11 of 1,032 episodes (1.1 %). CSF culture yielded Streptococcus pneumoniae in ten patients and Listeria monocytogenes in one. Adjunctive dexamethasone therapy was administered before or with the first dose of antibiotics in 9 of 11 patients; two patients were initially not treated with dexamethasone. All patients made good initial recovery, followed by sudden deterioration after 7-42 days. Cranial imaging studies showed multiple cerebral infarctions in all patients. The outcome was unfavorable in all but one patient. In an explorative analysis, patients with delayed cerebral thrombosis had eightfold higher complement C5a CSF concentrations on the diagnostic lumbar puncture as compared in those without delayed cerebral thrombosis (p = 0.04). CONCLUSION: Delayed cerebral thrombosis is a rare but devastating complication of bacterial meningitis. Adjunctive dexamethasone therapy seems to predispose patients with bacterial meningitis to this complication. We found some evidence that this thrombotic complication is associated with activation of the complement system.

Concepts: Bacteria, Streptococcus pneumoniae, Cerebrospinal fluid, Meningitis, Listeria monocytogenes, Listeriosis, Tuberculous meningitis, Lumbar puncture

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BACKGROUND: Intensified antibiotic treatment might improve the outcome of tuberculous meningitis. We assessed pharmacokinetics, safety, and survival benefit of several treatment regimens containing high-dose rifampicin and moxifloxacin in patients with tuberculous meningitis in a hospital setting. METHODS: In an open-label, phase 2 trial with a factorial design in one hospital in Indonesia, patients (aged >14 years) with tuberculous meningitis were randomly assigned to receive, according to a computer-generated schedule, first rifampicin standard dose (450 mg, about 10 mg/kg) orally or high dose (600 mg, about 13 mg/kg) intravenously, and second oral moxifloxacin 400 mg, moxifloxacin 800 mg, or ethambutol 750 mg once daily. All patients were given standard-dose isoniazid, pyrazinamide, and adjunctive corticosteroids. After 14 days of treatment all patients continued with standard treatment for tuberculosis. Endpoints included pharmacokinetic analyses of the blood and cerebrospinal fluid, adverse events attributable to tuberculosis treatment, and survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01158755. FINDINGS: 60 patients were randomly assigned to receive rifampicin standard dose (12 no moxifloxacin, ten moxifloxacin 400 mg, and nine moxifloxacin 800 mg) and high dose (ten no moxifloxacin, nine moxifloxacin 400 mg, and ten moxifloxacin 800 mg). A 33% higher dose of rifampicin, intravenously, led to a three times higher geometric mean area under the time-concentration curve up to 6 h after dose (AUC(0-6); 78·7 mg.h/L [95% CI 71·0-87·3] vs 26·0 mg.h/L [19·0-35·6]), maximum plasma concentrations (C(max); 22·1 mg/L [19·9-24·6] vs 6·3 mg/L [4·9-8·3]), and concentrations in cerebrospinal fluid (0·60 mg/L [0·46-0·78] vs 0·21 mg/L [0·16-0·27]). Doubling the dose of moxifloxacin resulted in a proportional increase in plasma AUC(0-6) (31·5 mg.h/L [24·1-41·1] vs 15·1 mg.h/L [12·8-17·7]), C(max) (7·4 mg/L [5·6-9·6] vs 3·9 mg/L [3·2-4·8]), and drug concentrations in the cerebrospinal fluid (2·43 mg/L [1·81-3·27] vs 1·52 mg/L [1·28-1·82]). Intensified treatment did not result in increased toxicity. 6 month mortality was substantially lower in patients given high-dose rifampicin intravenously (ten [35%] vs 20 [65%]), which could not be explained by HIV status or severity of disease at the time of presentation (adjusted HR 0·42; 95% CI 0·20-0·91; p=0·03). INTERPRETATION: These data suggest that treatment containing a higher dose of rifampicin and standard-dose or high-dose moxifloxacin during the first 2 weeks is safe in patients with tuberculous meningitis, and that high-dose intravenous rifampicin could be associated with a survival benefit in patients with severe disease. FUNDING: Royal Dutch Academy of Arts and Sciences, Netherlands Foundation for Scientific Research, and Padjadjaran University, Bandung, Indonesia.

Concepts: Tuberculosis, Cerebrospinal fluid, Meningitis, Tuberculous meningitis, Lumbar puncture, Tuberculosis treatment, Pyrazinamide, Rifampicin

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An antibacterial is a substance that kills bacteria or slows their growth. An antifungal are the agents that drugs use for treatment of fungal infections. 5- Chloro-1,3-benzoxazol-2(3H)-one (5-Chloro Benzoxazolinone) contains an azole ring structure. Numbers of azole compounds are reported as antibacterial and antifungal agents. Benzoxazolinones naturally occurs in plants. It plays role as defense compounds against bacteria, fungi and insects. Here is synthesis of six Benzoxazolinone derivatives with various substituents. Benzoxazolinone substituted with p-Aminobenzoic acids and sulphanilamide derivatives. The above both substituents are reported as potent antimicrobial agents. Attachment it with azole leads to increase its potency. The other substituents are with 2,4-dichlorobezylchloride. The same rings are found in miconazole and this may lead to increase its antifungal activity. Fluconazole also contains triazole moiety and triazole is having other number of activity like antimicrobial, anti-inflammatory, local anesthetic, antiviral, anticancer, antimalerial etc. Here there is substitution of azole ring at 5-Chloro position in that might increase antibacterial and antifungal activity. Here is the synthesis and interpretation of six final compounds and three intermediates. Synthesis of 5-Chloro Benzoxazolinone derivatives substituted with Halogenated rings, sulphonated and benzylated derivatives and azole derivatives. There was synthesis of P2A, P2B, P4A, P4B, P5A and P6A compounds and their Structures were characterized by UV-Visible, IR, MASS spectroscopy and NMR spectroscopy. The antibacterial activity of all six compounds is measured against various gm+ve and gm-ve bacteria and against fungi.Compound P4A and P4B has good antibacterial and anti fungal activity, half of the Ampicillin and Cephalexin. P4A, P4B, P6A has good activity against S.aureus and E.coli. Compound P2B has good antifungal activity, half of the Miconazole against C.albicans. P2A, P2B, P5A, P6A has almost equal antibacterial activity.

Concepts: Bacteria, Microbiology, Fungus, Meningitis, Antifungals, Antifungal drug, Fluconazole, Itraconazole

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Since September 18, 2012, public health officials have been investigating a large outbreak of fungal meningitis and other infections in patients who received epidural, paraspinal, or joint injections with contaminated lots of methylprednisolone acetate. Little is known about infections caused by Exserohilum rostratum, the predominant outbreak-associated pathogen. We describe the early clinical course of outbreak-associated infections.

Concepts: Inflammation, Health care, Medicine, Epidemiology, Bacteria, Meningitis, Lumbar puncture, Methylprednisolone