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.
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.
Listeria monocytogenes can asymptomatically inhabit the human intestine as a commensal bacterium. However, the mechanism by which L. monocytogenes is able to inhabit the intestine without pathogenic symptoms remains unclear. Here, we compared the invasion efficiency of L. monocytogenes strains with the 268- and 385-bp-long actA gene. Clinical strains SMFM-CI-3 and SMFM-CI-6 with 268-bp actA isolated from patients with listeriosis and strains SMFM-SI-1 and SMFM-SI-2 with the 385-bp gene isolated from carcasses were used for inoculum preparation. The invasion efficiency of these strains was evaluated using Caco-2 cells (intestinal epithelial cell line), prepared as normal and healthy cells with tightened tight junctions and senescent cells with loose tight junctions, which were loosened by adriamycin treatment. The invasion efficiency of L. monocytogenes strains with the 268-bp-long actA gene was 1.12.6-times lower than that of the strains with the 385-bp-long gene in normal and healthy cells. However, the invasion efficiency of both types of strains did not differ in senescent cells. Thus, L. monocytogenes strains with the 268-bp-long actA gene can inhabit the intestine asymptomatically as a commensal bacterium, but they may invade the intestinal epithelial cells and cause listeriosis in senescent cells.
Commensal organisms with the potential to cause disease pose a challenge in developing treatment options. Using the example featured in this study, pneumococcal disease begins with Streptococcus pneumoniae colonization, followed by triggering events that prompt the release of a virulent subpopulation of bacteria. Current vaccines focus on colonization prevention, which poses unintended consequences of serotype niche replacement. In this study, noncovalent colocalization of two classes of complementary antigens, one to prevent the colonization of the most aggressive S. pneumoniae serotypes and another to restrict virulence transition, provides complete vaccine effectiveness in animal subjects and the most comprehensive coverage of disease reported to date. As a result, the proposed vaccine formulation offers universal pneumococcal disease prevention with the prospect of effectively managing a disease that afflicts tens to hundreds of millions globally. The approach more generally puts forth a balanced prophylactic treatment strategy in response to complex commensal-host dynamics.
Current therapies for reducing raised intracranial pressure (ICP) under conditions such as idiopathic intracranial hypertension or hydrocephalus have limited efficacy and tolerability. Thus, there is a pressing need to identify alternative drugs. Glucagon-like peptide-1 receptor (GLP-1R) agonists are used to treat diabetes and promote weight loss but have also been shown to affect fluid homeostasis in the kidney. We investigated whether exendin-4, a GLP-1R agonist, is able to modulate cerebrospinal fluid (CSF) secretion at the choroid plexus and subsequently reduce ICP in rats. We used tissue sections and cell cultures to demonstrate expression of GLP-1R in the choroid plexus and its activation by exendin-4, an effect blocked by the GLP-1R antagonist exendin 9-39. Acute treatment with exendin-4 reduced Na(+)- and K(+)-dependent adenosine triphosphatase activity, a key regulator of CSF secretion, in cell cultures. Finally, we demonstrated that administration of exendin-4 to female rats with raised ICP (hydrocephalic) resulted in a GLP-1R-mediated reduction in ICP. These findings suggest that GLP-1R agonists can reduce ICP in rodents. Repurposing existing GLP-1R agonist drugs may be a useful therapeutic strategy for treating raised ICP.
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 .).
Streptococcus pneumoniae has a complex relationship with its obligate human host. On the one hand, the pneumococci are highly adapted commensals, and their main reservoir on the mucosal surface of the upper airways of carriers enables transmission. On the other hand, they can cause severe disease when bacterial and host factors allow them to invade essentially sterile sites, such as the middle ear spaces, lungs, bloodstream and meninges. Transmission, colonization and invasion depend on the remarkable ability of S. pneumoniae to evade or take advantage of the host inflammatory and immune responses. The different stages of pneumococcal carriage and disease have been investigated in detail in animal models and, more recently, in experimental human infection. Furthermore, widespread vaccination and the resulting immune pressure have shed light on pneumococcal population dynamics and pathogenesis. Here, we review the mechanistic insights provided by these studies on the multiple and varied interactions of the pneumococcus and its host.
A 70-year-old Caucasian woman was treated for Capnocytophaga canimorsus septicaemia. The source of bacteraemia was very likely to be her household pet, an Italian greyhound. The patient presented with a presumed complex partial seizure but deteriorated rapidly with sepsis and multiorgan dysfunction. Neither scratch nor bite was established, although close petting including licks was reported. Blood cultures grew Gram-negative rods, identified by molecular techniques as C. canimorsus-a bacterium frequently isolated in the oral cavities of dogs and cats. A full recovery was made following 2 weeks of intensive care support and broad-spectrum antibiotics. No underlying immune dysfunction was found.
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.
- Tropical medicine & international health : TM & IH
- Published almost 8 years ago
Tuberculous meningitis (TBM) comprises a significant proportion of TB cases globally and causes substantial morbidity and mortality, especially in children and HIV-infected patients. It is a challenging condition to diagnose due to its non-specific clinical presentation and the limited sensitivity of existing laboratory techniques. Smear microscopy and culture are the most widely available diagnostic tools yet are negative in a significant proportion of TBM cases. Simplified and more affordable nucleic acid amplification tests (NAATs) are increasing in use in resource-limited settings but have not been optimised for cerebrospinal fluid (CSF) samples. Novel diagnostic methods such as CSF interferon-gamma release assays and various biomarkers have been developed but require further evaluation to establish their utility as diagnostic tools. There is an urgent need for further research into optimal diagnostic strategies to decrease the morbidity and mortality as a result of delayed or missed diagnosis of TBM. In this review, we discuss current and novel diagnostic tests in TBM and areas where future research should be prioritised.