Host-pathogen interactions in sepsis

Sepsis is a major health problem. The concept that sepsis mortality is the result of an uncontrolled hyperinflammatory host response has recently been challenged. It is now widely thought that the host response to sepsis involves many, concomitant, integrated, and often antagonistic processes that involve both exaggerated inflammation and immune suppression. Several novel mediators and pathways have been shown to play a part. Moreover, evidence is accumulating that microbial virulence and bacterial load contribute to the host response and the outcome of severe infections. A complex and dynamic interaction exists between pathogens and host immune-defence mechanisms during the course of invasive infection. Some pathogens have acquired the capacity to communicate with each other and sense the host's vulnerabilities. Bidirectional signals are detectable at the critical interface between the host and microbial invaders. The outcome of this interaction determines the fate of the host at the outset of the septic process. A formidable array of innate and acquired immune defences must be breached if a pathogen is to successfully disseminate and cause severe sepsis and septic shock. This Review summarises current knowledge of microbial pathogenesis and host-pathogen interactions during sepsis and the ensuing development of potential therapeutics.     

Mutant Ataxin-1 Inhibits Neural Progenitor Cell Proliferation in SCA1

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by the expansion of a polyglutamine (Q) repeat tract in the protein ataxin-1 (ATXN1). Beginning as a cerebellar ataxic disorder, SCA1 progresses to involve the cerebral cortex, hippocampus, and brainstem. Using SCA1 knock-in mice that mirror the complexity of the human disease, we report a significant decrease in the capacity of adult neuronal progenitor cells (NPCs) to proliferate. Remarkably, a decrease in NPCs proliferation can be observed in vitro, outside the degenerative milieu of surrounding neurons or glia, demonstrating that mutant ATXN1 acting cell autonomously within progenitor cells interferes with their ability to proliferate. Our findings suggest that compromised adult neurogenesis contributes to the progressive pathology of the disease particularly in areas such as the hippocampus and cerebral cortex where stem cells provide neurotropic factors and participate in adult neurogenesis. These findings not only shed light on the biology of the disease but also have therapeutic implications in any future stem cell-based clinical trials.     

Detoxified Endotoxin Vaccine (J5dLPS/OMP) Protects Mice Against Lethal Respiratory Challenge with Francisella tularensis SchuS4

Francisella tularensis is a category A select agent. J5dLPS/OMP is a novel vaccine construct consisting of detoxified, O-polysaccharide side chain-deficient, lipopolysaccharide non-covalently complexed with the outer membrane protein of N. meningitidis group B. Immunization elicits high-titer polyclonal antibodies specific for the highly-conserved epitopes expressed within the glycolipid core that constitutes gram-negative bacteria (e.g., F. tularensis). Mice immunized intranasally with J5dLPS/OMP exhibited protective immunity to intratracheal challenge with the live vaccine strain, as well as the highly-virulent SchuS4 strain, of F. tularensis. The efficacy of J5dLPS/OMP vaccine suggests its potential utility in immunizing the general population against several different gram-negative select agents concurrently.     

Attention-deficit hyperactivity disorder symptoms in a clinic sample of children and adolescents with pervasive developmental disorders

OBJECTIVES: The aims of this systematic chart review were to determine the frequency of attention-deficit/hyperactivity disorder (ADHD) in a clinic sample of children and adolescents with autism spectrum disorders (ASD), to compare ADHD symptoms in children with Autistic Disorder, Asperger's Disorder, and pervasive developmental disorders-not otherwise specified (PDD-NOS), to compare ADHD symptoms in individuals with and without ADHD-related chief complaints, and to determine the correlation between ADHD Rating Scale (ADHD RS) scores and age. METHOD: This systematic chart review examined data from children and adolescents who were consecutively referred to a university-based autism psychopharmacology program. All individuals were diagnosed by semistructured interview for ASD and ADHD, and ADHD symptoms were assessed using ADHD RS scores. RESULTS: Of 83 children, 78% fulfilled Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria for ADHD and exceeded the 93rd percentile norm for the ADHD RS. Hyperactivity-impulsivity scores were significantly greater in individuals with autism than those with other ASDs. DSM-IV ADHD diagnosis was represented equally in individuals with and without ADHD as their chief complaints. ADHD RS hyperactivity-impulsivity and total scores were negatively correlated with age. CONCLUSION: ADHD symptoms are pervasive in clinically referred children and adolescents with ASD.     

A simple method for amplifying RNA targets (SMART)

We present a novel and simple method for amplifying RNA targets (named by its acronym, SMART), and for detection, using engineered amplification probes that overcome existing limitations of current RNA-based technologies. This system amplifies and detects optimal engineered ssDNA probes that hybridize to target RNA. The amplifiable probe-target RNA complex is captured on magnetic beads using a sequence-specific capture probe and is separated from unbound probe using a novel microfluidic technique. Hybridization sequences are not constrained as they are in conventional target-amplification reactions such as nucleic acid sequence amplification (NASBA). Our engineered ssDNA probe was amplified both off-chip and in a microchip reservoir at the end of the separation microchannel using isothermal NASBA. Optimal solution conditions for ssDNA amplification were investigated. Although KCl and MgCl(2) are typically found in NASBA reactions, replacing 70 mmol/L of the 82 mmol/L total chloride ions with acetate resulted in optimal reaction conditions, particularly for low but clinically relevant probe concentrations (≤100 fmol/L). With the optimal probe design and solution conditions, we also successfully removed the initial heating step of NASBA, thus achieving a true isothermal reaction. The SMART assay using a synthetic model influenza DNA target sequence served as a fundamental demonstration of the efficacy of the capture and microfluidic separation system, thus bridging our system to a clinically relevant detection problem.     

Intracranial infection by Vibrio alginolyticus following injury in salt water.

A 20-year-old man presented with an epidural abscess 3 months after a seawater diving accident. Cultures of the abscess cavity obtained by surgical drainage revealed a pure culture of Vibrio alginolyticus. Marine vibrios may produce serious intracranial infection after head injury in salt water.     

Relapse of Pneumocystis carinii pneumonia in the upper lobes during aerosol pentamidine prophylaxis.

Pneumocystis carinii pneumonia was diagnosed by bronchoalveolar lavage of the upper lobes in a patient with the acquired immunodeficiency syndrome (AIDS) receiving aerosol pentamidine prophylaxis. Serendipitous availability of a normal premorbid lung gallium scan indicated that pneumocystosis had developed during aerosol pentamidine prophylaxis; at the time of presentation a repeat gallium scan indicated disease limited to the upper lobes. The relation of this unusual form of isolated upper lobe Pneumocystis carinii pneumonia to aerosol pentamidine prophylaxis warrants further investigation.     

Investigation of a food-borne outbreak of salmonellosis among hospital employees

An explosive outbreak of Salmonella enterocolitis developed in 27 hospital employees in an acute-care community hospital in Rhode Island in 1987. Salmonella typhimurium was isolated from the stools of 19 employees during the outbreak. In each patient the implicated organism had an identical antibiotic susceptibility pattern, biotype, plasmid profile, and restriction endonuclease digestion pattern. The outbreak was limited to health care workers and other hospital employees; there were no cases in hospitalized patients. Of the afflicted employees 96% ate in the hospital cafeteria on July 11 or 12, 1987. Food-specific attack rates, based on the dietary histories of ill employees and 50 healthy employees who ate in the cafeteria that weekend, indicated an association between the ingestion of salads and illness (p less than 0.01). One food service employee, in whom symptoms of abdominal cramping and diarrhea had developed 6 days earlier, had prepared the implicated foods. S. typhimurium with the identical characteristics of the outbreak strain was isolated from the stools of this food service employee. Environmental cultures and cultures of meat, poultry, and dairy sources for the cafeteria all showed negative results. Food service employees need to be counseled against working during any symptomatic enteric illness and require thorough instruction on hygienic food handling.