Importance of heterogeneity in Porhyromonas gingivalis lipopolysaccharide lipid A in tissue specific inflammatory signaling

Lipopolysaccharide (LPS) of Porphyromonas gingivalis exists in at least two known forms, O-LPS and A-LPS. A-LPS shows heterogeneity in which two isoforms designated LPS1435/1449 and LPS1690 appear responsible for tissue specific immune signalingpathways activation and increased virulence. The modification of lipid A to tetra-acylated1435/1449 and/or penta-acylated1690 fatty acids indicates poor growth conditions and bioavailability of hemin. Hemin protects P. gingivalis from serum resistance and the lipid A serves as a site for its binding. The LPS1435/1449 and LPS1690 isoforms can produce opposite effects on the human Toll-like receptors (TLR) TLR 2 and TLR 4 activation. This enabless P. gingivalis to select the conditions for its entry, survival and that of its co-habiting species in the host, orchestrating its virulence to control innate immune pathway activation and biofilm dysbiosis. Thismini review describes a number of effects that LPS1435/1449 and LPS1690 can exert on the host tissues such as deregulation of the innate immune system, subversion of host cell autophagy, regulation of outer membrane vesicle production and adverse effects on pregnancy outcome. The ability to change its LPS1435/1449 and/or LPS1690 composition may enables P. gingivalis to paralyze local pro-inflammatory cytokine production, thereby gaining access to its primary location in periodontal tissue

Pediatric malignancies presenting as a possible infectious disease

<p>Abstract</p> <p>Background</p> <p>The clinical, laboratory, and radiological features of malignancy can overlap with those of infection. The purpose of this study was to determine the findings in children who were initially thought to have an infectious disease but ultimately proved to have a malignancy.</p> <p>Methods</p> <p>The database of patients diagnosed with a malignancy in the Northern Alberta Children's Cancer Program (NACCP) January 1, 1993 to December 31, 2003 was merged with the database of inpatients referred to the infectious diseases service at the Stollery Children's Hospital and charts were reviewed on all patients referred to the infectious diseases consult service prior to the diagnosis of malignancy.</p> <p>Results</p> <p>An infectious diseases consultation for diagnosis was requested in 21 of 561 patients prior to the confirmation of malignancy, and 3 of these 21 patients had both infection and malignancy (leukemia (N = 13), lymphoma (N = 3), rhabdomyosarcoma (N = 1), Langerhan's cell histiocytosis (N = 1), fibrous histicocytosis (N = 1), ependymoma (N = 1), and neuroblastoma (N = 1). The most common reason for infectious diseases consultation was suspected muskuloskeletal infection (N = 9). A palpable or radiographically enlarged spleen was noted in 11 patients (52%). All but 2 patients had abnormal hematologic parameters while an elevated lactate dehydrogenase (LDH) occurred in 10 patients (48%). Delay of diagnosis because of investigation or therapy for an infectious disease occurred in only 2 patients.</p> <p>Conclusion</p> <p>It is not common for treatment of pediatric malignancies to be delayed because infection is thought to be the primary diagnosis. However, pediatric infectious diseases physicians should consider malignancy in the differential diagnosis when they see patients with fever and bone pain, unexplained splenomegaly or abnormal complete blood cell counts. Other clues may include hepatomegaly or elevated LDH.</p

Burkholderia mallei expresses a unique lipopolysaccharide mixture that is a potent activator of human Toll-like receptor 4 complexes

Burkholderia mallei, the aetiologic agent of glanders, causes a variety of illnesses in animals and humans ranging from occult infections to acute fulminating septicaemias. To better understand the role of lipopolysaccharide (LPS) in the pathogenesis of these diseases, studies were initiated to characterize the structural and biological properties of lipid A moieties expressed by this organism. Using a combination of chemical analyses and MALDI-TOF mass spectrometry, B. mallei was shown to express a heterogeneous mixture of tetra- and penta-acylated lipid A species that were non-stoichiometrically substituted with 4-amino-4-deoxy-arabinose residues. The major penta-acylated species consisted of bisphosphorylated d-glucosamine disaccharide backbones possessing two amide linked 3-hydroxyhexadecanoic acids, two ester linked 3-hydroxytetradecanoic acids [C14:0(3-OH)] and an acyloxyacyl linked tetradecanoic acid, whereas, the major tetra-acylated species possessed all but the 3′-linked C14:0(3-OH) residues. In addition, although devoid of hexa-acylated species, B. mallei LPS was shown to be a potent activator of human Toll-like receptor 4 complexes and stimulated human macrophage-like cells (THP-1 and U-937), monocyte-derived macrophages and dendritic cells to produce high levels of TNF-α, IL-6 and RANTES. Based upon these results, it appears that B. mallei LPS is likely to play a significant role in the pathogenesis of human disease

Exploring the association between Alzheimer’s disease, oral health, microbial endocrinology and nutrition

Longitudinal monitoring of patients suggests a causal link between chronic periodontitis and the development of Alzheimer’s disease (AD). However, the explanation of how periodontitis can lead to dementia remains unclear. A working hypothesis links extrinsic inflammation as a secondary cause of AD. This hypothesis suggests a compromised oral hygiene leads to a dysbiotic oral microbiome whereby Porphyromonas gingivalis, a keystone periodontal pathogen, with its companion species, orchestrates immune subversion in the host. Brushing and chewing on teeth supported by already injured soft tissues leads to bacteraemias. As a result, a persistent systemic inflammatory response develops to periodontal pathogens. The pathogens, and the host’s inflammatory response, subsequently lead to the initiation and progression of multiple metabolic and inflammatory co-morbidities, including AD. Insufficient levels of essential micronutrients can lead to microbial dysbiosis through the growth of periodontal pathogens such as demonstrated for P. gingivalis under low hemin bioavailability. An individual’s diet also defines the consortium of microbial communities that take up residency in the oral and gastrointestinal (GI) tract microbiomes. Their imbalance can lead to behavioural changes. For example, probiotics enriched in Lactobacillus genus of bacteria, when ingested, exert some anti-inflammatory influence through common host/bacterial neurochemicals, both locally, and through sensory signalling back to the brain. Early life dietary behaviours may cause an imbalance in the host/microbial endocrinology through a dietary intake incompatible with a healthy GI tract microbiome later in life. This imbalance in host/microbial endocrinology may have a lasting impact on mental health. This observation opens up an opportunity to explore the mechanisms, which may underlie the previously detected relationship between diet, oral/GI microbial communities, to anxiety, cognition and sleep patterns. This review suggests healthy diet based interventions that together with improved life style/behavioural changes may reduce and/or delay the incidence of AD

Costs and outcomes of increasing access to bariatric surgery for obesity: cohort study and cost-effectiveness analysis using electronic health records

Background: Bariatric surgery is known to be an effective treatment for extreme obesity but access to these procedures is currently limited. Objective: This study aimed to evaluate the costs and outcomes of increasing access to bariatric surgery for severe and morbid obesity. Design and methods: Primary care electronic health records from the UK Clinical Practice Research: Datalink were analysed for 3045 participants who received bariatric surgery and 247,537 general population controls. The cost-effectiveness of bariatric surgery was evaluated in severe and morbid obesity through a probabilistic Markov model populated with empirical data from electronic health records. Results: In participants who did not undergo bariatric surgery, the probability of participants with morbid obesity attaining normal body weight was 1 in 1290 annually for men and 1 in 677 for women. Costs of health-care utilisation increased with body mass index category but obesity-related physical and psychological comorbidities were the main drivers of health-care costs. In a cohort of 3045 adult obese patients with first bariatric surgery procedures between 2002 and 2014, bariatric surgery procedure rates were greatest among those aged 35–54 years, with a peak of 37 procedures per 100,000 population per year in women and 10 per 100,000 per year in men. During 7 years of follow-up, the incidence of diabetes diagnosis was 28.2 [95% confidence interval (CI) 24.4 to 32.7] per 1000 person-years in controls and 5.7 (95% CI 4.2 to 7.8) per 1000 person-years in bariatric surgery patients (adjusted hazard ratio was 0.20, 95% CI 0.13 to 0.30; p<0.0001). In 826 obese participants with type 2 diabetes mellitus who received bariatric surgery, the relative rate of diabetes remission, compared with controls, was 5.97 (95% CI 4.86 to 7.33; p<0.001). There was a slight reduction in depression in the first 3 years following bariatric surgery that was not maintained. Incremental lifetime costs associated with bariatric surgery were £15,258 (95% CI £15,184 to £15,330), including costs associated with bariatric surgical procedures of £9164 per participant. Incremental quality-adjusted life-years (QALYs) were 2.142 (95% CI 2.031 to 2.256) per participant. The estimated cost per QALY gained was £7129 (95% CI £6775 to £7506). Estimates were similar across gender, age and deprivation subgroups. Limitations: Intervention effects were derived from a randomised trial with generally short follow-up and non-randomised studies of longer duration. Conclusions: Bariatric surgery is associated with increased immediate and long-term health-care costs but these are exceeded by expected health benefits to obese individuals with reduced onset of new diabetes, remission of existing diabetes and lower mortality. Diverse obese individuals have clear capacity to benefit from bariatric surgery at acceptable cost. Future work: Future research should evaluate longer-term outcomes of currently used procedures, and ways of delivering these more efficiently and safely

COGNITIVE DEVELOPMENTAL LEVEL AS A MODERATOR OF LANGUAGE SKILLS AND SOCIAL SKILLS AS WELL AS ACADEMIC ACHIEVEMENT AND SOCIAL SKILLS

Past research has provided evidence that social skills are correlated to both academic achievement and language skills. In addition, Piaget’s theory asserts that certain cognitive abilities develop independent of learning (both language and academic skills) that occurs in school. The present study examined the impact of cognitive developmental level as a moderator for the relationship between social skills and academic achievement. Cognitive developmental level was measured using conservation tasks. Social skills were measured with the Social Skills Inventory System. Academic achievement was measured by the Woodcock-Johnson Tests of Achievement, Third Edition, Normative Update. This study also assessed cognitive developmental level as a moderator between social skills and language skills. Language skills were measured with the Peabody Picture Vocabulary Test. A hierarchical linear regression yielded results indicating that when controlling for IQ, gender and ethnicity, cognitive developmental level did not moderate relationships between social skills and language and social skills and academic achievement. However, post hoc analyses demonstrated that ethnicity provides a significant amount of the variance and acts as a covariate. This study contributes to the literature by providing evidence that ethnicity significantly impacts teacher ratings of social skills.M.S. in Psychology, December 201