Oxygen delivery through high-flow nasal cannulae increase end-expiratory lung volume and reduce respiratory rate in post-cardiac surgical patients

Background: High-flow nasal cannulae (HFNC) create positive oropharyngeal airway pressure but it is unclear how their use affects lung volume. Electrical impedance tomography (EIT) allows assessment of changes in lung volume by measuring changes in lung impedance. Primary objectives were to investigate the effects of HFNC on airway pressure (Paw) and end-expiratory lung volume (EELV), and to identify any correlation between the two. Secondary objectives were to investigate the effects of HFNC on respiratory rate (RR), dyspnoea, tidal volume and oxygenation; and the interaction between body mass index (BMI) and EELV. Methods: Twenty patients prescribed HFNC post-cardiac surgery were investigated. Impedance measures, Paw, PaO2/FiO2 ratio, RR and modified Borg scores were recorded first on low flow oxygen (nasal cannula or Hudson face mask) and then on HFNC. Results: A strong and significant correlation existed between Paw and end-expiratory lung impedance (EELI) (r=0.7, p<0.001). Compared with low flow oxygen, HFNC significantly increased EELI by 25.6% (95% CI 24.3, 26.9) and Paw by 3.0 cmH2O (95% CI 2.4, 3.7). RR reduced by 3.4 breaths per minute (95% CI 1.7, 5.2) with HFNC use, tidal impedance variation increased by 10.5% (95% CI 6.1, 18.3) and PaO2/FiO2 ratio improved by 30.6 mmHg (95% CI 17.9, 43.3). HFNC improved subjective dyspnoea scoring (p=0.023). Increases in EELI were significantly influenced by BMI, with larger increases associated with higher BMIs (p<0.001). Conclusions: This study suggests that HFNC improve dyspnoea and oxygenation by increasing both EELV and tidal volume, and are most beneficial in patients with higher BMIs.

Non-pharmacological interventions for breathlessness management in patients with lung cancer : A systematic review

The aim is to review the published scientific literature for studies evaluating nonpharmacological interventions for breathlessness management in patients with lung cancer. The following selection criteria were used to systematically search the literature: studies were to be published research or systematic reviews; they were to be published in English and from 1990 to 2007; the targeted populations were adult patients with dyspnoea/breathlessness associated with lung cancer; and the study reported on the outcomes from use of non-pharmacological strategies for breathlessness. This review retrieved five studies that met all inclusion criteria. All the studies reported the benefits of non-pharmacological interventions in improving breathlessness regardless of differences in clinical contexts, components of programmes and methods for delivery. Analysis of the available evidence suggests that tailored instructions delivered by nurses with sufficient training and supervision may have some benefits over other delivery approaches. Based on the results, non-pharmacological interventions are recommended as effective adjunctive strategies in managing breathlessness for patients with lung cancer. In order to refine such interventions, future research should seek to explore the core components of such approaches that are critical to achieving optimal outcomes, the contexts in which the interventions are most effective, and to evaluate the relative benefits of different methods for delivering such interventions.

The role of the multiple banded antigen of ureaplasma parvum in intra-amniotic infection : major virulence factor or decoy?

The multiple banded antigen (MBA) is a predicted virulence factor of Ureaplasma species. Antigenic variation of the MBA is a potential mechanism by which ureaplasmas avoid immune recognition and cause chronic infections of the upper genital tract of pregnant women. We tested whether the MBA is involved in the pathogenesis of intra-amniotic infection and chorioamnionitis by injecting virulent or avirulent-derived ureaplasma clones (expressing single MBA variants) into the amniotic fluid of pregnant sheep. At 55 days of gestation pregnant ewes (n = 20) received intra-amniotic injections of virulent-derived or avirulent-derived U. parvum serovar 6 strains (2×104 CFU), or 10B medium (n = 5). Amniotic fluid was collected every two weeks post-infection and fetal tissues were collected at the time of surgical delivery of the fetus (140 days of gestation). Whilst chronic colonisation was established in the amniotic fluid of animals infected with avirulent-derived and virulent-derived ureaplasmas, the severity of chorioamnionitis and fetal inflammation was not different between these groups (p>0.05). MBA size variants (32–170 kDa) were generated in vivo in amniotic fluid samples from both the avirulent and virulent groups, whereas in vitro antibody selection experiments led to the emergence of MBA-negative escape variants in both strains. Anti-ureaplasma IgG antibodies were detected in the maternal serum of animals from the avirulent (40%) and virulent (55%) groups, and these antibodies correlated with increased IL-1β, IL-6 and IL-8 expression in chorioamnion tissue (p<0.05). We demonstrate that ureaplasmas are capable of MBA phase variation in vitro; however, ureaplasmas undergo MBA size variation in vivo, to potentially prevent eradication by the immune response. Size variation of the MBA did not correlate with the severity of chorioamnionitis. Nonetheless, the correlation between a maternal humoral response and the expression of chorioamnion cytokines is a novel finding. This host response may be important in the pathogenesis of inflammation-mediated adverse pregnancy outcomes.

Estimation on disease burden related to hepatitis B virus infection in Shandong province of China [山东省乙型肝炎病毒感染所致相关疾病的疾病负担研究]

Objective: To comprehensively measure the burden of hepatitis B, liver cirrhosis and liver cancer in Shandong province, using disability-adjusted life years (DALYs) to estimate the disease burden attribute to hepatitis B virus (HBV)infection. Methods: Based on the mortality data of hepatitis B, liver cirrhosis and liver cancer derived from the third National Sampling Retrospective Survey for Causes of Death during 2004 and 2005, the incidence data of hepatitis B and the prevalence and the disability weights of liver cancer gained from the Shandong Cancer Prevalence Sampling Survey in 2007, we calculated the years of life lost (YLLs), years lived with disability (YLDs) and DALYs of three diseases following the procedures developed for the global burden of disease (GBD) study to ensure the comparability. Results: The total burden for hepatitis B, liver cirrhosis and liver cancer were 211 616 (39 377 YLLs and 172 239 YLDs), 16 783 (13 497 YLLs and 3286 YLDs) and 247 795 (240 236 YLLs and 7559 YLDs) DALYs in 2005 respectively, and men were 2.19, 2.36 and 3.16 times as that for women, respectively in Shandong province. The burden for hepatitis B was mainly because of disability (81.39%). However, most burden on liver cirrhosis and liver cancer were due to premature death (80.42% and 96.95%). The burden of each patient related to hepatitis B, liver cirrhosis and liver cancer were 4.8, 13.73 and 11.11 respectively. Conclusion: Hepatitis B, liver cirrhosis and liver cancer caused considerable burden to the people living in Shandong province, indicating that the control of hepatitis B virus infection would bring huge potential benefits.

Risk factors for Mycobacterium tuberculosis infection among children in Greenland

Objective To examine the risk factors for Mycobacterium tuberculosis infection (MTI) among Greenlandic children for the purpose of identifying those at highest risk of infection. Methods Between 2005 and 2007, 1797 Greenlandic schoolchildren in five different areas were tested for MTI with an interferon gamma release assay (IGRA) and a tuberculin skin test (TST). Parents or guardians were surveyed using a standardized self-administered questionnaire to obtain data on crowding in the household, parents’ educational level and the child’s health status. Demographic data for each child – i.e. parents’ place of birth, number of siblings, distance between siblings (next younger and next older), birth order and mother’s age when the child was born – were also extracted from a public registry. Logistic regression was used to check for associations between these variables and MTI, and all results were expressed as odds ratios (ORs) and 95% confidence intervals (CIs). Children were considered to have MTI if they tested positive on both the IGRA assay and the TST. Findings The overall prevalence of MTI was 8.5% (152/1797). MTI was diagnosed in 26.7% of the children with a known TB contact, as opposed to 6.4% of the children without such contact. Overall, the MTI rate was higher among Inuit children (OR: 4.22; 95% CI: 1.55–11.5) and among children born less than one year after the birth of the next older sibling (OR: 2.48; 95% CI: 1.33–4.63). Self-reported TB contact modified the profile to include household crowding and low mother’s education. Children who had an older MTI-positive sibling were much more likely to test positive for MTI themselves (OR: 14.2; 95% CI: 5.75–35.0) than children without an infected older sibling. Conclusion Ethnicity, sibling relations, number of household residents and maternal level of education are factors associated with the risk of TB infection among children in Greenland. The strong household clustering of MTI suggests that family sources of exposure are important.

H. pylori-infection and antibody immune response in a rural Tanzanian population

Abstract Background: Helicobacter pylori (H. pylori) infection is ubiquitous in sub-Saharan Africa, but paradoxically gastric cancer is rare. Methods: Sera collected during a household-based survey in rural Tanzania in 1985 were tested for anti-H. pylori IgG and IgG subclass antibodies by enzyme immunoassay. Odds ratios (OR) and confidence intervals (CI) of association of seropositivity with demographic variables were computed by logistic regression models. Results: Of 788 participants, 513 were aged ≤17 years. H. pylori seropositivity increased from 76% at 0–4 years to 99% by ≥18 years of age. Seropositivity was associated with age (OR 11.5, 95% CI 4.2–31.4 for 10–17 vs. 0–4 years), higher birth-order (11.1; 3.6–34.1 for ≥3rd vs. 1st born), and having a seropositive next-older sibling (2.7; 0.9–8.3). Median values of IgG subclass were 7.2 for IgG1 and 2.0 for IgG2. The median IgG1/IgG2 ratio was 3.1 (IQR: 1.7–5.6), consistent with a Th2- dominant immune profile. Th2-dominant response was more frequent in children than adults (OR 2.4, 95% CI 1.3–4.4). Conclusion: H. pylori seropositivity was highly prevalent in Tanzania and the immunological response was Th2-dominant. Th2-dominant immune response, possibly caused by concurrent bacterial or parasitic infections, could explain, in part, the lower risk of H. pylori-associated gastric cancer in Africa.

PARP inhibition induces BAX/BAK-independent synthetic lethality of BRCA1-deficient non-small cell lung cancer

Evasion of apoptosis contributes to both tumourigenesis and drug resistance in non-small cell lung carcinoma (NSCLC). The pro-apoptotic BCL-2 family proteins BAX and BAK are critical regulators of mitochondrial apoptosis. New strategies for targeting NSCLC in a mitochondria-independent manner should bypass this common mechanism of apoptosis block. BRCA1 mutation frequency in lung cancer is low; however, decreased BRCA1 mRNA and protein expression levels have been reported in a significant proportion of lung adenocarcinomas. BRCA1 mutation/deficiency confers a defect in homologous recombination DNA repair that has been exploited by synthetic lethality through inhibition of PARP (PARPi) in breast and ovarian cells; however, it is not known whether this same synthetic lethal mechanism exists in NSCLC cells. Additionally, it is unknown whether the mitochondrial apoptotic pathway is required for BRCA1/PARPi-mediated synthetic lethality. Here we demonstrate that silencing of BRCA1 expression by RNA interference sensitizes NSCLC cells to PARP inhibition. Importantly, this sensitivity was not attenuated in cells harbouring mitochondrial apoptosis block induced by co-depletion of BAX and BAK. Furthermore, we demonstrate that BRCA1 inhibition cannot override platinum resistance, which is often mediated by loss of mitochondrial apoptosis signalling, but can still sensitize to PARP inhibition. Finally we demonstrate the existence of a BRCA1-deficient subgroup (11–19%) of NSCLC patients by analysing BRCA1 protein levels using immunohistochemistry in two independent primary NSCLC cohorts. Taken together, the existence of BRCA1-immunodeficient NSCLC suggests that this molecular subgroup could be effectively targeted by PARP inhibitors in the clinic and that PARP inhibitors could be used for the treatment of BRCA1-immunodeficient, platinum-resistant tumours.

Age of blood and recipient factors determine the severity of transfusion-related acute lung injury (TRALI)

Introduction Critical care patients frequently receive blood transfusions. Some reports show an association between aged or stored blood and increased morbidity and mortality, including the development of transfusion-related acute lung injury (TRALI). However, the existence of conflicting data endorses the need for research to either reject this association, or to confirm it and elucidate the underlying mechanisms. Methods Twenty-eight sheep were randomised into two groups, receiving saline or lipopolysaccharide (LPS). Sheep were further randomised to also receive transfusion of pooled and heat-inactivated supernatant from fresh (Day 1) or stored (Day 42) non-leucoreduced human packed red blood cells (PRBC) or an infusion of saline. TRALI was defined by hypoxaemia during or within two hours of transfusion and histological evidence of pulmonary oedema. Regression modelling compared physiology between groups, and to a previous study, using stored platelet concentrates (PLT). Samples of the transfused blood products also underwent cytokine array and biochemical analyses, and their neutrophil priming ability was measured in vitro. Results TRALI did not develop in sheep that first received saline-infusion. In contrast, 80% of sheep that first received LPS-infusion developed TRALI following transfusion with "stored PRBC." The decreased mean arterial pressure and cardiac output as well as increased central venous pressure and body temperature were more severe for TRALI induced by "stored PRBC" than by "stored PLT." Storage-related accumulation of several factors was demonstrated in both "stored PRBC" and "stored PLT", and was associated with increased in vitro neutrophil priming. Concentrations of several factors were higher in the "stored PRBC" than in the "stored PLT," however, there was no difference to neutrophil priming in vitro. Conclusions In this in vivo ovine model, both recipient and blood product factors contributed to the development of TRALI. Sick (LPS infused) sheep rather than healthy (saline infused) sheep predominantly developed TRALI when transfused with supernatant from stored but not fresh PRBC. "Stored PRBC" induced a more severe injury than "stored PLT" and had a different storage lesion profile, suggesting that these outcomes may be associated with storage lesion factors unique to each blood product type. Therefore, the transfusion of fresh rather than stored PRBC may minimise the risk of TRALI.

Wolbachia-mediated resistance to dengue virus infection and death at the cellular level

Dengue is currently the most important arthropod-borne viral disease of humans. Recent work has shown dengue virus displays limited replication in its primary vector, the mosquito Aedes aegypti, when the insect harbors the endosymbiotic bacterium Wolbachia pipientis. Wolbachia-mediated inhibition of virus replication may lead to novel methods of arboviral control, yet the functional and cellular mechanisms that underpin it are unknown.

The open window of susceptibility to infection after acute exercise in healthy young male elite athletes

The 'open window' theory is characterised by short term suppression of the immune system following an acute bout of endurance exercise. This window of opportunity may allow for an increase in susceptibility to upper respiratory illness (URI). Many studies have indicated a decrease in immune function in response to exercise. However, many studies do not indicate changes in immune function past 2 hours after the completion of exercise, consequently failing to determine whether these immune cells numbers, or importantly their function, return to resting levels before the start of another bout of exercise. Ten male 'A' grade cyclists (age 24.2 +/- 5.3 years; body mass 73.8 +/- 6.5 kg; VO(2peak) 65.9 +/- 7.1 mL.kg(-1).min(-1)) exercised for two hours at 90% of their second ventilatory threshold. Blood samples were collected pre-, immediately post-, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours post-exercise. Immune variables examined included total leukocyte counts, neutrophil function (oxidative burst and phagocytic function), lymphocyte subset counts (CD4(+), CD8(+), and CD16(+)/56(+)), natural killer cell activity (NKCA), and NK phenotypes (CD56(dim)CD16(+), and CD56(bright)CD16(-)). There was a significant increase in total lymphocyte numbers from pre-, to immediately post-exercise (p<0.01), followed by a significant decrease at 2 hours post-exercise (p<0.001). CD4(+) T-cell counts significantly increased from pre-exercise, to 4 hours post- (p<0.05), and 6 hours post-exercise (p<0.01). However, NK (CD16(+)/56(+)) cell numbers decreased significantly from pre-exercise to 4 h post-exercise (p<0.05), to 6 h post-exercise (p<0.05), and to 8 h post-exercise (p<0.01). In contrast, CD56(bright)CD16- NK cell counts significantly increased from pre-exercise to immediately post-exercise (p<0.01). Neutrophil oxidative burst activity did not significantly change in response to exercise, while neutrophil cell counts significantly increased from pre-exercise, to immediately post-exercise (p<0.05), and 2 hours post-exercise (p<0.01), and remained significantly above pre-exercise levels to 8 hours post-exercise (p<0.01). Neutrophil phagocytic function significantly decreased from 2 hours post-exercise, to 6 hours post- (p<0.05), and 24 hours post-exercise (p<0.05). Finally, eosinophil cell counts significantly increased from 2 hours post to 6 hours post- (p<0.05), and 8 hours post-exercise (p<0.05). This is the first study to show changes in immunological variables up to 8 hours post-exercise, including significant NK cell suppression, NK cell phenotype changes, a significant increase in total lymphocyte counts, and a significant increase in eosinophil cell counts all at 8 hours post-exercise. Suppression of total lymphocyte counts, NK cell counts and neutrophil phagocytic function following exercise may be important in the increased rate of URI in response to regular intense endurance training.

Vaccination to protect against infection of the female reproductive tract

Infection of the female genital tract can result in serious morbidities and mortalities from reproductive disability, pelvic inflammatory disease and cancer, to impacts on the fetus, such as infant blindness. While therapeutic agents are available, frequent testing and treatment is required to prevent the occurrence of the severe disease sequelae. Hence, sexually transmitted infections remain a major public health burden with ongoing social and economic barriers to prevention and treatment. Unfortunately, while there are two success stories in the development of vaccines to protect against HPV infection of the female reproductive tract, many serious infectious agents impacting on the female reproductive tract still have no vaccines available. Vaccination to prevent infection of the female reproductive tract is an inherently difficult target, with many impacting factors, such as appropriate vaccination strategies/mechanisms to induce a suitable protective response locally in the genital tract, variation in the local immune responses due to the hormonal cycle, selection of vaccine antigen(s) that confers effective protection against multiple variants of a single pathogen (e.g., the different serovars of Chlamydia trachomatis) and timing of the vaccine administration prior to infection exposure. Despite these difficulties, there are numerous ongoing efforts to develop effective vaccines against these infectious agents and it is likely that this important human health field will see further major developments in the next 5 years.