Variation in endogenous oxidative stress in Escherichia coli natural isolates during growth in urine

ABSTRACT: BACKGROUND: Uropathogenic strains of Escherichia coli cause symptomatic infections whereas asymptomatic bacteriuria (ABU) strains are well adapted for growth in the human urinary tract, where they establish long-term bacteriuria. Human urine is a very complex growth medium that could be perceived by certain bacteria as a stressful environment. To investigate a possible imbalance between endogenous oxidative response and antioxidant mechanisms, lipid oxidative damage estimated as thiobarbituric acid reactive substances (TBARS) content was evaluated in twenty-one E. coli belonging to various pathovars and phylogenetic groups. Antioxidant defense mechanisms were also analysed. RESULTS: During exponential growth in urine, TBARS level differs between strains, without correlation with the ability to grow in urine which was similarly limited for commensal, ABU and uropathogenic strains. In addition, no correlation between TBARS level and the phylogroup or pathogenic group is apparent. The growth of ABU strain 83972 was associated with a high level of TBARS and more active antioxidant defenses that reduce the imbalance. CONCLUSIONS: Our results indicate that growth capacity in urine is not a property of ABU strains. However, E. coli isolates respond very differently to this stressful environment. In strain ABU 83972, on one hand, the increased level of endogenous reactive oxygen species may be responsible for adaptive mutations. On the other hand, a more active antioxidant defense system could increase the capacity to colonize the bladder.     

Trends in malaria cases, hospital admissions and deaths following scale-up of anti-malarial interventions, 2000-2010, Rwanda

ABSTRACT: BACKGROUND: To control malaria, the Rwandan government and its partners distributed insecticide-treated nets (ITN) and made artemisinin-based combination therapy (ACT) widely available from 2005 onwards. The impact of these interventions on malaria cases, admissions and deaths was assessed using data from district hospitals and household surveys. METHODS: District records of ITN and ACT distribution were reviewed. Malaria and non-malaria indictors in 30 district hospitals were ascertained from surveillance records. Trends in cases, admissions and deaths for 2000 to 2010 were assessed by segmented log-linear regression, adjusting the effect size for time trends during the pre-intervention period, 2000-2005. Changes were estimated by comparing trends in post-intervention (2006-2010) with that of pre-intervention (2000-2005) period. All-cause deaths in children under-five in household surveys of 2005 and 2010 were also reviewed to corroborate with the trends of deaths observed in hospitals. RESULTS: The proportion of the population potentially protected by ITN increased from nearly zero in 2005 to 38% in 2006, and 76% in 2010; no major health facility stock-outs of ACT were recorded following their introduction in 2006. In district hospitals, after falling during 2006- 2008, confirmed malaria cases increased in 2009 coinciding with decreased potential ITN coverage and declined again in 2010 following an ITN distribution campaign. For all age groups, from the pre-intervention period, microscopically confirmed cases declined by 72%, (95% Confidence Interval [CI], 12-91%) in 2010, slide positivity rate declined 58%, (CI, 47%-68%), malaria inpatient cases declined 76% (CI, 49%-88%); and malaria deaths declined 47% (CI, 47%-81%). In children below five years of age, malaria inpatients decreased 82% (CI, 61%-92%) and malaria hospital deaths decreased 77% (CI, 40%-91%). Concurrently, outpatient cases, admissions and deaths due to non-malaria diseases in all age groups either increased or remained unchanged. Rainfall and temperature remained favourable for malaria transmission. The annual all-cause mortality in children under-five in household surveys declined from 152 per 1,000 live births during 2001-2005, to 76 per 1,000 live births in 2006-2010 (55% decline). The five-year cumulative number of all-cause deaths in hospital declined 28% (8,051 to 5,801) during the same period. CONCLUSIONS: A greater than 50% decline in confirmed malaria cases, admissions and deaths at district hospitals in Rwanda since 2005 followed a marked increase in ITN coverage and use of ACT. The decline occurred among both children under-five and in children five years and above, while hospital utilization increased and suitable conditions for malaria transmission persisted. Declines in malaria indicators were more striking than in the older age groups. The resurgence in cases associated with decreased ITN coverage in 2009 highlights the need for sustained high levels of anti-malarial interventions in Rwanda and other malaria endemic countries.     

Cervical Cancer Screening in Partly HPV Vaccinated Cohorts – A Cost-Effectiveness Analysis

Background

Vaccination against the oncogenic human papillomavirus (HPV) types 16 and 18 will reduce the prevalence of these types, thereby also reducing cervical cancer risk in unvaccinated women. This (measurable) herd effect will be limited at first, but is expected to increase over time. At a certain herd immunity level, tailoring screening to vaccination status may no longer be worth the additional effort. Moreover, uniform screening may be the only viable option. We therefore investigated at what level of herd immunity it is cost-effective to also reduce screening intensity in unvaccinated women.

Methods

We used the MISCAN-Cervix model to determine the optimal screening strategy for a pre-vaccination population and for vaccinated women (~80% decreased risk), assuming a willingness-to-pay of €50,000 per quality-adjusted life year gained. We considered HPV testing, cytology testing and co-testing and varied the start age of screening, the screening interval and the number of lifetime screens. We then calculated the incremental cost-effectiveness ratio (ICER) of screening unvaccinated women with the strategy optimized to the pre-vaccination population as compared to with the strategy optimized to vaccinated women, assuming different herd immunity levels.

Results

Primary HPV screening with cytology triage was the optimal strategy, with 8 lifetime screens for the pre-vaccination population and 3 for vaccinated women. The ICER of screening unvaccinated women 8 times instead of 3 was €28,085 in the absence of herd immunity. At around 50% herd immunity, the ICER reached €50,000.

Conclusion

From a herd immunity level of 50% onwards, screening intensity based on the pre-vaccination risk level becomes cost-ineffective for unvaccinated women. Reducing the screening intensity of uniform screening may then be considered.     

Transfection of murine LMTK− cells with purified HLA class I genes

The individual contributions of the first two external domains of the HLA-B7 heavy chain to the expression of allele-specific (B7) and locus-specific (B and C) antigenic determinants were investigated using hybrid class I genes. Hybrid genes were constructed in vitro by exon shuffling between the parent genes HLA-B7, HLA-Cw3, HLA-A3, and H-2K ^d, and their expression was monitored following transfection into mouse L cells. The results show that most allele-specific antigenic determinants are associated with the first external domain of the 137 heavy chain, whereas all the locus-specific antigenic determinants tested map to the second external domain.Abbreviations used in this paper BSA bovine serum albumin - FCS fetal calf serum - mAb monoclonal antibody - PBL peripheral blood lymphocytes - PBS phosphate-buffered saline     

Diverse signaling pathways regulate fibroblast differentiation and transformation through Rho kinase activation

This study examined the role of agonist-induced Rho kinase (ROCK) involvement in the morphological outcome of pulmonary-derived fibroblasts. Normal human lung fibroblasts (NHLF) spontaneously differentiate into network-like structures in a two-dimensional growth factor reduced Matrigel matrix-based assay. Sphingosine 1-phosphate (SPP), a bioactive phospholipid that regulates angiogenesis, inhibited fibroblast morphogenesis in a dose-dependent manner, virtually eliminating the presence of multi-cellular structures at 500 nM. Pretreatment with the Rho kinase-specific inhibitor, H1152, eradicated the high dose SPP-induced inhibition. Similarly, NHLFs transfected with Rho kinase siRNA prevented SPP-induced inhibition of the fibroblast morphogenesis. Alternatively, transforming growth factor-beta1 (TGF-beta1), a cytokine recognized as a key mediator of wound healing, terminally differentiates NHLF into myofibroblasts as evidenced by the expression of the smooth muscle cell isoform of alpha-actin (alpha-SMA). H1152 suppressed TGF-beta1-induced alpha-SMA expression in a dose-dependent manner. Similarly, treatment with Rho kinase siRNA reduced alpha-SMA expression by greater than 50%. SPP treatment had no effect on TGF-beta1-induced transformation into myofibroblasts, and TGF-beta1 treatment did not alter fibroblast morphogenesis. This study suggests a dual regulatory role for Rho kinase in cellular regulation of fibroblasts in which SPP-induced Rho kinase activation via a G-protein coupled receptor suppresses fibroblast morphogenesis while TGF-beta1-induced Rho kinase activation through a serine/threonine kinase receptor culminates in transformation into myofibroblasts.     

Words and Melody Are Intertwined in Perception of Sung Words: EEG and Behavioral Evidence

Language and music, two of the most unique human cognitive abilities, are combined in song, rendering it an ecological model for comparing speech and music cognition. The present study was designed to determine whether words and melodies in song are processed interactively or independently, and to examine the influence of attention on the processing of words and melodies in song. Event-Related brain Potentials (ERPs) and behavioral data were recorded while non-musicians listened to pairs of sung words (prime and target) presented in four experimental conditions: same word, same melody; same word, different melody; different word, same melody; different word, different melody. Participants were asked to attend to either the words or the melody, and to perform a same/different task. In both attentional tasks, different word targets elicited an N400 component, as predicted based on previous results. Most interestingly, different melodies (sung with the same word) elicited an N400 component followed by a late positive component. Finally, ERP and behavioral data converged in showing interactions between the linguistic and melodic dimensions of sung words. The finding that the N400 effect, a well-established marker of semantic processing, was modulated by musical melody in song suggests that variations in musical features affect word processing in sung language. Implications of the interactions between words and melody are discussed in light of evidence for shared neural processing resources between the phonological/semantic aspects of language and the melodic/harmonic aspects of music.     

Microphthalmia Gene Product as a Signal Transducer in cAMP-Induced Differentiation of Melanocytes

Islets of Langerhans are microorgans scattered throughout the pancreas, and are responsible for synthesizing and secreting pancreatic hormones. While progress has recently been made concerning cell differentiation of the islets of Langerhans, the mechanism controlling islet morphogenesis is not known. It is thought that these islets are formed by mature cell association, first differentiating in the primitive pancreatic epithelium, then migrating in the extracellular matrix, and finally associating into islets of Langerhans. This mechanism suggests that the extracellular matrix has to be degraded for proper islet morphogenesis. We demonstrated in the present study that during rat pancreatic development, matrix metalloproteinase 2 (MMP-2) is activated in vivo between E17 and E19 when islet morphogenesis occurs. We next demonstrated that when E12.5 pancreatic epithelia develop in vitro, MMP-2 is activated in an in vitro model that recapitulates endocrine pancreas development (Miralles, F., P. Czernichow, and R. Scharfmann. 1998. Development. 125: 1017–1024). On the other hand, islet morphogenesis was impaired when MMP-2 activity was inhibited. We next demonstrated that exogenous TGF-β1 positively controls both islet morphogenesis and MMP-2 activity. Finally, we demonstrated that both islet morphogenesis and MMP-2 activation were abolished in the presence of a pan-specific TGF-β neutralizing antibody. Taken together, these observations demonstrate that in vitro, TGF-β is a key activator of pancreatic MMP-2, and that MMP-2 activity is necessary for islet morphogenesis.     

Reproductive effort of both male and female Bar‐throated Apalis Apalis thoracica is predicted by ornamentation of self and mate

Melanin‐based plumage ornaments have been shown to play an important role in male–male competition, but also influence inter‐sexual communication. Consequently, ornaments may be associated with reproductive effort of both males and females. Females mated to males with larger melanin ornaments may acquire access to better territories or benefit from increased paternal care. Here we investigated whether the melanin‐based breast‐band of male and female Bar‐throated Apalis Apalis thoracica is a signal of information about its bearer and is associated with male and female reproductive effort. Breast‐band size was a highly variable morphometric trait in both sexes, but only in males was it associated with body mass. We then assessed whether male and female breast‐band size predicted maternal and paternal investment. Egg mass increased with male breast‐band size, but decreased with female breast‐band size. Whether females adjust maternal hormone allocation in response to their partner's ornamentation remains a contentious issue. We found that yolk testosterone and androstenedione concentrations were not predicted by male ornamentation or body mass. Finally, males with larger breast‐bands provided their mates with more food, allowing those females to spend more time incubating. Reproductive effort of both parents is therefore predicted by their own and their mate's ornamentation in Bar‐throated Apalis, and thus breast‐band size potentially acts as a signal of reproductive performance in both sexes. These results highlight the need for more comprehensive analyses of a relationship between melanin‐based ornaments and fitness, incorporating multiple behavioural variables associated with reproductive effort.