bluuebunny/crossref_metadata_2025 huggingface dataset:
Incidence and prediction of outcome in hypoxic–ischemic encephalopathy in Japan
Authors: Hayakawa Masahiro , Ito Yushi , Saito Shigeru , Mitsuda Nobuaki , Hosono Sigeharu , Yoda Hitoshi , Cho Kazutoshi , Otsuki Katsufumi , Ibara Satoshi , Terui Katsuo , Masumoto Kouji , Murakoshi Takeshi , Nakai Akihito , Tanaka Mamoru , Nakamura Tomohiko ,   Executive Committee, Symposium on Japan Society of Perinatal and Neonatal Medicine
Published: October 2013

Background

Hypoxic–ischemic encephalopathy (HIE) is one of the most critical pathologic conditions in neonatal medicine due to the potential for neurological deficits in later life. We investigated the incidence of term infants with moderate or severe HIE in Japan and identified prognostic risk factors for poor outcome in HIE.

Methods

Data on 227 infants diagnosed with moderate or severe HIE and born between January and December 2008 were collected via nationwide surveys from 263 responding hospitals. Using logistic regression, we examined the relationship between maternal, antepartum, intrapartum, and neonatal risk factors and clinical outcome at 18 months following birth.

Results

In Japan, the incidence of moderate or severe HIE was 0.37 per 1000 term live births. Outborn births, low Apgar score at 5 min, use of epinephrine, and low cord blood pH were intrapartum factors significantly associated with neurodevelopmental delay and death at 18 months. Serum lactate, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase (all, P < 0.001) and creatine kinase (P = 0.002) were significantly higher in infants with poor outcome compared to those with favorable outcomes. Abnormal brain magnetic resonance imaging (MRI), an important prognostic factor, was significantly associated with poor outcome (odds ratio, 11.57; 95% confidence interval: 5.66–23.64; P < 0.001).

Conclusions

Risk factors predicting poor outcome in HIE include outborn birth, low Apgar score at 5 min, use of epinephrine, laboratory abnormalities, and abnormal MRI findings.
Role of IL‐4Rα during acute schistosomiasis in mice
Authors: Ndlovu H. , Brombacher F.
Published: October 2013

Schistosomiasis is an important parasitic disease that causes major host morbidity and mortality in endemic areas. Research conducted in mouse models of schistosomiasis has provided great insights and understanding of how host protective immunity is orchestrated and key cellular populations involved in this process. Earlier studies using cytokine‐deficient mice demonstrated the importance of IL‐4 and IL‐10 in mediating host survival during acute schistosomiasis. Subsequent studies employing transgenic mice carrying cell‐specific deletion of IL‐4Rα generated using the Cre/LoxP recombination system have been instrumental in providing more in‐depth understanding of the mechanisms conferring host resistance to Schistosoma mansoni infection. In this review, we will summarize the contributions of IL‐4/IL‐13‐responsive cellular populations in host resistance during acute schistosomiasis and their role in limiting tissue pathology.
Why is it so difficult to identify a single indicator of water stress in plants? A proposal for a multivariate analysis to assess emergent properties
Authors: Bertolli S. C. , Mazzafera P. , Souza G. M.
Published: October 2013

Because of the complexity of plant responses to water deficit, researchers have attempted to identify simplified models to understand critical aspects of the problem by searching for single indicators that would enable evaluations of the effects of environmental changes on the entire plant. However, this reductionist approach, which is often used in plant sciences, makes it difficult to distinguish systemic emergent behaviours. Currently, a new class of models and epistemology have called attention to the fundamental properties of complex systems. These properties, termed ‘emergent’, are observed at a large scale of the system (top hierarchical level) but cannot be observed or inferred from smaller scales of observation in the same system. We propose that multivariate statistical analysis can provide a suitable tool to quantify global responses to water deficit, allowing a specific and partially quantitative assessment of emergent properties. Based on an experimental study, our results showed that the classical approach of the individual analysis of different data sets might provide different interpretations for the observed effects of water deficit. These results support the hypothesis that a cross‐scale multivariate analysis is an appropriate method to establish models for systemic understanding of the interactions between plants and their changing environment.
Clustering of Neonatal Deaths inBangladesh: Results From theProjahnmo Studies
Authors: Nonyane Bareng A. S. , Williams Emma K. , Blauvelt Carla , Shah Mohammad R. , Darmstadt Gary L. , Moulton Lawrence , Baqui Abdullah H.
Published: October 2013

Background

Neonatal mortality (NM) tends to be clustered within a small subset of mothers, households and/or geographical areas. Knowledge of the maternal and newborn factors associated withNMcan help identify high‐risk mothers and guide the targeting of intervention programmes.

Method

Data from pregnancy history surveys conducted as part of theProject forAdvancing theHealth ofNewborns andMothers (Projahnmo) inSylhet andMirzapur districts ofBangladesh were used to investigate risk factors forNM. We analysed data from babies born between 2001 and 2005 in the control clusters of theProjahnmo trials. Generalised linear mixed models were applied to quantify the heterogeneity among mothers and to investigate factors that contribute to this heterogeneity.

Results

There was an indication of correlation among siblings' outcomes. Neonates whose preceding sibling had died as a neonate in the mothers' lifetime pregnancy history were more likely (up to 1.9 times) to die than those with a living sibling. Factors that varied at the child and mother levels as well as the preceding siblings' outcome explained a large proportion (60% inSylhet and 70% inMirzapur) of the between‐mother variation inNM.

Conclusion

The preceding sibling's outcome may be a surrogate for genetic and other maternal health factors such as nutrition, infection or environmental factors that were not measured withinProjahnmo. Further research into these factors is required in order to explain the variation in the risk forNM.
Association Between Transient Hypothyroxinaemia of Prematurity and Adult Autism Spectrum Disorder in a Low‐Birthweight Cohort: An Exploratory Study
Authors: Korzeniewski Steven J. , Pinto‐Martin Jennifer A. , Whitaker Agnes H. , Feldman Judith F. , Lorenz John M. , Levy Susan E. , Movsas Tammy Z. , Pappas Athina , Paneth Nigel
Published: October 2013

Background

Transient hypothyroxinaemia of prematurity (THOP) is associated with increased risk of cerebral palsy and lower IQ in low‐birthweight infants. This study explores whether THOP is also associated with increased risk of autism spectrum disorders (ASD).

Methods

This secondary analysis uses data from a birth cohort of newborns weighing 500 –2000 g (n = 1105) who were followed to age 21 years, when they were assessed for ASD in the second of a two‐stage process. Of the 187 assessed at age 21, 14 had ASD. Neonatal thyroxine results were available for 12/14 and 165/173 participants diagnosed with and without ASD, respectively. THOP was defined as thyroxine z‐score <−2.6. Unadjusted relative risks (RR) and confidence intervals (CI) were calculated.

Results

The mean neonatal thyroxine z‐score in young adults diagnosed with ASD was 0.5 SD lower [95% CI −0.16, 1.06] than in those without ASD. Participants with THOP were at 2.5‐fold greater risk of ASD (RR 2.5 [95% CI 0.7, 8.4]). While neither of these differences was statistically significant, in a secondary subgroup analysis of those whose mothers did not have hypertension during pregnancy, THOP significantly increased the RR for ASD (5.0 [95% CI 1.2, 20.5]).

Conclusion

While the primary relation between THOP and ASD found here is not statistically significant, the magnitude of association and significant relationship observed in the subgroup whose mothers did not have hypertension during pregnancy suggest that it is worthy of further investigation.
Liberal Ethnic Nationalism, Universality, and Cornish Identity
Authors: Willett Joanie
Published: October 2013

Within the liberal paradigm, ethnic nationalism and identity are often conceptualized as ‘exclusive’, lacking the capacity for universal membership (Ipperciel 2007; Kohn 1946; Kymlicka 1995), and is juxtaposed against ‘inclusive’, civic forms of identity. This article problematizes this claim, asking whether civic territorial identities also contain their own forms of exclusion. Using the New Regionalism and the identity politics of contemporary economic development, this article explores civic/ethnic identities in Cornwall in the context of Agnew's (2005) observations about contemporary liberal values. The article finds that, in Cornwall, civic forms of territorial identity that distance themselves from ethnic Cornishness are more exclusive than contemporary ethnic nationalism in the region, introducing economic rather than ethnic exclusions. This raises questions about why ethnic identity can be negatively characterized in regional development discourses and what the effects of this might be.
Performing Identities on a Dutch River Dike: National Identity and Diverging Lifestyles
Authors: Terlouw Kees
Published: October 2013

The creation of a national identity shared by the whole population becomes increasingly difficult in individualizing and globalizing national societies. The national population fragments into many lifestyle groups with very different social and cultural orientations. The enactment of these different lifestyle identities during leisure activities accentuates these differences. However, these different identities are sometimes performed on the same spatial stage. The main part of this article analyses the use of the dike along the river Linge, a part the Rhine estuary, which, lined with apple trees, cuts through an iconic Dutch river landscape with polders, old villages and meadows with quietly grazing cattle. Especially during the weekends, it is a stage crowded by walkers, cyclists, classic car drivers, and motorcyclists. The importance attached to this river dike is linked to a shared traditional form of Dutch collective national identity. The different uses of the river dike are based to the diverging values on which the different lifestyles are based. This results in conflicts over the use of and access to the dike. The role of the state in regulating these conflicts results in a more limited form of national identity.
Tuning in to Teens: Improving Parent Emotion Socialization to Reduce Youth Internalizing Difficulties
Authors: Kehoe Christiane E. , Havighurst Sophie S. , Harley Ann E.
Published: October 2013

Research in child development suggests that parents' emotional competence and emotion socialization practices are related to children's emotional functioning, including child internalizing difficulties. This research has not yet been translated into intervention or prevention programs targeting parents of older children and adolescents. The current study examined the efficacy of the Tuning in to Teens parenting program in improving emotion socialization practices in parents of preadolescents and reducing youth internalizing difficulties. Schools were randomized into intervention and control conditions. Data were collected from 225 parents and 224 youth during the young person's final year of elementary school (sixth grade) and again 10 months later in their first year of secondary school (seventh grade). Multilevel analyses showed significant improvements in parental emotion socialization and reductions in youth internalizing difficulties for the intervention condition. This study provides support for the efficacy of the TINT parenting program with a community sample.
Single‐nucleotide polymorphisms at the 9p21.3 genomic region not associated with the risk of cardiovascular disease in patients with rheumatoid arthritis
Authors: García‐Bermúdez M. , López‐Mejías R. , Genre F. , Castañeda S. , González‐Juanatey C. , Llorca J. , Corrales A. , Miranda‐Filloy J. A. , Pina T. , Gómez‐Vaquero C. , Rodríguez‐Rodríguez L. , Fernández‐Gutiérrez B. , Pascual‐Salcedo D. , Balsa A. , López‐Longo F. J. , Carreira P. , Blanco R. , González‐Álvaro I. , Martín J. , González‐Gay M. A.
Published: October 2013

Rheumatoid arthritis (RA) is a chronic polygenic inflammatory disease associated with accelerated atherosclerosis and high risk of cardiovascular disease (CVD). In this study, we evaluated the potential association of 9p21.3 single‐nucleotide polymorphisms (SNPs) – previously linked to coronary artery disease – and CVD risk in 2001 Spanish RA patients genotyped for 9p21.3 SNPs using TaqMan™ assays. Carotid intima media thickness (cIMT) and presence of carotid plaques were also analyzed. Cox regression model did not disclose significant differences between patients who experienced CVD and those who did not. Neither association was found between cIMT or carotid plaques and SNPs allele distribution. In conclusion, results do not support a role of rs10116277 or rs1537375 SNPs in CVD risk in Spanish RA patients.
Diabetes mellitus in Jamaica: sex differences in burden, risk factors, awareness, treatment and control in a developing country
Authors: Cunningham‐Myrie Colette , Younger‐Coleman Novie , Tulloch‐Reid Marshall , McFarlane Shelly , Francis Damian , Ferguson Trevor , Gordon‐Strachan Georgiana , Wilks Rainford
Published: October 2013

Objective

The objective of this study was to provide valid estimates of the burden of and risk factors for diabetes mellitus by sex in Jamaica, a predominantly Black, middle‐income and developing country.

Methods

The Jamaica Health and Lifestyle Survey 2008 examined a nationally representative sample of 2848 Jamaicans aged 15–74. Parameter estimates and 95% confidence intervals [CI] were weighted for non‐response as well as age and sex of the source population. Sex differences in risk factors and diabetes prevalence, awareness, treatment and control were estimated in multivariable models. Population‐attributable fractions (PAFs) of obesity on diabetes mellitus were estimated in both sexes.

Results

The prevalence of diabetes mellitus was 7.9% (95% CI: 6.7–9.1%), significantly higher in women than men 9.3% vs. 6.4% (P = 0.02) and increasing with age. Seventy‐six percentage of persons with diabetes mellitus were aware of their status; urban women and rural men were less likely to be aware. Diabetes control (43% overall) was less common in higher‐income men, but more common in higher‐income women. Persons without health insurance were less likely to control their diabetes. The prevalence of diabetes risk factors was higher in women than men. Increased waist circumference (≥94 cm [men]/≥80 cm [women]), overweight/obesity (body mass index ≥ 25 kg/m2) and low physical activity/inactivity were associated with PAFs for diabetes mellitus of 27%, 37% and 15%, respectively, in men and 77%, 54% and 24%, respectively, in women.

Conclusions

Prevalence of diabetes mellitus and its risk factors is high in Jamaica, especially among women, and national programmes to stem the diabetes mellitus epidemic should take these sex differences into consideration.
Clinical outcome and cyclo‐oxygenase‐2 expression in five dogs with solar dermatitis/actinic keratosis treated with firocoxib
Authors: Albanese Francesco , Abramo Francesca , Caporali Chiara , Vichi Gaia , Millanta Francesca
Published: October 2013

Background

The conversion of arachidonic acid into prostaglandin is catalysed by the cyclo‐oxygenases (COX‐1/COX‐2). Several studies indicate that COX‐2 is overexpressed in actinic keratosis in humans and dogs. Firocoxib is a COX‐2‐selective inhibitor that blocks the biochemical activity of COX‐2.

Hypothesis/Objectives

To evaluate the efficacy of firocoxib (5 mg/kg orally once daily) for the treatment of dogs with solar dermatitis/actinic keratosis.

Methods

Firocoxib 5 mg/kg was given orally once daily for 180 days to five dogs with clinical signs and histopathological lesions consistent with solar dermatitis/actinic keratosis. On days 0, 50 and 180, the severity of erythema, skin shine, induration and the number of comedones were evaluated by a clinical scoring system. On the same days, samples were collected for histopathology from ‘target lesions’ and COX‐2 expression was evaluated by immunohistochemistry.

Results

The clinical follow‐up showed that four of five dogs improved with the treatment; improvement in terms of histological findings was correlated with the regularization of the epidermal proliferation rather than the recovery of dermal changes.

Conclusions and clinical importance

A role for COX‐2 might thus be hypothesized in the pathogenesis of canine solar dermatitis.
The Self‐Assessment for Organizational Capacity Instrument for Evidence‐Informed Health Policy: Preliminary Reliability and Validity of an Instrument
Authors: Catallo Cristina , Sidani Souraya
Published: October 2013

Background

Health policymakers work in organizations that involve multiple competing demands and limited time to make decisions. Influential international policy organizations continue to publish guidance and recommendations without the use of high‐quality research evidence. Few studies have described the process with which governments, including health ministries, use evidence to support health policymaking decisions. Research is needed to better understand the psychometric properties of instruments that assess health policy organizations’ capacity to use research evidence.

Aim

The purpose of this study was to assess the preliminary psychometric properties of an instrument which assesses organizational capacity for evidence use.

Methods

The instrument was administered by telephone survey from January to June 2011 using a purposeful sample of 57 Canadian health policymakers (policy analyst and senior management levels). Reliability of the instrument was assessed with Cronbach'sαcoefficient and item‐to‐total correlation for internal consistency; interitem coefficients were used to identify particular item redundancy. Discriminant validity was assessed using the known‐group comparison approach, with the independent samplet‐test to assess subscale responses of policy analysts and senior managers.

Findings

Cronbach'sαindicated acceptable internal consistency across its subscales. Discriminant validity analysis revealed a statistically significant difference between policy analysts and senior managers for one subscale.

Linking Evidence to Action

Our study provides a first look at the Self‐assessment for Organizational Capacity Instrument's psychometric properties and demonstrates that this instrument can be useful when evaluating government and other organizations’ use of evidence to inform decision making. Further testing of this instrument is needed using large and varied samples of policymakers, from policy analysts to senior managers, across varied policymaking contexts. This instrument can be a starting point for government and related organizations to better understand how well it supports evidence use, including its acquisition, appraisal, and use in health policy decision making.
A Sequential Linear Programming Matrix Method to Insensitive H∞ Output Feedback for Linear Discrete-Time Systems
Authors: Guo Xiang-Gui , Yang Guang-Hong
Published: October 2013

This paper studies the problem of designing insensitive H∞ output-feedback controllers for linear discrete-time systems. The designed controllers are insensitive to additive/multiplicative controller coefficient variations. An LMI-based procedure, which is a sequential linear programming matrix method (SLPMM), is proposed to solve the considered problem which is a nonconvex problem itself. It is worth mentioning that the nonfragile control design method is adopted to obtain an effective solution for accelerating convergence of SLPMM algorithm due to the fact that a good starting point for the iteration is very important.
Reevaluation of Ceftazidime Dosing Recommendations in Patients on Continuous Ambulatory Peritoneal Dialysis
Authors: Cardone Katie E. , Grabe Darren W. , Zasowski Evan J. , Lodise Thomas P.
Published: October 2013

While intraperitoneal (i.p.) ceftazidime is commonly used to treat continuous ambulatory peritoneal dialysis (CAPD)-related infections, the ability of i.p. regimens to achieve critical pharmacodynamic targets in both blood and dialysate has not been reported. To understand the pharmacodynamic profile of ceftazidime during CAPD, data were obtained from a single-dose pharmacokinetic (PK) i.p. ceftazidime study that included 10 CAPD patients who received i.p. ceftazidime at 15 mg/kg of body weight. The probability of target attainment (concentrations maintained above the MIC for >60% of the dosing interval [60%
T
> MIC]) was determined for six simulated regimens. A 3-compartment model with each dialysis dwell modeled as a separate differential equation was fit to ceftazidime concentrations using BigNPAG. Embedded with the final PK model, serum and dialysate concentration-time profiles of ceftazidime at 1, 1.5, and 2 g i.p. every 24 h (q24h) to q48h were simulated using ADAPT 5. The mean population pharmacokinetic parameters were as follows: apparent volume of the central compartment (

V
c

), 7.57 liter; apparent volume of the peritoneal cavity (
V
pd), 2.44 liter; clearance from the central compartment (CL), 0.379 liter/h; intercompartmental transfer rate constants (first order) between the central and peripheral compartments (
k
12
and
k
21
), 4.66 and 4.88 h
−1
, respectively; and intercompartmental transfer rate constants (first order) between the central and peritoneal compartments (
k
13
and
k
31
), 0.111 and 0.227 h
−1
, respectively. In serum, the probability of target attainment for MICs of ≤8 mg/liter exceeded 90% for 1.5 to 2 g i.p. q24h to q48h. However, no tested regimen provided adequate dialysate exposure at MICs of ≥8 mg/liter on day 1 without the use of a 3-g loading dose (
post hoc
analysis). On day 2, 1.5 to 2 g i.p. q24h or 2 g i.p. q48h provided adequate exposure in the peritoneal cavity. These results should be validated in the presence of infection. Ceftazidime i.p. at 1.5 or 2 g q24h to q48h is recommended for nonperitoneal infections. For peritonitis, a 3-g load with maintenance dosing of 1 to 2 g i.p. q24h or 2 g i.p. q48h is recommended.
New 2-Thiopyridines as Potential Candidates for Killing both Actively Growing and Dormant Mycobacterium tuberculosis Cells
Authors: Salina Elena , Ryabova Olga , Kaprelyants Arseny , Makarov Vadim
Published: October 2013

From
in vivo
observations, a majority of
M. tuberculosis
cells in latently infected individuals are in a dormant and probably nonculturable state, display little metabolic activity, and are phenotypically resistant to antibiotics. Despite many attempts, no specific antimicrobials effective against latent tuberculosis have yet been found, partly because of a lack of reliable and adequate
in vitro
models for screening of drug candidates. We propose here a novel
in vitro
model of
M. tuberculosis
dormancy that meets the important criteria of latency, namely, nonculturability of cells, considerable reduction of metabolic activity, and significant phenotypic resistance to the first-line antibiotics rifampin and isoniazid. Using this model, we found a new group of 2-thiopyridine derivatives that had potent antibacterial activity against both actively growing and dormant
M. tuberculosis
cells. By means of the model of
M. tuberculosis
nonculturability, several new 2-thiopyridine derivatives were found to have potent antitubercular activity. The compounds are effective against both active and dormant
M. tuberculosis
cells. The bactericidal effects of compounds against dormant
M. tuberculosis
was confirmed by using three different
in vitro
models of tuberculosis dormancy. The model of nonculturability could be used as a reliable tool for screening drug candidates, and 2-thiopyridine derivatives may be regarded as prominent compounds for further development of new drugs for curing latent
M. tuberculosis
infection.
KAY-2-41, a Novel Nucleoside Analogue Inhibitor of OrthopoxvirusesIn VitroandIn Vivo
Authors: Duraffour Sophie , Drillien Robert , Haraguchi Kazuhiro , Balzarini Jan , Topalis Dimitri , van den Oord Joost J. , Andrei Graciela , Snoeck Robert
Published: October 2013

The availability of adequate treatments for poxvirus infections would be valuable not only for human use but also for veterinary use. In the search for novel antiviral agents, a 1′-methyl-substituted 4′-thiothymidine nucleoside, designated KAY-2-41, emerged as an efficient inhibitor of poxviruses.In vitro, KAY-2-41 was active in the micromolar range against orthopoxviruses (OPVs) and against the parapoxvirus orf. The compound preserved its antiviral potency against OPVs resistant to the reference molecule cidofovir. KAY-2-41 had no noticeable toxicity on confluent monolayers, but a cytostatic effect was seen on growing cells. Genotyping of vaccinia virus (VACV), cowpox virus, and camelpox virus selected for resistance to KAY-2-41 revealed a nucleotide deletion(s) close to the ATP binding site or a nucleotide substitution close to the substrate binding site in the viral thymidine kinase (TK;J2R) gene. These mutations resulted in low levels of resistance to KAY-2-41 ranging from 2.7- to 6.0-fold and cross-resistance to 5-bromo-2′-deoxyuridine (5-BrdU) but not to cidofovir. The antiviral effect of KAY-2-41 relied, at least in part, on activation (phosphorylation) by the viral TK, as shown through enzymatic assays. The compound protected animals from disease and mortality after a lethal challenge with VACV, reduced viral loads in the serum, and abolished virus replication in tissues. In conclusion, KAY-2-41 is a promising nucleoside analogue for the treatment of poxvirus-induced diseases. Our findings warrant the evaluation of additional 1′-carbon-substituted 4′-thiothymidine derivatives as broad-spectrum antiviral agents, since this molecule also showed antiviral potency against herpes simplex virus 1 in earlier studies.
Frequency of
fks
Mutations among Candida glabrata Isolates from a 10-Year Global Collection of Bloodstream Infection Isolates
Authors: Castanheira Mariana , Woosley Leah N. , Messer Shawn A. , Diekema Daniel J. , Jones Ronald N. , Pfaller Michael A.
Published: October 2013

Among 119 echinocandin non-wild-type (non-WT)
Candida glabrata
strains from two global surveys, mutations in
fks
hot spots (HSs) were detected in 28 (from 7 countries and 8 U.S. states): 24 strains (85.7%) had non-WT MICs for micafungin, 22 (78.6%) for anidulafungin, and 25 (89.3%) for caspofungin. The most common FKS substitutions among non-WT strains were at positions F659 (
n
= 7) and S663 (
n
= 7). Three isolates displaying WT MIC results had F625Y, L630I, and D632Y substitutions or non-HS mutations. Mutations that have been reported to decrease the echinocandin binding to the 1,3-β-
d
-glucan synthase were categorized as resistant by applying the new CLSI breakpoint criteria for all three echinocandins.
Outpatient Antibiotic Use in France between 2000 and 2010: after the Nationwide Campaign, It Is Time To Focus on the Elderly
Authors: Bernier Adeline , Delarocque-Astagneau Elisabeth , Ligier Caroline , Vibet Marie-Anne , Guillemot Didier , Watier Laurence
Published: October 2013

Antibiotic overconsumption is the main force driving the emergence of multidrug-resistant bacterial strains. To promote better antibiotic use in France, a nationwide campaign has been run every year from October to March since 2002. In 2007, it was shown that winter outpatient antibiotic consumption had decreased by 26.5% compared to the 2000-2002 baseline period. Here, we quantified outpatient antibiotic use between 2000 and 2010 as a follow-up analysis of the nationwide campaign. Reimbursed outpatient antibiotic prescriptions were extracted from computerized French National Health Insurance databases. Entire series and age group and antibiotic class analyses were computed. Time series analyses used autoregressive moving-average models with exogenous variables and intervention functions. Two periods were considered: October to March “campaign” periods and April to September “warm” periods. Compared to the precampaign (2000-2002) baseline period, the numbers of weekly antibiotic prescriptions per 1,000 inhabitants during campaign periods decreased until winter 2006 to 2007 (−30% [95% confidence interval {CI}, −36.3 to −23.8%];
P
< 0.001) and then stabilized except for individuals >60 years of age, for whom prescriptions reached the precampaign level. During the warm periods from April to September, no significant differences were estimated compared to the baseline level for the entire series, but seniors had an increasing trend that became significant as of 2005, reaching +21% (95% CI, +12.9 to +29.6%) in 2009 (
P
< 0.0001). These results highlight the need for a better understanding of antibiotic use by the elderly, requiring research with targeted and tailored public health actions for this population.
Terbinafine in Combination with Other Antifungal Agents for Treatment of Resistant or Refractory Mycoses: Investigating Optimal Dosing Regimens Using a Physiologically Based Pharmacokinetic Model
Authors: Dolton Michael J. , Perera Vidya , Pont Lisa G. , McLachlan Andrew J.
Published: October 2013

Terbinafine is increasingly used in combination with other antifungal agents to treat resistant or refractory mycoses due to synergisticin vitroantifungal activity; high doses are commonly used, but limited data are available on systemic exposure, and no assessment of pharmacodynamic target attainment has been made. Using a physiologically based pharmacokinetic (PBPK) model for terbinafine, this study aimed to predict total and unbound terbinafine concentrations in plasma with a range of high-dose regimens and also calculate predicted pharmacodynamic parameters for terbinafine. Predicted terbinafine concentrations accumulated significantly during the first 28 days of treatment; the area under the concentration-time curve (AUC)/MIC ratios and AUC for the free, unbound fraction (fAUC)/MIC ratios increased by 54 to 62% on day 7 of treatment and by 80 to 92% on day 28 compared to day 1, depending on the dose regimen. Of the high-dose regimens investigated, 500 mg of terbinafine taken every 12 h provided the highest systemic exposure; on day 7 of treatment, the predicted AUC, maximum concentration (Cmax), and minimum concentration (Cmin) were approximately 4-fold, 1.9-fold, and 4.4-fold higher than with a standard-dose regimen of 250 mg once daily. Close agreement was seen between the concentrations predicted by the PBPK model and the observed concentrations, indicating good predictive performance. This study provides the first report of predicted terbinafine exposure in plasma with a range of high-dose regimens.
Activation of NLRP3 and AIM2 Inflammasomes by Porphyromonas gingivalis Infection
Authors: Park Eunjoo , Na Hee Sam , Song Yu-Ri , Shin Seong Yeol , Kim You-Me , Chung Jin
Published: October 2013

Porphyromonas gingivalis
, a major periodontopathogen, is involved in the pathogenesis of periodontitis. Interleukin-1β (IL-1β), a proinflammatory cytokine, regulates innate immune responses and is critical for the host defense against bacterial infection. However, excessive IL-1β is linked to periodontal destruction. IL-1β synthesis, maturation, and secretion are tightly regulated by Toll-like receptor (TLR) signaling and inflammasome activation. We found much higher levels of inflammasome components in the gingival tissues from patients with chronic periodontitis than in those from healthy controls. To investigate the molecular mechanisms by which
P. gingivalis
infection causes IL-1β secretion, we examined the characteristics of
P. gingivalis
-induced signaling in differentiated THP-1 cells. We found that
P. gingivalis
induces IL-1β secretion and inflammatory cell death via caspase-1 activation. We also found that
P. gingivalis
-induced IL-1β secretion and pyroptic cell death required both NLRP3 and AIM2 inflammasome activation. The activation of the NLRP3 inflammasome was mediated by ATP release, the P2X
7
receptor, and lysosomal damage. In addition, we found that the priming signal via TLR2 and TLR4 activation precedes
P. gingivalis
-induced IL-1β release. Our study provides novel insight into the innate immune response against
P. gingivalis
infection which could potentially be used for the prevention and therapy of periodontitis.
Hexa-Acylated Lipid A Is Required for Host Inflammatory Response to Neisseria gonorrhoeae in Experimental Gonorrhea
Authors: Zhou Xiyou , Gao Xi , Broglie Peter M. , Kebaier Chahnaz , Anderson James E. , Thom Natalie , Apicella Michael A. , Sempowski Gregory D. , Duncan Joseph A.
Published: October 2013

Neisseria gonorrhoeae
causes gonorrhea, a sexually transmitted infection characterized by inflammation of the cervix or urethra. However, a significant subset of patients with
N. gonorrhoeae
remain asymptomatic, without evidence of localized inflammation. Inflammatory responses to
N. gonorrhoeae
are generated by host innate immune recognition of
N. gonorrhoeae
by several innate immune signaling pathways, including lipooligosaccharide (LOS) and other pathogen-derived molecules through activation of innate immune signaling systems, including toll-like receptor 4 (TLR4) and the interleukin-1β (IL-1β) processing complex known as the inflammasome. The lipooligosaccharide of
N. gonorrhoeae
has a hexa-acylated lipid A.
N. gonorrhoeae
strains that carry an inactivated
msbB
(also known as
lpxL1
) gene produce a penta-acylated lipid A and exhibit reduced biofilm formation, survival in epithelial cells, and induction of epithelial cell inflammatory signaling. We now show that
msbB
-deficient
N. gonorrhoeae
induces less inflammatory signaling in human monocytic cell lines and murine macrophages than the parent organism. The penta-acylated LOS exhibits reduced toll-like receptor 4 signaling but does not affect
N. gonorrhoeae
-mediated activation of the inflammasome. We demonstrate that
N. gonorrhoeae
msbB
is dispensable for initiating and maintaining infection in a murine model of gonorrhea. Interestingly, infection with
msbB
-deficient
N. gonorrhoeae
is associated with less localized inflammation. Combined, these data suggest that TLR4-mediated recognition of
N. gonorrhoeae
LOS plays an important role in the pathogenesis of symptomatic gonorrhea infection and that alterations in lipid A biosynthesis may play a role in determining symptomatic and asymptomatic infections.
In VitroInfection of Bovine Monocytes with Mycoplasma bovis Delays Apoptosis and Suppresses Production of Gamma Interferon and Tumor Necrosis Factor Alpha but Not Interleukin-10
Authors: Mulongo Musa , Prysliak Tracy , Scruten Erin , Napper Scott , Perez-Casal Jose
Published: October 2013

Mycoplasma bovisis one of the major causative pathogens of bovine respiratory complex disease (BRD), which is characterized by enzootic pneumonia, mastitis, pleuritis, and polyarthritis.M. bovisenters and colonizes bovine respiratory epithelial cells through inhalation of aerosol from contaminated air. The nature of the interaction betweenM. bovisand the bovine innate immune system is not well understood. We hypothesized thatM. bovisinvades blood monocytes and regulates cellular function to support its persistence and systemic dissemination. We used bovine-specific peptide kinome arrays to identify cellular signaling pathways that could be relevant toM. bovis-monocyte interactionsin vitro. We validated these pathways using functional, protein, and gene expression assays. Here, we show that infection of bovine blood monocytes withM. bovisdelays spontaneous or tumor necrosis factor alpha (TNF-α)/staurosporine-driven apoptosis, activates the NF-κB p65 subunit, and inhibits caspase-9 activity. We also report thatM. bovis-infected bovine monocytes do not produce gamma interferon (IFN-γ) and TNF-α, although the level of production of interleukin-10 (IL-10) is elevated. Our findings suggest thatM. bovistakes over the cellular machinery of bovine monocytes to prolong bacterial survival and to possibly facilitate subsequent systemic distribution.
Ethanolamine and Choline Promote Expression of Putative and Characterized Fimbriae in Enterohemorrhagic Escherichia coli O157:H7
Authors: Gonyar Laura A. , Kendall Melissa M.
Published: October 2013

Enterohemorrhagic
Escherichia coli
(EHEC) O157:H7 is an important food-borne pathogen responsible for disease outbreaks worldwide. In order to colonize the human gastrointestinal (GI) tract and cause disease, EHEC must be able to sense the host environment and promote expression of virulence genes essential for adherence. Ethanolamine (EA) is an important metabolite for EHEC in the GI tract, and EA is also a signal that EHEC uses to activate virulence traits. Here, we report that EA influenced EHEC adherence to epithelial cells and fimbrial gene expression. Quantitative reverse transcriptase PCR indicated that EA promoted the transcription of the genes in characterized and putative fimbrial operons. Moreover, putative fimbrial structures were produced by EHEC cells grown with EA but not in medium lacking EA. Additionally, we defined two previously uncharacterized EA-regulated fimbrial operons,
loc10
and
loc11
. We also tested whether choline or serine, both of which are also components of cell membranes, activated fimbrial gene expression. In addition to EA, choline activated fimbrial gene expression in EHEC. These findings describe for the first time the transcription of several putative fimbrial loci in EHEC. Importantly, the biologically relevant molecules EA and choline, which are abundant in the GI tract, promoted expression of these fimbriae.
Yersinia enterocolitica Inhibits Salmonella enterica Serovar Typhimurium and Listeria monocytogenes Cellular Uptake
Authors: Habyarimana Fabien , Swearingen Matthew C. , Young Glenn M. , Seveau Stephanie , Ahmer Brian M. M.
Published: October 2013

Yersinia enterocolitica
biovar 1B employs two type three secretion systems (T3SS), Ysa and Ysc, which inject effector proteins into macrophages to prevent phagocytosis. Conversely,
Salmonella enterica
serovar Typhimurium uses a T3SS encoded by
Salmonella
pathogenicity island 1 (SPI1) to actively invade cells that are normally nonphagocytic and a second T3SS encoded by SPI2 to survive within macrophages. Given the distinctly different outcomes that occur with regard to host cell uptake of
S
. Typhimurium and
Y. enterocolitica
, we investigated how each pathogen influences the internalization outcome of the other.
Y. enterocolitica
reduces
S
. Typhimurium invasion of HeLa and Caco-2 cells to a level similar to that observed using an
S
. Typhimurium SPI1 mutant alone. However,
Y. enterocolitica
had no effect on
S
. Typhimurium uptake by J774.1 or RAW264.7 macrophage-like cells.
Y. enterocolitica
was also able to inhibit the invasion of epithelial and macrophage-like cells by
Listeria monocytogenes
.
Y. enterocolitica
mutants lacking either the Ysa or Ysc T3SS were partially defective, while double mutants were completely defective, in blocking
S
. Typhimurium uptake by epithelial cells.
S
. Typhimurium encodes a LuxR homolog, SdiA, which detects
N
-acylhomoserine lactones (AHLs) produced by
Y. enterocolitica
and upregulates the expression of an invasin (Rck) and a putative T3SS effector (SrgE). Two different methods of constitutively activating the
S
. Typhimurium SdiA regulon failed to reverse the uptake blockade imposed by
Y. enterocolitica
.
Secondary Lymphoid Organ Homing Phenotype of Human Myeloid Dendritic Cells Disrupted by an Intracellular Oral Pathogen
Authors: Miles Brodie , Zakhary Ibrahim , El-Awady Ahmed , Scisci Elizabeth , Carrion Julio , O'Neill John C. , Rawlings Aaron , Stern J. Kobi , Susin Cristiano , Cutler Christopher W.
Published: October 2013

Several intracellular pathogens, including a key etiological agent of chronic periodontitis,Porphyromonas gingivalis, infect blood myeloid dendritic cells (mDCs). This infection results in pathogen dissemination to distant inflammatory sites (i.e., pathogen trafficking). The alteration in chemokine-chemokine receptor expression that contributes to this pathogen trafficking function, particularly toward sites of neovascularization in humans, is unclear. To investigate this, we utilized human monocyte-derived DCs (MoDCs) and primary endothelial cellsin vitro, combined withex vivo-isolated blood mDCs and serum from chronic periodontitis subjects and healthy controls. Our results, using conditional fimbria mutants ofP. gingivalis, show thatP. gingivalisinfection of MoDCs induces an angiogenic migratory profile. This profile is enhanced by expression of DC-SIGN on MoDCs and minor mfa-1 fimbriae onP. gingivalisand is evidenced by robust upregulation of CXCR4, but not secondary lymphoid organ (SLO)-homing CCR7. This disruption of SLO-homing capacity in response to respective chemokines closely matches surface expression of CXCR4 and CCR7 and is consistent with directed MoDC migration through an endothelial monolayer.Ex vivo-isolated mDCs from the blood of chronic periodontitis subjects, but not healthy controls, expressed a similar migratory profile; moreover, sera from chronic periodontitis subjects expressed elevated levels of CXCL12. Overall, we conclude thatP. gingivalisactively “commandeers” DCs by reprogramming the chemokine receptor profile, thus disrupting SLO homing, while driving migration toward inflammatory vascular sites.
Enzymatic Modification of Lipid A by ArnT Protects Bordetella bronchiseptica against Cationic Peptides and Is Required for Transmission
Authors: Rolin Olivier , Muse Sarah J. , Safi Chetan , Elahi Shokrollah , Gerdts Volker , Hittle Lauren E. , Ernst Robert K. , Harvill Eric T. , Preston Andrew
Published: October 2013

Pathogen transmission cycles require many steps: initial colonization, growth and persistence, shedding, and transmission to new hosts. Alterations in the membrane components of the bacteria, including lipid A, the membrane anchor of lipopolysaccharide, could affect any of these steps via its structural role protecting bacteria from host innate immune defenses, including antimicrobial peptides and signaling through Toll-like receptor 4 (TLR4). To date, lipid A has been shown to affect only the within-host dynamics of infection, not the between-host dynamics of transmission. Here, we investigate the effects of lipid A modification in a mouse infection and transmission model. Disruption of the
Bordetella bronchiseptica
locus (
BB4268
) revealed that ArnT is required for addition of glucosamine (GlcN) to
B. bronchiseptica
lipid A. ArnT modification of lipid A did not change its TLR4 agonist activity in J774 cells, but deleting
arnT
decreased resistance to killing by cationic antimicrobial peptides, such as polymyxin B and β-defensins. In the standard infection model, mutation of
arnT
did not affect
B. bronchiseptica
colonization, growth, persistence throughout the respiratory tract, recruitment of neutrophils to the nasal cavity, or shedding of the pathogen. However, the number of bacteria necessary to colonize a host (50% infective dose [ID
50
]) was 5-fold higher for the
arnT
mutant. Furthermore, the
arnT
mutant was defective in transmission between hosts. These results reveal novel functions of the ArnT lipid A modification and highlight the sensitivity of low-dose infections and transmission experiments for illuminating aspects of infectious diseases between hosts. Factors such as ArnT can have important effects on the burden of disease and are potential targets for interventions that can interrupt transmission.
Effect of teenage motherhood on cognitive outcomes in children: a population-based cohort study
Authors: Morinis Julia , Carson Claire , Quigley Maria A
Published: October 2013

Objective

To examine the association between teenage motherhood and cognitive development at 5 years.

Design

Data from Millennium Cohort Study, a prospective, nationally representative UK cohort of 18 818 infants born between 2000 and 2001.

Participants

12 021 (64%) mother-child pairs from white, English-speaking, singleton pregnancies were included.

Methods

Cognitive ability at 5 years was measured by the British Ability Scales II. Difference in mean cognitive scores across maternal age groups was estimated using linear regression, with adjustment for potential confounders and mediators.

Results

617 (5%) children were born to mothers aged ≤18 years. Our analysis revealed that children of teenage mothers had significantly lower cognitive scores compared with children of mothers aged 25–34 years: difference in mean score for verbal ability −8.9 (−10.88 to −6.86, p<0.001); non-verbal ability −7.8 (−10.52 to −5.19, p<0.001); spatial ability −4.7 (−6.39 to −3.07, p<0.001), which is equivalent to an average delay of 11, 7 and 4 months, respectively. After adjustment for perinatal and sociodemographic factors, the effect of young maternal age on non-verbal and spatial ability mean scores was attenuated. A difference persisted in the mean verbal ability scores −3.8 (−6.34 to −1.34, p=0.003), equivalent to an average delay of 5 months.

Conclusions

Results suggest that the difference observed in the initial analyses for non-verbal and spatial skills are almost entirely explained by marked inequalities in sociodemographic circumstances and perinatal risk. However, there remains a significant adverse effect on verbal abilities in the children born to teenage mothers.
Neonatal Currarino’s syndrome presenting as intestinal obstruction
Authors: Patel Ramnik V , Shepherd Gregory , Kumar Hemant , Patwardhan Nitin
Published: October 2013

This article has been retracted at the request of the parents of the patient discussed in the case report.
Management of haemangioma with sclerosing agent: a case report
Authors: M K Parvathidevi , Koppal Shrinivas , Rukmangada Thriveni , Byatnal Amit R
Published: October 2013

The use of multiple weekly intralesional injections of 3% sodium tetradecyl sulfate as a sclerosing agent for the management of facial haemangiomas is a safe treatment with acceptable results. As presented in this case report, this technique offers the patient considerable relief of symptoms with minimal complications. However, the possibility of second-stage surgery to correct residual deformity is still considered. Sclerotherapy with 3% sodium tetradecyl sulfate provides a good preparation for further surgery.
Multifocal necrotising fasciitis and septic shock complicating varicella infection in an adult
Authors: Mifsud Simon , Schembri Emma Louise , Mallia Azzopardi Charles , Zammit Maria Alessandra
Published: October 2013

A 35-year-old woman with a 3-day history of chickenpox, presented to the hospital in septic shock and with multifocal, non-adjacent lesions of necrotising fasciitis. Necrotising fasciitis is a rare yet life-threatening complication of chickenpox. Blood cultures and wound swabs confirmed the presence ofStreptococcus pyogenes. The initial emergency management included oxygen, aggressive fluid resuscitation and antimicrobial therapy. Once the patient was stabilised, surgical management ensued. This included debridement and eventual grafting of the necrotic skin lesions. Intensive management and follow-up for 8 weeks were required before the patient was deemed fit for discharge.