Cecum Lymph Node Dendritic Cells Harbor Slow-Growing Bacteria Phenotypically Tolerant to Antibiotic Treatment

In vivo, antibiotics are often much less efficient than ex vivo and relapses can occur. The reasons for poor in vivo activity are still not completely understood. We have studied the fluoroquinolone antibiotic ciprofloxacin in an animal model for complicated Salmonellosis. High-dose ciprofloxacin treatment efficiently reduced pathogen loads in feces and most organs. However, the cecum draining lymph node (cLN), the gut tissue, and the spleen retained surviving bacteria. In cLN, approximately 10%–20% of the bacteria remained viable. These phenotypically tolerant bacteria lodged mostly within CD103⁺CX₃CR1⁻CD11c⁺ dendritic cells, remained genetically susceptible to ciprofloxacin, were sufficient to reinitiate infection after the end of the therapy, and displayed an extremely slow growth rate, as shown by mathematical analysis of infections with mixed inocula and segregative plasmid experiments. The slow growth was sufficient to explain recalcitrance to antibiotics treatment. Therefore, slow-growing antibiotic-tolerant bacteria lodged within dendritic cells can explain poor in vivo antibiotic activity and relapse. Administration of LPS or CpG, known elicitors of innate immune defense, reduced the loads of tolerant bacteria. Thus, manipulating innate immunity may augment the in vivo activity of antibiotics.     

Prenatal exposure to bereavement and type-2 diabetes: a danish longitudinal population based study

Background

The etiology of type-2 diabetes is only partly known, and a possible role of prenatal stress in programming offspring for insulin resistance has been suggested by animal models. Previously, we found an association between prenatal stress and type-1 diabetes. Here we examine the association between prenatal exposure to maternal bereavement during preconception and pregnancy and development of type-2 diabetes in the off-spring.

Methods

We utilized data from the Danish Civil Registration System to identify singleton births in Denmark born January 1^st 1979 through December 31^st 2008 (N = 1,878,246), and linked them to their parents, grandparents, and siblings. We categorized children as exposed to bereavement during prenatal life if their mothers lost an elder child, husband or parent during the period from one year before conception to the child’s birth. We identified 45,302 children exposed to maternal bereavement; the remaining children were included in the unexposed cohort. The outcome of interest was diagnosis of type-2 diabetes. We estimated incidence rate ratios (IRRs) from birth using log-linear poisson regression models and used person-years as the offset variable. All models were adjusted for maternal residence, income, education, marital status, sibling order, calendar year, sex, and parents’ history of diabetes at the time of pregnancy.

Results

We found children exposed to bereavement during their prenatal life were more likely to have a type-2 diabetes diagnosis later in life (aIRR: 1.31, 1.01–1.69). These findings were most pronounced when bereavement was caused by death of an elder child (aIRR: 1.51, 0.94–2.44). Results also indicated the second trimester of pregnancy to be the most sensitive period of bereavement exposure (aIRR:2.08, 1.15–3.76).

Conclusions

Our data suggests that fetal exposure to maternal bereavement during preconception and the prenatal period may increase the risk for developing type-2 diabetes in childhood and young adulthood.     

International Multispecialty Consensus on How to Evaluate Ultrasound Competence: A Delphi Consensus Survey

Objectives

To achieve international consensus across multiple specialties on a generic ultrasound rating scale using a Delphi technique.

Methods

Ultrasound experts from Obstetrics-Gynaecology, Surgery, Urology, Radiology, Rheumatology, Emergency Medicine, and Gastro-Enterology representing North America, Australia, and Europe were identified. A multi-round survey was conducted to obtain consensus between these experts. Of 60 invited experts, 44 experts agreed to participate in the first Delphi round, 41 remained in the second round, and 37 completed the third Delphi round. Seven key elements of the ultrasound examination were identified from existing literature and recommendations from international ultrasound societies. All experts rated the importance of these seven elements on a five-point Likert scale in the first round and suggested potential new elements for the assessment of ultrasound skills. In the second round, the experts re-rated all elements and a third round was conducted to allow final comments. Agreement on which elements to include in the final rating scale was pre-defined as more than 80% of the experts rating an element four or five, on importance to the ultrasound examination.

Results

Two additional elements were suggested by more than 10% of the experts in the first Delphi round. Consensus was obtained to include these two new elements along with five of the original elements in the final assessment instrument: 1) Indication for the examination 2) Applied knowledge of ultrasound equipment 3) Image optimization 4) Systematic examination 5) Interpretation of images 6) Documentation of examination and 7) Medical decision making.

Conclusion

International multispecialty consensus was achieved on the content of a generic ultrasound rating scale. This is the first step to ensure valid assessment of clinicians in different medical specialties using ultrasound.     

Chemical modifications in therapeutic protein aggregates generated under different stress conditions

In this study, we characterized the chemical modifications in the monoclonal antibody (IgG(2)) aggregates generated under various conditions, including mechanical, chemical, and thermal stress treatment, to provide insight into the mechanism of protein aggregation and the types of aggregate produced by the different stresses. In a separate study, additional biophysical characterization was performed to arrange these aggregates into a classification system (Joubert, M. K., Luo, Q., Nashed-Samuel, Y., Wypych, J., and Narhi, L. O. (2011) J. Biol. Chem. 286, 25118-25133). Here, we report that different aggregates possessed different types and levels of chemical modification. For chemically treated samples, metal-catalyzed oxidation using copper showed site-specific oxidation of Met(246), His(304), and His(427) in the Fc portion of the antibody, which might be attributed to a putative copper-binding site. For the hydrogen peroxide-treated sample, in contrast, four solvent-exposed Met residues in the Fc portion were completely oxidized. Met and/or Trp oxidation was observed in the mechanically stressed samples, which is in agreement with the proposed model of protein interaction at the air-liquid interface. Heat treatment resulted in significant deamidation but almost no oxidation, which is consistent with thermally induced aggregates being generated by a different pathway, primarily by perturbing conformational stability. These results demonstrate that chemical modifications are present in protein aggregates; furthermore, the type, locations, and severity of the modifications depend on the specific conditions that generated the aggregates.     

Principal component and factor analytic models in international sire evaluation

Background

Interbull is a non-profit organization that provides internationally comparable breeding values for globalized dairy cattle breeding programmes. Due to different trait definitions and models for genetic evaluation between countries, each biological trait is treated as a different trait in each of the participating countries. This yields a genetic covariance matrix of dimension equal to the number of countries which typically involves high genetic correlations between countries. This gives rise to several problems such as over-parameterized models and increased sampling variances, if genetic (co)variance matrices are considered to be unstructured.

Methods

Principal component (PC) and factor analytic (FA) models allow highly parsimonious representations of the (co)variance matrix compared to the standard multi-trait model and have, therefore, attracted considerable interest for their potential to ease the burden of the estimation process for multiple-trait across country evaluation (MACE). This study evaluated the utility of PC and FA models to estimate variance components and to predict breeding values for MACE for protein yield. This was tested using a dataset comprising Holstein bull evaluations obtained in 2007 from 25 countries.

Results

In total, 19 principal components or nine factors were needed to explain the genetic variation in the test dataset. Estimates of the genetic parameters under the optimal fit were almost identical for the two approaches. Furthermore, the results were in a good agreement with those obtained from the full rank model and with those provided by Interbull. The estimation time was shortest for models fitting the optimal number of parameters and prolonged when under- or over-parameterized models were applied. Correlations between estimated breeding values (EBV) from the PC19 and PC25 were unity. With few exceptions, correlations between EBV obtained using FA and PC approaches under the optimal fit were ≥ 0.99. For both approaches, EBV correlations decreased when the optimal model and models fitting too few parameters were compared.

Conclusions

Genetic parameters from the PC and FA approaches were very similar when the optimal number of principal components or factors was fitted. Over-fitting increased estimation time and standard errors of the estimates but did not affect the estimates of genetic correlations or the predictions of breeding values, whereas fitting too few parameters affected bull rankings in different countries.     

The Role of Marital Status in the Association between Benzodiazepines,Psychotropics and Injurious Road Traffic Crashes: A Register-Based Nationwide Study of Senior Drivers in Sweden

Background

Among senior drivers, benzodiazepines (BZDs) have a documented effect on the risk of road traffic crashes (RTCs). It remains unclear however if BZDs play the same role when considering marital status. Therefore, we aimed to investigate the role of marital status in the association between BZD use and injurious RTCs among senior drivers.

Methods

Matched case-control study based on five national Swedish registers (n = 154 225). Cases comprised the first non-alcohol-related injurious RTC sustained by drivers aged 50–80 years from July 2005 to December 2009 and controls included registered residents with a valid license who did not crash during that period. Four controls were matched to each case by sex, age and place of residence. Conditional logistic regression analysis for injurious RTC was performed with adjustment for occupation and number of medications. The main exposure was dispensation of BZDs, alone or in combination with other psychotropic medications, 1–30 days prior to the crash date stratified by marital status.

Results

BZD use, alone or in combination with other psychotropic medications, increased the risk of being involved in an RTC (BZD only: adjusted OR: 1.26, 95% CI: 1.17–1.36; BZDs and other psychotropics: adjusted OR: 1.25, 95% CI: 1.12–1.41). Compared to married drivers, those divorced (1.48, 1.43–1.53) and widowed (1.54; 1.45–1.63) had higher adjusted ORs. Marital status modified the association between BZDs and RTCs, particularly among younger male drivers.

Conclusions

Both BZDs and marital status independently affect the risk for senior drivers to be involved in an RTC. However, marital status plays a role in the association between BZD use and RTCs and this may have implications for targeting risk populations for RTCs among senior drivers.     

Epidemiological Concepts Regarding Disease Monitoring and Surveillance

Definitions of epidemiological concepts regarding disease monitoring and surveillance can be found in textbooks on veterinary epidemiology. This paper gives a review of how the concepts: monitoring, surveillance, and disease control strategies are defined. Monitoring and surveillance systems (MO&SS) involve measurements of disease occurrence, and the design of the monitoring determines which types of disease occurrence measures can be applied. However, the knowledge of the performance of diagnostic tests (sensitivity and specificity) is essential to estimate the true occurrence of the disease. The terms, disease control programme (DCP) or disease eradication programme (DEP), are defined, and the steps of DCP/DEP are described to illustrate that they are a process rather than a static MO&SS.

     

Type,Number or Both? A Population-Based Matched Case-Control Study on the Risk of Fall Injuries among Older People and Number of Medications beyond Fall-Inducing Drugs

Objectives

Drug use is a modifiable risk factor for fall-related injuries in older people. Whereas the injurious effect of polypharmacy is established, that of low numbers of medications has not been fully ascertained. Neither do we know whether it is the number per se or the type of medications that actually matters. We assessed this question for fall injuries leading to hospitalization.

Design

National register-based, population-based, matched case-control study.

Setting

Community dwellers aged 65+ years living in Sweden between March 2006 and December 2009.

Methods

Cases (n = 64,399) were identified in the national inpatient register and four controls per case were randomly matched by gender, date of birth and residential area. The association between number of prescribed medications, assessed through linkage with the Swedish prescribed drug register, and the risk of injurious falls was estimated with odds ratios with 95% confidence intervals using conditional logistic regression, adjusted for demographic and health status.

Results

The number of medications was associated with an increased risk of fall injury in a dose-response fashion, even after adjustment for marital status, comorbidity and number of fall-risk-inducing drugs (FRIDs). Using ten or more medications was associated with an almost two-fold higher risk (adjusted OR: 1.76, 95% CI: 1.66 to 1.88). When stratified by use (or not) of at least one FRID, the association weakened slightly among both non-users (adjusted OR: 1.50, 95% CI: 1.34 to 1.67) and users (adjusted OR: 1.67, 95% CI: 1.58 to 1.77).

Conclusion

In older people, not only large but also small numbers of medications may affect the risk for them to sustain injurious falls. Although the mechanisms lying behind this are complex, the finding challenges the prevention strategies targeting either specific types of medications (FRIDs) or high numbers of them.     

Severity of Depression,Anxious Distress and the Risk of Cardiovascular Disease in a Swedish Population-Based Cohort

Background

Depression is known to be associated with cardiovascular diseases (CVD). This population-based cohort study aimed to determine the association between depression of varying severity and risk for CVD and to study the effect of concomitant anxious distress on this association.

Methods

We utilized data from a longitudinal cohort study of mental health, work and relations among adults (20–64 years), with a total of 10,443 individuals. Depression and anxious distress were assessed using psychiatric rating scales and defined according to DSM-5. Outcomes were register-based and self-reported cardiovascular diseases.

Findings

Overall increased odds ratios of 1.5 to 2.6 were seen for the different severity levels of depression, with the highest adjusted OR for moderate depression (OR 2.1 (95% CI 1.3, 3.5). Similar odds ratios were seen for sub-groups of CVD: ischemic/hypertensive heart disease and stroke, 2.4 (95% CI 1.4, 3.9) and OR 2.1 (95%CI 1.2, 3.8) respectively. Depression with anxious distress as a specifier of severity showed OR of 2.1 (95% CI 1.5, 2.9) for CVD.

Conclusion

This study found that severity level of depression seems to be of significance for increased risk of CVD among depressed persons, although not in a dose-response manner which might be obscured due to treatment of depression. Further, we found a higher risk of CVD among depressed individuals with symptoms of anxious distress.