Influence of body mass index on the choice of therapy for depression and follow‐up care

Objective: Overweight and obese patients commonly suffer from depression and choice of depression therapy may alter weight. We conducted a cohort study to investigate whether obesity is associated with treatment choices for depression; and whether obesity is associated with appropriate duration of depression treatment and receipt of follow‐up visits. Design and Methods: Adults with a diagnosis of depression between January 1, 2006 and March 31, 2010 who had 1+ new episodes of an antidepressant medication and/or psychotherapy were eligible. Medication use, encounters, diagnoses, height, and weight were collected from health plan databases. We modeled receipt of the different therapies (medication and psychotherapy) by BMI and BMI trajectory during the 9‐months prior to initiation of therapy using logistic regression models that accommodated correlation within provider and adjusted for covariates. We modeled BMI via a restricted cubic spline. Fluoxetine was the reference treatment option in the medication models. Results: Lower BMI was associated with greater use of mirtazapine, and a declining BMI prior to treatment was associated with greater odds of initiating mirtazapine and paroxetine. Higher BMI was associated with greater odds of initiating bupropion even after adjustment for smoking status. Obese patients were less likely to receive psychotherapy and less likely to receive appropriate duration (180‐days) of depression treatment compared to normal weight subjects. Conclusions: Our study provides evidence that BMI is considered when choosing therapy but associations were weak. Our results should prompt discussion about recommending and choosing depression treatment plans that optimize depression care and weight management concurrently. Differences in care and follow‐up by BMI warrant additional research.     

Non-benzimidazole containing inhibitors of respiratory syncytial virus

Several non-benzimidazole containing inhibitors of respiratory syncytial virus are described. Core template modification, analysis of antiviral activity, physicochemistry and optimisation of properties led to the thiazole-imidazole 13, that showed a good potency and pharmacokinetic profile in the rat.     

The influence of value choices in life cycle impact assessment of stressors causing human health damage

Purpose

This study analyzes the influence of value choices in impact assessment models for human health, such as the choice of time horizon, on life cycle assessment outcomes.

Methods

For 756 products, the human health damage score is calculated using three sets of characterization factors (CFs). The CFs represent seven human health impact assessment categories: water scarcity, tropospheric ozone formation, particulate matter formation, human toxicity, ionizing radiation, stratospheric ozone depletion, and climate change. Each set of CFs embeds a combination of value choices following the Cultural Theory, and reflects the individualist, hierarchist, or egalitarian perspective.

Results

We found that the average difference in human health damage score goes from 1 order of magnitude between the individualist and hierarchist perspectives to 2.5 orders of magnitude between the individualist and egalitarian perspectives. The difference in damage score of individual materials among perspectives depends on the combination of emissions driving the impact of both perspectives and can rise up to 5 orders of magnitude.

Conclusions

The value choices mainly responsible for the differences in results among perspectives are the choice of time horizon and inclusion of highly uncertain effects. A product comparison can be affected when the human health damage score of two products differ less than a factor of 5, or the comparing products largely differ in their emitted substances. Overall, our study implies that value choices in impact assessment modeling can modify the outcomes of a life cycle assessment (LCA) and thus the practical implication of decisions based on the results of an LCA.     

Identifying best existing practice for characterization modeling in life cycle impact assessment

Purpose

Life cycle impact assessment (LCIA) is a field of active development. The last decade has seen prolific publication of new impact assessment methods covering many different impact categories and providing characterization factors that often deviate from each other for the same substance and impact. The LCA standard ISO 14044 is rather general and unspecific in its requirements and offers little help to the LCA practitioner who needs to make a choice. With the aim to identify the best among existing characterization models and provide recommendations to the LCA practitioner, a study was performed for the Joint Research Centre of the European Commission (JRC).

Methods

Existing LCIA methods were collected and their individual characterization models identified at both midpoint and endpoint levels and supplemented with other environmental models of potential use for LCIA. No new developments of characterization models or factors were done in the project. From a total of 156 models, 91 were short listed as possible candidates for a recommendation within their impact category. Criteria were developed for analyzing the models within each impact category. The criteria addressed both scientific qualities and stakeholder acceptance. The criteria were reviewed by external experts and stakeholders and applied in a comprehensive analysis of the short-listed characterization models (the total number of criteria varied between 35 and 50 per impact category). For each impact category, the analysis concluded with identification of the best among the existing characterization models. If the identified model was of sufficient quality, it was recommended by the JRC. Analysis and recommendation process involved hearing of both scientific experts and stakeholders.

Results and recommendations

Recommendations were developed for 14 impact categories at midpoint level, and among these recommendations, three were classified as “satisfactory” while ten were “in need of some improvements” and one was so weak that it has “to be applied with caution.” For some of the impact categories, the classification of the recommended model varied with the type of substance. At endpoint level, recommendations were only found relevant for three impact categories. For the rest, the quality of the existing methods was too weak, and the methods that came out best in the analysis were classified as “interim,” i.e., not recommended by the JRC but suitable to provide an initial basis for further development.

Discussion, conclusions, and outlook

The level of characterization modeling at midpoint level has improved considerably over the last decade and now also considers important aspects like geographical differentiation and combination of midpoint and endpoint characterization, although the latter is in clear need for further development. With the realization of the potential importance of geographical differentiation comes the need for characterization models that are able to produce characterization factors that are representative for different continents and still support aggregation of impact scores over the whole life cycle. For the impact categories human toxicity and ecotoxicity, we are now able to recommend a model, but the number of chemical substances in common use is so high that there is a need to address the substance data shortage and calculate characterization factors for many new substances. Another unresolved issue is the need for quantitative information about the uncertainties that accompany the characterization factors. This is still only adequately addressed for one or two impact categories at midpoint, and this should be a focus point in future research. The dynamic character of LCIA research means that what is best practice will change quickly in time. The characterization methods presented in this paper represent what was best practice in 2008–2009.     

Primary antibiotic resistance and associated mechanisms in Helicobacter pylori isolates from Senegalese patients

Background

Antibiotic combination therapy for Helicobacter pylori eradication must be adapted to local resistance patterns, but the epidemiology of H. pylori resistance to antibiotics is poorly documented in Africa. The aim was to determine the antibiotic resistance rates, as well as the associated molecular mechanisms, of strains isolated in Dakar, Senegal.

Methods

One hundred and eight H. pylori strains were isolated between 2007 and 2009 from 108 patients presenting with upper abdominal pain to the Gastroenterology Department of Le Dantec Hospital. Antimicrobial susceptibility testing was performed for amoxicillin, clarithromycin, metronidazole, levofloxacin and tetracyclin using the E-test method. Mutations in the 23S rRNA gene of clarithromycin-resistant strains and in gyrA and gyrB of levofloxacin-resistant strains were investigated.

Results

Isolates were characterized by no resistance to amoxicillin (0%), tetracycline (0%), and very low rate of resistance to clarithromycin (1%), but a high rate of resistance to metronidazole (85%). The clarithromycin-resistant strain displayed the A2143G mutation. A worrying rate of levofloxacin resistance was detected (15%). N87I and D91N were the most common mutations in the quinolone-resistance-determining region of gyrA.

Conclusions

The first-line empirical regimen for H. pylori eradication in Senegal should include clarithromycin. Increasing rates of fluoroquinolone resistance detected should discourage the use of levofloxacin-containing regimens without prior antimicrobial susceptibility testing.     

Chikungunya virus envelope-specific human monoclonal antibodies with broad neutralization potency

Chikungunya virus (CHIKV) is an alphavirus responsible for numerous epidemics in Africa and Asia. Infection by CHIKV is often characterized by long-lasting, incapacitating arthritis, and some fatal cases have been described among elderly and newborns. Currently, there is no available vaccine or specific treatment against CHIKV. Blood B cells from a donor with history of CHIKV infection were activated, immortalized, amplified, and cloned. Two human mAbs against CHIKV, 5F10 and 8B10, were identified, sequenced, and expressed in recombinant form for characterization. In a plaque reduction neutralization test, 5F10 and 8B10 show mean IC(50) of 72 and 46 ng/ml, respectively. Moreover, both mAbs lead to a strong decrease in extracellular spreading of infectious viral particles from infected to uninfected cells. Importantly, the mAbs neutralize different CHIKV isolates from Singapore, Africa, and Indonesia, as well as O'nyong-nyong virus, but do not recognize other alphaviruses tested. Both mAbs are specific for the CHIKV envelope: 5F10 binds to the E2 glycoprotein ectodomain and 8B10 to E1 and/or E2. In conclusion, these two unique human mAbs strongly, broadly, and specifically neutralize CHIKV infection in vitro and might become possible therapeutic tools against CHIKV infection, especially in individuals at risk for severe disease. Importantly, these mAbs will also represent precious tools for future studies on host-pathogen interactions and the rational design of vaccines against CHIKV.     

Examination of Taxonomic Uncertainties Surrounding Brucella abortus bv. 7 by Phenotypic and Molecular Approaches

Brucella taxonomy is perpetually being reshuffled, at both the species and intraspecies levels. Biovar 7 of Brucella abortus was suspended from the Approved Lists of Bacterial Names Brucella classification in 1988, because of unpublished evidence that the reference strain 63/75 was a mixture of B. abortus biovars 3 and 5. To formally clarify the situation, all isolates previously identified as B. abortus bv. 7 in the AHVLA and ANSES strain collections were characterized by classical microbiological and multiple molecular approaches. Among the 14 investigated strains, including strain 63/75, only four strains, isolated in Kenya, Turkey, and Mongolia, were pure and showed a phenotypic profile in agreement with the former biovar 7, particularly agglutination with both anti-A/anti-M monospecific sera. These results were strengthened by molecular strategies. Indeed, genus- and species-specific methods allowed confirmation that the four pure strains belonged to the B. abortus species. The combination of most approaches excluded their affiliation with the recognized biovars (biovars 1 to 6 and 9), while some suggested that they were close to biovar 3.These assays were complemented by phylogenetic and/or epidemiological methods, such as multilocus sequence analysis (MLSA) and variable-number tandem repeat (VNTR) analysis. The results of this polyphasic investigation allow us to propose the reintroduction of biovar 7 into the Brucella classification, with at least three representative strains. Interestingly, the Kenyan strain, sharing the same biovar 7 phenotype, was genetically divergent from other three isolates. These discrepancies illustrate the complexity of Brucella taxonomy. This study suggests that worldwide collections could include strains misidentified as B. abortus bv. 7, and it highlights the need to verify their real taxonomic position.     

ACTIN-RELATED PROTEIN6 Regulates Female Meiosis by Modulating Meiotic Gene Expression in Arabidopsis

In flowering plants, meiocytes develop from subepidermal cells in anthers and ovules. The mechanisms that integrate gene-regulatory processes with meiotic programs during reproductive development remain poorly characterized. Here, we show that Arabidopsis thaliana plants deficient in ACTIN-RELATED PROTEIN6 (ARP6), a subunit of the SWR1 ATP-dependent chromatin-remodeling complex, exhibit defects in prophase I of female meiosis. We found that this meiotic defect is likely due to dysregulated expression of meiotic genes, particularly those involved in meiotic recombination, including DMC1 (DISRUPTED MEIOTIC cDNA1). Analysis of DMC1 expression in arp6 mutant plants indicated that ARP6 inhibits expression of DMC1 in the megasporocyte and surrounding nonsporogeneous ovule cells before meiosis. After cells enter meiosis, however, ARP6 activates DMC1 expression specifically in the megasporocyte even as it continues to inhibit DMC1 expression in the nonsporogenous ovule cells. We further show that deposition of the histone variant H2A.Z, mediated by the SWR1 chromatin-remodeling complex at the DMC1 gene body, requires ARP6. Therefore, ARP6 regulates female meiosis by determining the spatial and temporal patterns of gene expression required for proper meiosis during ovule development.     

Semapimod Sensitizes Glioblastoma Tumors to Ionizing Radiation by Targeting Microglia

Glioblastoma is the most malignant and lethal form of astrocytoma, with patients having a median survival time of approximately 15 months with current therapeutic modalities. It is therefore important to identify novel therapeutics. There is mounting evidence that microglia (specialized brain-resident macrophages) play a significant role in the development and progression of glioblastoma tumors. In this paper we show that microglia, in addition to stimulating glioblastoma cell invasion, also promote glioblastoma cell proliferation and resistance to ionizing radiation in vitro. We found that semapimod, a drug that selectively interferes with the function of macrophages and microglia, potently inhibits microglia-stimulated GL261 invasion, without affecting serum-stimulated glioblastoma cell invasion. Semapimod also inhibits microglia-stimulated resistance of glioblastoma cells to radiation, but has no significant effect on microglia-stimulated glioblastoma cell proliferation. We also found that intracranially administered semapimod strongly increases the survival of GL261 tumor-bearing animals in combination with radiation, but has no significant benefit in the absence of radiation. In conclusion, our observations indicate that semapimod sensitizes glioblastoma tumors to ionizing radiation by targeting microglia and/or infiltrating macrophages.