Holy Smoke in Medieval Funerary Rites: Chemical Fingerprints of Frankincense in Southern Belgian Incense Burners

Frankincense, the oleogum resin from Boswellia sp., has been an early luxury good in both Western and Eastern societies and is particularly used in Christian funerary and liturgical rites. The scant grave goods in late medieval burials comprise laterally perforated pottery vessels which are usually filled with charcoal. They occur in most regions of western Europe and are interpreted as incense burners but have never been investigated with advanced analytical techniques. We herein present chemical and anthracological results on perforated funerary pots from 4 Wallonian sites dating to the 12–14^th century AD. Chromatographic and mass spectrometric analysis of lipid extracts of the ancient residues and comparison with extracts from four Boswellia species clearly evidence the presence of degraded frankincense in the former, based on characteristic triterpenoids, viz. boswellic and tirucallic acids, and their myriad dehydrated and oxygenated derivatives. Cembrane-type diterpenoids indicate B. sacra (southern Arabia) and B. serrata (India) as possible botanical origins. Furthermore, traces of juniper and possibly pine tar demonstrate that small amounts of locally available fragrances were mixed with frankincense, most likely to reduce its cost. Additionally, markers of ruminant fats in one sample from a domestic context indicate that this vessel was used for food preparation. Anthracological analysis demonstrates that the charcoal was used as fuel only and that no fragrant wood species were burned. The chars derived from local woody plants and were most likely recovered from domestic fires. Furthermore, vessel recycling is indicated by both contextual and biomarker evidence. The results shed a new light on funerary practices in the Middle Ages and at the same time reveal useful insights into the chemistry of burned frankincense. The discovery of novel biomarkers, namely Δ²-boswellic acids and a series of polyunsaturated and aromatic hydrocarbons, demonstrates the high potential for organic chemical analyses of incense residues.     

ELLIPSE Study: A Phase 1 study evaluating the tolerance of bevacizumab nasal spray in the treatment of epistaxis in hereditary hemorrhagic telangiectasia

Background: Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited genetic vascular disorder in which epistaxis is the most frequent manifestation, responsible for high morbidity. Management of this symptom has no standard, and local treatments are often aggressive. Their efficacy is variable and has not been proven. Anti-angiogenic drugs, such as bevacizumab, are a new treatment strategy. Its systemic administration in patients with HHT improves liver damage-related symptoms and epistaxis. To limit the systemic adverse effects of bevacizumab and to ease administration, a local administration seems suitable. Primary objective: To evaluate the tolerance of increasing doses of bevacizumab administered as a nasal spray in patients with HHT-related epistaxis. Secondary objectives were to study the bioavailability and efficacy of bevacizumab against epistaxis when given as a nasal spray. Methodology: Phase 1, randomized, double-blind, placebo-controlled, monocentric study performed sequentially (dose escalation) on 5 groups of 8 patients. Each group was made up of 6 verum and 2 placebos. Five increasing doses of bevacizumab nasal spray (25 mg/mL) were evaluated: 12.5, 25, 50, 75 and 100 mg. Results: A total of 40 patients were included between October 2011 and October 2012. Bevacizumab nasal spray was well tolerated in all patients and the drug was not detected in their serum. No dose limiting toxicity was observed. No efficacy was observed at any dose in this study. Conclusion: Based on these results, bevacizumab nasal spray is a safe treatment of epistaxis in HHT. However, a randomized Phase 2 study is needed to determine its efficacy. Trial Registration: ClinicalTrials.gov Identifier #{"type":"clinical-trial","attrs":{"text":"NCT01507480","term_id":"NCT01507480"}}NCT01507480     

Obesity and Physical and Emotional Well‐Being: Associations between Body Mass Index,Chronic Illness,and the Physical and Mental Components of the SF‐36 Questionnaire

Objective: To clarify the associations between obesity and health‐related quality of life by exploring the associations between physical and emotional well‐being in relation to obesity and the presence of other chronic illness. Research Methods and Procedures: The study data were collected as part of a postal‐survey within the old Oxford Regional Health Authority of England in 1997. Completed questionnaires were returned by 8889 of 13,800 randomly selected adults aged 18 to 64 years. The main outcome measures were body mass index in five categories (underweight, normal weight, overweight, moderately obese, morbidly obese); chronic illness status (any vs. none and number of such illnesses 0, 1 to 2, 3+); and mean SF‐36 questionnaire score in two summary component measures reflecting physical and emotional well‐being. Results: Of the subjects, 31% were overweight and an additional 11% were obese. Body mass index was significantly associated with health status, but the pattern varied according to whether the measure reflected physical or emotional well‐being. Physical, but not emotional, well‐being deteriorated markedly with increasing degree of overweight and was limited in subjects who were obese but had no other chronic condition; subjects with chronic illnesses other than obesity were compromised in both dimensions. In terms of the number of chronic illnesses reported, the additional presence of obesity was associated with a significant deterioration in physical but not emotional well‐being. Discussion: Overweight and obesity are associated with poor levels of subjective health status, particularly in terms of physical well‐being. The limitations in emotional well‐being that are reported here and in other studies may be a result of confounding by the presence of accompanying chronic illness.     

Synergistic Antitumor Effect between Gefitinib and Fractionated Irradiation in Anaplastic Oligodendrogliomas Cannot Be Predicted by the Egfr Signaling Activity

In high-grade gliomas, the identification of patients that could benefit from EGFR inhibitors remains a challenge, hindering the use of these agents. Using xenografts models, we evaluated the antitumor effect of the combined treatment “gefitinib + radiotherapy” and aimed to identify the profile of responsive tumors. Expression of phosphorylated proteins involved in the EGFR-dependent signaling pathways was analyzed in 10 glioma models. We focused on three models of anaplastic oligodendrogliomas (TCG2, TCG3 and TCG4) harboring high levels of phospho-EGFR, phospho-AKT and phospho-MEK1. They were treated with gefitinib (GEF 75 mg/kg/day x 5 days/week, for 2 weeks) and/or fractionated radiotherapy (RT: 5x2Gy/week for 2 weeks). Our results showed that GEF and/or RT induced significant tumor growth delays. However, only the TCG3 xenografts were highly responsive to the combination GEF+RT, with ∼50% of tumor cure. Phosphoproteins analysis five days after treatment onset demonstrated in TCG3 xenografts, but not in TCG2 model, that the EGFR-dependent pathways were inhibited after GEF treatment. Moreover, TCG3-bearing mice receiving GEF monotherapy exhibited a transient beneficial therapeutic response, rapidly followed by tumor regrowth, along with a major vascular remodeling. Taken together, our data evoked an “EGFR-addictive” behavior for TCG3 tumors. This study confirms that combination of gefitinib with fractionated irradiation could be a potent therapeutic strategy for anaplastic oligodendrogliomas harboring EGFR abnormalities but this treatment seems mainly beneficial for “EGFR-addictive” tumors. Unfortunately, neither the usual molecular markers (EGFR amplification, PTEN loss) nor the basal overexpression of phosphoproteins were useful to distinguish this responsive tumor. Evaluating the impact of TKIs on the EGFR-dependent pathways during the treatment might be more relevant, and requires further validation.     

Adaptive divergence in experimental populations of Pseudomonas fluorescens. II. Role of the GGDEF regulator WspR in evolution and development of the wrinkly spreader phenotype

Wrinkly spreader (WS) genotypes evolve repeatedly in model Pseudomonas populations undergoing adaptive radiation. Previous work identified genes contributing to the evolutionary success of WS. Here we scrutinize the GGDEF response regulator protein WspR and show that it is both necessary and sufficient for WS. Activation of WspR occurs by phosphorylation and different levels of activation generate phenotypic differences among WS genotypes. Five alleles of wspR, each encoding a protein with a single amino acid substitution, were generated by mutagenesis. Two alleles are constitutively active and cause the ancestral genotype to develop a WS phenotype; the phenotypic effects are allele specific and independent of phosphorylation. Three alleles contain changes in the GGDEF domain and when overexpressed in WS cause reversion to the ancestral phenotype. Ability to mimic this effect by overexpression of a liberated N-terminal domain shows that in WS, regulatory components upstream of WspR are overactive. To connect changes at the nucleotide level with fitness, the effects of variant alleles were examined in both structured and unstructured environments: alleles had adaptive and deleterious effects with trade-offs evident across environments. Despite the proclivity of mutations within wspR to generate WS, sequence analysis of wspR from 53 independently obtained WS showed no evidence of sequence change in this gene.     

Electron transfer to the active site of the bacterial nitric oxide reductase is controlled by ligand binding to heme b₃

The active site of the bacterial nitric oxide reductase from Paracoccus denitrificans contains a dinuclear centre comprising heme b? and non heme iron (Fe(B)). These metal centres are shown to be at isopotential with midpoint reduction potentials of E(m) ≈ +80 mV. The midpoint reduction potentials of the other two metal centres in the enzyme, heme c and heme b, are greater than the dinuclear centre suggesting that they act as an electron receiving/storage module. Reduction of the low-spin heme b causes structural changes at the dinuclear centre which allow access to substrate molecules. In the presence of the substrate analogue, CO, the midpoint reduction potential of heme b? is raised to a region similar to that of heme c and heme b. This leads us to suggest that reduction of the electron transfer hemes leads to an opening of the active site which allows substrate to bind and in turn raises the reduction potential of the active site such that electrons are only delivered to the active site following substrate binding.     

The Patient- And Nutrition-Derived Outcome Risk Assessment Score (PANDORA): Development of a Simple Predictive Risk Score for 30-Day In-Hospital Mortality Based on Demographics,Clinical Observation,and Nutrition

ObjectiveTo develop a simple scoring system to predict 30 day in-hospital mortality of in-patients excluding those from intensive care units based on easily obtainable demographic, disease and nutrition related patient data.MethodsScore development with general estimation equation methodology and model selection by P-value thresholding based on a cross-sectional sample of 52 risk indicators with 123 item classes collected with questionnaires and stored in an multilingual online database.SettingWorldwide prospective cross-sectional cohort with 30 day in-hospital mortality from the nutritionDay 2006-2009 and an external validation sample from 2012.ResultsWe included 43894 patients from 2480 units in 32 countries. 1631(3.72%) patients died within 30 days in hospital. The Patient- And Nutrition-Derived Outcome Risk Assessment (PANDORA) score predicts 30-day hospital mortality based on 7 indicators with 31 item classes on a scale from 0 to 75 points. The indicators are age (0 to 17 points), nutrient intake on nutritionDay (0 to 12 points), mobility (0 to 11 points), fluid status (0 to 10 points), BMI (0 to 9 points), cancer (9 points) and main patient group (0 to 7 points). An appropriate model fit has been achieved. The area under the receiver operating characteristic curve for mortality prediction was 0.82 in the development sample and 0.79 in the external validation sample.ConclusionsThe PANDORA score is a simple, robust scoring system for a general population of hospitalised patients to be used for risk stratification and benchmarking.     

The impact of climate suitability,urbanisation, and connectivity on the expansion of dengue in 21st century Brazil

Dengue is hyperendemic in Brazil, with outbreaks affecting all regions. Previous studies identified geographical barriers to dengue transmission in Brazil, beyond which certain areas, such as South Brazil and the Amazon rainforest, were relatively protected from outbreaks. Recent data shows these barriers are being eroded. In this study, we explore the drivers of this expansion and identify the current limits to the dengue transmission zone. We used a spatio-temporal additive model to explore the associations between dengue outbreaks and temperature suitability, urbanisation, and connectivity to the Brazilian urban network. The model was applied to a binary outbreak indicator, assuming the official threshold value of 300 cases per 100,000 residents, for Brazil’s municipalities between 2001 and 2020. We found a nonlinear relationship between higher levels of connectivity to the Brazilian urban network and the odds of an outbreak, with lower odds in metropoles compared to regional capitals. The number of months per year with suitable temperature conditions for Aedes mosquitoes was positively associated with the dengue outbreak occurrence. Temperature suitability explained most interannual and spatial variation in South Brazil, confirming this geographical barrier is influenced by lower seasonal temperatures. Municipalities that had experienced an outbreak previously had double the odds of subsequent outbreaks. We identified geographical barriers to dengue transmission in South Brazil, western Amazon, and along the northern coast of Brazil. Although a southern barrier still exists, it has shifted south, and the Amazon no longer has a clear boundary. Few areas of Brazil remain protected from dengue outbreaks. Communities living on the edge of previous barriers are particularly susceptible to future outbreaks as they lack immunity. Control strategies should target regions at risk of future outbreaks as well as those currently within the dengue transmission zone.     

Linkage and segregation analysis of black and brindle coat color in domestic dogs

Mutations of pigment type switching have provided basic insight into melanocortin physiology and evolutionary adaptation. In all vertebrates that have been studied to date, two key genes, Agouti and Melanocortin 1 receptor (Mc1r), encode a ligand-receptor system that controls the switch between synthesis of red-yellow pheomelanin vs. black-brown eumelanin. However, in domestic dogs, historical studies based on pedigree and segregation analysis have suggested that the pigment type-switching system is more complicated and fundamentally different from other mammals. Using a genomewide linkage scan on a Labrador x greyhound cross segregating for black, yellow, and brindle coat colors, we demonstrate that pigment type switching is controlled by an additional gene, the K locus. Our results reveal three alleles with a dominance order of black (K(B)) > brindle (k(br)) > yellow (k(y)), whose genetic map position on dog chromosome 16 is distinct from the predicted location of other pigmentation genes. Interaction studies reveal that Mc1r is epistatic to variation at Agouti or K and that the epistatic relationship between Agouti and K depends on the alleles being tested. These findings suggest a molecular model for a new component of the melanocortin signaling pathway and reveal how coat-color patterns and pigmentary diversity have been shaped by recent selection.