Maximum Likelihood Estimation of Long‐Term HIV Dynamic Models and Antiviral Response

Summary HIV dynamics studies, based on differential equations, have significantly improved the knowledge on HIV infection. While first studies used simplified short‐term dynamic models, recent works considered more complex long‐term models combined with a global analysis of whole patient data based on nonlinear mixed models, increasing the accuracy of the HIV dynamic analysis. However statistical issues remain, given the complexity of the problem. We proposed to use the SAEM (stochastic approximation expectation‐maximization) algorithm, a powerful maximum likelihood estimation algorithm, to analyze simultaneously the HIV viral load decrease and the CD4 increase in patients using a long‐term HIV dynamic system. We applied the proposed methodology to the prospective COPHAR2–ANRS 111 trial. Very satisfactory results were obtained with a model with latent CD4 cells defined with five differential equations. One parameter was fixed, the 10 remaining parameters (eight with between‐patient variability) of this model were well estimated. We showed that the efficacy of nelfinavir was reduced compared to indinavir and lopinavir.     

Ntann12 annexin expression is induced by auxin in tobacco roots

Ntann12, encoding a polypeptide homologous to annexins, was found previously to be induced upon infection of tobacco with the bacterium Rhodococcus fascians. In this study, Ntann12 is shown to bind negatively charged phospholipids in a Ca(2+)-dependent manner. In plants growing in light conditions, Ntann12 is principally expressed in roots and the corresponding protein was mainly immunolocalized in the nucleus. Ntann12 expression was inhibited following plant transfer to darkness and in plants lacking the aerial part. However, an auxin (indole-3-acetic acid) treatment restored the expression of Ntann12 in the root system in dark conditions. Conversely, polar auxin transport inhibitors such as 1-naphthylphthalamic acid (NPA) or 2,3,5-triiodobenzoic acid (TIBA) inhibited Ntann12 expression in light condition. These results indicate that the expression of Ntann12 in the root is linked to the perception of a signal in the aerial part of the plant that is transmitted to the root via polar auxin transport.     

Nodulation of Crotalaria podocarpa DC. by Methylobacterium nodulans displays very unusual features

Crotalaria are plants of the Fabaceae family whose nodulation characteristics have been little explored despite the recent discovery of their unexpected ability to be efficiently nodulated in symbiosis with bacteria of the genus Methylobacterium. It has been shown that methylotrophy plays a key role in this unusual symbiotic system, as it is expressed within the nodule and as non-methylotroph mutants had a depleting effect on plant growth response. Within the nodule, Methylobacterium is thus able to obtain carbon both from host plant photosynthesis and from methylotrophy. In this context, the aim of the present study was to show the histological and cytological impacts of both symbiotic and methylotrophic metabolism within Crotalaria podocarpa nodules. It was established that if Crotalaria nodules are multilobed, each lobe has the morphology of indeterminate nodules but with a different anatomy; that is, without root hair infection or infection threads. In the fixation zone, bacteroids display a spherical shape and there is no uninfected cell. Crotalaria nodulation by Methylobacterium displayed some very unusual characteristics such as starch storage within bacteroid-filled cells of the fixation zone and also the complete lysis of apical nodular tissues (where bacteria have a free-living shape and express methylotrophy). This lysis could possibly reflect the bacterial degradation of plant wall pectins through bacterial pectin methyl esterases, thus producing methanol as a substrate, allowing bacterial multiplication before release from the nodule.     

Mutations of the Huntington’s Disease Protein Impact on the ATM-Dependent Signaling and Repair Pathways of the Radiation-Induced DNA Double-Strand Breaks: Corrective Effect of Statins and Bisphosphonates

Huntington’s disease (HD) is a neurodegenerative syndrome caused by mutations of the IT15 gene encoding for the huntingtin protein. Some research groups have previously shown that HD is associated with cellular radiosensitivity in quiescent cells. However, there is still no mechanistic model explaining such specific clinical feature. Here, we examined the ATM-dependent signaling and repair pathways of the DNA double-strand breaks (DSB), the key damage induced by ionizing radiation, in human HD skin fibroblasts. Early after irradiation, quiescent HD fibroblasts showed an abnormally low rate of recognized DSB managed by non-homologous end-joining reflected by a low yield of nuclear foci formed by phosphorylated H2AX histones and by 53BP1 protein. Furthermore, HD cells elicited a significant but moderate yield of unrepaired DSB 24 h after irradiation. Irradiated HD cells also presented a delayed nucleo-shuttling of phosphorylated forms of the ATM kinase, potentially due to a specific binding of ATM to mutated huntingtin in the cytoplasm. Our results suggest that HD belongs to the group of syndromes associated with a low but significant defect of DSB signaling and repair defect associated with radiosensitivity. A combination of biphosphonates and statins complements these impairments by facilitating the nucleo-shuttling of ATM, increasing the yield of recognized and repaired DSB.     

Writing In and Reading ICU Diaries: Qualitative Study of Families' Experience in the ICU

Purpose

Keeping an ICU patient diary has been reported to benefit the patient''s recovery. Here, we investigated the families'' experience with reading and writing in patient ICU diaries kept by both the family and the staff.

Methods

We conducted a qualitative study involving 32 semi-structured in-depth interviews of relatives of 26 patients (34% of all family members who visited patients) who met our ICU-diary criterion, i.e., ventilation for longer than 48 hours. Grounded theory was used to conceptualise the interview data via a three-step coding process (open coding, axial coding, and selective coding).

Results

Communicative, emotional, and humanising experiences emerged from our data. First, family members used the diaries to access, understand, and assimilate the medical information written in the diaries by staff members, and then to share this information with other family members. Second, the diaries enabled family members to maintain a connection with the patient by documenting their presence and expressing their love and affection. Additionally, families confided in the diaries to maintain hope. Finally, family members felt the diaries humanized the medical staff and patient.

Conclusions

Our findings indicate positive effects of diaries on family members. The diaries served as a powerful tool to deliver holistic patient- and family-centered care despite the potentially dehumanising ICU environment. The diaries made the family members aware of their valuable role in caring for the patient and enhanced their access to and comprehension of medical information. Diaries may play a major role in improving the well-being of ICU-patient families.     

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     

Nest Grouping Patterns of Bonobos (Pan paniscus) in Relation to Fruit Availability in a Forest-Savannah Mosaic

A topic of major interest in socio-ecology is the comparison of chimpanzees and bonobos'' grouping patterns. Numerous studies have highlighted the impact of social and environmental factors on the different evolution in group cohesion seen in these sister species. We are still lacking, however, key information about bonobo social traits across their habitat range, in order to make accurate inter-species comparisons. In this study we investigated bonobo social cohesiveness at nesting sites depending on fruit availability in the forest-savannah mosaic of western Democratic Republic of Congo (DRC), a bonobo habitat which has received little attention from researchers and is characterized by high food resource variation within years. We collected data on two bonobo communities. Nest counts at nesting sites were used as a proxy for night grouping patterns and were analysed with regard to fruit availability. We also modelled bonobo population density at the site in order to investigate yearly variation. We found that one community density varied across the three years of surveys, suggesting that this bonobo community has significant variability in use of its home range. This finding highlights the importance of forest connectivity, a likely prerequisite for the ability of bonobos to adapt their ranging patterns to fruit availability changes. We found no influence of overall fruit availability on bonobo cohesiveness. Only fruit availability at the nesting sites showed a positive influence, indicating that bonobos favour food ‘hot spots’ as sleeping sites. Our findings have confirmed the results obtained from previous studies carried out in the dense tropical forests of DRC. Nevertheless, in order to clarify the impact of environmental variability on bonobo social cohesiveness, we will need to make direct observations of the apes in the forest-savannah mosaic as well as make comparisons across the entirety of the bonobos'' range using systematic methodology.     

Cytosolic PTEN-induced Putative Kinase 1 Is Stabilized by the NF-κB Pathway and Promotes Non-selective Mitophagy

The potential cellular function of the 53-kDa cytosolic form of PINK1 (PINK1-53) is often overlooked because of its rapid degradation by the proteasome upon its production. Although a number of recent studies have suggested various roles for PINK1-53, how this labile PINK1 species attains an adequate expression level to fulfil these roles remains unclear. Here we demonstrated that PINK1-53 is stabilized in the presence of enhanced Lys-63-linked ubiquitination and identified TRAF6-related NF-κB activation as a novel pathway involved in this. We further showed that a mimetic of PINK1-53 promotes mitophagy but, curiously, in apparently healthy mitochondria. We speculate that this “non-selective” form of mitophagy may potentially help to counteract the build-up of reactive oxygen species in cells undergoing oxidative stress and, as such, represent a cytoprotective response.