Rapid response system for critically ill patients with haematological malignancies: A pre- and post-intervention study.

BACKGROUND: This study aimed to determine whether implementing a rapid response system (RRS) is associated with improved short-term outcomes in critically ill patients with haematological malignancies. METHODS: Our monocentric pre- versus post-intervention study was conducted between January 2012 and April 2020. RRS was activated at early signs of haemodynamic or respiratory failure. The primary outcome was the reduction in Sequential Organ Failure Assessment (SOFA) score on Day 3 after intensive care unit (ICU) admission. Secondary outcomes included time to ICU admission and mortality. RESULTS: A total of 209 patients with a median age of 59 years were enrolled (108 in the pre-intervention period and 101 in the post-intervention period). 22% of them had received an allogeneic transplant. The post-intervention period was associated with a shorter time to ICU admission (195 vs. 390 min, p < .001), a more frequent favourable trend in SOFA score (57% vs. 42%, adjusted odds ratio, 2.02, 95% confidence interval, 1.09 to 3.76), no significant changes in ICU (22% vs. 26%, p = .48) and 1-year (62% vs. 58%, p = .62) mortality rates. CONCLUSION: Detection of early organ failure and activation of an RRS was associated with faster ICU admission and lower SOFA scores on Day 3 of admission in critically ill patients with haematological malignancies.

Refined high-content imaging-based phenotypic drug screening in zebrafish xenografts.

Zebrafish xenotransplantation models are increasingly applied for phenotypic drug screening to identify small compounds for precision oncology. Larval zebrafish xenografts offer the opportunity to perform drug screens at high-throughput in a complex in vivo environment. However, the full potential of the larval zebrafish xenograft model has not yet been realized and several steps of the drug screening workflow still await automation to increase throughput. Here, we present a robust workflow for drug screening in zebrafish xenografts using high-content imaging. We established embedding methods for high-content imaging of xenografts in 96-well format over consecutive days. In addition, we provide strategies for automated imaging and analysis of zebrafish xenografts including automated tumor cell detection and tumor size analysis over time. We also compared commonly used injection sites and cell labeling dyes and show specific site requirements for tumor cells from different entities. We demonstrate that our setup allows us to investigate proliferation and response to small compounds in several zebrafish xenografts ranging from pediatric sarcomas and neuroblastoma to glioblastoma and leukemia. This fast and cost-efficient assay enables the quantification of anti-tumor efficacy of small compounds in large cohorts of a vertebrate model system in vivo. Our assay may aid in prioritizing compounds or compound combinations for further preclinical and clinical investigations.

Burden of visible [face and hands] skin diseases: Results from a large international survey.

BACKGROUND: While numerous surveys over the last decade have evaluated the burden of skin diseases, none have focused on the specific impact of disease-location on the hands and face. AIM: The purpose of our study was to evaluate the burden of 8 skin diseases on the multidimensional aspects of subjects' daily lives in respect to their location on visible body areas (face or hands) versus non-visible areas. METHODS: This was a population-based study in a representative sample of the Canadian, Chinese, Italian, Spanish, German and French populations, aged over 18 years using the proportional quota sampling method. All participants were asked (i) to complete a specific questionnaire including socio-demographic characteristics, (ii) to declare if they had a skin disease. All respondents with a skin disease were asked (iii) to specify the respective disease locations (hands, face, body) and (iv) to complete the DLQI questionnaire. Respondents with 8 selected skin diseases were asked (v) to complete a questionnaire evaluating the impact of the skin disease on their daily life, including their professional activity, social relations, emotional and intimate life, leisure, sports activities and perceived stigma. RESULTS: A total of 13,138 adult participants responded to the questionnaire, of whom 26.2 % (n = 3,450) had skin diseases, and 23.4 % (n = 3,072) reported having one of the 8 selected skin diseases. Fifty-three percent were women and the mean age was 39.6 ±â€¯15.5 years. The QoL was mostly impaired when the visible localization was solely on the hands as compared with the face (38 % had a DLQI > 10 versus 22 % respectively). More subjects with a visible localization on the hands reported felt-stigma, having difficulty falling asleep and felt that their sex life had been affected. CONCLUSION: Special attention should be given to patients with skin disease on the hands and face as they are at higher risk of social exclusion and lower quality of life.

Do children and adolescents with type 1 diabetes suffer from a lack of resources in France? Results from a benchmark study in the New Aquitaine region.

BACKGROUND: A benchmark study was conducted in the southwest of France, in the New Aquitaine region, to investigate metabolic outcomes and availability of resources in pediatric diabetes units. We assessed whether the level of care was in accordance with the International Society for Pediatric and Adolescent Diabetes recommendations. METHODS: Demographic and clinical data were collected, as were all HbA1c tests for the 2017 calendar year. Pediatricians specialized in diabetes care were invited to complete an online survey concerning means allocated to the management of type 1 diabetes in their centers. RESULTS: Sixteen centers provided data for 1277 patients and 3873 clinical visits. A total of 1115 children suffering from diabetes for more than 1 year were studied. Median HbA1c was 8% (7.4-8.6) for the whole region. Only 29.2% of children had good metabolic control in accordance with the <7.5% target. We identified slight but significant variation in glycemic control among centers (P=0.029). The use of an insulin pump varied greatly among centers but did not explain HbA1c differences. We did not identify a correlation between medical or paramedical time dedicated to the follow-up of diabetic patients and the mean HbA1c of each center. For 100 diabetic patients, follow-up was provided by 0.42 physicians (0.23-1.50), 0.15 nurses (0-0.56), 0.12 dietitians (0-0.48), and 0.07 psychologists (0-0.30). CONCLUSION: This study demonstrates a lack of human resources allocated to the management of type 1 diabetes in the region that is far below international recommendations. The proportion of children achieving the international glycemic target is low. There is a clear need to improve glycemic control in children, which will only be possible with improved professional practices, encouraged by benchmark studies, and by increasing the size of our multidisciplinary teams.

Total body irradiation using helical tomotherapy: Set-up experience and in-vivo dosimetric evaluation.

PURPOSE: Helical Tomotherapy (HT) appears as a valuable technique for total body irradiation (TBI) to create highly homogeneous and conformal dose distributions with more precise repositioning than conventional TBI techniques. The aim of this work is to describe the technique implementation, including treatment preparation, planning and dosimetric monitoring of TBI delivered in our institution from October 2016 to March 2019. MATERIAL AND METHOD: Prior to patient care, irradiation protocol was set up using physical phantoms. Gafchromic films were used to assess dose distribution homogeneity and evaluate imprecise patient positioning impact. Sixteen patients' irradiations with a prescribed dose of 12Gy were delivered in 6 fractions of 2Gy over 3 days. Pre-treatment quality assurance (QA) was performed for the verification of dose distributions at selected positions. In addition, in-vivo dosimetry was carried out using optically stimulated luminescence dosimeters (OSLD). RESULTS: Planning evaluation, as well as results of pre-treatment verifications, are presented. In-vivo dosimetry showed the strong consistency of OSLD measured doses. OSLD mean relative dose differences between measurement and calculation were respectively +0,96% and -2% for armpit and hands locations, suggesting better reliability for armpit OSLD positioning. Repercussion of both longitudinal and transversal positioning inaccuracies on phantoms is depicted up to 2cm shifts. CONCLUSION: The full methodology to set up TBI protocol, as well as dosimetric evaluation and pre-treatment QA, were presented. Our investigations reveal strong correspondence between planned and delivered doses shedding light on the dose reliability of OSLD for HT based TBI in-vivo dosimetry.

Low expression of ANT1 confers oncogenic properties to rhabdomyosarcoma tumor cells by modulating metabolism and death pathways.

Rhabdomyosarcoma (RMS) is the most frequent form of pediatric soft-tissue sarcoma. It is divided into two main subtypes: ERMS (embryonal) and ARMS (alveolar). Current treatments are based on chemotherapy, surgery, and radiotherapy. The 5-year survival rate has plateaued at 70% since 2000, despite several clinical trials. RMS cells are thought to derive from the muscle lineage. During development, myogenesis includes the expansion of muscle precursors, the elimination of those in excess by cell death and the differentiation of the remaining ones into myofibers. The notion that these processes may be hijacked by tumor cells to sustain their oncogenic transformation has emerged, with RMS being considered as the dark side of myogenesis. Thus, dissecting myogenic developmental programs could improve our understanding of RMS molecular etiology. We focused herein on ANT1, which is involved in myogenesis and is responsible for genetic disorders associated with muscle degeneration. ANT1 is a mitochondrial protein, which has a dual functionality, as it is involved both in metabolism via the regulation of ATP/ADP release from mitochondria and in regulated cell death as part of the mitochondrial permeability transition pore. Bioinformatics analyses of transcriptomic datasets revealed that ANT1 is expressed at low levels in RMS. Using the CRISPR-Cas9 technology, we showed that reduced ANT1 expression confers selective advantages to RMS cells in terms of proliferation and resistance to stress-induced death. These effects arise notably from an abnormal metabolic switch induced by ANT1 downregulation. Restoration of ANT1 expression using a Tet-On system is sufficient to prime tumor cells to death and to increase their sensitivity to chemotherapy. Based on our results, modulation of ANT1 expression and/or activity appears as an appealing therapeutic approach in RMS management.

[Idiosyncratic drug-induced agranulocytosis: 7 year-analysis in a French university hospital]. / Agranulocytoses médicamenteuses idiosyncrasiques : analyse de 7 ans dans un hôpital universitaire français.

INTRODUCTION: Idiosyncratic drug-induced agranulocytosis is a rare but potentially serious haematological disorder. The pathophysiological mechanisms are complex and poorly understood. We aimed at investigating agranulocytosis drug related causes from the myelograms with "myeloid maturation arrest" performed in our university hospital over the last seven years. METHODS: A retrospective analysis of myelograms collected for agranulocytosis was performed from 1st January 2010 to 31th December 2016. We used the method of Bégaud et al. for drug causality assessment. RESULTS: Among the 104 myelograms analysed, 41 agranulocytosis were drug-induced, whose 28 were idiosyncratic. Among these 28 cases, 26 different drugs were involved. Agranulocytosis was a known adverse reaction in the summary of the product characteristics for 24 drugs, mainly associated with undetermined frequency (n=7). Mean onset latency was 38.1 days after starting the drug (calculated for n=23 cases) and granulocyte growth factors were used in 50% of cases without shortening the mean delay of blood count recovery. Bone marrow presented hypereosinophilia in 29% of cases. Pharmacovigilance reporting rate was 48%. CONCLUSION: A "maturation arrest" in the myelogram is not pathognomonic for idiosyncratic drug-induced agranulocytosis. This rare event require multidisciplinary care involving haematologists, biologists and pharmacovigilance experts. Agranulocytosis reporting rate was high compared with usual adverse drug reaction reporting rate (5 to 10%), probably related to the potential severity of this event.

Maternal adherence to guidance on breast milk collection process.

INTRODUCTION: Breast milk expression with a breast pump increases the risk of contaminating milk with pathogenic bacteria; how to decontaminate breast pumps is controversial. The aim of this study was to investigate maternal adherence to updated French guidance on the breast milk collection process, including breast pump decontamination, and to identify potential sources of increased bacterial counts in breast milk in order to improve prevention messages to mothers. METHODS: Descriptive prospective study conducted between November 2015 and April 2016 in a French tertiary perinatal center. Oral and written instructions on the breast milk collection process and breast pump decontamination were given to mothers by trained healthcare professionals. Mothers whose neonates were admitted to the neonatal care unit and expressing milk for the human milk bank were eligible if breast milk bacterial counts before pasteurization were≥106 colony-forming units (cfu)/mL for total aerobic flora or ≥104 cfu/mL for Staphylococcus aureus. Maternal adherence to the guidance was investigated with a questionnaire and a face-to-face interview. RESULTS: One hundred and fourteen mothers with neonates admitted to the neonatal care unit expressed milk for the milk bank; 44 (39%) were eligible and 29 (66%) included: most of them (76%) with increased counts of total aerobic flora in breast milk and 24% with increased counts of S. aureus. At least three divergences from the guidance provided were reported for 16 mothers (55%). The most frequent ones were inadequate storage of the breast pump collection kit (62%), ineffective decontamination of the breast pump collection kit (52%), inappropriate cleaning of the breast pump (48%), and inadequate breast milk transport from home to hospital (31%). CONCLUSION: Despite standardized instructions, mothers with increased bacterial counts in breast milk frequently declared several divergences from the guidance on the breast milk collection process. Giving mothers and any person of their choice repeated clear instructions with illustrated guidance, demonstrations, and practice may help improve the microbiological safety of expressed breast milk.

Measuring contact area in a sliding human finger-pad contact.

BACKGROUND/PURPOSE: The work outlined in this paper was aimed at achieving further understanding of skin frictional behaviour by investigating the contact area between human finger-pads and flat surfaces. METHODS: Both the static and the dynamic contact areas (in macro- and micro-scales) were measured using various techniques, including ink printing, optical coherence tomography (OCT) and Digital Image Correlation (DIC). RESULTS: In the studies of the static measurements using ink printing, the experimental results showed that the apparent and the real contact area increased with load following a piecewise linear correlation function for a finger-pad in contact with paper sheets. Comparisons indicated that the OCT method is a reliable and effective method to investigate the real contact area of a finger-pad and allow micro-scale analysis. The apparent contact area (from the DIC measurements) was found to reduce with time in the transition from the static phase to the dynamic phase while the real area of contact (from OCT) increased. CONCLUSIONS: The results from this study enable the interaction between finger-pads and contact object surface to be better analysed, and hence improve the understanding of skin friction.

Olesoxime favors oligodendrocyte differentiation through a functional interplay between mitochondria and microtubules.

Multiple sclerosis (MS) is a neurodegenerative disease characterized by episodes of immune attacks and oligodendrocyte death leading to demyelination and progressive functional deficits. New therapeutic strategies are needed to stimulate the spontaneous regenerative process observed in some patients. Spontaneous myelin repair relies on the mobilization and differentiation of endogenous oligodendrocyte progenitors at the lesion site. Olesoxime, a cholesterol-like compound, has been shown to favor oligodendrocyte maturation in culture and promote myelin regeneration in rodents. Here, we study the mode of action of this compound and show that it binds to oligodendrocyte mitochondria, leading to their hyperfilamentation. This is accompanied by a reduction of basal superoxide levels, and accumulation of End Binding Protein 1 (EB1) at growing ends of microtubules. In parallel, we demonstrate that Reactive Oxygen Species (ROS) scavengers also promote oligodendrocyte differentiation, together with increasing mitochondrial filamentation and EB1-dependent microtubule polymerization. Altogether, our data uncover the mechanisms by which olesoxime promotes oligodendrocyte maturation. They also reveal that a bidirectional relationship between mitochondria hyperfilamentation and ROS level modulation controls oligodendrocyte maturation. This study identifies new cellular mechanisms to target for the development of regenerative treatments for MS.

ß-blockers increase response to chemotherapy via direct antitumour and anti-angiogenic mechanisms in neuroblastoma.

BACKGROUND: The use of ß-blockers for the management of hypertension has been recently associated with significant clinical benefits in cancer patients. Herein, we investigated whether ß-blockers could be used in combination with chemotherapy for the treatment of neuroblastoma. METHODS: Seven ß-blockers were tested for their antiproliferative and anti-angiogenic properties alone, and in combination with chemotherapy in vitro; the most potent drug combinations were evaluated in vivo in the TH-MYCN mouse model of neuroblastoma. RESULTS: Three ß-blockers (i.e., carvedilol, nebivolol and propranolol) exhibited potent anticancer properties in vitro and interacted synergistically with vincristine, independently of P-glycoprotein expression. ß-blockers potentiated the anti-angiogenic, antimitochondrial, antimitotic and ultimately pro-apoptotic effects of vincristine. In vivo, ß-blockers alone transiently slowed tumour growth as compared with vehicle only (P<0.01). More importantly, when used in combination, ß-blockers significantly increased the tumour regression induced by vincristine (P<0.05). This effect was associated with an increase in tumour angiogenesis inhibition (P<0.001) and ultimately resulted in a four-fold increase in median survival, as compared with vincristine alone (P<0.01). CONCLUSION: ß-blockers can increase treatment efficacy against neuroblastoma, and their combination with chemotherapy may prove beneficial for the treatment of this disease and other drug-refractory cancers.

[Consumption of the probiotic Lactobacillus planctarum CECT 7315/7316 improves general health in the elderly subjects]. / El consumo del probiótico Lactobacillus plantarum CECT 7315/7316 mejora el estado de salud general en personas de edad avanzada.

INTRODUCTION: Ageing induces changes in gut microbiota that may affect the quality of life. In this work we analyze the effect of Lactobacillus plantarum CECT 7315/7316 on the regulation of intestinal transit and on nutritional status. METHODS: We carried out a double-blind, randomized and controlled by placebo clinical trial. We evaluated the evolution of the weekly defecation frequency and blood levels of total proteins, albumin, cholesterol and reactive C-protein. RESULTS: Lactobacillus plantarum CECT 7315/7316 helps to regulate intestinal transit and improves the nutritional status in elderly. CONCLUSIONS: Consumption of functional foods containing L. plantarum CECT 7315/7316 improves the quality of life in elderly subjects.

El consumo del probiótico Lactobacillus plantarum CECT 7315/7316 mejora el estado de salud general en personas de edad avanzada / Consumption of the probiotic lactobacillus planctarum CECT 7315/7316 improves general health in the elderly subjects

Fundamentos: Con la edad avanzada se producen cambios en la microflora intestinal que pueden afectar alestado de salud general. En este trabajo analizamos el efecto de Lactobacillus plantarum CECT 7315/7316 sobre la regulación del tránsito intestinal y el estado nutricional. Métodos: Hemos realizado un estudio clínico doble ciego, controlado por placebo y aleatorizado. Hemos evaluado la evolución de la frecuencia de defecación semana ly los niveles en sangre de proteínas totales, albúmina, colesterol y proteína C-reactiva .Resultados: Lactobacillus plantarum CECT 7315/7316ayuda a regular el tránsito intestinal y mejora el estado nutricional en personas mayores. Conclusiones: El consumo de productos funcionales que contengan L. plantarum CECT 7315/7316 mejora la calidad de vida de personas de la tercera edad (AU)

Introduction: Ageing induces changes in gut microbiota that may affect the quality of life. In this work we analyze the effect of Lactobacillus plantarum CECT7315/7316 on the regulation of intestinal transit and on nutritional status. Methods: We carried out a double-blind, randomized and controlled by placebo clinical trial. We evaluated the evolution of the weekly defecation frequency and blood levels of total proteins, albumin, cholesterol and reactive C-protein. Results: Lactobacillus plantarum CECT 7315/7316 helps to regulate intestinal transit and improves the nutritional status in elderly. Conclusions: Consumption of functional foods containingL. plantarum CECT 7315/7316 improves the quality of life in elderly subjects (AU)

Microtubule-targeted agents: when mitochondria become essential to chemotherapy.

Microtubule-Targeting Agents (MTAs) constitute a class of drugs largely used for cancer treatment in adults and children. In cancer cells, they suppress microtubule dynamics, and induce cell death via the mitochondrial intrinsic pathway. To date, links between mitochondria and microtubule network disturbance in MTAs mechanism of action are not obvious. The aim of the present contribution is to provide elements that could answer to the question: how far are mitochondria essential to anticancer chemotherapy that targets the microtubule cytoskeleton? We review the main molecular candidates to link microtubule alteration with the apoptotic mitochondrial pathway control. Involvement of direct targeting of mitochondria in MTA efficacy is also discussed. Furthermore, we line up current evidence and emerging concepts on the participation of both mitochondria and microtubule in MTA neurotoxic side effects. To decipher the interconnections between the mitochondrial and the microtubule networks may help to improve cancer cell response to chemotherapy.

Patupilone-induced apoptosis is mediated by mitochondrial reactive oxygen species through Bim relocalization to mitochondria.

Among the new microtubule-targeted agents, the epothilone family of molecules has shown promising anticancer potential, and clinical trials are currently underway for patupilone (epothilone B) in various cancer indications. In this study, we characterized novel aspects of patupilone's cellular action that may underlie its potent cytotoxicity in human neuroblastoma cells. Patupilone induced mitochondrial membrane potential collapse, mitochondrial morphological changes, and cytochrome c release, leading to apoptosis. Within the first 2 h, patupilone increased the generation of reactive oxygen species (ROS; i.e., superoxides and hydrogen peroxide, 33+/-6 and 51+/-3% increase, respectively), specifically from mitochondria. ROS scavengers and mitochondrial DNA depletion [rho(-) cells] significantly protected cells against patupilone cytotoxicity, indicating that ROS generation is a key event in the initial phase of apoptosis. Although the Bim expression level was not modified by patupilone, this proapoptotic protein accumulated in the mitochondrial compartment (2.4-fold increase at IC70) after only a 6-h treatment. In contrast, Bax and Bcl-2 mitochondrial levels were not changed during treatment. It is noteworthy that ROS inhibition prevented Bim relocalization to mitochondria and mitochondrial membrane changes induced by patupilone. Altogether, our data reveal that patupilone-mediated ROS production by mitochondria initiates the intrinsic signaling cascade by inducing Bim accumulation in mitochondria. These results might explain the superior activity of patupilone in tumor cells compared with paclitaxel that is, until now, the clinical reference among microtubule-stabilizing agents. Furthermore, our data highlight the importance of mitochondria that simultaneously assume the role of activator and integrator of apoptotic signals triggered by patupilone.

Dairy cattle exploratory and social behaviors: is there an effect of cloning?

While an increasing number of animals are produced by means of somatic cloning, behavioral studies on cloned animals are still rare. The aim of this study was to investigate whether the somatic cloning procedure has an influence on locomotion, exploratory, vocal and social behaviors of heifers. Ten heifers were used in the present study. Five of them were cloned heifers derived from somatic cells of three different Prim'Holstein cows and five others were same-age control heifers produced by artificial insemination. In addition to observations of social behaviors in the stable group, each animal was placed individually for a short time in an unfamiliar environment. Our results failed to show any statistical differences between clones and their controls both in frequencies of agonistic and non-agonistic behaviors. However, cloned heifers showed significantly more non-agonistic and less agonistic behaviors towards other cloned partners than towards control ones. This result also stood for control heifers. As far as their Hierarchical Index was concerned, three cloned heifers were highest ranking and two others lowest ranking. In this herd, social dominance appeared to be linked to body weight and age rather than to a cloning effect. In an unfamiliar environment, cloned and control subjects exhibited the same level of locomotion and vocalization. However, cloned heifers showed more exploratory behaviors than did control ones. This difference could be due to environmental factors during the postnatal period rather than to cloning.

Microtubules in apoptosis induction: are they necessary?

Microtubule-Targeting Agents (MTAs) constitute a class of drugs largely used in cancer treatment. Among them, both taxanes and Vinca-alkaloids are known to inhibit cancer cell proliferation by inducing cell cycle arrest and subsequent apoptosis. These agents modify the cytoskeleton by affecting the tubulin/microtubule system. In cancer cells, both classes suppress microtubule dynamics through inhibition of microtubule dynamic instability and treadmilling, and commonly induce diverse signals responsible for cell death initiation and execution via the mitochondrial intrinsic pathway. However, links between microtubule network disturbance and the involvement of mitochondria in apoptosis are not obvious, and one may think that they could be independent. Nevertheless, several intracellular proteins could connect microtubules and the apoptotic machinery. The aim of the present review is to provide elements that could answer to the question: is microtubule disruption dispensable for MTA-induced apoptosis? The first section is focused on the mechanisms responsible for the MTA-mediated apoptosis. Then, links between cell cycle regulators and apoptosis are underlined since MTA induce cell cycle arrest by inhibiting microtubules. In the third part, the potential involvement of microtubule-sequestered and/or -transported proteins in apoptotic signalisation is discussed. Lastly, the possible role of the tubulin/microtubule system in direct effects of MTAs on mitochondria is summarized. Thus, it becomes clear that microtubule network and apoptosis are deeply linked in MTA effectiveness, through a cascade of cellular events. It could lead to identification of new biomarkers of MTA effectiveness, that could improve combinatorial therapy with MTAs and provide crucial arms to circumvent resistance of cancer cells.