Exploring ITM2A as a new potential target for brain delivery.

BACKGROUND: Integral membrane protein 2A (ITM2A) is a transmembrane protein expressed in a variety of tissues; little is known about its function, particularly in the brain. ITM2A was found to be highly enriched in human brain versus peripheral endothelial cells by transcriptomic and proteomic studies conducted within the European Collaboration on the Optimization of Macromolecular Pharmaceutical (COMPACT) Innovative Medicines Initiative (IMI) consortium. Here, we report the work that was undertaken to determine whether ITM2A could represent a potential target for delivering drugs to the brain. METHODS: A series of ITM2A constructs, cell lines and specific anti-human and mouse ITM2A antibodies were generated. Binding and internalization studies in Human Embryonic Kidney 293 (HEK293) cells overexpressing ITM2A and in brain microvascular endothelial cells from mouse and non-human primate (NHP) were performed with these tools. The best ITM2A antibody was evaluated in an in vitro human blood brain barrier (BBB) model and in an in vivo mouse pharmacokinetic study to investigate its ability to cross the BBB. RESULTS: Antibodies specifically recognizing extracellular parts of ITM2A or tags inserted in its extracellular domain showed selective binding and uptake in ITM2A-overexpressing cells. However, despite high RNA expression in mouse and human microvessels, the ITM2A protein was rapidly downregulated when endothelial cells were grown in culture, probably explaining why transcytosis could not be observed in vitro. An attempt to directly demonstrate in vivo transcytosis in mice was inconclusive, using either a cross-reactive anti-ITM2A antibody or in vivo phage panning of an anti-ITM2A phage library. CONCLUSIONS: The present work describes our efforts to explore the potential of ITM2A as a target mediating transcytosis through the BBB, and highlights the multiple challenges linked to the identification of new brain delivery targets. Our data provide evidence that antibodies against ITM2A are internalized in ITM2A-overexpressing HEK293 cells, and that ITM2A is expressed in brain microvessels, but further investigations will be needed to demonstrate that ITM2A is a potential target for brain delivery.

Bioactive compounds from Artemisia dracunculus L. activate AMPK signaling in skeletal muscle.

An extract from Artemisia dracunculus L. (termed PMI-5011) improves glucose homeostasis by enhancing insulin action and reducing ectopic lipid accumulation, while increasing fat oxidation in skeletal muscle tissue in obese insulin resistant male mice. A chalcone, DMC-2, in PMI-5011 is the major bioactive that enhances insulin signaling and activation of AKT. However, the mechanism by which PMI-5011 improves lipid metabolism is unknown. AMPK is the cellular energy and metabolic sensor and a key regulator of lipid metabolism in muscle. This study examined PMI-5011 activation of AMPK signaling using murine C2C12 muscle cell culture and skeletal muscle tissue. Findings show that PMI-5011 increases Thr172-phosphorylation of AMPK in muscle cells and skeletal muscle tissue, while hepatic AMPK activation by PMI-5011 was not observed. Increased AMPK activity by PMI-5011 affects downstream signaling of AMPK, resulting in inhibition of ACC and increased SIRT1 protein levels. Selective deletion of DMC-2 from PMI-5011 demonstrates that compounds other than DMC-2 in a "DMC-2 knock out extract" (KOE) are responsible for AMPK activation and its downstream effects. Compared to 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) and metformin, the phytochemical mixture characterizing the KOE appears to more efficiently activate AMPK in muscle cells. KOE-mediated AMPK activation was LKB-1 independent, suggesting KOE does not activate AMPK via LKB-1 stimulation. Through AMPK activation, compounds in PMI-5011 may regulate lipid metabolism in skeletal muscle. Thus, the AMPK-activating potential of the KOE adds therapeutic value to PMI-5011 and its constituents in treating insulin resistance or type 2 diabetes.

[Terbinafine-resistant dermatophytoses and onychomycosis due to Trichophyton rubrum]. / Terbinafin-resistente Dermatophytosen und Onychomykose durch Trichophyton rubrum.

BACKGROUND: In recent years, therapy-refractory courses of dermatophytoses have increasingly become the focus of attention. The most frequent pathogens are Trichophyton (T.) rubrum and T. mentagrophytes. In addition to local therapy, first-line treatment includes terbinafine, an allylamine antifungal agent that acts by inhibiting squalene epoxidase and thus interfering with ergosterol synthesis. In refractory cases, terbinafine resistance due to point mutation in the squalene epoxidase gene has been frequently detected. OBJECTIVES: The aim is to present specific aspects in the epidemiology of dermatophytoses with terbinafine resistance and to illustrate them on the basis of four patient cases including diagnostic procedures. MATERIALS AND METHODS: A review of handbook knowledge, a selective literature search, and a review of four patient cases were performed. RESULTS: Detection of the terbinafine resistance was performed by in vitro testing using the breakpoint method as well as sequencing of the Trichophyton isolate and detection of the point mutation with amino acid substitution at position L393F or F397L of squalene epoxidase. CONCLUSION: In refractory and recurrent dermatophytoses, terbinafine resistance should be considered, especially in T. mentagrophytes and T. rubrum, and in vitro resistance testing of the dermatophyte and point mutation analysis of squalene epoxidase (SQLE) should be performed. Therapeutically, intermittent administration of itraconazole in combination with antifungal local therapy is recommended. Nevertheless, a recurrent course is to be expected and long-term therapy with itraconazole is usually necessary.

Impact of adjuvant radiotherapy on biological and clinical parameters in right-sided breast cancer.

PURPOSE: In patients with right-sided breast cancer (BC) the liver might be partially irradiated during adjuvant radiotherapy (RT). Thus, we performed a prospective observational study to evaluate the dose delivered to the liver, and its potential biological impact. PATIENTS AND METHODS: We enrolled 34 patients with right-sided BC treated with adjuvant RT. The RT schedules were either the Canadian (42.5Gy in 16 fx) or standard fractionated (50Gy in 25 fx) regimen respectively with 9 (26.5%) and 25 (73.5%) patients each, ± a boost of 10-16Gy. Each patient had a complete blood count and liver enzymes analysis, before starting and during the last week of treatment. RESULTS: A significant decrease in white blood cells and thrombocytes counts was observed during RT. We observed a significant correlation between certain hepatic parameters and the volume of the irradiated liver and/or the mean liver dose. A significant correlation between the volume of the right lung and the liver mean dose was found (P=0.008). In the bivariate analysis, a significant correlation between fatigue and the white blood cell count's evolution was observed (P<0.025). CONCLUSION: With the standard RT technique, incidental irradiation of the liver was documented in a large number of patients, and some significant hepatic parameters alterations were observed, without an apparent clinical impact, but this study cannot exclude them. The liver mean dose was correlated with the right lung volume suggesting that deep inspiration breath hold (DIBH) techniques may represent a way to decrease the liver dose. These findings need to be evaluated in further larger studies.

COVID-19 in children at Strasbourg University Hospital: A retrospective study of the first 2months of the epidemic.

CONTEXT: The emergence and rapid spread of coronavirus disease 2019 (COVID-19) have shaken the planet, both in terms of health and economical aspects, constituting a real challenge for the scientific community. PROBLEM: At the time of the arrival of the epidemic in France, there were limited data regarding how COVID-19 could affect children. A lesser severity compared with adults was described, but knowledge concerning clinical forms and screening strategies was missing. METHODOLOGY: In this retrospective and non-interventional epidemiological study, we aimed to describe the epidemiology and the clinical features of COVID-19 pediatric disease in the first university hospital affected by the epidemic in France. We included all underage patients who tested positive for SARS-CoV-2 by polymerase chain reaction (PCR) assays on nasopharyngeal smears performed between February 25, 2020 and April 30, 2020. RESULTS: The presence of fever and respiratory signs was frequent (>50%), as was the presence of general or digestive signs, but patients were also frequently asymptomatic, making the discovery of a positive smear fortuitous. There were no deaths in our cohort. CONCLUSION: No patient with a serious form of COVID-19 was treated in the pediatrics departments of Strasbourg University Hospital during the first 2 months of the epidemic. Diagnostic strategies have evolved over the course of the epidemic, ranging from exploring relevant symptoms to systematic screening.

[Propositions for perinatal care at extremely low gestational ages - Working group on "Extremely low gestational ages" for SFMP, CNGOF, and SFN]. / Propositions sur la prise en charge en cas d'extrême prématurité ­ Le groupe de travail « Extrême Prématurité ¼ pour la SFMP, le CNGOF et la SFN.

OBJECTIVES: International literature suggests that active perinatal management at extremely low gestational ages improves survival without increasing the risk of impairment in survivors, compared to less active management. Although these results are limited to a small number of countries, they question current practices in France. New propositions on perinatal management of extremely preterm infants have carried out by the French Society of Perinatal Medicine, the French Society of Neonatology and the National College of French Obstetricians and Gynecologists. METHODS: This group was set up in 2015 on the initiative of the professional societies and in collaboration with parents' and users' associations. The work was based on a review of the literature on the prognosis of extremely preterm children, as well as on recommendations by European societies. Based on this information, a text was produced, submitted to all members of the working group and definitively validated in April 2019. RESULTS: This text offers a decision-making guideline for the management at extremely low gestational ages. Its principles are: the administration of steroids independently of management (resuscitation or comfort care); a prognostic evaluation and a collegial decision, outside the context of the emergency; a consensus on the information to be given to parents before going to inform them and gather their opinion. CONCLUSIONS: These new propositions will contribute to modifying perinatal care at extremely low gestational ages in France.

Recommendation for hygiene and topical in neonatology from the French Neonatal Society.

We sought to establish guidelines for hygiene care in newborns based on a systematic review of the literature and grading of evidence using the Groupe de Réflexion et d'Evaluation de l'Environement des Nouveau-nés (GREEN) methodology. We examined 45 articles and 4 reports from safety agencies. These studies recommend a tub bath (rather than a sponge bath) for full-term infants and a swaddle bath for preterm newborns. They also recommend against daily cleansing of preterm infants. The literature emphasized that hygiene care must consider the clinical state of the newborn, including the level of awareness and behavioral responses. Hospitalized newborns treated with topical agents may also experience high exposure to potentially harmful excipients of interest. Caregivers should therefore be aware of the excipients present in the different products they use. In high-resource countries, the available data do not support the use of protective topical agents for preterm infants.Conclusions: We recommend individualization of hygiene care for newborns. There is increasing concern regarding the safety of excipients in topical agents that are used in neonatology. A multidisciplinary approach should be used to identify an approach that requires lower levels of excipients and alternative excipients. What is known: • Hygiene care is one of the most basic and widespread types of care received by healthy and sick newborns worldwide. • There is no current guideline on hygiene for preterm or hospitalized term newborn. What is new: • The French Group of Reflection and Evaluation of the environment of Newborns (GREEN) provided here guidelines based on the current body of evidence. • Caregivers should be aware of the many issues related to hygiene care of newborns including newborns' behavioral responses to hygiene care, exposition to excipients of interest, and the potential risk of protective topical agents in a preterm infant. provided here guidelines based on the current body of evidence. • Caregivers should be aware of the many issues related to hygiene care of newborns including newborns' possible behavioral responses to hygiene care, exposition to excipients of interest and the potential risk of protective topical agents in a preterm infant.

[The care of extremely preterm infants: A French view of the Swedish experience]. / Prise en charge de la prématurité extrême : vision française de l'expérience suédoise.

Extreme prematurity, defined as birth occurring before 27 weeks of gestation in Sweden, is managed according to the latest data of the most recent literature, with monitoring of the results through a continuous perinatal registry. National guidelines were issued in 2013. They highlight the importance of infant developmentally supportive and family-centered care focused on the child and the family, nutritional support, pain management, management of ductus arteriosus, and brain damage. However, there remain areas without national consensus including respiratory support management. The French vision of the Swedish approach highlights the proactive attitude of neonatologists, the coherent and narrow collaboration between neonatologists and obstetricians, and the active presence and involvement of parents in the care of their infants.

How to assess hemodynamic status in very preterm newborns in the first week of life?

BACKGROUND: Assessing hemodynamic status in preterm newborns is an essential task, as many studies have shown increased morbidity when hemodynamic parameters are abnormal. Although oscillometric monitoring of arterial blood pressure (BP) is widely used due to its simplicity and lack of side effects, these values are not always correlated with microcirculation and oxygen delivery. OBJECTIVES: This review focuses on different tools for the assessment of hemodynamic status in preterm newborns. These include the measurement of clinical (BP, capillary refill time and urinary output (UO)) or biological parameters (lactate analysis), functional echocardiography, and near-infrared spectroscopy (NIRS). We describe the concepts and techniques involved in these tools in detail, and examine the interest and limitations of each type of assessment. CONCLUSIONS: This review highlights the complementarities between the different parameters used to assess hemodynamic status in preterm newborns during the first week of life. The analysis of arterial BP measured by oscillometric monitoring must take into account other clinical data, in particular capillary refill time and UO, and biological data such as lactate levels. Echocardiography improves noninvasive hemodynamic management in newborns but requires specific training. In contrast, NIRS may be useful in monitoring the clinical course of infants at risk of, or presenting with, hypotension. It holds the potential for early and noninvasive identification of silent hypoperfusion in critically ill preterm infants. However, more data are needed to confirm the usefulness of this promising tool in significantly changing the outcome of these infants.

Complex terrain experiments in the New European Wind Atlas.

The New European Wind Atlas project will create a freely accessible wind atlas covering Europe and Turkey, develop the model chain to create the atlas and perform a series of experiments on flow in many different kinds of complex terrain to validate the models. This paper describes the experiments of which some are nearly completed while others are in the planning stage. All experiments focus on the flow properties that are relevant for wind turbines, so the main focus is the mean flow and the turbulence at heights between 40 and 300 m. Also extreme winds, wind shear and veer, and diurnal and seasonal variations of the wind are of interest. Common to all the experiments is the use of Doppler lidar systems to supplement and in some cases replace completely meteorological towers. Many of the lidars will be equipped with scan heads that will allow for arbitrary scan patterns by several synchronized systems. Two pilot experiments, one in Portugal and one in Germany, show the value of using multiple synchronized, scanning lidar, both in terms of the accuracy of the measurements and the atmospheric physical processes that can be studied. The experimental data will be used for validation of atmospheric flow models and will by the end of the project be freely available.This article is part of the themed issue 'Wind energy in complex terrains'.

Collaborating to Compete: Blood Profiling Atlas in Cancer (BloodPAC) Consortium.

The cancer community understands the value of blood profiling measurements in assessing and monitoring cancer. We describe an effort among academic, government, biotechnology, diagnostic, and pharmaceutical companies called the Blood Profiling Atlas in Cancer (BloodPAC) Project. BloodPAC will aggregate, make freely available, and harmonize for further analyses, raw datasets, relevant associated clinical data (e.g., clinical diagnosis, treatment history, and outcomes), and sample preparation and handling protocols to accelerate the development of blood profiling assays.

Cancer Moonshot Connecting International Liquid Biopsy Efforts Through Academic Partnership.

The Kuhn Laboratory at the University of Southern California and the Dive Laboratory at the Cancer Research UK's Manchester Institute are teaming up to apply new cancer cell detection technology to identify patients who will progress after initial treatment. Researchers will take a simple blood sample to identify early those patients whose cancer has returned, while analyzing circulating tumor cells (CTCs) in great detail, providing new clues on the most effective therapy for the patient's cancer.

Lessons Learned: Transfer of the High-Definition Circulating Tumor Cell Assay Platform to Development as a Commercialized Clinical Assay Platform.

Planning and transfer of a new technology platform developed in an academic setting to a start-up company for medical diagnostic product development may appear daunting and costly in terms of complexity, time, and resources. In this review we outline the key steps taken and lessons learned when a technology platform developed in an academic setting was transferred to a start-up company for medical diagnostic product development in the interest of elucidating development toolkits for academic groups and small start-up companies starting on the path to commercialization and regulatory approval.

[Palliative care after neonatal intensive care: Contributions of Leonetti Law and remaining challenges]. / Soins palliatifs au décours d'une réanimation néonatale : apports de la loi Léonetti et défis persistants.

The 2005 enactment of the "Patients' rights and end-of-life care" act, known as the Leonetti law, has been accompanied by practical changes in the processes of withdrawal and withholding of active life-sustaining treatments. This law has also promoted the implementation of palliative care in perinatal medicine to avoid unreasonable therapeutic interventions and to preserve the dying patient's quality of life and human dignity. Recently, a new law has been voted by the French National Assembly and new reflections on the ethical aspects of the end of life in neonatal medicine should resume again within the French Society of Neonatology in the working group on ethical issues in neonatology. This is why it appears important to discuss the perceived benefits and the persistent difficulties related to the implementation of the Leonetti law in neonatology. Collegiality in the decision-making processes as well as withdrawal and withholding of life-sustaining treatments that were already present in the practices of many centers has been stipulated within a legal framework and promoted in clinical practice. It has brought serenity within perinatal nursing and medical teams. It has helped them face the always-difficult end-of-life situations with parents and deal with decision-making processes in an intense emotional climate. However, new questions inherent to the law have appeared. The most important ones concern the withholding of artificial nutrition and hydration, the time pressure in the management of the decision-making process, and the management of the duration of palliative care. Challenges remain in addressing various persistent ethical dilemmas such as the possible survival of newborns with significant brain lesions detected after the period of life-sustaining treatments that have allowed their survival. The new law carried by Mr. Clayes and Mr. Léonetti should provide answers to some of these ethical issues, but it would probably not solve all of them.

Circulating Tumor Cells: Fluid Surrogates of Solid Tumors.

Evaluation of circulating tumor cells (CTCs) has demonstrated clinical validity as a prognostic tool based on enumeration, but since the introduction of this tool to the clinic in 2004, further clinical utility and widespread adoption have been limited. However, immense efforts have been undertaken to further the understanding of the mechanisms behind the biology and kinetics of these rare cells, and progress continues toward better applicability in the clinic. This review describes recent advances within the field, with a particular focus on understanding the biological significance of CTCs, and summarizes emerging methods for identifying, isolating, and interrogating the cells that may provide technical advantages allowing for the discovery of more specific clinical applications. Included is an atlas of high-definition images of CTCs from various cancer types, including uncommon CTCs captured only by broadly inclusive nonenrichment techniques.

[Neonatal palliative care at home: Contribution of the regional pediatric palliative care team]. / Soins palliatifs néonatals à domicile : apport des équipes régionales de soins palliatifs pédiatriques.

The "patients' rights and end-of-life care" act, known as the Leonetti law, has allowed implementation of palliative care in neonatology as an alternative to unreasonable therapeutic interventions. A palliative care project can be offered to newborns suffering from intractable diseases. It must be focused on the newborn's quality of life and comfort and on family support. Palliative care for newborns can be provided in the delivery room, in the neonatal unit, and also at home. Going home is possible but requires medical support. Here we describe the potential benefits of the intervention of a regional team of pediatric palliative care for newborns, both in the hospital and at home. Two clinical situations of palliative care at home started in the neonatal period and the neonatal unit are presented. They are completed by a retrospective national survey focusing on the type of support to newborns in palliative care in 2014, which was conducted in 22 French regional pediatric palliative care teams. It shows that 26 newborns benefited from this support at home in 2014. Sixteen infants were born after a pregnancy with a palliative care birth plan and ten entered palliative care after a decision to limit life-sustaining treatments. Twelve of them returned home before the 20th day of life. Sixteen infants died, six of them at home. The regional pediatric palliative care team first receives in-hospital interventions: providing support for ethical reflection in the development of the infant's life project, meeting with the child and its family, helping organize the care pathway to return home. When the child is at home, the regional pediatric palliative care team can support the caregiver involved, provide home visits to continue the clinical monitoring of the infant, and accompany the family. The follow-up of the bereavement and the analysis of the practices with caregivers are also part of its tasks.

[Intraoperative multidimensional visualization]. / Intraoperative mehrdimensionale Visualisierung.

Modern intraoperative techniques of visualization are increasingly being applied in general and visceral surgery. The combination of diverse techniques provides the possibility of multidimensional intraoperative visualization of specific anatomical structures. Thus, it is possible to differentiate between normal tissue and tumor tissue and therefore exactly define tumor margins. The aim of intraoperative visualization of tissue that is to be resected and tissue that should be spared is to lead to a rational balance between oncological and functional results. Moreover, these techniques help to analyze the physiology and integrity of tissues. Using these methods surgeons are able to analyze tissue perfusion and oxygenation. However, to date it is not clear to what extent these imaging techniques are relevant in the clinical routine. The present manuscript reviews the relevant modern visualization techniques focusing on intraoperative computed tomography and magnetic resonance imaging as well as augmented reality, fluorescence imaging and optoacoustic imaging.

[Parental perception of their involvement in the care of their children in French neonatal units]. / Perception des parents de leur participation aux soins de leur enfant dans les unités de néonatologie en France.

BACKGROUND: The experience of becoming the parent of a sick or premature newborn can be particularly distressing for parents. They often encounter challenges to the development of their parenting roles. Perception of the hospital stay has never been analyzed on a large scale. OBJECTIVE: To analyze parents' perception of their involvement in the care of their newborn. METHODS: An internet-based survey started in France in February 2014 on the basis of a validated questionnaire composed of 222 neonatal care-related items. A quantitative and qualitative analysis was performed on the items dealing with parents' involvement until August 2014. RESULTS: The survey was completed by 1500 parents, 98 % of whom were mothers. The infants had a mean GA of 32 weeks and a mean birth weight of 1600g. Parents rated their first care of their infant with mixed emotions (joy, stress, etc.). Parents were willing to practice new skills through guided participation, even for more complex care. Skin-to-skin care was only proposed after 7 days for 20 % of the parents; 10 % of the parents did not feel secure during this practice. The need for privacy and professional guidance was essential for meaningful skin-to-skin contact. DISCUSSION: Parents' perception of participating actively in their infant's care was positive and they felt guided by the nursing team. Most of them would have been more active with guidance. Skin-to-skin care was appreciated and desired, but could become stressful if the conditions were not optimal.

[Language Delay: What is the Prognosis of Late Bloomers?]. / Sprachentwicklungsverzögerung: Was wird aus Late Bloomern?

BACKGROUND: 30-50% of late talkers catch-up their language delay during the third year of life. So far it is unclear whether this is a permanent or an illusionary recovery. The aim of the study was to examine the further language development of late bloomers. METHOD: Language skills of 83 three-year-old children (16 late bloomers [LB], 29 late talkers [LT] with persistent language problems, 38 Non-LT) were assessed with a standardized language test. Before school entry formal language skills, expressive and receptive vocabulary and precursors of written language (verbal memory, phonological awareness, verbal information-processing speed) were assessed. RESULTS: At follow-up before school entry LB scored below Non-LT on phonological memory test. 31% of the LB in contrast to 3% of the Non-LT had slight language problems. 38% had received speech-language therapy. Nevertheless, no LB met the criteria of developmental language disorder. The language skills of LT with persistent language problems remained significantly below the level of LB and Non-LT. Every fourth of these children was language impaired. CONCLUSION: LB as a group are not at risk for later clinically relevant language disorders. However, their language abilities are often within the lower range of normal variation. Therefore, it is recommended to facilitate their language acquisition either by kindergarten training programs or by parent-directed intervention programs to provide a more stimulating environment.

Improved reaction conditions for the synthesis of new NKP-1339 derivatives and preliminary investigations on their anticancer potential.

The very promising results of Na-trans-[RuCl4(1H-indazole)2] (NKP-1339) in clinical studies have fuelled renewed interest in the research and development of ruthenium(III) coordination compounds for cancer therapy. By applying an improved synthetic approach to this class of coordination compounds, six new examples of the general formula (cation)-trans-[RuCl4(azole)2], where (cation) = tetrabutylammonium (Bu4N)(+) (1, 2), sodium (3, 4), azolium (5, 6), and azole = 1-methyl-indazole (1, 3, 5), 1-ethyl-indazole (2, 4, 6), have been prepared. All compounds have been characterized by elemental analysis, electrospray ionization (ESI) mass spectrometry, UV-vis-, and NMR-spectroscopy and, if possible, X-ray diffraction analysis. Furthermore, the influence of the alkyl substituent at the position N1 of the indazole backbone on the stability in aqueous media as well as on the biological activity in three human cancer cell lines (CH1, A549, and SW480) and on the cellular accumulation in SW480 cells is discussed.