[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.

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.

[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.

Temsirolimus combined with sorafenib in hepatocellular carcinoma: a phase I dose-finding trial with pharmacokinetic and biomarker correlates.

BACKGROUND: Based upon preclinical evidence for improved antitumor activity in combination, this phase I study investigated the maximum-tolerated dose (MTD), safety, activity, pharmacokinetics (PK), and biomarkers of the mammalian target of rapamycin inhibitor, temsirolimus, combined with sorafenib in hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Patients with incurable HCC and Child Pugh score ≤B7 were treated with sorafenib plus temsirolimus by 3 + 3 design. The dose-limiting toxicity (DLT) interval was 28 days. The response was assessed every two cycles. PK of temsirolimus was measured in a cohort at MTD. RESULTS: Twenty-five patients were enrolled. The MTD was temsirolimus 10 mg weekly plus sorafenib 200 mg twice daily. Among 18 patients at MTD, DLT included grade 3 hand-foot skin reaction (HFSR) and grade 3 thrombocytopenia. Grade 3 or 4 related adverse events at MTD included hypophosphatemia (33%), infection (22%), thrombocytopenia (17%), HFSR (11%), and fatigue (11%). With sorafenib, temsirolimus clearance was more rapid (P < 0.05). Two patients (8%) had a confirmed partial response (PR); 15 (60%) had stable disease (SD). Alpha-fetoprotein (AFP) declined ≥50% in 60% assessable patients. CONCLUSION: The MTD of sorafenib plus temsirolimus in HCC was lower than in other tumor types. HCC-specific phase I studies are necessary. The observed efficacy warrants further study.

Implementing enzyme-linked immunosorbent assays on a microfluidic chip to quantify intracellular molecules in single cells.

Cell-to-cell differences play a key role in the ability of cell populations to adapt and evolve, and they are considered to impact the development of several diseases. Recent advances in microsystem technology provide promising solutions for single-cell studies. However, the quantitative chemical analysis of single-cell lysates remains difficult. Here, we combine a microfluidic device with the analytical strength of enzyme-linked immunosorbent assays (ELISA) for single-cell studies to reliably identify intracellular proteins, secondary messengers, or metabolites. The microfluidic device allows parallel single-cell trapping and isolation in 625-pL microchambers, repeated treatment and washing steps, subsequent lysis and analysis by ELISA. Using a sandwich ELISA, we quantitatively determined the concentration of the enzyme GAPDH in single U937 cells and HEK 293 cells, and found amounts within a range of a few (1-4) attomol per cell. Furthermore, a competitive ELISA is performed to determine the concentration of the secondary messenger cyclic adenosine monophosphate (cAMP) in MLT cells, in response to the hormone lutropin. We found the half maximal effective concentration (EC50) of lutropin to have an average value of 2.51 ± 0.44 ng/mL. Surprisingly, there were large cell-to-cell variations for all supplied lutropin concentrations, ranging from 36 to 536 attomol cAMP for nonstimulated cells and from 80 to 1040 attomol cAMP for a concentration around the EC50 (3 ng/mL). Because of the high sensitivity and specificity of ELISA and the large number of antibodies available, we believe that our device provides a new, powerful means for single-cell proteomics and metabolomics.

F-spondin regulates neuronal survival through activation of disabled-1 in the chicken ciliary ganglion.

The extracellular membrane-associated protein F-spondin has been implicated in cell-matrix and cell-cell adhesion and plays an important role in axonal pathfinding. We report here that F-spondin is expressed in non-neuronal cells in the embryonic chicken ciliary ganglion (CG) and robustly promotes survival of cultured CG neurons. Using deletion constructs of F-spondin we found that the amino-terminal Reelin/Spondin domain cooperates with thrombospondin type 1 repeat (TSR) 6, a functional TGFß-activation domain. In ovo treatment with blocking antibodies raised against the Reelin/Spondin domain or the TSR-domains caused increased apoptosis of CG neurons during the phase of programmed cell death and loss of about 30% of the neurons compared to controls. The Reelin/Spondin domain receptor - APP and its downstream signalling molecule disabled-1 are expressed in CG neurons. F-spondin induced rapid phosphorylation of disabled-1. Moreover, both blocking the central APP domain and interference with disabled-1 signalling disrupted the survival promoting effect of F-spondin. Taken together, our data suggest that F-spondin can promote neuron survival by a mechanism involving the Reelin/Spondin and the TSR domains.

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.

[Complex umbilical cord vein pulsations in cases with twin-twin transfusion syndrome: prognostic implications]. / Komplexe Pulsationen in der Nabelschnurvene beim feto-fetalen Transfusionssyndrom: prognostische Aussagekraft.

PURPOSE: Umbilical vein pulsations (UV-P) are due to various etiologies. The aim of the present study was to investigate the incidence and type of UV-P in monochorionic twins with twin-twin transfusion syndrome (TTTS). MATERIALS AND METHODS: TTTS cases diagnosed between 1999 and 2009 were examined retrospectively. The UV flow pattern taken from a free floating loop of the umbilical cord was classified as "non-pulsatile" (NP), "monophasic" (MP) and "complex" (CP). Only Doppler flow analyses prior to intervention were examined. RESULTS: Of 106 cases seen during the study period, 56 cases met the inclusion criteria. Of those, 62.5% were classified as stage III TTTS, and fetoscopic laser therapy was performed in 45 cases. NP flow patterns were more likely found in the donor twin (80.4 vs. 28.6%; p < 0.0001), while the incidence of MP (50 vs. 17.9%; p < 0.0006) and CP flow patterns (21.4 vs. 1.7%; p < 0.01) was higher in the recipient twin. Moreover, the perinatal mortality was highest in cases with CP (CP: 76.9 vs. MP 42.1 vs. NP: 26.2%; p < 0.01) as well as the rate of cases with double death. CONCLUSION: CP patterns are more frequently found in the recipient twin and are associated with a considerably high mortality rate. Studying the umbilical vein flow pattern in TTTS may provide additional information for counseling and prognosis similar to that obtained by expensive fetal echocardiography.

[Diagnostic accuracy of language tests and parent rating for identifying language disorders]. / Diagnostische Zuverlässigkeit von Sprachtests und Elternrating bei Sprachentwicklungsstörungen.

BACKGROUND: Until now German language tests have been rarely evaluated for their diagnostic accuracy. The goal of the study was to determine whether frequently used German language instruments are valid measures for identifying developmental language disorders in 3-year-old children. MATERIAL AND METHODS: The language test SETK 3-5 (including the short version SSV) and the parent questionnaire SBE-3-KT were administered to 88 children with and without language impairment. The procedure of the selection of children enabled an extrapolation to general population. A language sample rating was used as a gold standard. RESULTS: Depending on case definition 6-22% of children were classified as language impaired by SETK 3-5, 9% by SSV and 15% by SBE-3-KT. Sensitivity, specificity and positive predictive values of SETK 3-5 for specified cut-offs were 35-93%, 86-97% and 41-58%, respectively. The corresponding values of SSV were 49%, 96%, 56% and of SBE-3-KT 92%, 93%, 59%. CONCLUSIONS: 3-year-old children with developmental language disorders can been identified with sufficient accuracy by means of SETK 3-5, an individual language test, as well as by SBE-3-KT, a parent questionnaire. However, the number of false positive classifications is relatively high. The hit rate of SSV, an individual short test, was too low for clinical use.

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.

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.

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.

[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.

Clear air turbulence: detection by infrared observations of water vapor.

"Forward-looking" infrared measurements of water vapor from the C-141A Kuiper Airborne Observatory of the National Aeronautics and Space Administration Ames Research Center show large, distinctly identifiable, signal anomalies from 4 to 10 minutes in advance of subsequent encounters with clear air turbulence (CAT). These anomalies are characteristically different from the signals not followed by CAT encounters. Results of airborne field trials in which the infrared radiometer was used indicate that, out of 51 situations, 80 percent were CAT alerts followed by CAT encounters, 12 percent were "false alarms" (CAT alerts not followed by CAT encounters), and 8 percent were CAT encounters not preceded by an infrared signal anomaly or CAT alert.

Spectral analysis of tropospheric aerosol measurements obtained with a new fast response sensor.

A new fast response sensor was used in aircraft studies of fluctuations in the size distributions of tropospheric aerosol and their relation to fluctuations of trace gas concentrations and light scattering coefficients. Spectral analysis of data upwind of Buffalo, New York, and Houston, Texas, suggests important roles for atmospheric turbulence and chemical reaction in aerosol fluctuations.

Water vapor: stratospheric injection by thunderstorms.

Infrared radiometric inference measurements of the mass of water vapor injected into the lower stratosphere and upper troposphere by a number of plains thunderstorms show an average threefold increase over the fair weather background mass of water vapor. These airborne measurements, made from the National Aeronautics and Space Admninistration Convair 990 jet laboratory, extended over a sample size much larger than that possible by balloon and other techniques.

Clear air turbulence: an airborne alert system.

An infrared radiometer system has been developed that can alert a pilot of an aircraft 2 to 9 minutes in advance of an encounter with clear air turbulence. The time between the warning and the clear air turbulence event varies with the flight altitude of the aircraft. In turbulence-free areas, the incidence of false alarms is found to be less than one in 3.4 hours of flight time compared to less than one per 10 hours of flight time in areas with turbulence.

Crystal structures of human topoisomerase I in covalent and noncovalent complexes with DNA.

Topoisomerases I promote the relaxation of DNA superhelical tension by introducing a transient single-stranded break in duplex DNA and are vital for the processes of replication, transcription, and recombination. The crystal structures at 2.1 and 2.5 angstrom resolution of reconstituted human topoisomerase I comprising the core and carboxyl-terminal domains in covalent and noncovalent complexes with 22-base pair DNA duplexes reveal an enzyme that "clamps" around essentially B-form DNA. The core domain and the first eight residues of the carboxyl-terminal domain of the enzyme, including the active-site nucleophile tyrosine-723, share significant structural similarity with the bacteriophage family of DNA integrases. A binding mode for the anticancer drug camptothecin is proposed on the basis of chemical and biochemical information combined with these three-dimensional structures of topoisomerase I-DNA complexes.

Effect of monovalent salt on the conformation of polyelectrolyte-surfactant complexes.

We study the conformation of polyelectrolyte-surfactant complexes in the presence of monovalent salt. A simple model for the formation of these structures is presented in the framework of the Debye-Hückel-Bjerrum-Manning and Flory theories, with the hydrophobic interactions between the hydrocarbon tails of surfactant molecules treated in the spirit of van der Waals theory as an effective attraction. The extension of the polyelectrolyte-surfactant complexes is analyzed as a function of the salt concentration and a discrete conformational transition between a compact globule and an elongated coil is found, in agreement with experimental results for the unfolding transition of a DNA-cationic surfactant complex.

[Minimally invasive fixation of a sacral bilateral fracture with lumbopelvic dissociation]. / Minimal-invasive Stabilisierung einer bilateralen Sakrumfraktur mit lumbopelviner Dissoziation.

This case report describes our technique of percutaneous sacroiliac screw fixation of a bilateral sacral fracture with spinopelvic dissociation. It is based on the description of an iliosacroiliac bony corridor delimited by the following landmarks: the sacral ala in a superior-anterior direction, the first sacral foramen on both sides in an inferior-posterior direction, and the sacral channel posteriorly. The described operating method, which uses a 6.5-mm parallel drill sleeve, allows the safe and strictly transversal positioning of a 7.3-mm screw on each side with the threads interlocking. It provides a separate and fracture-adapted compression of the screws. The interlocking SI screw threads increase the pull-out strength. Operating time and radiation dose can be reduced significantly by this method.