The development of a stable oral solution of captopril for paediatric patients

Study objectives: Many major drugs are not available in paediatric form. The aim of this study was to develop a stable liquid solution of captopril for oral paediatric use allowing individualised dosage and easy administration to newborn and young patients. Methods: A specific HPLC-UV method was developed. In a pilot study, a number of formulations described in the literature as affording one-month stability were examined. In the proper long-term study, the formulation that gave the best results was then prepared in large batches and its stability monitored for two years at 5°C and room temperature, and for one year at 40°C. Results: Most formulations described in the literature were found wanting in our pilot study. A simple solution of the drug (1 mg/mL) in purified water (European Pharmacopeia) containing 0.1% disodium edetate (EDTA-Na) as preservative proved chemically and microbiologically stable at 5°C and room temperature for two years. Conclusion: The proposed in-house formulation fulfils stringent criteria of purity and stability and is fully acceptable for oral administration to newborn and young patients.

Parenteral nutrition in the intensive care unit: cautious use improves outcome.

Critical illness is characterised by nutritional and metabolic disorders, resulting in increased muscle catabolism, fat-free mass loss, and hyperglycaemia. The objective of the nutritional support is to limit fat-free mass loss, which has negative consequences on clinical outcome and recovery. Early enteral nutrition is recommended by current guidelines as the first choice feeding route in ICU patients. However, enteral nutrition alone is frequently associated with insufficient coverage of the energy requirements, and subsequently energy deficit is correlated to worsened clinical outcome. Controlled trials have demonstrated that, in case of failure or contraindications to full enteral nutrition, parenteral nutrition administration on top of insufficient enteral nutrition within the first four days after admission could improve the clinical outcome, and may attenuate fat-free mass loss. Parenteral nutrition is cautious if all-in-one solutions are used, glycaemia controlled, and overnutrition avoided. Conversely, the systematic use of parenteral nutrition in the ICU patients without clear indication is not recommended during the first 48 hours. Specific methods, such as thigh ultra-sound imaging, 3rd lumbar vertebra-targeted computerised tomography and bioimpedance electrical analysis, may be helpful in the future to monitor fat-free mass during the ICU stay. Clinical studies are warranted to demonstrate whether an optimal nutritional management during the ICU stay promotes muscle mass and function, the recovery after critical illness and reduces the overall costs.

Notes et extraits de Pierre-François CHIFFLET, concernant principalement la Franche-Comté et la Bourgogne.

On remarque : « Ex Glossario pervetusto » (f. 3) ; — « Ex chartis ecclesiae de Caritate » (f. 10) ; — « Ex veteri membrana et ex antiquo circulo depicto propè altare Maurimonasterii in Alsatia » (f. 10) ; — « Ex chartis R. P. Stephani Voyrin » (f. 11) ; — « Episcopi Metenses, ex ms. codice Sancti Arnulfi Metensis » (f. 12 v°) ; — Lettre de Hugues Métel à Gerland (f. 14) ; — « Ex variis catalogis sanctorum » (f. 14) ; — « Ex archivio ecclesiae Beatae Magdalenae [Bisuntinae] » (f. 17) ; — « Ex archivio Sancti Vincentii Bisont[ini] » (f. 18) ; — « Ex archivio monasterii Bellaevallis » [Bisuntinae dioecesis] (f. 20) ; — « Ex veteri necrologio Sancti Stephani [Bisuntini], quod est ad margines Martyrologii Bedae perantiqui, ad ejusdem ecclesiae usum accommodati » [cf. ms. de Besançon 712] (f. 23 v°) ; — « Inter martyrologium et regulam, seu librum primum concilii Aquisgranensis, habetur haec sententia absolutionis » (f. 25) ; — « Ante veterem Ordinem Romanum, qui est Liber Pontificalis, habentur sequentes formulae praestandae obedientiae archiepiscopis et ecclesiae Bisuntinae » (f. 25 v°) ; — « Alia ex archivo archiepiscopi [Bisuntini] » (f. 26 v°) ; — « Ex archivio Balernensi » (f. 27 v°) ; — « Ex variis sanctorum historiis manuscriptis » (f. 30) ; — « Extraits concernant Tournus » (f. 34 v°), — notamment : « Ex codice manuscripto Trenorchiensi, membraneo, quod vocare possis Registrum Trenorchiense, incipiens ab anno 1222 et desinens in 1296 ; inscribitur : Feoda ecclesiae Trenorchiensis » (f. 37) ; — « Ex notis R. P. Voyrini » [cf. supra, f. 11] (f. 49) ; — « Inscriptio vetus Luxoviensis » (f. 50 v°) ; — Notes historiques, concernant principalement des abbayes comtoises (f. 51) ; — « Scriptores rerum Burgundicarum » (f. 52) ; — « Ex parvo chartulari Sancti Benigni [Divionensis] » (f. 52 v°) ; — « Ex libro anniversariorum Sancti Benigni [Divionensis] », 1579-1629 (f. 52 v°) ; — « Ex chartulari Sancti Symphoriani Augustodunensis » (f. 53) ; — « Ex chartulari Sancti Marcelli Cabilonensis » (f. 53 v°) ; — « Ex chartulari S. Sequani » [Lingonensis dioecesis] (f. 54 v°) ; — « Ex chartulari Sanctae Capellae Divionensis » (f. 55) ; — « Ex chartulari cathedralis Augustodunensis » (f. 55 v°) ; — « Ex tomo priore chartularis Sancti Stephani Divionensis » (f. 56) ; — « Ex chartulari Cluniacensi » (f. 57) ; — « Ex apographo chartularis Matisconensis, cujus autographum vetus dicebatur Liber catenatus » (f. 57 v°) ; — « Ex chartulari Patriciaci, qui est prioratus dependens a Floriacensi abbatia, situs in comitatu Kadrellensi, dioecesi Augustodunensi » (f. 58 v°) ; — Extraits concernant Autun et les comtes d'Autun (f. 60 v°) ; — « Ex autographis Sancti Benigni Divionensis » (f. 61) ; — « Iterum ex chartulari Sancti Stephani Divionensis » (f. 61) ; — « Ex autographis monasterii puellarum Tartensis » (f. 62) ; — « Iterum ex tabulario Cluniacensi, adnotatis paginis » (f. 62 v°) ; — « Ex majore tabulario ecclesiae Cabilonensis, quod digessit Johannes Germani, Cabilonensis episcopus » (f. 64 v°) ; — « Ex tabulario abbatiae de Buxeria » (f. 65) ; — « Ex autographis monialium Benedictinarum de Pralon » (f. 66) ; — « Ex autographis prioratus Vallis Beatae Mariae juxta Talant, de Ordine Vallis Scholarium, vulgò Bonvau » (f. 66) ; — « Ex kalendario pervetusto Sancti Benigni Divionensis » (f. 66 v°) ; — « Ex martyrologio proprio Sancti Martini Eduensis » (f. 67) ; — « Ex necrologio Sancti Lazari Aeduensis » (f. 67) ; — « Ex chronico Sancti Petri Vivi Senonensis » (f. 67) ; — « Ex chronico S. Medardi Suessionensis » (f. 68) ; — « Ex brevi chronico Sancti Dionysii ad cyclos paschales » (f. 68) ; — « De Saracenis in Gallia profligatis » (f. 69) ; — « Ex necrologio Sancti Augendi Jurensis » (f. 74) ; — « Ex necrologio Sancti Petri Bisuntini » (f. 74) ; — « Ex necrologio veteri Sancti Stephani [Bisuntini] » (f. 74 v°) ; — « Ex registro Innocentii papae VI, anni IX pontificatus, Christi 1361 » (f. 82) ; — « Ex tabulis capituli Sancti Dionysii de Vergeyo, nunc Nuciacensis » (f. 83) ; — « Ex manuscripto codice donationum 208 Joannis, comitis Burgundiae et domini Salinensis, super puteum Salinarum » (f. 89 v°) ; — « Ex archivo Sancti Anatolii Salinensis ; ex magno necrologio chartaceo eique simili membraneo, composito 1390 » (f. 92) ; — « Ex chartis prioratus de Marthereto prope Vesulium » (f. 94) ; — « Ex archivo Sancti Pauli Bisonticensis » (f. 95) ; — « Ex veteri chartulario Sancti Pauli [Bisonticensis] » (f. 95 v°) ; — « Ex veteri manuscripto codice Sancti Pauli [Bisonticensis] » (f. 96) ; — « Ex antiquioribus libris ecclesiae Sancti Stephani [Bisonticensis], scriptis aut in usum adhibitis tempore Hugonis primi, [archiepiscopi Bisonticensis] » (f. 96 v°) ; — « Ex codice Sancti Stephani [Bisonticensis] pervetusto, qui Bisonticensis ecclesiae sacros ritus continet » (f. 97) ; — « Ex antiquis codicibus Sancti Pauli [Bisonticensis] » (f. 98) ; — « Ex antiquo rituum libro » (f. 98) ; — « Ex antiquis letaniis, tempore Hugonis I, [archiepiscopi Bisuntini], in ecclesia Bisontina cani solitis ; ex manuscriptis Sancti Stephani et Sancti Pauli » (f. 99) ; — « Extraits de plusieurs manuscrits de Saint-Paul de Besançon » (f. 99 v°) ; — « Ex manuscripto codice Sanctae Magdalenae [Bisuntinae] » (f. 101) ; — Inscription trouvée à Saint-Ferjeux, en 1627 (f. 101 v°) ; — « Ex antiquis membranis archivii ecclesiae metropolitanae Bisontinae », extraits de bulles pontificales, etc. (f. 102) ; — « Ex archivio Loci Crescentis seu Trium Regum » (f. 105) ; — Notes empruntées, « ut videtur », à Anselme « de Marenchiis » (f. 106) ; — « Ex actis capituli Bisontini » (f. 106 v°) ; — « Ex obitibus adnotatis ad marginem martyrologii cathedralis Aeduensis » (f. 106 v°) ; — Fragment de chronique, 563-1033, tiré « ex veteri membrana monasterii Sancti Augendi » (f. 107) ; — « Ex alia membrana, post chronicon Engolismense » (f. 107) ; — « Ex archivio abbatiae de Aceyo » (f. 108) ; — « Ex archivio abbatiae de Roseriis » (f. 109) ; — « Extrait d'un tome des recognoissances des fiefs du Charolois » (f. 109 v°) ; — « Ex polypthico Sancti Vincentii Cabilonensis » (f. 114) ; — « Ex Aeneae, Parisiensis episcopi, collectione contra Graecos, Biblioth. Thuan., n. 444 » (f. 114) ; — « Consuetudines Cluniacenses, auctore Wdalrico, monacho Cluniacensi » (f. 115) ; — Inscriptions copiées « in pervetusto manuscripto codice, post Persii satyras », etc. (f. 116) ; — Extraits d'une « Vita metrica sancti Eustachii martyris, cognomine Placidae », contenue « in manuscripto codice Cisterciensi », etc. (f. 116 v°) ; — « De archiepiscopis Bisontinis » (f. 119) ; — « Ex archivio capituli Bisontini » (f. 120 v°) ; — « Notitia nostrorum diplomatum » (f. 124-135 r° , 141 r° , 142 v° et 143 r°) ; — « De comitibus Burgundiae in Sancti Stephani basilica Bisontina sepultis, ex veteri membrana archivi ecclesiae metropolitanae » (f. 135 v°) ; — Lettre autogr. de « Pierre-François Chifflet » [à Baluze], Dijon, 18 mars 1657 (f. 161) ; — Fragment de charte, « extrait du thresor de S. Anatoile de Salins » (f. 162) ; — Lettre autogr. de « [fr.] François Du Chemin » à Chifflet, Cîteaux, 16 mai 1657 (f. 167) ; — « Nova regum Francorum series, a quâ Theodericus II et omnes ejus posteri excluduntur, ex manuscripto codice Fontanetensi » (f. 171) ; — « Vita sancti Theutbaldi, Viennensis archiepiscopi », incomplète [Bibliotheca hagiographica latina, 8044 b] (f. 172 et 172 bis) ; — « Ex chartulario Sancti Germani Autisiodorensis », diplômes carolingiens (f. 174) ; — Fragment d'une lettre [adressée vraisemblablement à Chifflet], Paris, octobre 1670 (f. 177) ; — Extraits « ex vitâ sancti Theutbaldi, Viennensis archiepiscopi..., ex manuscripto codice monasterii Sancti Theuderii, ubi sanctus Theobaldus, Viennensis archiepiscopus, requiescit » [extraits de la vie dont un fragment occupe les feuillets 172 et 172 bis] (f. 178) ; — Lettre autogr. de « P[ierre-] F[rançois] Chifflet » [à Baluze], 10 mars (f. 180) ; — Notes sur saint Théobald, archevêque de Vienne (f. 181). Cf. Ulysse Robert, Catalogue des manuscrits relatifs à la Franche-Comté, qui sont conservés dans les bibliothèques publiques de Paris (1878), p. 161-162.

Changes of beta-amyloid precursor protein splice patterns in brain cell aggregate cultures.

The splice pattern of beta-amyloid precursor protein (beta-APP) has been studied in a variety of neuronal and glial cells and in brain cell aggregate cultures by the polymerase chain reaction (PCR). The brain-typical pattern, in which beta-APP695 is the dominant form, has been found only in aggregate cultures but not in any of the other cell types including neuronal cell lines. Selective elimination of glial cells from aggregates resulted in increased quantities of beta-APP695, whereas removal of neurons led to a reduction of beta-APP695 and to an elevation of beta-APP751 and beta-APP770. This shift of splice pattern was not observed in cocultures of the neuronal cell line PC 12 with primary astrocytes combined in a variety of cellular ratios. Blood serum, which is an essential component of these cultures, tested on aggregates, did not reduce the amount of beta-APP695 or have any marked effects on splice patterns generally. From these results it is concluded that investigations on brain-typical splicing of beta-APP require primary neurons. Neuronal cell lines may be no suitable model systems. Splicing events favoring production of beta-APP695 may mark an important, very early step of amyloid formation in the brain.

SOCS3 Transactivation by PPARγ Prevents IL-17-Driven Cancer Growth.

Activation of the transcription factor PPARγ by the n-3 fatty acid docosahexaenoic acid (DHA) is implicated in controlling proinflammatory cytokine secretion, but the intracellular signaling pathways engaged by PPARγ are incompletely characterized. Here, we identify the adapter-encoding gene SOCS3 as a critical transcriptional target of PPARγ. SOCS3 promoter binding and gene transactivation by PPARγ was associated with a repression in differentiation of proinflammatory T-helper (TH)17 cells. Accordingly, TH17 cells induced in vitro displayed increased SOCS3 expression and diminished capacity to produce interleukin (IL)-17 following activation of PPARγ by DHA. Furthermore, naïve CD4 T cells derived from mice fed a DHA-enriched diet displayed less capability to differentiate into TH17 cells. In two different mouse models of cancer, DHA prevented tumor outgrowth and angiogenesis in an IL-17-dependent manner. Altogether, our results uncover a novel molecular pathway by which PPARγ-induced SOCS3 expression prevents IL-17-mediated cancer growth. Cancer Res; 73(12); 3578-90. ©2013 AACR.

Comparison of C-reactive protein and white blood cell count with differential in neonates at risk for septicaemia.

We prospectively compared the diagnostic value of C-reactive protein (CRP) and white blood cell counts for detection of neonatal septicaemia. Sensitivity and specifity in receiver operating characteristics, and positive and negative predictive value of CRP and white blood cell count were compared in 195 critically ill preterm and term newborns clinically suspected of infection. Blood cultures were positive in 33 cases. During the first 3 days after birth CRP elevation (sensitivity 75%, specifity 86%), leukopenia (67%/90%), neutropenia (78%/80%) and immature to total neutrophil count (I/T) ratio (78%/73%) were good diagnostic parameters, as opposed to band forms with absolute count (84%/66%) or percentage (79%/71%), thrombocytopenia (65%/57%) and toxic granulations (44%/94%). Beyond 3 days of age elevated CRP (88%/87%) was the best parameter. Increased total (84%/66%) or percentage band count (79%/71%) were also useful. Leukocytosis (74%/56%), increased neutrophils (67%/65%), I/T ratio (79%/47%), thrombocytopenia (65%/57%) and toxic granulations had a low specifity. The positive predictive value of CRP was 32% before and 37% after 3 days of age, that of leukopenia was 37% in the first 3 days. CONCLUSION: During the first 3 days of life CRP, leukopenia and neutropenia were comparably good tests while after 3 days of life CRP was the best single test in early detection of neonatal septicaemia. Serial CRP estimations confirm the diagnosis, monitor the course of infection and the efficacy of antibiotic treatment.

Quantitative analysis of crystal/grain sizes and their distributions in 2D and 3D

We review methods to estimate the average crystal (grain) size and the crystal (grain) size distribution in solid rocks. Average grain sizes often provide the base for stress estimates or rheological calculations requiring the quantification of grain sizes in a rock's microstructure. The primary data for grain size data are either 1D (i.e. line intercept methods), 2D (area analysis) or 3D (e.g., computed tomography, serial sectioning). These data have been used for different data treatments over the years, whereas several studies assume a certain probability function (e.g., logarithm, square root) to calculate statistical parameters as the mean, median, mode or the skewness of a crystal size distribution. The finally calculated average grain sizes have to be compatible between the different grain size estimation approaches in order to be properly applied, for example, in paleo-piezometers or grain size sensitive flow laws. Such compatibility is tested for different data treatments using one- and two-dimensional measurements. We propose an empirical conversion matrix for different datasets. These conversion factors provide the option to make different datasets compatible with each other, although the primary calculations were obtained in different ways. In order to present an average grain size, we propose to use the area-weighted and volume-weighted mean in the case of unimodal grain size distributions, respectively, for 2D and 3D measurements. The shape of the crystal size distribution is important for studies of nucleation and growth of minerals. The shape of the crystal size distribution of garnet populations is compared between different 2D and 3D measurements, which are serial sectioning and computed tomography. The comparison of different direct measured 3D data; stereological data and direct presented 20 data show the problems of the quality of the smallest grain sizes and the overestimation of small grain sizes in stereological tools, depending on the type of CSD. (C) 2011 Published by Elsevier Ltd.

In vivo imaging of T cell delivery to tumors after adoptive transfer therapy.

Adoptive transfer therapy of in vitro-expanded tumor-specific cytolytic T lymphocytes (CTLs) can mediate objective cancer regression in patients. Yet, technical limitations hamper precise monitoring of posttherapy T cell responses. Here we show in a mouse model that fused single photon emission computed tomography and x-ray computed tomography allows quantitative whole-body imaging of (111)In-oxine-labeled CTLs at tumor sites. Assessment of CTL localization is rapid, noninvasive, three-dimensional, and can be repeated for longitudinal analyses. We compared the effects of lymphodepletion before adoptive transfer on CTL recruitment and report that combined treatment increased intratumoral delivery of CTLs and improved antitumor efficacy. Because (111)In-oxine is a Food and Drug Administration-approved clinical agent, and human SPECT-CT systems are available, this approach should be clinically translatable, insofar as it may assess the efficacy of immunization procedures in individual patients and lead to development of more effective therapies.

Nutrition parentérale compé- mentaire de la nutrition entérale aux soins intensifs: une association logique [Supplemental parenteral nutrition for intensive care patients: a logical combination with enteral nutrition]

Undernutrition is a widespread problem in the intensive care and is associated with a worse clinical outcome. Enteral nutrition is the recommended nutritional support in ICU patients. However, enteral nutrition is frequently insufficient to cover protein-energy needs. The initiation of supplemental parenteral nutrition, when enteral nutrition is insufficient, could optimize the nutritional therapy. Such a combination could allow reducing morbidity, length of stay and recovery, as well as improving quality of life and health care costs. Prospective studies are currently underway to test this hypothesis.