Chesterfield County, Virginia, its history and present condition. Prepared under the supervision of John B. Watkins, as authorized by the Board of Supervisors of the county, August, 1906.

Mode of access: Internet.

TAC3/TACR3 Mutations Reveal Preferential Activation of Gonadotropin-Releasing Hormone Release by Neurokinin B in Neonatal Life Followed by Reversal in Adulthood

Context: Mutations in TAC3 and TACR3 (encoding neurokinin B and its receptor) have been identified in Turkish patients with idiopathic hypogonadotropic hypogonadism (IHH), but broader populations have not yet been tested and genotype-phenotype correlations have not been established. Objective: A broad cohort of normosmic IHH probands was screened for mutations in TAC3/TACR3 to evaluate the prevalence of such mutations and define the genotype/phenotype relationships. Design and Setting: The study consisted of sequencing of TAC3/TACR3, in vitro functional assays, and neuroendocrine phenotyping conducted in tertiary care centers worldwide. Patients or Other Participants: 345 probands, 18 family members, and 292 controls were studied. Intervention: Reproductive phenotypes throughout reproductive life and before and after therapy were examined. Main Outcome Measure: Rare sequence variants in TAC3/TACR3 were detected. Results: In TACR3, 19 probands harbored 13 distinct coding sequence rare nucleotide variants [three nonsense mutations, six nonsynonymous, four synonymous (one predicted to affect splicing)]. In TAC3, one homozygous single base pair deletion was identified, resulting in complete loss of the neurokinin B decapeptide. Phenotypic information was available on 16 males and seven females with coding sequence variants in TACR3/TAC3. Of the 16 males, 15 had microphallus; none of the females had spontaneous thelarche. Seven of the 16 males and five of the seven females were assessed after discontinuation of therapy; six of the seven males and four of the five females demonstrated evidence for reversibility of their hypogonadotropism. Conclusions: Mutations in the neurokinin B pathway are relatively common as causes of hypogonadism. Although the neurokinin B pathway appears essential during early sexual development, its importance in sustaining the integrity of the hypothalamic-pituitary-gonadal axis appears attenuated over time. (J Clin Endocrinol Metab 95: 2857-2867, 2010)

A randomized trial of amphotericin B alone or in combination with itraconazole in the treatment of mucocutaneous leishmaniasis

A randomized trial of amphotericin B (AB) alone and in combination with oral itraconazole (IZ) is carried out in two groups of 10 mucocutaneous leishmaniasis patients from Bolivia and Peru. AB+IZ combination is no better than AB monotherapy, as far as efficacy and tolerability are concerned. No antagonism was detected.

When do we dare to stop biological or immunomodulatory therapy for Crohn's disease? Results of a multidisciplinary European expert panel.

BACKGROUND: Safety and economic issues have increasingly raised concerns about the long term use of immunomodulators or biologics as maintenance therapies for Crohn's disease (CD). Despite emerging evidence suggesting that stopping therapy might be an option for low risk patients, criteria identifying target groups for this strategy are missing, and there is a lack of recommendations regarding this question. METHODS: Multidisciplinary European expert panel (EPACT-II Update) rated the appropriateness of stopping therapy in CD patients in remission. We used the RAND/UCLA Appropriateness Method, and included the following variables: presence of clinical and/or endoscopic remission, CRP level, fecal calprotectin level, prior surgery for CD, and duration of remission (1, 2 or 4 years). RESULTS: Before considering withdrawing therapy, the prerequisites of a C-reactive protein (CRP) and fecal calprotectin measurement were rated as "appropriate" by the panellists, whereas a radiological evaluation was considered as being of "uncertain" appropriateness. Ileo-colonoscopy was considered appropriate 1 year after surgery or after 4 years in the absence of prior surgery. Stopping azathioprine, 6-mercaptopurine or methotrexate mono-therapy was judged appropriate after 4 years of clinical remission. Withdrawing anti-TNF mono-therapy was judged appropriate after 2 years in case of clinical and endoscopic remission, and after 4 years of clinical remission. In case of combined therapy, anti-TNF withdrawal, while continuing the immunomodulator, was considered appropriate after two years of clinical remission. CONCLUSION: A multidisciplinary European expert panel proposed for the first time treatment stopping rules for patients in clinical and/or endoscopic remission, with normal CRP and fecal calprotectin levels.

Vitamin E but not 17B-estradiol protect against vascular toxicity induced by B-amyloid wild type and the Dutch amyploid variant

Amyloid β-peptide (Aβ) fibril deposition on cerebral vessels produces cerebral amyloid angiopathy that appears in the majority of Alzheimer's disease patients. An early onset of a cerebral amyloid angiopathy variant called hereditary cerebral hemorrhage with amyloidosis of the Dutch type is caused by a point mutation in Aβ yielding AβGlu22→Gln. The present study addresses the effect of amyloid fibrils from both wild-type and mutated Aβ on vascular cells, as well as the putative protective role of antioxidants on amyloid angiopathy. For this purpose, we studied the cytotoxicity induced by Aβ1–40 Glu22→Gln and Aβ1–40 wild-type fibrils on human venule endothelial cells and rat aorta smooth muscle cells. We observed that AβGlu22→Gln fibrils are more toxic for vascular cells than the wild-type fibrils. We also evaluated the cytotoxicity of Aβ fibrils bound with acetylcholinesterase (AChE), a common component of amyloid deposits. Aβ1–40 wild-type–AChE fibrillar complexes, similar to neuronal cells, resulted in an increased toxicity on vascular cells. Previous reports showing that antioxidants are able to reduce the toxicity of Aβ fibrils on neuronal cells prompted us to test the effect of vitamin E, vitamin C, and 17β-estradiol on vascular damage induced by Aβwild-type and AβGlu22→Gln. Our data indicate that vitamin E attenuated significantly the Aβ-mediated cytotoxicity on vascular cells, although 17β-estradiol and vitamin C failed to inhibit the cytotoxicity induced by Aβ fibrils.

Recueil de documents relatifs principalement aux guerres de religion en France, en 1587 et 1591, et aux négociations pour la paix entre les Pays-Bas et l'Espagne, en 1607 et 1608.

Contient : 1 « Prothocolle journal... dressé par [PHILIPPE DE] LA HUGUERIE,... de toutes les actions, deliberations et conseils du dernier voyage de guerre fait en France pour le secours des eglises reformées dudit royaulme » par le baron Fabien de Donaw ; 2 Lettres écrites au baron de Donaw ou en sa faveur ; 1 à 8 Huit lettres de « HENRY » IV ; 1 à 6 au baron de Donaw ; 1 « De Castelgeloux, ce 17 febvrier 1586 ». Copie ; 2 « 25 janvier 1587 ». Copie ; 3 « 12 may 1587 » ; 4 « 3 juin 1587 » ; 5 « A Baugency, ce 21 may 1589 ». Copie ; 6 « Escrit au camp devant Noyon, ce 8 jour d'aoust 1591 ». Copie ; 7 « à Mr l'electeur palatin [Frédéric IV]... Escrit au camp de Marueil, le 12 jour de juillet 1591 ». Copie ; 8 « à Mr le marquis d'Anspach,... Escrit au camp de Marueil, 12 juillet 1591 ». Copie ; 9 Lettre de « HENRY DE BOURBON,... prince DE CONDE,... A S. Jean d'Angely, le 20 may 1587 ». Copie ; 10 « Copie de la « lettre de [FRANÇOIS DE COLIGNY, seigneur DE] CHASTILLON [gouverneur de Montpellier]... à Mgr le duc Casimir,... A Monpelier, ce 17 fevrier... 1588 » ; 3 Pièces concernant le baron de Donaw et sa famille ; 1 à 5 Recueil de pièces relatives au rôle joué par le baron de Donaw en France, durant l'année 1587 ; 1 Protestation du baron DE DONAW contre un libelle diffamatoire. En allemand et en latin ; 2 Explication de la conduite du duc Jean Casimir pendant la guerre de Cologne, en 1583, et pendant la guerre de France, en 1587. Cette pièce paraît avoir été placée ici principalement pour la justification du baron de Donaw, qui fut un des chefs de l'armée étrangère dans l'expédition de 1587. En latin. Copie ; 3 Autre justification de la conduite du baron de Donaw pendant l'expédition de 1587. Copie ; 4 Factum portant pour titre : « Reistres d'Auneau ». Ce factum est dirigé contre Philippe de La Huguerie et le baron de Donaw, accusés de la défaite d'Auneau. Copie ; 5 Lettre de JEAN DE CHAUMONT, seigneur DE « QUITRY,... à Mr de Higny, à Francfort... De Geneve, ce 26 decembre 1587 ». Cette lettre porte pour titre : « La deffaicte d'Auneau et aultres particularités » ; 6 « Fidele et sommaire Recit... pour representer aux yeux de tout le monde le commancement et progres de l'accusation dont on a voulucharger le Sr Henry... de Duna et le docteur Laurent Biderman, chancelier » des princes d'Anhalt, « à cause d'un coup d'harquebuze, qu'on dit avoir esté tiré apres Mr l'electeur de Saxe [Christian II], au [8] d'avril [1603], à Graven Heiniguen, bourg scitué gueres loing de la principaulté d'Anhalt ». Du 8 avril 1603 au mois d'avril 1604. Copie ; 7 et 8 « De familia burgraviorum et baronum a Dona... ex MATHAEI DRESSERI isagoge millenarii 6 ». En latin. Copie ; 8 « De Donaeis baronibus ». En latin. Copie ; 4 « Extrait de la capitulation de la lieutenance generale de Mgr le prince Christian d'Anhalt,... comte d'Ascanie, seigneur de Zerbst et Bernbourg », chef de l'armée de secours envoyée à Henri IV par les princes allemands. 24 avril 1591. Copie ; 5 Pièces concernant Élisabeth, reine d'Angleterre ; 1 « Extraict de la lectre de la roine d'Angleterre [ÉLISABETH] à son ambassadeur en France », en faveur du duc de Bouillon, accusé de complicité avec le duc de Biron ; 2 « In foelicem memoriam Elisabethae, Angliae reginae ». Éloge de la reine Élizabeth, attribué par une note du manuscrit à François Bacon. En latin. Copie ; 6 Pièces relatives aux négociations pour la paix entre l'Espagne et les Pays-Bas. 1607 et 1608 ; 1 « Substance de la declaration qui a esté faicte par le Sr audiancier VERREICKEN, en l'assemblée de messeigneurs les Estatz generaulx des provinces unyes des Pays Bas, apres que le sieur de Neyen, commissaire general, avoit faict sa harangue, le matin sur l'unze heures, en la mesme assemblée de mesd. seigneurs Estats, le XXXme jour d'octobre 1607 ». Traduction ; 2 Déclaration « presentée en l'assemblée de messeigneurs les Estats generaulx des provinces unyes du Pays Bas par B. I. NEIJEN, commissaire general, le [25e] octobre 1607 ». Traduction ; 3 Ratification par PHILIPPE III, roi d'Espagne, des ouvertures de paix ou trêve à long terme, faites par les archiducs Albert d'Autriche et Claire-Isabelle-Eugénie aux États généraux des Pays-Bas. Madrid, 18 septembre 1607. Traduction ; 4 Relation d'une conférence « touchant ce qui concerne la voye de paix », entre le prince Maurice de Nassau et un ambassadeur français. Copie ; 5 « Memoire des plus importantes raisons pour lesquelles les seigneurs Estatz ne doibvent aucunement quitter le trafficq et navigation des Indes ». Copie ; 6 Déclaration faite aux États généraux des Pays-Bas par les « deputtez des roys » de France et d'Angleterre, sur la « trefve à longues années », proposée par lesdits députés et rejetée par « plusieurs du costé des Estats ». Copie ; 7 et 8 Deux lettres de « MAURICE, prince D'ORANGE, comte DE NASSAU », aux États généraux des Pays-Bas, pour les détourner d'accepter les ouvertures de paix faites par les archiducs. La Haye, 21 septembre et 15 novembre 1608. Copies

Identification of renin progenitors in the mouse bone marrow that give rise to B-cell leukaemia

cell of origin and triggering events for leukaemia are mostly unknown. Here we show that the bone marrow contains a progenitor that expresses renin throughout development and possesses a B-lymphocyte pedigree. This cell requires RBP-J to differentiate. Deletion of RBP-J in these renin-expressing progenitors enriches the precursor B-cell gene programme and constrains lymphocyte differentiation, facilitated by H3K4me3 activating marks in genes that control the pre-B stage. Mutant cells undergo neoplastic transformation, and mice develop a highly penetrant B-cell leukaemia with multi-organ infiltration and early death. These reninexpressing cells appear uniquely vulnerable as other conditional models of RBP-J deletion do not result in leukaemia. The discovery of these unique renin progenitors in the bone marrow and the model of leukaemia described herein may enhance our understanding of normal and neoplastic haematopoiesis.

Estrategia de intervención militar de Estados Unidos en Medio Oriente: dinámicas y consecuencias del uso de drones en Yemen y Pakistán entre 2009 a 2013

Este es un estudio sobre la estrategia de guerra estadounidense en Medio Oriente basada en el uso sistemático de drones durante el periodo comprendido entre 2009 y 2013. Se busca explicar de qué manera puede considerarse el uso de este tipo de armamento como una práctica basada en la proyección de poder sin mayor vulnerabilidad. Los casos de Pakistán y Yemen son abordados, ya que evidencian las características de las operaciones selectivas por las que ha abogado el Presidente Obama. El estudio se inscribe dentro del realismo ofensivo, haciendo también referencia a sus limitaciones explicativas. Empero, se afirma que las dinámicas y consecuencias de la utilización de drones son intrínsecas a la necesidad estadounidense de combatir actores no estatales mediante prácticas que garanticen su seguridad y pretensiones hegemónicas a pesar de las implicaciones políticas , legales y sociales en las que puede incurrir.

El uso de e-portafolios en las pr??cticas del B??txelor en Enfermer??a

Resumen basado en el de la publicaci??n

Structural Properties Induced by the Composition of Biocompatible Phospholipid-Based Microemulsion and Amphotericin B Association

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

B-type cytochromes of the DOMON domain superfamily (Novel redox elements of plant plasma membrane)

The aim of the present study is understanding the properties of a new group of redox proteins having in common a DOMON-type domain with characteristics of cytochromes b. The superfamily of proteins containing a DOMON of this type includes a few protein families. With the aim of better characterizing this new protein family, the present work addresses both a CyDOM protein (a cytochrome b561) and a protein only comprised of DOMON(AIR12), both of plant origin. Apoplastic ascorbate can be regenerated from monodehydroascorbate by a trans-plasma membrane redox system which uses cytosolic ascorbate as a reductant and comprises a high potential cytochrome b. We identified the major plasma membrane (PM) ascorbate-reducible b-type cytochrome of bean (Phaseolus vulgaris) and soybean (Glycine max) hypocotyls as orthologs of Arabidopsis auxin-responsive gene air12. The protein, which is glycosylated and glycosylphosphatidylinositol-anchored to the external side of the PM in vivo, was expressed in Pichia pastoris in a recombinant form, lacking the glycosylphosphatidylinositol-modification signal, and purified from the culture medium. Recombinant AIR12 is a soluble protein predicted to fold into a β-sandwich domain and belonging to the DOMON superfamily. It is shown to be a b-type cytochrome with a symmetrical α-band at 561 nm, to be fully reduced by ascorbate and fully oxidized by monodehydroascorbate. Redox potentiometry suggests that AIR12 binds two high-potential hemes (Em,7 +135 and +236 mV). Phylogenetic analyses reveal that the auxin-responsive genes AIR12 constitute a new family of plasma membrane b-type cytochromes specific to flowering plants. Although AIR12 is one of the few redox proteins of the PM characterized to date, the role of AIR12 in trans-PM electron transfer would imply interaction with other partners which are still to be identified. Another part of the present project was aimed at understanding of a soybean protein comprised of a DOMON fused with a well-defined b561 cytochrome domain (CyDOM). Various bioinformatic approaches show this protein to be composed of an N-terminal DOMON followed by b561 domain. The latter contains five transmembrane helices featuring highly conserved histidines, which might bind haem groups. The CyDOM has been cloned and expressed in the yeast Pichia pastoris, and spectroscopic analyses have been accomplished on solubilized yeast membranes. CyDOM clearly reveal the properties of b-type cytochrome. The results highlight the fact that CyDOM is clearly able to lead an electron flux through the plasmamembrane. Voltage clamp experiments demonstrate that Xenopus laevis oocytes transformed with CyDOM of soybean exhibit negative electrical currents in presence of an external electron acceptor. Analogous investigations were carried out with SDR2, a CyDOM of Drosophila melanogaster which shows an electron transport capacity even higher than plant CyDOM. As quoted above, these data reinforce those obtained in plant CyDOM on the one hand, and on the other hand allow to attribute to SDR2-like proteins the properties assigned to CyDOM. Was expressed in Regenerated tobacco roots, transiently transformed with infected a with chimeral construct GFP: CyDOM (by A. rhizogenes infection) reveals a plasmamembrane localization of CyDOM both in epidermal cells of the elongation zone of roots and in root hairs. In conclusion. Although the data presented here await to be expanded and in part clarified, it is safe to say they open a new perspective about the role of this group of proteins. The biological relevance of the functional and physiological implications of DOMON redox domains seems noteworthy, and it can but increase with future advances in research. Beyond the very finding, however interesting in itself, of DOMON domains as extracellular cytochromes, the present study testifies to the fact that cytochrome proteins containing DOMON domains of the type of “CyDOM” can transfer electrons through membranes and may represent the most important redox component of the plasmamembrane as yet discovered.

Ms. Ff. Mus. 1587 - [Arien und Duette]

[Georg Philipp Telemann]