RESUMEN
BACKGROUND: During 2016-2018, 15 critically ill neonatal foals with acute respiratory distress associated with Chlamydia psittaci infection were presented to three referral hospitals in New South Wales. Chlamydia psittaci has not previously been associated with the development of neonatal respiratory disease. OBJECTIVES: To investigate and describe the clinical features and outcome of C. psittaci infection in neonatal foals. STUDY DESIGN: Multicentre retrospective case series. METHODS: The clinical, clinicopathological, necropsy and histological features of 15 foals with confirmed C. psittaci infection were reviewed and reported. RESULTS: Thirteen foals with C. psittaci infection died or were subjected to euthanasia within 36 h of hospitalisation and two foals survived to discharge. Findings during post-mortem examination of nonsurviving foals included bronchopneumonia, pulmonary congestion, hepatic congestion and hepatic inflammation. Detection of C. psittaci was achieved using polymerase chain reaction (PCR) testing of swabs of nasal secretions (4/6) and rectal mucosa (5/7) from live foals, lung tissues of foals at necropsy (11/14) and foetal membranes (4/5). MAIN LIMITATIONS: Small numbers of confirmed cases of neonatal C. psittaci infection and inconsistent sampling methods. CONCLUSIONS: Chlamydia psittaci should be considered a differential diagnosis for neonatal foals with signs of severe systemic disease, including equine neonatal acute respiratory distress syndrome (EqNARDS). Chlamydia psittaci is a zoonotic pathogen and a personal protective equipment (PPE) should be worn for the management of foals with suspected or confirmed infection.
Asunto(s)
Chlamydophila psittaci , Psitacosis/veterinaria , Enfermedades Respiratorias/veterinaria , Animales , Enfermedades de los Caballos , Caballos , Humanos , Recién Nacido , Pulmón , Estudios RetrospectivosRESUMEN
The aim of this study was to determine beta-bend structures and the role of the N- and C-terminus in the antagonist halpha CGRP(8 - 37) at the rat pulmonary artery CGRP receptor mediating halpha CGRP relaxation. Halpha CGRP(8 - 37) Pro(16) (10(-6) M), with a bend-biasing residue (proline) at position 16, did not antagonize halpha CGRP responses, while a structure-conserving amino acid (alanine(16)) at the same position retained antagonist activity (apparent pK(B) 6.6+/-0.1; 10(-6) M). Halpha CGRP(8 - 37) Pro(19) (10(-6) M), with proline at position 19 was an antagonist (apparent pK(B) 6.9+/-0.1). Incorporation of a beta-bend forcing residue, BTD (beta-turn dipeptide), at positions 19 and 20 in halpha CGRP(8 - 37) (10(-6) M) antagonized halpha CGRP responses (apparent pK(B) 7.2+/-0.2); and BTD at positions 19,20 and 33,34 within halpha CGRP(8 - 37) was a competitive antagonist (pA(2) 7.2; Schild plot slope 1.0+/-0.1). Halpha CGRP(8 - 37) analogues, substituted at the N-terminus by either glycine(8) or des-NH(2) valine(8) or proline(8) were all antagonists (apparent pK(B) 6.9+/-0.1; (10(-6) M), 7.0+/-0.1 (10(-6) M), and pA(2) 7.0 (slope 1.0+/-0.2), respectively); while replacements by proline(8) together with glutamic acid(10,14) in halpha CGRP(8 - 37) (10(-6) M) or alanine amide(37) at the C-terminus of halpha CGRP(8 - 37) (10(-5) M) were both inactive compounds. In conclusion, possible bioactive structures of halpha CGRP(8 - 37) include two beta-bends (at 18 - 21 and 32 - 35), which were mimicked by BTD incorporation. Within halpha CGRP(8 - 37), the N-terminus is not essential for antagonism while the C-terminus may interact directly with CGRP(1) receptors in the rat pulmonary artery.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Péptido Relacionado con Gen de Calcitonina/química , Péptido Relacionado con Gen de Calcitonina/farmacología , Fragmentos de Péptidos/química , Fragmentos de Péptidos/farmacología , Arteria Pulmonar/efectos de los fármacos , Alanina/química , Sustitución de Aminoácidos , Animales , Ácido Glutámico/química , Glicina/química , Técnicas In Vitro , Masculino , Conformación Molecular , Relajación Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Prolina/química , Ratas , Ratas Sprague-DawleyRESUMEN
1. The main aim of this study was to identify putative beta-bends and the role of the N- and C-terminus in the CGRP receptor antagonist halpha CGRP8-37, which was measured against halpha CGRP inhibition of twitch responses in the rat prostatic vas deferens. 2. With a bend-biasing residue (proline) at position 16 in halpha CGRP8-37 (10(-5) M) an inactive compound was produced, while alanine at the same position retained antagonist activity (apparent pKB 5.6+/-0.1 at 10(-5) M). Proline at position 19 within halpha CGRP8-37 (10(-5) M) was an antagonist (apparent pKB 5.8+/-0.1). 3. Incorporation of a bend-forcing structure (beta-turn dipeptide or BTD) at either positions 19,20 or 33,34 in halpha CGRP8-37 (10(-5) M) antagonized halpha CGRP responses (apparent pKB 6.0+/-0.1 and 6.1+/-0.1, respectively). Replacement by BTD at both positions 19,20 and 33,34 within halpha CGRP8-37 competitively antagonized responses to halpha CGRP (pA2 6.2; Schild plot slope 1.0+/-0.1). 4. Halpha CGRP8-37 analogues (10(-5) M), substituted at the N-terminus by either glycine8, or des-NH2 valine8 or proline8 were all antagonists against halpha CGRP (apparent pKB 6.1+/-0.1, 6.5+/-0.1 and 6.1+/-0.1, respectively), while halpha CGRP8-37 (10(-5) M) substituted in three places by proline8 and glutamic acid10,14 was inactive. 5. Replacement of the C-terminus by alanine amide37 in halpha CGRP8-37 (10(-5) M) failed to antagonize halpha CGRP responses. 6. Peptidase inhibitors did not alter either the agonist potency of halpha CGRP or the antagonist affinities of halpha CGRP8-37 BTD19,20 and 33,34 and halpha CGRP8-37 Gly8 (against halpha CGRP responses). 7. In conclusion, two beta-bends at positions 18-21 and 32-35 are compatible with high affinity by BTD and is the first approach of modelling the bioactive structure of halpha CGRP8-37. Further, the N-terminus of halpha CGRP8-37 is not essential for antagonism, while the C-terminus interacts directly with CGRP receptor binding sites of the rat vas deferens.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina/química , Fragmentos de Péptidos/química , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Conducto Deferente/efectos de los fármacos , Alanina/química , Alanina/farmacología , Sustitución de Aminoácidos , Animales , Péptido Relacionado con Gen de Calcitonina/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Biosíntesis de Péptidos , Fragmentos de Péptidos/farmacología , Prolina/química , Prolina/farmacología , Próstata/efectos de los fármacos , Próstata/metabolismo , Inhibidores de Proteasas/farmacología , Estructura Secundaria de Proteína , Ratas , Ratas Sprague-Dawley , Receptores de Péptido Relacionado con el Gen de Calcitonina/efectos de los fármacos , Conducto Deferente/metabolismoRESUMEN
The aqueous solution structure of the cyclic pentapeptide cyclo(-Ser-D-Leu-Asp-Val-Pro-) has been determined by two-dimensional 1H-NMR spectroscopy, combined with a conformational search and distance-geometry calculations. As many as five conformers in slow exchange were observed, and the rate of interconversion between components was measured from the build-up rates of exchange peaks. NMR data allowed the structures of the two predominant conformers to be determined. The major component (66%) contained a cis-proline as part of a type-VIa2 beta-turn encompassing residues Asp-Val-cis-Pro-Ser. The second component (16%) contained only trans-amide bonds, and a type-VIII beta-turn formed by residues Val-Pro-Ser-D-Leu. These structures are discussed in relation to the (phi, psi), space available to the cyclic pentapeptide, determined by a conformational search, and in relation to previously published cyclic-pentapeptide structures. The molecule exhibits activity in a scintillation-proximity assay for the inhibition of the interaction between the integrin very-late antigen-4 (VLA-4; alpha 4 beta 1) and vascular-cell-adhesion molecule-1 (VCAM-1). The structure/activity relationship of the LDV sequence is discussed and related to the recently published X-ray structure of VCAM-1. The relevance of the work to the design of anti-inflammatory drugs is discussed.
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Integrinas/metabolismo , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Conformación Proteica , Molécula 1 de Adhesión Celular Vascular/efectos de los fármacos , Molécula 1 de Adhesión Celular Vascular/metabolismo , Secuencia de Aminoácidos , Humanos , Inmunoglobulina G , Indicadores y Reactivos , Integrinas/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Péptidos Cíclicos/síntesis química , Reacción en Cadena de la Polimerasa , Estructura Secundaria de Proteína , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/metabolismo , Soluciones , Relación Estructura-ActividadRESUMEN
Premature cardiovascular disease is common in insulin-dependent diabetic (IDDM) patients who develop diabetic nephropathy. Genetic polymorphism within the renin-angiotensin system has been implicated in the aetiology of a number of cardiovascular disorders; these loci are therefore candidate genes for susceptibility to diabetic renal disease. We have examined the angiotensin converting enzyme insertion/deletion polymorphism and angiotensinogen methionine 235 threonine polymorphism in a large cohort of Caucasian patients with IDDM and diabetic nephropathy. Patients were classified as having nephropathy by the presence of persistent dipstick positive proteinuria (in the absence of other causes), retinopathy and hypertension (n = 242). Three groups were examined for comparison: ethnically matched non-diabetic subjects (n = 187); a geographically defined cohort of newly diagnosed diabetic patients (n = 341); and IDDM patients with long duration of disease (> 15 years) and no evidence of overt nephropathy (n = 166). No significant difference was seen in distribution of angiotensin converting enzyme or angiotensinogen genotypes between IDDM patients with nephropathy and recently diagnosed diabetic subjects (p = 0.282 and 0.584, respectively), nor the long-duration non-nephropathy diabetic subjects (p = 0.701 and 0.190, respectively). We conclude that these genetic loci are unlikely to influence susceptibility to diabetic nephropathy in IDDM in the United Kingdom.