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We report the observation of the sign reversal of the magnetic correlation from antiferromagnetic to ferromagnetic in a dissipative Fermi gas in double wells, utilizing the dissipation caused by on-site two-body losses in a controlled manner. We systematically measure dynamics of the nearest-neighbor spin correlation in an isolated double-well optical lattice, as well as a crossover from an isolated double-well lattice to a one-dimensional uniform lattice. In a wide range of lattice configurations over an isolated double-well lattice, we observe a ferromagnetic spin correlation, which is consistent with a Dicke type of correlation expected in the long-time limit. This work demonstrates the control of quantum magnetism in open quantum systems with dissipation.
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The kisspeptin (Kp, Kp-54, metastin)/KISS1R system plays crucial roles in regulating the secretion of gonadotropin-releasing hormone. Continuous administration of nonapeptide Kp analogs caused plasma testosterone depletion, whereas bolus administration caused strong plasma testosterone elevation in male rats. To develop a new class of small peptide drugs, we focused on stepwise N-terminal truncation of Kp analogs and discovered potent pentapeptide analogs. Benzoyl-Phe-azaGly-Leu-Arg(Me)-Trp-NH2 (16) exhibited high agonist activity for KISS1R and excellent metabolic stability in rat serum. A single injection of a 4-pyridyl analog (19) at the N-terminus of 16 into male Sprague Dawley rats caused a robust increase in plasma luteinizing hormone levels, but unlike continuous administration of nonapeptide Kp analogs, continuous administration of 19 maintained moderate testosterone levels in rats. These results indicated that small peptide drugs can be successfully developed for treating sex hormone deficiency.
Assuntos
Gônadas/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Kisspeptinas/agonistas , Hipófise/efeitos dos fármacos , Animais , Hormônio Liberador de Gonadotropina/metabolismo , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Neuropeptide Y2 receptor (Y2R) agonism is an important anorectic signal and a target of antiobesity drug discovery. Recently, we synthesized a short-length Y2R agonist, PYY-1119 (4-imidazolecarbonyl-[d-Hyp24,Iva25,Pya(4)26,Cha27,36,γMeLeu28,Lys30,Aib31]PYY(23-36), 1) as an antiobesity drug candidate. Compound 1 induced marked body weight loss in diet-induced obese (DIO) mice; however, 1 also induced severe vomiting in dogs at a lower dose than the minimum effective dose administered to DIO mice. The rapid absorption of 1 after subcutaneous administration caused the severe vomiting. Polyethylene glycol (PEG)- and alkyl-modified derivatives of 1 were synthesized to develop Y2R agonists with improved pharmacokinetic profiles, i.e., lower maximum plasma concentration (Cmax) and longer time at maximum concentration (Tmax). Compounds 5 and 10, modified with 20â¯kDa PEG at the N-terminus and eicosanedioic acid at the Lys30 side chain of 1, respectively, showed high Y2R binding affinity and induced significant body weight reduction upon once-daily administration to DIO mice. Compounds 5 and 10, with their relatively low Cmax and long Tmax, partially attenuated emesis in dogs compared with 1. These results indicate that optimization of pharmacokinetic properties of Y2R agonists is an effective strategy to alleviate emesis induced by Y2R agonism.
Assuntos
Fármacos Antiobesidade/química , Obesidade/tratamento farmacológico , Peptídeo YY/química , Polietilenoglicóis/química , Alquilação , Sequência de Aminoácidos , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/uso terapêutico , Cães , Eméticos/química , Eméticos/uso terapêutico , Eméticos/toxicidade , Meia-Vida , Infusões Subcutâneas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/patologia , Peptídeo YY/farmacocinética , Peptídeo YY/uso terapêutico , Receptores de Neuropeptídeo Y/agonistas , Receptores de Neuropeptídeo Y/metabolismo , Vômito/etiologiaRESUMO
The natriuretic peptide (NP) system is a critical endocrine, autocrine, and paracrine system and has been investigated for potential use against cardiovascular and metabolic diseases. The clearance of NPs is regulated by the proteolysis of neutral endopeptidase (NEP) and by endocytosis via natriuretic peptide receptor-3 (NPR3). A linear NPR3-selective peptide, [Cha8]-ANP(7-16)-NH2 (1), showed potent binding affinity for NPR3 but poor predicted chemical stability due to its free thiol group. A 12-mer peptide (9) without a thiol group was designed by the hybridization of two NPR3-binding peptides: a linear ANP fragment peptide analog and musclin, a murine member of the bHLH family of transcription factors, possessed high binding affinity and strict selectivity for NPR3. To increase the proteolytic resistance of 9, amino acid substitutions at the cleavage sites led to hydroxyacetyl-[d-Phe5,d-Hyp7,Cha8,d-Ser9,Hyp11,Arg(Me)14]-ANP(5-15)-NHCH3 (23), showing high and selective binding affinity for NPR3 over NPR1 and excellent stability in mouse serum. Compound 23 increased intracellular cGMP concentrations in primary cultured adipocytes, and continuous administration induced substantial plasma cGMP elevation in mice, suggesting its potential to clarify the physiological role of NPR3 and its therapeutic application.
Assuntos
Fator Natriurético Atrial/farmacologia , Proteínas Musculares/farmacologia , Fragmentos de Peptídeos/farmacologia , Receptores do Fator Natriurético Atrial/antagonistas & inibidores , Fatores de Transcrição/farmacologia , Sequência de Aminoácidos , Animais , Fator Natriurético Atrial/administração & dosagem , Fator Natriurético Atrial/sangue , Fator Natriurético Atrial/química , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Musculares/administração & dosagem , Proteínas Musculares/sangue , Proteínas Musculares/química , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/química , Receptores do Fator Natriurético Atrial/metabolismo , Fatores de Transcrição/administração & dosagem , Fatores de Transcrição/sangue , Fatores de Transcrição/químicaRESUMO
Neuromedin U (NMU) mediates various physiological functions via NMUR1 and NMUR2 receptors. NMUR2 has been considered a promising treatment option for diabetes and obesity. Although NMU-8, a shorter peptide, has potent agonist activity for both receptors, it is metabolically unstable. Therefore, NMU-8 analogs modified with long-chain alkyl moieties via a linker were synthesized. An octadecanoyl analog (17) with amino acid substitutions [αMePhe19, Nle21, and Arg(Me)24] and a linker [Tra-γGlu-PEG(2)] dramatically increased NMUR2 selectivity, with retention of high agonist activity. Subcutaneous administration of 17 induced anorectic activity in C57BL/6J mice. Owing to its high metabolic stability, 17 would be useful in clarifying the physiological role and therapeutic application of NMU.
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Depressores do Apetite/metabolismo , Peptídeos/metabolismo , Receptores de Neurotransmissores/metabolismo , Alquilação , Sequência de Aminoácidos , Animais , Depressores do Apetite/química , Depressores do Apetite/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos/agonistas , Receptores de Neurotransmissores/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
The gastrointestinal peptide, peptide YY3-36 (PYY3-36) and its shorter peptide analogues have been reported to reduce appetite by activating the neuropeptide Y2 receptor (Y2R), which is associated with obesity and other metabolic diseases. A 14-amino acid PYY analogue, Ac-[d-Pro24,Cha27,28,36,Aib31]PYY(23-36) (3), showed high binding affinity and agonist activity for the Y2R, similar to that of PYY3-36, but had weak anorectic activity upon continuous administration in lean mice. Three amino acid substitutions [Pya(4)26, Aib28, Lys30], which contributed to the decreased hydrophobicity of 3, efficiently increased its anorectic activity. The compound containing these three amino acids, Ac-[d-Pro24,Pya(4)26,Cha27,36,Aib28,31,Lys30]PYY(23-36) (22), exerted more potent and durable food intake suppression than that by PYY3-36 in lean mice, as well as excellent Y2R agonist activity (EC50: 0.20nM) and good subcutaneous bioavailability (66.6%). The 11-day continuous administration of 22 at 1mg/kg/day successfully produced antiobese and antidiabetic effects, with more than 20% body weight loss in obese and Type 2 diabetes ob/ob model mice.
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Fármacos Antiobesidade/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Obesidade/tratamento farmacológico , Peptídeo YY/farmacologia , Animais , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/química , Relação Dose-Resposta a Droga , Injeções Intravenosas , Injeções Subcutâneas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Estrutura Molecular , Peptídeo YY/administração & dosagem , Peptídeo YY/química , Receptores de Neuropeptídeo Y/agonistas , Relação Estrutura-AtividadeRESUMO
Neuromedin U (NMU) is a neuropeptide known to regulate food intake and energy homeostasis that is widely distributed in the gastrointestinal tract, hypothalamus, and pituitary. A short form of NMU, porcine NMU-8 has potent agonist activity for the receptors NMUR1 and NMUR2; however, its short half-life precludes its effective use in vivo. To address this limitation, we designed and synthesized NMU-8 analogs modified by polyethylene glycol (PEG) with a molecular weight of 30kDa (PEG30k) via a variety of linkers (i.e., ω-amino- and ω-imino-carboxylic acid linker). Integrated evaluation of NMUR1 and NMUR2 binding affinities in vitro and anorectic activity in mice revealed that the introduction of a linker with a rigid ring group, e.g., 2-(piperazin-1-yl)acetic acid (PipAc), yielded a highly potent anorectic peptide, PEG30k-PipAc-NMU-8 (14), possessing improved receptor binding affinity. Subsequent optimization of the molecular weight of the PEG moiety led to the discovery of a PEG20k conjugate (15), which exhibited significant anti-obesity effect upon once-daily subcutaneous administration in diet-induced obese mice with 10% and 22% body weight loss at doses of 10 and 30nmol/kg, respectively. In addition, 15 reduced the weights of the liver and adipose tissue in a dose-dependent manner and improved the plasma biochemical parameters, e.g., insulin, glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, and total cholesterol. Thus, our results suggest that 15 (NMU-0002), which showed potent and long-lasting biological profiles in vivo, represents a candidate peptide for investigating the central and peripheral actions of NMU and its potential for clinical use.
Assuntos
Fármacos Antiobesidade/farmacologia , Neuropeptídeos/farmacologia , Polietilenoglicóis/química , Animais , Fármacos Antiobesidade/farmacocinética , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuropeptídeos/química , Neuropeptídeos/farmacocinética , Suínos , Redução de Peso/efeitos dos fármacosRESUMO
Continuous administration of a 14-amino acid peptide YY (PYY) analog, Ac-[d-Pro24,Pya(4)26,Cha27,36,Aib28,31,Lys30]PYY(23-36) (4), which has a high binding affinity and agonist activity for the neuropeptide Y2 receptor (Y2R), has previously shown an antiobesity effect in a 2-week diet-induced obesity (DIO) study in mice. However, there remained a possibility to obtain more potent analogs by further improving its pharmacokinetic profile. A combination of the N-terminal 4-imidazolecarbonyl moiety and three amino acid substitutions, trans-4-hydroxy-d-proline (d-Hyp)24, isovaline (Iva)25, and γ-methylleucine (γMeLeu)28, not only improved the binding affinity of the peptide for Y2R but also increased its anorectic activity in lean mice. In a 2-week DIO study in mice, continuous administration of 4-imidazolecarbonyl-[d-Hyp24,Iva25,Pya(4)26,Cha27,36,γMeLeu28,Lys30,Aib31]PYY(23-36) (31, PYY-1119) at a dose of 0.03mg/kg/day showed a highly potent antiobesity effect, with more than 10% body weight reduction.
Assuntos
Peso Corporal/efeitos dos fármacos , Peptídeo YY/química , Peptídeo YY/farmacologia , Sequência de Aminoácidos , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Dieta , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Knockout , Estrutura Molecular , Peptídeo YY/agonistasRESUMO
There is a lack of data regarding the safety and effectiveness of implanting the Pipeline Embolization Device with Shield technology (PED-Shield) compared with the previous generation of Pipeline (PED-Flex). This retrospective single-center study aimed to compare treatment outcomes between the PED-Shield and PED-Flex for treating unruptured internal carotid artery aneurysms. The PED-Flex was used in 62 procedures (67 aneurysms, 59 patients) and the PED-Shield in 53 procedures (59 aneurysms, 58 patients). The mean aneurysm diameter was significantly lower in the PED-Shield group than in the PED-Flex group (11.9 ± 7.0 mm vs. 15.2 ± 6.9 mm, p < 0.001). At the 12-month follow-up, the complete angiographic occlusion rate was 72.1% and 72.3% in the PED-Flex and PED-Shield groups, respectively (p = 0.9808). Limited to aneurysms larger than 10 mm, 70.6% and 68.0%, respectively (p = 0.8175). The incidence of more than three high signal intensity areas on diffusion-weighted imaging after treatment was significantly lower in the PED-Shield group than in the PED-Flex group (27.7% vs. 67.7%; p < 0.001). Limited to aneurysms larger than 10 mm, 41.1% and 69.6%, respectively (p < 0.0117). Symptomatic ischemic complications occurred within 30 days of four PED-Flex procedures (6.5%) and one PED-Shield procedure (2.0%) (p = 0.2315). Limited to aneurysms larger than 10 mm, 1.8% and 3.2%, respectively (p = 0.6677). The incidence of mRS score worsening at 6 months was 3.2% and 1.9% in the PED-Flex and PED-Shield groups, respectively (p = 0.6534). The PED-Shield can achieve outcomes equivalent to or better than the PED-Flex. Further large-scale studies are warranted to confirm our findings.
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Doenças das Artérias Carótidas , Artéria Carótida Interna , Embolização Terapêutica , Aneurisma Intracraniano , Humanos , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Embolização Terapêutica/instrumentação , Embolização Terapêutica/métodos , Resultado do Tratamento , Idoso , Aneurisma Intracraniano/terapia , Aneurisma Intracraniano/diagnóstico por imagem , Doenças das Artérias Carótidas/terapia , Doenças das Artérias Carótidas/diagnóstico por imagem , AdultoRESUMO
Background: Extracranial internal carotid artery (ICA)-dissecting aneurysms (DAs) rarely cause re-entry tears and lower cranial nerve palsies. The therapeutic strategies for these pathologies are not well established. This report presents a case of an extracranial ICA -DA with a re-entry tear that caused lower cranial nerve palsy. Case Description: A 60-year-old man presented with left neck pain, hoarseness, and dysphagia. Physical examination and laryngoscopy determined palsies of the left cranial nerves IX, X, and XII. Digital subtraction angiography (DSA) revealed a DA in the left extracranial ICA, and three-dimensional DSA showed entry and re-entry tears in the intimal flap. Flow-diverting stents (FDSs) were placed on the lesion that covered the entry and re-entry tears because the symptoms did not improve after five weeks of conservative treatment. A post-procedural angiogram indicated flow stagnation in the DA. Symptoms improved remarkably immediately after the procedure, and the aneurysm was almost completely occluded six months later. Conclusion: Herein, an extracranial ICA -DA with a re-entry tear that caused lower cranial nerve palsy did not improve after five weeks of conservative treatment. FDS placement promptly resolved the aneurysm and symptoms. Thus, FDS placement may be an effective treatment option for extracranial ICA-DAs with re-entry tears or lower cranial nerve palsies.
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Background: Intracranial infectious aneurysms (IIAs) are very rare, and fungal aneurysms are infrequently reported. We report a case of an unruptured IIA caused by fungal rhinosinusitis and treated with a flow-diverting stent. Case Description: An 81-year-old woman visited the ophthalmology department with impaired eye movement and ptosis and was placed under follow-up. A week later, she also developed a headache; magnetic resonance angiography revealed an aneurysm measuring 2 mm in the C4 portion of the right internal carotid artery. A 3-week follow-up with contrast-enhanced magnetic resonance imaging showed an increase in its size to 10 mm, and a contrast lesion was observed surrounding the right cavernous sinus. The patient started treatment with voriconazole and steroids on the same day. Ten weeks later, despite improvements in inflammation, the size of the aneurysm was unchanged; we, therefore, treated the aneurysm with a flow-diverting stent. Oculomotor nerve palsy improved, and the patient was discharged to a rehabilitation hospital 28 days after the placement, with a modified Rankin Scale of 4. A 1-year follow-up angiogram showed a partial decrease in the size of the aneurysm, with an O'Kelly-Marotta grading scale of B3. Conclusion: IIAs grow rapidly, and the risk of rupture is high due to the weakening of the aneurysmal wall. To reduce the risks of rupture and recurrence after treatment, the infection should be treated before inserting a flow-diverting stent. Flow-diverting stent placement may be an effective treatment for IIA once the original infection has been cured.
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OBJECTIVE: Traumatic middle meningeal artery (MMA)-middle meningeal vein (MMV) fistula (MMA-MMV fistula) and MMA pseudoaneurysm are the 2 main MMA-related vascular diseases occurring after blunt head trauma. These are rare but known causes of delayed intracranial hemorrhage. This study investigated predictors that may aid in the diagnosis of these diseases. METHODS: In our department, screening digital subtraction angiography (DSA) is performed for patients with blunt head trauma accompanied by intracranial hemorrhage and skull or facial bone fracture. This study included 87 patients who underwent screening DSA without craniotomy from January 2019 to June 2023. The patients' clinical characteristics were retrospectively collected from the database. Statistical analysis was performed to examine the associations of various evaluation items with MMA-related vascular diseases. RESULTS: The first DSA examination revealed 34 MMA-MMV fistulas and 1 MMA pseudoaneurysm. The second follow-up DSA examination revealed 13 MMA-MMV fistulas and four MMA pseudoaneurysms. Temporal/parietal bone fracture (odds ratio, 5.33; P = 0.0005; 95% confidence interval, 1.95-14.60) was significantly associated with MMA-related vascular diseases. Endovascular treatments were performed in 9 patients. All procedures were successfully completed without complications; no delayed bleeding was observed. CONCLUSIONS: Temporal/parietal bone fracture in patients with blunt head trauma is a likely predictor of MMA-related vascular diseases. When initial head computed tomography reveals this pathology, we recommend careful imaging follow-up (e.g., DSA) and treatment as needed, while considering the possibility of MMA-related vascular diseases.
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Falso Aneurisma , Fístula , Traumatismos Cranianos Fechados , Fraturas Cranianas , Humanos , Falso Aneurisma/etiologia , Falso Aneurisma/complicações , Artérias Meníngeas/diagnóstico por imagem , Artérias Meníngeas/lesões , Estudos Retrospectivos , Fraturas Cranianas/complicações , Fraturas Cranianas/diagnóstico por imagem , Fraturas Cranianas/cirurgia , Traumatismos Cranianos Fechados/complicações , Traumatismos Cranianos Fechados/diagnóstico por imagem , Hemorragias Intracranianas/complicaçõesRESUMO
Metastin/kisspeptin is an amidated peptide with 54 amino acid residues isolated from human placental tissues as a ligand of the orphan G-protein-coupled receptor KISS1R that is expressed throughout the central nervous system and in a variety of endocrine and gonadal tissues. Compared to the full-length metastin protein, the N-terminal truncated peptide metastin(45-54) has 3-10 times higher receptor affinity and enhanced ability to increase intracellular calcium concentration which is essential for activation of protein kinases involved in intracellular signaling in a number of pathways that affect reproduction and cell migration. However, metastin(45-54) is rapidly inactivated in serum. In this study, we designed and synthesized a number of metastin(45-54) analogs and evaluated their agonistic activity and trypsin resistance. Among analogs with substitutions of arginine at position 53, N(ω)(-)methylarginine analog 8 showed 3-fold more potent agonistic activity compared with metastin(45-54). Furthermore, analog 8 was shown to resist trypsin cleavage between positions 53 and 54. This substitution may be useful in the development of other Arg-containing peptides for which the avoidance of cleavage is desired.
Assuntos
Arginina/análogos & derivados , Kisspeptinas/química , Kisspeptinas/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Tripsina/metabolismo , Sequência de Aminoácidos , Humanos , Kisspeptinas/farmacologia , Receptores de Kisspeptina-1RESUMO
Metastin/kisspeptin, a 54-amino acid peptide, is the ligand of the G-protein-coupled receptor KISS1R which plays a key role in pathways that regulate reproduction and cell migration in many endocrine and gonadal tissues. The N-terminally truncated decapeptide, metastin(45-54), has 3-10 times higher receptor affinity and intracellular calcium ion-mobilizing activity but is rapidly inactivated in serum. In this study we designed and synthesized stable KISS1R agonistic decapeptide analogs with selected substitutions at positions 47, 50, and 51. Replacement of glycine with azaglycine (azaGly) in which the α-carbon is replaced with a nitrogen atom at position 51 improved the stability of amide bonds between Phe(50)-Gly(51) and Gly(51)-Leu(52) as determined by in vitro mouse serum stability studies. Substitution for tryptophan at position 47 with other amino acids such as serine, threonine, ß-(3-pyridyl)alanine, and D-tryptophan (D-Trp), produced analogs that were highly stable in mouse serum. D-Trp(47) analog 13 showed not only high metabolic stability but also excellent KISS1R agonistic activity. Other labile peptides may have increased serum stability using amino acid substitution.
Assuntos
Kisspeptinas/sangue , Kisspeptinas/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Alanina/análogos & derivados , Alanina/química , Sequência de Aminoácidos , Aminoácidos/química , Animais , Glicina/análogos & derivados , Humanos , Kisspeptinas/química , Kisspeptinas/farmacologia , Camundongos , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Kisspeptina-1 , Soro/metabolismo , Triptofano/químicaRESUMO
Background: Evidence supports endovascular coiling for ruptured intracranial aneurysms (RIAs). However, in some cases, it is difficult to achieve complete occlusion by coiling, such as with wide-neck aneurysms. We report our experience with intentional staged RIA treatment using targeted endovascular coiling at the rupture point in the acute phase, followed by delayed stent-assisted coiling, flow diverter stenting, or surgical clipping. Methods: Consecutive patients with RIAs treated between April 2015 and June 2021 were retrospectively investigated. Clinical characteristics, treatment complications, and patient outcomes data were collected. Results: Among 108 RIAs treated in our hospital, 60 patients underwent initial coiling; 10 patients underwent staged treatment. The aneurysm locations were the anterior communicating artery (n = 5), internal carotid-posterior communicating artery (n = 3), internal carotid-paraclinoid (n = 1), and vertebral artery-posterior inferior cerebellar artery (n = 1). The mean ± standard deviation aneurysmal diameter was 9.6 ± 5.4 mm and the mean aspect ratio was 1.2 ± 0.7. As the second treatment to obliterate blood flow to the neck area, we performed five stent-assisted coiling, two flow-diverter stentings, and three surgical clippings. Only one minor perioperative complication occurred. The median duration between the first and second treatments was 18 days (range, 14- 42 days). Good clinical outcome (modified Rankin scale score 0-2) at 90 days was achieved in 5 (50%) cases. The median follow-up duration was 6.5 months (range, 3-35 months); no rerupture occurred. Conclusion: Intentional staged treatment with a short time interval for RIA was effective and feasible.
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BACKGROUND: Stent infection after carotid artery stenting (CAS) can be a life-threatening postoperative complication, but there is a paucity of data due to its exceedingly low frequency. We report a case of stent infection with pseudoaneurysm formation after CAS that was treated through replacing the infected stent and pseudoaneurysm with a polytetrafluoroethylene (PTFE) synthetic vessel graft. CASE DESCRIPTION: An 86-year-old man was treated for the right internal carotid artery with CAS in local hospital. One month after stenting, he suffered aspiration pneumonia and septicemia. Three months after stenting, swelling and tenderness of the right side of his neck appeared. His general condition deteriorated due to septicemia and he was unable to ingest anything by mouth as a result of decreasing levels of consciousness. He was transferred to our hospital. Computed tomography and digital subtraction angiography showed the presence of a pseudoaneurysm around the stent. The neck mass enlarged daily and surgical intervention was required to prevent closure of the airway. Stent and pseudoaneurysm resection and in situ reconstruction with a PTFE synthetic vessel graft were performed. The patient returned to his local hospital 36 days after surgery and had a modified Rankin Score of 5. CONCLUSION: Although the risk of reinfection is high due to the nature of artificial material, stent/pseudoaneurysm resection and in situ reconstruction with a PTFE synthetic vessel graft might be one of the best options for patients suffering stent infection after CAS. To the best of our knowledge, this is the first report of treatment using this material.
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The regulatory role of plasma nitrosothiols (R-SNOs) under steady-state conditions and their possible contribution to pharmacological vasodilation were systematically examined in anesthetized rabbits. Nitrosocystein (Cys-NO), S-nitrosoglutathione (G-SNO), and S-nitrosoalbumin (Alb-SNO) were determined by HPLC-Saville's method with respective sensitivities of 1, 1, and 5 nM. These R-SNOs were not detected under steady-state conditions even in the presence of N-ethylmaleimide, a thiol protective agent used to prevent transnitrosation of R-SNOs. Development of plasma Alb-SNO below 300 nM was observed after intravenous injection (i.v.) of nitric oxide (NO) solution (0.1 to 3 ml/g), NOC7 (an NO releasing agent, above 1 µg/kg), and a low dose of Alb-SNO (10 nmol/kg). However, blood pressure was not significantly reduced by NO solution or Alb-SNO. Intravenous injection of a high dose of Alb-SNO (300 nmol/kg) significantly reduced blood pressure with the appearance not only Alb-SNO in micromolar level in plasma, but also G-SNO in lesser degree. Conversely, the hypotensive effect of Cys-NO (300 nmol/kg, i.v.) and G-SNO (300 nmol/kg, i.v.) accompanied development of Alb-SNO (micromolar level), but not Cys-NO or G-SNO in plasma. R-SNOs were not found in plasma during profound hypotension induced by acetylcholine (10 and 30 µg/kg/min, continuous i.v.), glyceryl trinitrate (100 µg/kg, i.v.), sodium nitroprusside (100 µg/kg, i.v.), and isosorbide dinitrate (300 µg/kg, i.v.). These results indicate that R-SNOs do not play an important role under unstimulated condition. In addition, plasma R-SNOs may not be involved in pharmacological vasodilation where contributions of NO or R-SNOs are suggested.
Assuntos
Acetilcolina/farmacologia , Pressão Sanguínea/fisiologia , Hipotensão/induzido quimicamente , S-Nitrosotióis/sangue , Vasodilatação/fisiologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Etilmaleimida/farmacologia , Hipotensão/sangue , Óxido Nítrico/farmacologia , Coelhos , S-Nitrosotióis/farmacologiaRESUMO
A possible cause of arterio-venous (A-V) differences in plasma nitrite (NO(2)(-)) levels under steady-state conditions and kinetic features of NO(2)(-) in arterial and venous blood were examined. In isolated rabbit blood, plasma NO(2)(-) in venous blood disappeared faster than that in arterial blood and was accompanied by a concomitant increase in nitrate (NO(3)(-)), implicating oxidation as the main pertinent metabolic pathway. When data were corrected with respective elimination constants and time durations before plasma separation, no A-V difference was estimated under steady-state. Even after these corrections for NO(2)(-) loading in anesthetized rabbits, a large A-V difference in NO(2)(-) levels (arterial venous) was observed, followed by an exponential decrease in NO(2)(-) levels without a reciprocal increase in NO(3)(-) levels. There was a marked difference in NO(2)(-) decay between in vivo and ex vivo experiments, but no increases in the circulating blood were detected for other substances derived from NO(2)(-), such as methemoglobin or low- and high-molecular weight nitrosothiols. In rats and guinea pigs, absence and presence of the A-V difference were detected under steady-state conditions and after NO(2)(-) loading, respectively. These observations indicate that apparent A-V differences under steady-state are artifacts arising from different rates of NO(2)(-) disappearance in arterial versus venous plasma during sample handling, and that tissue compartments may contribute to changes in NO(2)(-) levels in circulating blood. Therefore, caution is required when evaluating plasma NO(2)(-) levels, especially in venous blood.
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Artérias/metabolismo , Nitratos/sangue , Nitritos/sangue , Veias/metabolismo , Animais , Transporte Biológico , Cobaias , Redes e Vias Metabólicas , Oxirredução , Coelhos , Ratos , Ratos Sprague-DawleyRESUMO
Sustainable and efficient manufacturing methods for N-methylated peptides remain underexplored despite growing interest in therapeutic N-methylated peptides within the pharmaceutical industry. A methodology for the coupling of C-terminally unprotected N-methylamino acids mediated by an isostearic acid halide (ISTAX) and silylating reagent has been developed. This approach allows for the coupling of a wide variety of amino acids and peptides in high yields under mild conditions without the need for a C-terminal deprotection step in the process of C-terminal elongation. These advantages make this a useful synthetic method for the production of peptide therapeutics and diagnostics containing N-methylamino acids.
Assuntos
Anidridos/química , Indicadores e Reagentes/química , Peptídeos/química , Aminoácidos , Estrutura Molecular , EstereoisomerismoRESUMO
Nitrite (NO(2)(-)) is assumed to play an important role in regulation of vascular tone as a reservoir of nitric oxide (NO). To examine its physiological contribution, however, a sensitive method is required for determination of the true level of NO(2)(-) in biological samples. To this end, practical consideration to avoid NO(2)(-) contamination through the quantification procedure is important. We present here a highly sensitive and accurate method for determining NO(2)(-) in plasma by improving the HPLC-Griess system with minimal NO(2)(-) contamination in the samples. The system achieved high sensitivity (detection limit of 2 nM and sensitivity to 1 nM) and complete separation of the NO(2)(-) signal peak by modifying the system setup and mobile phase. Using this method, we achieved acceptable quantification of low NO(2)(-) levels in plasma. Deproteinization by ultrafiltration and exposure to atmosphere before measurement were identified as the major sources of NO(2)(-) contamination during sample processing. We addressed these issues by the use of methanol for deproteinization and gas-tight caps. These countermeasures allowed us to detect small arterio-venous NO(2)(-) differences in rabbit plasma that may indicate kinetic difference of NO(2)(-) in a small number of samples (n = 6). This difference became prominent when NO(2)(-) or a NO releasing agent, NOR1, was intravenously applied. Our results indicate that application of a sensitive method with careful handling is important for accurate determination of NO(2)(-) and that our method is applicable for further examination of the kinetic features of NO(2)(-) in vivo.