RESUMO
BACKGROUND: Postoperative nausea and vomiting (PONV) as a clinically most common postoperative complication requires multimodal antiemetic medications targeting at a wide range of neurotransmitter pathways. Lacking of neurobiological mechanism makes this 'big little problem' still unresolved. We aim to investigate whether gut-vagus-brain reflex generally considered as one of four typical emetic neuronal pathways might be the primary mediator of PONV. METHODS: Three thousand two hundred twenty-three patients who underwent vagus nerve trunk resection (esophagectomy and gastrectomy) and non-vagotomy surgery (hepatectomy, pulmonary lobectomy and colorectomy) from December 2016 to January 2019 were enrolled. Thirty cases of gastrectomy with selective resection on the gastric branch of vagus nerve were also recruited. Nausea and intensity of vomiting was recorded within 24 h after the operation. RESULTS: PONV occurred in 11.9% of 1187 patients who underwent vagus nerve trunk resection and 28.7% of 2036 non-vagotomy patients respectively. Propensity score matching showed that vagotomy surgeries accounted for 19.9% of the whole PONV incidence, much less than that observed in the non-PONV group (35.1%, P < 0.01). Multivariate logistic regression result revealed that vagotomy was one of underlying factor that significantly involved in PONV (OR = 0.302, 95% CI, 0.237-0.386). Nausea was reported in 5.9% ~ 8.6% vagotomy and 12 ~ 17% non-vagotomy patients. Most vomiting were mild, being approximately 3% in vagotomy and 8 ~ 13% in non-vagotomy patients, while sever vomiting was much less experienced. Furthermore, lower PONV occurrence (10%) was also observed in gastrectomy undergoing selective vagotomy. CONCLUSION: Patients undergoing surgeries with vagotomy developed less PONV, suggesting that vagus nerve dependent gut-brain signaling might mainly contribute to PONV.
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Analgesia/métodos , Eixo Encéfalo-Intestino/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Náusea e Vômito Pós-Operatórios/epidemiologia , Nervo Vago/efeitos dos fármacos , Nervo Vago/cirurgia , Encéfalo/fisiopatologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vias Neurais/efeitos dos fármacos , Reflexo/efeitos dos fármacosRESUMO
Olfactory ensheathing cells (OECs) are a specialized class of glia, wrapping around olfactory sensory axons that target the olfactory bulb (OB) and cross the peripheral nervous system/central nervous system boundary during development and continue to do so post-natally. OEC subpopulations perform distinct subtype-specific functions dependent on their maturity status. Disrupted OEC development is thought to be associated with abnormal OB morphogenesis, leading to anosmia, a defining characteristic of Kallmann syndrome. Hence, anosmin-1 encoded by Kallmann syndrome gene (KAL-1) might modulate OEC differentiation/maturation in the OB. We performed in ovo electroporation of shRNA in the olfactory placode to knock-down kal in chick embryos, resulting in abnormal OB morphogenesis and loss of olfactory sensory axonal innervation into OB. BLBP-expressing OECs appeared to form a thinner and poorly organized outmost OB layer where SOX10 expressing OECs were completely absent with emergence of GFAP-expressing OECs. Furthermore, in embryonic day 10 chick OB explant cultures, GFAP expression in OECs accumulating along the OB nerve layers was dramatically reduced by recombinant anosmin-1. We then purified immature OECs from embryonic day 10 chick OB. These cells express GFAP after 7 days in vitro, exhibiting a multipolar morphology. Overexpression of chick anosmin, exogenous anosmin-1 or FGF2 could inhibit GFAP expression with cells presenting elongated morphology, which was blocked by the FGF receptor inhibitor Su5402. These data demonstrate that anosmin-1 functions via FGF signalling in regulating OEC maturation, thereby providing a permissive glial environment for axonal innervation into the OB during development.
Assuntos
Neuroglia/citologia , Animais , Proliferação de Células/efeitos dos fármacos , Embrião de Galinha , Proteína 7 de Ligação a Ácidos Graxos/biossíntese , Fator 2 de Crescimento de Fibroblastos/biossíntese , Proteínas do Tecido Nervoso/metabolismo , Neuroglia/metabolismo , Bulbo Olfatório/efeitos dos fármacos , Bulbo Olfatório/crescimento & desenvolvimento , Pirróis/farmacologia , RNA Interferente Pequeno/farmacologiaRESUMO
PURPOSE: Congenital hypogonadotropic hypogonadism (CHH) and split hand/foot malformation (SHFM) are two rare genetic conditions. Here we report a clinical entity comprising the two. METHODS: We identified patients with CHH and SHFM through international collaboration. Probands and available family members underwent phenotyping and screening for FGFR1 mutations. The impact of identified mutations was assessed by sequence- and structure-based predictions and/or functional assays. RESULTS: We identified eight probands with CHH with (n = 3; Kallmann syndrome) or without anosmia (n = 5) and SHFM, seven of whom (88%) harbor FGFR1 mutations. Of these seven, one individual is homozygous for p.V429E and six individuals are heterozygous for p.G348R, p.G485R, p.Q594*, p.E670A, p.V688L, or p.L712P. All mutations were predicted by in silico analysis to cause loss of function. Probands with FGFR1 mutations have severe gonadotropin-releasing hormone deficiency (absent puberty and/or cryptorchidism and/or micropenis). SHFM in both hands and feet was observed only in the patient with the homozygous p.V429E mutation; V429 maps to the fibroblast growth factor receptor substrate 2α binding domain of FGFR1, and functional studies of the p.V429E mutation demonstrated that it decreased recruitment and phosphorylation of fibroblast growth factor receptor substrate 2α to FGFR1, thereby resulting in reduced mitogen-activated protein kinase signaling. CONCLUSION: FGFR1 should be prioritized for genetic testing in patients with CHH and SHFM because the likelihood of a mutation increases from 10% in the general CHH population to 88% in these patients.
Assuntos
Hipogonadismo/congênito , Hipogonadismo/genética , Deformidades Congênitas dos Membros/genética , Mutação , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Sequência de Aminoácidos , Animais , Sequência Conservada , Feminino , Estudos de Associação Genética , Humanos , Hipogonadismo/metabolismo , Deformidades Congênitas dos Membros/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Proteínas de Membrana/metabolismo , Dados de Sequência Molecular , Linhagem , Fosforilação , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismoRESUMO
BACKGROUND: Intraoperative persistent hypotension (IPH) during pancreaticoduodenectomy (PD) is linked to adverse postoperative outcomes, yet its risk factors remain unclear. AIM: To clarify the risk factors associated with IPH during PD, ensuring patient safety in the perioperative period. METHODS: A retrospective analysis of patient records from January 2018 to December 2022 at the First Affiliated Hospital of Nanjing Medical University identified factors associated with IPH in PD. These factors included age, gender, body mass index, American Society of Anesthesiologists classification, comorbidities, medication history, operation duration, fluid balance, blood loss, urine output, and blood gas parameters. IPH was defined as sustained mean arterial pressure < 65 mmHg, requiring prolonged deoxyepinephrine infusion for > 30 min despite additional deoxyepinephrine and fluid treatments. RESULTS: Among 1596 PD patients, 661 (41.42%) experienced IPH. Multivariate logistic regression identified key risk factors: increased age [odds ratio (OR): 1.20 per decade, 95% confidence interval (CI): 1.08-1.33] (P < 0.001), longer surgery duration (OR: 1.15 per additional hour, 95%CI: 1.05-1.26) (P < 0.01), and greater blood loss (OR: 1.18 per 250-mL increment, 95%CI: 1.06-1.32) (P < 0.01). A novel finding was the association of arterial blood Ca2+ < 1.05 mmol/L with IPH (OR: 2.03, 95%CI: 1.65-2.50) (P < 0.001). CONCLUSION: IPH during PD is independently associated with older age, prolonged surgery, increased blood loss, and lower plasma Ca2+.
RESUMO
BACKGROUND: Trigeminocardiac reflex (TCR) is a brainstem reflex that can lead to hemodynamic instability manifested as bradycardia, decrease/increase of mean arterial pressure (MAP) and, in the worst case scenario, asystole during surgery. The effective intraoperative management of recurrent and profound TCR has yet to be established. This randomized paired study was performed to identify the effect of a prophylactic intra-arterial injection of lidocaine to prevent TCR caused by Onyx embolization during cerebrovascular intervention surgery. METHODS: A total of 136 patients who received Onyx embolization under general anesthesia were assigned to a control group pretreated with intra-arterial saline injection or a lidocaine group pretreated with an intra-arterial injection of 20 mg lidocaine. Heart rate (HR) and MAP were closely monitored during the embolization procedures and the incidence of TCR, mainly characterized by a decrease in HR of ≥20%, and perioperative adverse events was recorded. RESULTS: During dimethyl sulfoxide (DMSO)/Onyx injection, HR was much slower in the control group than in the lidocaine group (p<0.05). TCR occurred in 12 patients (17.6%) in the control group (cardiac arrest in 3 patients) with decreased (7 cases) or increased (5 cases) MAP, whereas no TCR was observed in the lidocaine group. Notably, most TCR episodes occurred in patients with dural arteriovenous fistula and middle meningeal artery being affected. The composite adverse events were significantly higher in the control group than in the lidocaine group (p<0.05). CONCLUSION: This prospective study shows that a prophylactic intra-arterial injection of 20 mg lidocaine could be recommended as a novel strategy to effectively and safely prevent TCR during endovascular embolization.
Assuntos
Malformações Vasculares do Sistema Nervoso Central , Embolização Terapêutica , Parada Cardíaca , Reflexo Trigêmino-Cardíaco , Humanos , Malformações Vasculares do Sistema Nervoso Central/terapia , Dimetil Sulfóxido , Embolização Terapêutica/efeitos adversos , Embolização Terapêutica/métodos , Parada Cardíaca/etiologia , Injeções Intra-Arteriais , Lidocaína/farmacologia , Lidocaína/uso terapêutico , Polivinil/efeitos adversos , Estudos Prospectivos , Reflexo Trigêmino-Cardíaco/fisiologia , Resultado do TratamentoRESUMO
BACKGROUND Trigeminocardiac reflex (TCR) is a unique brain stem reflex that manifests as the sudden onset of hemodynamic perturbation in heart rate and blood pressure as a result of stimulation of any branches of the trigeminal nerve. Onyx™ embolization in cerebrovascular interventional surgery can trigger TCR, leading to severe hemodynamic fluctuations and even cardiac arrest. Appropriate prophylactic approaches to prevent Onyx™ embolization-induced TCR are still lacking. CASE REPORT We report the cases of 2 patients with recurrent and profound bradycardia due to TCR during endovascular Onyx™ embolization for a dural arteriovenous fistula. Prophylactic intra-arterial injection of lidocaine (10-20 mg) effectively and safely blocked the recurrence and potential occurrence of TCR. These 2 patients had reduced heart rate with either hypotension or hypertension during their TCR episodes, suggesting that stimulating a distinct cerebral artery (occipital artery versus vertebral artery branch) can initiate TCR by provoking the vagus nerve via the common neuronal pathway while simultaneously inhibiting or exciting the sympathetic pathway. CONCLUSIONS Intra-arterial injection of lidocaine during endovascular procedures can be recommended as an effective prophylactic approach for use in the treatment of the cerebrovascular disorder where there is high risk of embolization-induced TCR.
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Malformações Vasculares do Sistema Nervoso Central , Embolização Terapêutica , Reflexo Trigêmino-Cardíaco , Malformações Vasculares do Sistema Nervoso Central/terapia , Humanos , Injeções Intra-Arteriais , LidocaínaRESUMO
PURPOSE: The present study aimed to determine the effectiveness of intravenous dexmedetomidine of different concentrations and to evaluate its maternal and neonatal safety when combined with butorphanol in parturients undergoing cesarean section. PATIENTS AND METHODS: A total of 114 parturients between 24 and 43 years of age, with singleton pregnancy who underwent elective cesarean section under epidural anesthesia, were randomly allocated to four groups: group C received 0.9% sodium chloride after delivery, followed by butorphanol (3 µg·kg-1·h-1); patients in groups D1, D2, and D3 received 0.5 µg·kg-1·h-1 dexmedetomidine after delivery, followed by butorphanol (3 µg·kg-1·h-1) combined with dexmedetomidine 0.03, 0.05, and 0.08 µg·kg-1·h-1, respectively. The primary outcome was the visual analogue scale (VAS) score at 6 h after delivery when patients were at rest. Secondary outcome measures included VAS after delivery when patients were on movement and uterine cramping, Ramsay sedation scale (RSS), relative infant dose (RID) of dexmedetomidine, satisfaction with analgesia after surgery and symptoms of CNS depression in neonates. RESULTS: There were no significant differences in patient characteristics among the groups (P > 0.05). The VAS at all timepoints after delivery in groups D2 and D3 were significantly lower than in groups C and D1 (P < 0.001). RSS scores were clearly higher in group D3 than in the other three groups at 6 h and 12 h (P < 0.0001). RID in groups D1, D2, and D3 was 0.171%, 0.197%, and 0.370%, respectively. Compared with group D1, RID was higher in group D3 (P = 0.0079). Degree of satisfaction with analgesia was higher in groups D2 and D3 (P < 0.005). CONCLUSION: Continuous intravenous infusion of 0.05 µg·kg-1·h-1 dexmedetomidine combined with 3 µg·kg-1·h-1 butorphanol could be safely applied in healthy parturients with satisfactory analgesia after cesarean section without changes in sedation.
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Analgésicos Opioides/uso terapêutico , Butorfanol/uso terapêutico , Dexmedetomidina/uso terapêutico , Dor Pós-Operatória/tratamento farmacológico , Adulto , Analgesia Controlada pelo Paciente , Analgésicos Opioides/administração & dosagem , Butorfanol/administração & dosagem , Cesárea , Dexmedetomidina/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Injeções Intravenosas , Estrutura Molecular , Dor Pós-Operatória/cirurgia , Gravidez , Relação Estrutura-Atividade , Adulto JovemRESUMO
Activation of fibroblast growth factor (FGF) signaling is initiated by a multiprotein complex formation between FGF, FGF receptor (FGFR), and heparan sulfate proteoglycan on the cell membrane. Cross-talk with other factors could affect this complex assembly and modulate the biological response of cells to FGF. We have previously demonstrated that anosmin-1, a glycosylated extracellular matrix protein, interacts with the FGFR1 signaling complex and enhances its activity in an IIIc isoform-specific and HS-dependent manner. The molecular mechanism of anosmin-1 action on FGFR1 signaling, however, remains unknown. Here, we show that anosmin-1 directly binds to FGFR1 with high affinity. This interaction involves domains in the N terminus of anosmin-1 (cysteine-rich region, whey acidic protein-like domain and the first fibronectin type III domain) and the D2-D3 extracellular domains of FGFR1. In contrast, anosmin-1 binds to FGFR2IIIc with much lower affinity and displays negligible binding to FGFR3IIIc. We also show that FGFR1-bound anosmin-1, although capable of binding to FGF2 alone, cannot bind to a FGF2.heparin complex, thus preventing FGFR1.FGF2.heparin complex formation. By contrast, heparin-bound anosmin-1 binds to pre-formed FGF2.FGFR1 complex, generating an anosmin-1.FGFR1.FGF2.heparin complex. Furthermore, a functional interaction between anosmin-1 and the FGFR1 signaling complex is demonstrated by immunofluorescence co-localization and Transwell migration assays where anosmin-1 was shown to induce opposing effects during chemotaxis of human neuronal cells. Our study provides molecular and cellular evidence for a modulatory action of anosmin-1 on FGFR1 signaling, whereby binding of anosmin-1 to FGFR1 and heparin can play a dual role in assembly and activity of the ternary FGFR1.FGF2.heparin complex.
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Proteínas da Matriz Extracelular/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Heparitina Sulfato/metabolismo , Complexos Multiproteicos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/fisiologia , Animais , Células COS , Membrana Celular/genética , Membrana Celular/metabolismo , Quimiotaxia/fisiologia , Chlorocebus aethiops , Proteínas da Matriz Extracelular/genética , Fator 2 de Crescimento de Fibroblastos/genética , Heparitina Sulfato/genética , Humanos , Complexos Multiproteicos/genética , Proteínas do Tecido Nervoso/genética , Neurônios/citologia , Neurônios/metabolismo , Ligação Proteica/fisiologia , Estrutura Terciária de Proteína/fisiologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismoRESUMO
Postoperative cognitive dysfunction (POCD) has been hypothesized to be mediated by surgery-induced neuroinflammation, which is also a key element in the pathobiology of neurodegenerative diseases, stroke, and neuropsychiatric disorders. There is extensive communication between the immune system and the central nervous system (CNS). Inflammation resulting from activation of the innate immune system cells in the periphery can impact central nervous system behaviors, such as cognitive performance. Mast cells (MCs), as the"first responders" in the CNS, can initiate, amplify, and prolong other immune and nervous responses upon activation. In addition, MCs and their secreted mediators modulate inflammatory processes in multiple CNS pathologies and can thereby either contribute to neurological damage or confer neuroprotection. Neuroinflammation has been considered to be linked to neurovascular dysfunction in several neurological disorders. This review will provide a brief overview of the bidirectional relationship of MCs-neurovascular unit communication in neuroinflammation and its involvement in POCD, providing a new and unique therapeutic target for the adjuvant treatment of POCD.
Assuntos
Barreira Hematoencefálica/imunologia , Disfunção Cognitiva/imunologia , Inflamação/fisiopatologia , Mastócitos/imunologia , Complicações Pós-Operatórias/imunologia , Animais , Disfunção Cognitiva/etiologia , Humanos , Inflamação/psicologia , Neuroimunomodulação/fisiologia , Complicações Pós-Operatórias/psicologiaRESUMO
Objective To investigate the neonatal effect and placental transfer of dexmedetomidine during caesarean section under epidural anaesthesia. Methods Forty parturients with a single newborn who were scheduled for caesarean section were enrolled. Patients received 0.5 µg/kg dexmedetomidine 10 min after epidural anaesthesia, followed by 0.5 µg/kg/h until abdominal closure (Dex group) or infusion of normal saline (NS group). Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were monitored before infusion (T0), 10 min after infusion (T1), at delivery (T2), and at the end of the operation (T3). Umbilical vein and artery blood was collected. Apgar scores were evaluated at 1 and 5 min after delivery. Results SBP, DBP, and HR in the Dex group were decreased at T3 compared with T0 (116 ± 10.4 vs 111 ± 9.2 mmHg, 74 ± 6.7 vs 66 ± 7.9 mmHg, 91 ± 12.1 vs 71 ± 8.4 beats/min, respectively, P < 0.05). HR was lower at T1, T2, and T3 in the Dex group compared with the NS group ( P < 0.05). There were no significant differences in blood gases and Apgar scores between the groups ( P > 0.05). Conclusion Dexmedetomidine during caesarean section under epidural anaesthesia is beneficial to parturients. The placental transfer rate is 0.68.
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Anestesia Epidural , Cesárea , Dexmedetomidina/uso terapêutico , Hipnóticos e Sedativos/uso terapêutico , Placenta/metabolismo , Adulto , Dexmedetomidina/farmacocinética , Dexmedetomidina/farmacologia , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Hipnóticos e Sedativos/farmacocinética , Hipnóticos e Sedativos/farmacologia , Troca Materno-Fetal , Gravidez , Adulto JovemRESUMO
Kallmann's syndrome corresponds to a loss of sense of smell and hypogonadotrophic hypogonadism. Defects in anosmin-1 result in the X-linked inherited form of Kallmann's syndrome. Anosmin-1 is an extracellular matrix protein comprised of an N-terminal, cysteine-rich (Cys-box) domain and a whey acidic protein-like (WAP) domain, followed by four fibronectin type III (FnIII) domains. The solution structures of recombinant proteins containing the first three domains (PIWF1) and all six domains (PIWF4) were determined by X-ray scattering and analytical ultracentrifugation. Guinier analyses showed that PIWF1 and PIWF4 have different radii of gyration (R(G)) values of 3.1 nm and 6.7 nm, respectively, but similar cross-sectional radii of gyration (R(XS)) values of 1.5 nm and 1.9 nm, respectively. Distance distribution functions showed that the maximum lengths of PIWF1 and PIWF4 were 11 nm and 23 nm, respectively. Analytical ultracentrifugation gave sedimentation coefficients of 2.52 S and 3.55 S for PIWF1 and PIWF4, respectively. The interpretation of the scattering data by constrained modelling requires homology models for all six domains in anosmin-1. While models were already available for the WAP and FnIII domains, searches suggested the Cys-box domain may resemble the cysteine-rich region of the insulin-like growth factor receptor. Automated constrained molecular modelling based on joining the anosmin-1 domains with structurally randomised linkers resulted in 10,000 models for anosmin-1. A trial-and-error search showed that about 0.1-1.4% of these models fitted the X-ray data. The best models showed that the three domains and six domains in PIWF1 and PIWF4, respectively, were extended. The inter-domain linkers in anosmin-1 could not all be extended at the same time, and there was evidence for inter-domain flexibility. Models with folded-back domain arrangements do not fit the data. These solution structures account for the known biological function of anosmin-1, in particular its ability to interact with its three macromolecular ligands.
Assuntos
Proteínas da Matriz Extracelular/química , Proteínas do Tecido Nervoso/química , Sequência de Aminoácidos , Animais , Bases de Dados de Proteínas , Drosophila , Eletroforese em Gel de Poliacrilamida , Receptores ErbB/metabolismo , Fibronectinas/química , Humanos , Ligantes , Proteínas do Leite/química , Modelos Biológicos , Modelos Moleculares , Dados de Sequência Molecular , Peptídeos/química , Conformação Proteica , Estrutura Terciária de Proteína , Receptores de Somatomedina/metabolismo , Proteínas Recombinantes/química , Espalhamento de Radiação , Ultracentrifugação , Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Raios XRESUMO
BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are a key part of multimodal perioperative analgesia. This study aimed to evaluate the influence of perioperative NSAIDs application on complications after gastrointestinal surgery by using meta-analysis. METHODS: A systematic review of published literature was conducted by searching computerized databases including PubMed, CBM, Springer, Chinese Academic Journals, and China Info since the databases were published until June 2015. The articles and retrospective references regarding complications after gastrointestinal surgery were collected to compare postoperative complications associated with NSAIDs or other analgesics. After they were assessed by randomized controlled trials and extracted by the standard of the Jadad systematic review, the homogeneous studies were pooled using RevMan 5.3 software. The meta-analysis was performed on five postoperative complications: postoperative anastomotic leak, cardiovascular events, surgical site infection, nausea and vomiting, and intestinal obstruction. RESULTS: Twelve randomized controlled trials involving 3829 patients met the inclusion criteria. The results of meta-analyses showed the following: (1) postoperative anastomotic leak: NSAIDs (including selective and nonselective NSAIDs) increased the incidence of anastomotic leak [odds ratio (OR)=3.02, 95% confidence interval (CI): 2.16-4.23, p=0.00001]. Further results showed that nonselective NSAIDs significantly increased the incidence of anastomotic leak (OR=2.96, 95% CI: 1.99-4.42, p<0.00001), and selective NSAIDs had no significant difference as compared with the control group using other analgesics (OR=2.27, 95% CI: 0.68-7.56, p=0.18); (2) postoperative cardiovascular events: NSAIDs (selective and nonselective NSAIDs) had no difference when compared with other analgesics (OR=0.50, 95% CI: 0.23-1.12, p=0.09); (3) postoperative surgical site infection: NSAIDs (selective and nonselective NSAIDs) and other analgesics had no difference in surgical site infection (OR=0.77, 95% CI: 0.52-1.15, p=0.20); (4) postoperative nausea and vomiting: NSAIDs (selective and nonselective NSAIDs) decreased the incidence of nausea and vomiting (OR=0.53, 95% CI: 0.34-0.81, p=0.003); (5) postoperative intestinal obstruction: NSAIDs (selective and nonselective NSAIDs) decreased the incidence of intestinal obstruction (OR=0.35, 95% CI: 0.13-0.89, p=0.03). CONCLUSIONS: The meta-analysis suggests that postoperative NSAIDs, especially nonselective NSAIDs, could increase the incidence of anastomotic leak. NSAIDs could decrease postoperative nausea and vomiting and intestinal obstruction, but showed no difference in cardiovascular events and surgical site infection as compared with other analgesics.
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Anti-Inflamatórios não Esteroides/uso terapêutico , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Complicações Pós-Operatórias/prevenção & controle , Fístula Anastomótica/prevenção & controle , Humanos , Obstrução Intestinal/prevenção & controle , Náusea e Vômito Pós-Operatórios/prevenção & controle , Infecção da Ferida Cirúrgica/prevenção & controleRESUMO
Defects of either anosmin-1 or fibroblast growth factor receptor 1 (FGFR1) are known to underlie hereditary Kallmann's syndrome (KS), a human disorder of olfactory and gonadotropin-releasing hormone (GnRH) neuronal ontogeny. Here, we report a functional interaction between anosmin-1 and the FGFR1-FGF2-heparan sulfate complex, leading to amplified responses in the FGFR1 signaling pathway. In human embryonic GnRH olfactory neuroblasts, wild-type anosmin-1, but not proteins with loss-of-function KS mutations, induces neurite outgrowth and cytoskeletal rearrangements through FGFR1-dependent mechanisms involving p42/44 and p38 mitogen-activated protein kinases and Cdc42/Rac1 activation. Furthermore, anosmin-1 enhances FGF2 signaling specifically through FGFR1 IIIc in heterologous BaF3 lymphoid cells in a heparan sulfate-dependent manner. Our study provides compelling evidence for anosmin-1 as an isoform-specific co-ligand modulator of FGFR signaling that amplifies and specifies FGFR1 signaling responses during human nervous system development and defines a mechanism underlying the link between autosomal and X-linked KS.
Assuntos
Proteínas da Matriz Extracelular/fisiologia , Hormônio Liberador de Gonadotropina/metabolismo , Heparitina Sulfato/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Neurônios/fisiologia , Condutos Olfatórios/citologia , Receptores Proteína Tirosina Quinases/fisiologia , Receptores de Fatores de Crescimento de Fibroblastos/fisiologia , Células Cultivadas , Citoesqueleto/metabolismo , Citoesqueleto/ultraestrutura , Embrião de Mamíferos/metabolismo , Ativação Enzimática , Proteínas da Matriz Extracelular/metabolismo , Fator 2 de Crescimento de Fibroblastos/fisiologia , Proteoglicanas de Heparan Sulfato/fisiologia , Humanos , Imuno-Histoquímica , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neuritos/fisiologia , Neurônios/metabolismo , Condutos Olfatórios/embriologia , Isoformas de Proteínas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Proteína cdc42 de Ligação ao GTP/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
Defective function of anosmin-1, the protein encoded by KAL-1, underlies X-linked Kallmann's syndrome (X-KS), a human hereditary developmental disorder. Anosmin-1 appears to play a role in neurite outgrowth and axon branching, although molecular mechanisms of its action are still unknown. Anosmin-1 contains a WAP (whey acidic protein-like) domain and four contiguous FnIII (fibronectin-like type III) repeats; its WAP domain shows similarity to known serine protease inhibitors, whereas the FnIII domains contain HS (heparan sulphate)-binding sequences. To investigate the functional role of these domains, we have generated both wild-type and mutant recombinant anosmin-1 proteins using a Drosophila S2 cell expression system. Here we present the first biochemical evidence demonstrating the high-binding affinity between HS and anosmin-1, as measured by SPR (surface plasmon resonance) (K(d)=2 nM). The FnIII domains, particularly the first, are essential for dose-dependent HS binding and HS-mediated cell surface association. Furthermore, we have identified uPA (urokinase-type plasminogen activator) as an anosmin-1 interactant. Anosmin-1 significantly enhances the amidolytic activity of uPA in vitro; and anosmin-1-HS-uPA co-operation induces cell proliferation in the PC-3 prostate carcinoma cell line. Both the HS interaction and an intact WAP domain are required for the mitogenic activity of anosmin-1. These effects appear to be mediated by a direct protein interaction between anosmin-1 and uPA, since anosmin-1-uPA could be co-immunoprecipitated from PC-3 cell lysates, and their direct binding with high affinity (K(d)=6.91 nM) was demonstrated by SPR. We thus propose that anosmin-1 may modulate the catalytic activity of uPA and its signalling pathway, whereas HS determines cell surface localization of the anosmin-1-uPA complex.
Assuntos
Cromossomos Humanos X , Proteínas da Matriz Extracelular/metabolismo , Heparitina Sulfato/metabolismo , Síndrome de Kallmann , Proteínas do Tecido Nervoso/metabolismo , Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Animais , Bovinos , Linhagem Celular , Proliferação de Células , Cromossomos Humanos X/genética , Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Proteínas da Matriz Extracelular/química , Proteínas da Matriz Extracelular/genética , Vetores Genéticos/genética , Heparina/metabolismo , Humanos , Síndrome de Kallmann/genética , Cinética , Complexos Multiproteicos/química , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Ligação Proteica , Estrutura Terciária de Proteína , Ressonância de Plasmônio de Superfície , Trombina/metabolismoRESUMO
Heparan sulphate proteoglycans (HSPGs) exist in pancreatic beta cells, and HS seems to modulate important interactions in the islet microenvironment. However, the intra-islet structures of HS in health or altered glucose homeostasis are currently unknown. Here we show that distinct spatial distribution of HS motifs is present in islets in the adult, that intra-islet HS motifs are mostly conserved between rodents and humans, and that HS is abundant in glucagon producing islet alpha cells. In beta cells HS is characterised by 2-O, 6-O and N-sulphated moieties, whereas HS in alpha cells is N-acetylated, N-, and 2-O sulphated and low in 6-O groups. Differential expression of three HS modifying genes in alpha and beta cells was observed and may account for the different HS patterns. Furthermore, we found that FGF1 and FGF2 were present in alpha cells, whereas functional FGFRs exist in beta cells, but not in the alpha cell line aTC1-6, or in primary alpha cells in islets. FGF1 induced signalling was dependent on 2-O, and 6-O HS sulphation in beta cells, and HS desulphation reduced beta cell proliferation and potentiated oxidant induced apoptosis. In leptin resistant animals and in islets from streptozotocin treated rats there was a reduction in alpha cell HS expression. These data demonstrate the distinct HS expression patterns in alpha and beta islet cells and propose a novel role for alpha cells as a source of paracrine FGF ligands to neighbouring beta cells with specific cell-associated HS domains mediating the activation and diffusion of paracrine ligands.
Assuntos
Regulação da Expressão Gênica/fisiologia , Células Secretoras de Glucagon/metabolismo , Heparitina Sulfato/metabolismo , Células Secretoras de Insulina/metabolismo , Comunicação Parácrina/fisiologia , Animais , Fator 1 de Crescimento de Fibroblastos/genética , Fator 1 de Crescimento de Fibroblastos/metabolismo , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/metabolismo , Células Secretoras de Glucagon/citologia , Heparitina Sulfato/genética , Células Secretoras de Insulina/citologia , Ratos , Ratos Sprague-Dawley , Ratos ZuckerRESUMO
KAL1 is implicated in 5% of Kallmann syndrome cases, a disorder which genotypically overlaps with septo-optic dysplasia (SOD). To date, a reporter-based assay to assess the functional consequences of KAL1 mutations is lacking. We aimed to develop a luciferase assay for novel application to functional assessment of rare KAL1 mutations detected in a screen of 422 patients with SOD. Quantitative analysis was performed using L6-myoblasts stably expressing FGFR1, transfected with a luciferase-reporter vector containing elements of the FGF-responsive osteocalcin promoter. The two variants assayed [p.K185N, p.P291T], were detected in three females with SOD (presenting with optic nerve hypoplasia, midline and pituitary defects). Our novel assay revealed significant decreases in transcriptional activity [p.K185N: 21% (p < 0.01); p.P291T: 40% (p < 0.001)]. Our luciferase-reporter assay, developed for assessment of KAL1 mutations, determined that two variants in females with hypopituitarism/SOD are loss-of-function; demonstrating that this assay is suitable for quantitative assessment of mutations in this gene.
Assuntos
Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Luciferases/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Polimorfismo de Nucleotídeo Único , Displasia Septo-Óptica/genética , Animais , Células COS , Chlorocebus aethiops , Feminino , Humanos , Técnicas In Vitro , Modelos Moleculares , Linhagem , Hipófise/metabolismo , Displasia Septo-Óptica/metabolismo , Displasia Septo-Óptica/patologiaRESUMO
Kallmann's syndrome (KS) is a genetic condition characterised by hypogonadotrophic hypogonadism (HH) and anosmia; although these are the defining features of the condition, additional neurological and non-neurological sequel may also occur depending on the specific mode of inheritance. KS affects about 1 in 8000 males and 1 in 40,000 females, with most presentations being of the 'sporadic' type. Of the inherited forms, hitherto, only the gene responsible for the X-linked form (X-KS), namely KAL-1, has been identified and the encoded protein, anosmin-1, consists primarily of a whey acidic protein (WAP) and fibronectin-like type III (FnIII) domains which appear to mediate distinctly different protein functions. The WAP/FnIII combination is conserved in anosmins across species and recent studies in rodents and in Caenorhabditis elegans demonstrate that anosmin functions in both axonal targeting and branching. Screening for loci that modify these phenotypes in C. elegans has identified heparan-6-O-sulphotransferase as a key interactor mediating anosmin-1 function. Furthermore, over-expression and loss of function of the C. elegans Kal-1 gene disrupt epidermal morphogenesis, resulting in ventral enclosure and male tail formation defects. These findings provide novel insights into the molecular pathogenesis of X-KS.
Assuntos
Proteínas da Matriz Extracelular/metabolismo , Síndrome de Kallmann/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Sequência de Aminoácidos , Animais , Proteínas da Matriz Extracelular/genética , Feminino , Fibronectinas/genética , Fibronectinas/metabolismo , Proteoglicanas de Heparan Sulfato/metabolismo , Humanos , Síndrome de Kallmann/genética , Masculino , Proteínas do Leite/genética , Proteínas do Leite/metabolismo , Dados de Sequência Molecular , Mutação , Proteínas do Tecido Nervoso/genética , Condutos Olfatórios/embriologia , Condutos Olfatórios/metabolismoRESUMO
Fibroblast growth factor (FGF) signaling is essential for both olfactory bulb (OB) morphogenesis and the specification, migration, and maturation of the GnRH-secreting neurons. Disruption of FGF signaling contributes to Kallmann syndrome characterized by both anosmia and sexual immaturity. However, several unanswered questions remain as to which specific FGF receptor (FGFR)-1 signaling pathways are necessary for OB and GnRH neuronal development. Here, using pharmacological phosphatidylinositol 3-kinase (PI3K) isoform-specific inhibitors, we demonstrate a central role for the PI3K p110α isoform as a downstream effector of FGFR1 signaling for both GnRH neuronal migration and OB development. We show that signaling via the PI3K p110α isoform is required for GnRH neuronal migration in explant cultures of embryonic day (E) 4 chick olfactory placodes. We also show that in ovo administration of LY294002, a global PI3K inhibitor as well as an inhibitor to the PI3K p110α isoform into the olfactory placode of E3 chick embryo impairs GnRH neuronal migration toward the forebrain. In contrast, in ovo PI3K inhibitor treatment produced no obvious defects on primary olfactory sensory neuron axonal targeting and bundle formation. We also demonstrate that anosmin-1 and FGF2 induced neuronal migration of immortalized human embryonic GnRH neuroblast cells (FNC-B4-hTERT) is mediated by modulating FGFR1 signaling via the PI3K p110α isoform, specifically through phosphorylation of the PI3K downstream effectors, Akt and glycogen synthase kinase-3ß. Finally, we show that neurite outgrowth and elongation of OB neurons in E10 chick OB explants are also dependent on the PI3K p110α isoform downstream of FGFR1. This study provides mechanistic insight into the etiology of Kallmann syndrome.
Assuntos
Movimento Celular/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/metabolismo , Neuritos/efeitos dos fármacos , Neurônios/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Isoformas de Proteínas/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Animais , Embrião de Galinha , Cromonas/farmacologia , Morfolinas/farmacologia , Neurônios/efeitos dos fármacos , Bulbo Olfatório/citologia , Bulbo Olfatório/efeitos dos fármacos , Bulbo Olfatório/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Isoformas de Proteínas/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacosRESUMO
The gene for X-linked Kallmann's syndrome (KAL-1, encoding anosmin-1) was cloned in 1991. Over a decade elapsed before autosomal forms of KS and most of other genetic forms of isolated hypogonadotrophic hypogonadism (IHH) became characterized, and the genetic diversity of these disorders fully appreciated. Although KAL-1 mutations appear to cause a more severe reproductive phenotype than other IHH genes, the biology of this multidomain extracellular matrix protein has only been partially characterized. Initial studies suggested a central role of anosmin-1, in GnRH neuron ontogeny - specifically in GnRH neuronal migration from the cribriform plate area into the brain - as well as in olfactory bulb development. Anosmin-1 is expressed extracellularly, with high affinity binding to cell membrane heparan sulphate proteoglycans. It is expressed in the outer layers of the developing olfactory bulb, the neuroretina, the cerebellum, spinal cord and developing kidney. Recent observations have demonstrated an anosmin-1 heparan sulphate dependent functional interaction with the product of the autosomal dominant KAL-2 (FGFR1: anosmin-2) gene, thereby modulating FGFR1 signalling. Although these genes are frequently co-expressed in developing tissues, this may not represent the sole mode of action of anosmin-1, and FGFR1 independent actions of the protein have also been identified. Structural and in vitro functional studies have shown that anosmin-1 may have complex biological actions. Anosmin-1 interactions with FGFR1 have however been best characterized and represent the dominant focus of this chapter.
Assuntos
Proteínas da Matriz Extracelular/genética , Genes Ligados ao Cromossomo X , Hormônio Liberador de Gonadotropina/deficiência , Hormônio Liberador de Gonadotropina/genética , Mutação , Proteínas do Tecido Nervoso/genética , Neurônios/fisiologia , Animais , Biologia do Desenvolvimento , Proteínas da Matriz Extracelular/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Humanos , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismoRESUMO
Disrupted fibroblast growth factor receptor (FGFR)1 signalling has been shown to cause Kallmann syndrome (KS), a human genetic disorder characterised by olfactory bulb dysgenesis and hypogonadotrophic hypogonadism. Loss-of-function mutations in the KS gene KAL-2/FGFR1 account for roughly 10% of KS cases, leading to the autosomal dominant form of the disease. Anosmin-1, the KAL-1 gene product underlying X-linked KS, modulates FGFR1 signalling via regulation of FGF2/FGFR1/heparin signalling complex assembly and activity. This review covers recent advances in the potential interactions of KS-associated molecules within the FGFR1 signalling complex, and demonstrates a novel mechanism of pre-signalling modulation that mechanistically links an autosomal dominant and sex-linked mode of inheritance of this disease, highlighting the central role of FGFR1 signalling in KS.