RESUMEN
AIM: To investigate the clinical features of the ocular surface in patients with different degrees of myopia. METHODS: A cross-sectional study was conducted involving 122 participants with myopia in Beijing Tongren Hospital from February to June, 2023. After completing the Ocular Surface Disease Index (OSDI) score scale, measurements were taken for refraction, biometric parameters and ocular surface parameters. The prevalence, severity and related parameters of the dry eye among different groups based on axial length (AL) were compared. Correlation analysis was performed between ocular surface parameters and refraction/biometric measurement parameters. RESULTS: Statistically significant differences were observed in refractive error, corneal thickness, anterior chamber depth, and subfoveal choroidal thickness among the groups (all P<0.05). With the increase in AL, the incidence and severity of dry eye increased significantly (P<0.05). Moreover, the tear film break-up time (BUT) shortened (P<0.05), and the corneal fluorescein staining (CFS) points increased significantly (P<0.05). OSDI scores were positively correlated with AL and spherical equivalent (SE; both P<0.05); BUT was negatively correlated with AL, SE, and corneal astigmatism (AST; all P<0.05); Schirmer I test (SIT) results were negatively correlated with AL and SE (both P<0.05). CONCLUSION: AL elongation is a risk factor for dry eye onset in myopic participants. The longer the AL, the more severe the dry eye is, with the increased CFS spots and tear film instability. Additionally, SE and AST exhibit negative correlations with dry eye symptom scores and ocular surface parameters.
RESUMEN
PURPOSE: To investigate the rate of axial length elongation and high myopia progression in operated eyes before and after posterior scleral reinforcement (PSR) surgery. METHODS: This was a retrospective study. Children with pathological myopia treated with PSR at Beijing Tongren Hospital between May 2013 and May 2020 were recruited into the PSR surgery group. Children matched for age and myopia were recruited into the control group. All children underwent comprehensive ophthalmologic examinations. The presurgical and postsurgical rates of axial length elongation and myopic (spherical equivalent) progression were calculated. RESULTS: A total of 35 PSR patients were included in the study. The mean age was 6.5±3.0 years (range 2 to 14 years). Mean follow-up was 544 days (range 216 to 1657 days). The rate of axial length elongation was significantly less after posterior scleral reinforcement surgery (0.505±0.048mm per year prior to surgery; 0.382±0.045mm per year after surgery, P<0.001). The rate of myopic progression decreased after posterior scleral reinforcement surgery (1.162±0.118 D per year prior to surgery; 0.153±0.437 D per year after surgery, P=0.0239). There was no statistically significant difference in axial length elongation or myopic progression between pre-inclusion and post-inclusion in the control group. Moreover, the children's best-corrected visual acuity was significantly improved after posterior scleral reinforcement surgery (P<0.001). CONCLUSION: Posterior scleral reinforcement surgery effectively decreased the rate of high myopic progression and axial length elongation in children.
RESUMEN
Purpose: By reporting clinical characteristics and retinal image quality before and after refractive lens replacement surgery in early-onset high myopia (eoHM) patients presenting with partial cataract, we emphasized the need for an objective way to grade the severity of partial cataracts. Methods: This retrospective, consecutive case series included six Chinese patients (nine eyes). Analysis of previous medical records, visual acuity, optometry, retinal image quality, and axial length (AXL) before surgery and after surgery was performed. Results: Five females and one male (nine eyes) with a mean (± SD) age of 11.6 ± 7.9 years (range: 4-25 years) were included in this study. The preoperative spherical power ranged from -7.5 to -42 D. The mean follow-up time was 36 months (range: 24-48 months). Phacoemulsification was followed by in-the-bag implantation of intraocular lens. For patients who were under 6 years old, posterior capsulotomy + anterior vitrectomy were performed simultaneously. All surgeries were uneventful and no postoperative complications occurred during the entire follow-up period. All patients' uncorrected visual acuity improved by ≥2 lines postoperatively(Snellen acuity). LogMAR best-corrected visual acuity was improved at 24-month (P = 0.042) and endpoint (P = 0.046) follow-ups. Modulation transfer function cutoff frequency (MTFcutoff) and objective scatter index (OSI) was significantly improved at 12-month (P = 0.025, P = 0.038), 24-month (P = 0.005, P = 0.007) and endpoint (P = 0.005, P = 0.008) follow-ups. Postoperative AXL remained stable during 2-4 year follow-ups (P > 0.05). Conclusion: Refractive lens replacement surgery is safe and effective for improving functional vision in eoHM patients presenting with partial cataract. Retinal image quality could provide a useful and objective way to facilitate partial cataract severity evaluation and surgery decision making.
RESUMEN
BACKGROUND: In recent years, visual quality has been extensively investigated in various conditions. In this community-based population study, we analyzed the effects of aging, refraction, and Lens Opacification Classification System III (LOCSIII) score on retinal imaging quality in healthy Chinese adults. METHODS: This cross-sectional study was conducted on sub-group subjects from The Handan Eye Study between October 2012 and January 2013. Healthy subjects over 30-years-old with logarithm of the minimal angle of resolution (logMAR) best-corrected visual acuity (BCVA) less than 0 were included. Retinal image quality was measured by optical quality analysis system (OQAS) and recorded as modulation transfer function cutoff frequency (MTFcutoff), OQAS value (OV) 100%, OV20%, OV9%, Strehl ratio (SR), and objective scatter index (OSI). The correlation between age, spherical equivalent refraction (SE), LOCSIII score, and optical quality parameters were investigated by multivariate analysis. RESULTS: Among 1108 verified subjects, 690 subjects (1380 eyes) met the inclusion criteria. Their age ranged from 30 to 76 years, SE ranged from -4.75 to 2.75 D. They were divided into five age groups (30-39, 40-49, 50-59, 60-69, and ≥70 years) for further analysis. After multivariate analysis by mixed-effect linear model, SR (tâ=â -3.03, Pâ=â0.002), OV20% (tâ=â-2.39, Pâ=â0.017), and OV9% (tâ=â-3.16, Pâ=â0.001) significantly decreased with the increasing age, whereas logMAR BCVA (tâ=â4.42, Pâ<â0.001) and OSI (tâ=â4.46, Pâ<â0.001) significantly increased with age. As SE increased, SR (tâ=â2.74, Pâ=â0.01), OV20% (tâ=â2.31, Pâ=â0.02), and OV9% (tâ=â2.79, Pâ=â0.005) significantly elevated, and OSI (tâ=â-3.38, Pâ<â0.001) significantly decreased. With the increase in cortical opacity score, all optical quality parameters except for SR significantly decreased, including MTFcutoff (tâ=â-2.78, Pâ=â0.01), OV100% (tâ=â-2.78, Pâ=â0.005), OV20% (tâ=â-2.60, Pâ=â0.009), and OV9% (tâ=â-2.05, Pâ=â0.040). As posterior sub capsular opacity score increased, MTFcutoff (tâ=â-2.40, Pâ=â0.02) and OV100% (tâ=â-2.40, Pâ=â0.01) significantly decreased, while OSI (tâ=â7.56, Pâ<â0.001) significantly increased. CONCLUSIONS: In healthy Chinese adult population, optical quality-related parameters significantly decrease with the increasing age, and OSI significantly increases with age. In normal BCVA subjects, optical quality is significantly impacted by cortical and posterior sub capsular opacity rather than by nuclear opacity.
Asunto(s)
Envejecimiento , Retina , Adulto , Anciano , China , Estudios Transversales , Humanos , Persona de Mediana Edad , Agudeza VisualRESUMEN
AIMS: The present study aims to investigate the role of Akt in the regulation of urinary bladder organ hypertrophy caused by partial bladder outlet obstruction (pBOO). MAIN METHODS: Male rats were surgically induced for pBOO. Real-time PCR and western blot were used to examine the levels of mRNA and protein. A phosphoinositide 3-kinase (PI3K) inhibitor LY294002 was used to inhibit the activity of endogenous Akt. KEY FINDINGS: The urinary bladder developed hypertrophy at 2â¯weeks of pBOO. The protein but not mRNA levels of type I collagen and α-smooth muscle actin (αSMA) were increased in pBOO bladder when compared to sham control. The phosphorylation (activation) levels of Akt1 (p-Ser473), mammalian target of rapamycin (mTOR), p70S6 kinase (p70S6K), and 4E-BP1 were also increased in pBOO bladder. LY294002 treatment reduced the phosphorylation levels of Akt1 and 4E-BP1, and the protein levels of type I collagen and αSMA in pBOO bladder. The mRNA and protein levels of proliferating cell nuclear antigen (PCNA) were increased in pBOO bladder, and PCNA up-regulation occurred in urothelial not muscular layer. LY294002 treatment had no effect on the mRNA and protein levels of PCNA in pBOO bladder. LY294002 treatment partially reduced the bladder weight caused by pBOO. SIGNIFICANCE: pBOO-induced urinary bladder hypertrophy is attributable to fibrosis, smooth muscle cellular hypertrophy, and urothelium cell hyper-proliferation. Akt1-mediated protein synthesis in pBOO bladder contributes to type I collagen and αSMA but not PCNA up-regulation. Target of Akt1 is necessary but not sufficient in treatment of urinary bladder hypertrophy following pBOO.
Asunto(s)
Proteínas Proto-Oncogénicas c-akt/biosíntesis , Proteínas Proto-Oncogénicas c-akt/genética , Vejiga Urinaria/patología , Animales , Vías Biosintéticas/genética , Cromonas/farmacología , Inhibidores Enzimáticos , Fibrosis , Hipertrofia , Masculino , Morfolinas/farmacología , Tamaño de los Órganos/efectos de los fármacos , Inhibidores de las Quinasa Fosfoinosítidos-3 , ARN Mensajero/biosíntesis , Ratas , Ratas Sprague-Dawley , Obstrucción del Cuello de la Vejiga Urinaria/patología , Urotelio/patologíaRESUMEN
The transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor or vanilloid receptor 1 (VR1), is expressed in nociceptive neurons in the dorsal root ganglia (DRG) and participates in the transmission of pain. The present study investigated the underlying molecular mechanisms by which TRPV1 was regulated by nerve growth factor (NGF) signaling pathways in colonic hypersensitivity in response to colitis. We found that during colitis TRPV1 protein levels were significantly increased in specifically labeled colonic afferent neurons in both L1 and S1 DRGs. TRPV1 protein up-regulation in DRG was also enhanced by NGF treatment. We then found that TRPV1 protein up-regulation in DRG was regulated by activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway both in vivo and in vitro. Suppression of endogenous PI3K/Akt activity during colitis or NGF treatment with a specific PI3K inhibitor LY294002 reduced TRPV1 protein production in DRG neurons, and also reduced colitis-evoked TRPV1-mediated visceral hypersensitivity tested by hyper-responsiveness to colorectal distention (CRD) and von Frey filament stimulation of abdomen. Further studies showed that TRPV1 mRNA levels in the DRG were not regulated by either colitis or NGF. We then found that an up-regulation of the protein synthesis pathway was involved by which both colitis and NGF caused a PI3K-dependent increase in the phosphorylation level of eukaryotic translation initiation factor 4E-binding protein (4E-BP)1. These results suggest a novel mechanism in colonic hypersensitivity which involves PI3K/Akt-mediated TRPV1 protein, not mRNA, up-regulation in primary afferent neurons, likely through activation of the protein synthesis pathways.
Asunto(s)
Colitis/fisiopatología , Hipersensibilidad/fisiopatología , Proteína Oncogénica v-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Canales Catiónicos TRPV/genética , Animales , Cromonas/farmacología , Colitis/metabolismo , Ganglios Espinales/metabolismo , Hiperalgesia/fisiopatología , Hipersensibilidad/metabolismo , Masculino , Morfolinas/farmacología , Factor de Crecimiento Nervioso/metabolismo , Neuronas Aferentes , Proteína Oncogénica v-akt/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3 , Estimulación Física , Ratas , Ratas Sprague-Dawley , Transducción de Señal/genética , Canales Catiónicos TRPV/antagonistas & inhibidoresRESUMEN
BACKGROUND: Visceral hypersensitivity is a complex pathophysiological paradigm with unclear mechanisms. Primary afferent neuronal plasticity marked by alterations in neuroactive compounds such as calcitonin gene-related peptide is suggested to underlie the heightened sensory responses. Signal transduction that leads to calcitonin gene-related peptide expression thereby sensory neuroplasticity during colitis remains to be elucidated. RESULTS: In a rat model with colitis induced by 2,4,6-trinitrobenzene sulfonic acid, we found that endogenously elevated brain-derived neurotrophic factor elicited an up-regulation of calcitonin gene-related peptide in the lumbar L1 dorsal root ganglia. At seven days of colitis, neutralization of brain-derived neurotrophic factor with a specific brain-derived neurotrophic factor antibody reversed calcitonin gene-related peptide up-regulation in the dorsal root ganglia. Colitis-induced calcitonin gene-related peptide transcription was also inhibited by brain-derived neurotrophic factor antibody treatment. Signal transduction studies with dorsal root ganglia explants showed that brain-derived neurotrophic factor-induced calcitonin generelated peptide expression was mediated by the phospholipase C gamma, but not the phosphatidylinositol 3-kinase/Akt or the mitogen-activated protein kinase/extracellular signal-regulated protein kinase pathway. Application of PLC inhibitor U73122 in vivo confirmed that colitis-induced and brain-derived neurotrophic factor-mediated calcitonin gene-related peptide up-regulation in the dorsal root ganglia was regulated by the phospholipase C gamma pathway. In contrast, suppression of the phosphatidylinositol 3-kinase activity in vivo had no effect on colitis-induced calcitonin gene-related peptide expression. During colitis, calcitonin gene-related peptide also co-expressed with phospholipase C gamma but not with p-Akt. Calcitonin gene-related peptide up-regulation during colitis correlated to the activation of cAMP-responsive element binding protein in the same neurons. Consistently, colitis-induced cAMP-responsive element binding protein activation in the dorsal root ganglia was attenuated by brain-derived neurotrophic factor antibody treatment. CONCLUSION: These results suggest that colitis-induced and brain-derived neurotrophic factor-mediated calcitonin generelated peptide expression in sensory activation is regulated by a unique pathway involving brain-derived neurotrophic factorphospholipase C gamma-cAMP-responsive element binding protein axis.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Péptido Relacionado con Gen de Calcitonina/metabolismo , Colitis/complicaciones , Fosfolipasa C gamma/metabolismo , Dolor Visceral/etiología , Dolor Visceral/metabolismo , Animales , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Ganglios Espinales/metabolismo , Vértebras Lumbares/metabolismo , Vértebras Lumbares/patología , Masculino , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Transporte de Proteínas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Sprague-Dawley , Transducción de Señal , Regulación hacia ArribaRESUMEN
Patients with inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS) often experience increased sensory responsiveness in the urinary bladder reflecting neurogenic bladder overactivity. Here we demonstrate that colitis-induced up-regulation of the phospholipase C gamma (PLCγ) pathway downstream of brain-derived neurotrophic factor (BDNF) in bladder afferent neurons in the dorsal root ganglia (DRG) plays essential roles in activating these neurons thereby leading to bladder hyperactivity. Upon induction of colitis with 2,4,6-trinitrobenzenesulfonic acid (TNBS) in rats, we found that the phosphorylation (activation) level of cAMP responsive element-binding (p-CREB) protein, a molecular switch of neuronal plasticity, was increased in specifically labeled bladder afferent neurons in the thoracolumbar and lumbosacral DRGs. In rats having reduced levels of BDNF (BDNF+/-), colitis failed to elevate CREB protein activity in bladder afferent neurons. Physiological examination also demonstrated that colitis-induced urinary frequency was not shown in BDNF+/- rats, implicating an essential role of BDNF in mediating colon-to-bladder sensory cross-sensitization. We further implemented in vivo and in vitro studies and demonstrated that BDNF-mediated colon-to-bladder sensory cross-activation involved the TrkB-PLCγ-calcium/calmodulin-dependent protein kinase II (CaMKII) cascade. In contrast, the PI3K/Akt pathway was not activated in bladder afferent neurons during colitis and was not involved in BDNF action in the DRG. Our results suggest that colon-to-bladder sensory cross-sensitization is regulated by specific signal transduction initiated by the up-regulation of BDNF in the DRG.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Colitis/patología , Ganglios Espinales/patología , Neuronas/fisiología , Fosfolipasa C gamma/metabolismo , Transducción de Señal/fisiología , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Proteína de Unión a CREB/metabolismo , Colitis/inducido químicamente , Modelos Animales de Enfermedad , Masculino , Ratones Noqueados , Neuronas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Ácido Trinitrobencenosulfónico/toxicidad , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiología , Vejiga Urinaria/inervaciónRESUMEN
AIM: To evaluate intra-session repeatability and reproducibility of optical quality parameters measured at objective and subjective best focuses in a double-pass system. METHODS: Thirty Chinese healthy adults (19 to 40 years old) meeting our inclusion criterion were enrolled in the study. After a basic eye examination, two methods of optical quality measurement, based on subjective and objective best focuses were performed using the Optical Quality Analysis System (OQAS) with an artificial pupil diameter of 4.0 mm. RESULTS: With each method, three consecutive measurements of the following parameters: the modulation transfer function cutoff frequency (MTFcutoff), the Strehl(2D) ratio, the OQAS values (OVs) at contrasts of 100%, 20%, 9% and the objective scatter index (OSI) were performed by an experienced examiner. The repeatability of each method was evaluated by the repeatability limit (RL) and the coefficient of repeatability (COR). Reproducibility of the two methods was evaluated by intra-class correlation coefficient (ICC) and the 95% limits of agreement (Bland and Altman analysis). Thirty subjects, seven females and twenty three males, of whom 15 right eyes and 15 left eyes were selected randomly for recruitment in the study. The RLs (percentage) for the six parameters measured at objective focus and subjective focus ranged from 8.44% to 15.13% and 10.85% to 16.26%, respectively. The CORs for the two measurement methods ranged from 8.27% to 14.83% and 10.63% to 15.93%, respectively. With regard to reproducibility, the ICCs for the six parameters of OQAS ranged from 0.024 to 0.276. The 95% limits of agreement obtained for the six parameters (in comparison of the two methods) ranged from -0.57 to 42.18 (MTFcutoff), -0.01 to 0.23 (Strehl(2D) ratio), -0.02 to 1.40 (OV100%), -0.10 to 1.75 (OV20%), -0.14 to 1.80 (OV9%) and -1.46 to 0.18 (OSI). CONCLUSION: Measurements provided by OQAS with either method showed a good repeatability. However, the results obtained from the two different measurement methods showed a poor reproducibility. These findings suggest that it might be best to evaluate patients' optical quality by OQAS using the best focus as chosen automatically by the instrument.
RESUMEN
BACKGROUND: Spinal central sensitization is an important process in the generation and maintenance of visceral hypersensitivity. The release of brain-derived neurotrophic factor (BDNF) from the primary afferent neurons to the spinal cord contributes to spinal neuronal plasticity and increases neuronal activity and synaptic efficacy. The N-Methyl-D-aspartic acid (NMDA) receptor possesses ion channel properties, and its activity is modulated by phosphorylation of its subunits including the NMDA receptor 1 (NR1). METHODS: Colonic inflammation was induced by a single dose of intracolonic instillation of tri-nitrobenzene sulfonic acid (TNBS). NR1 phosphorylation by BDNF in vivo and in culture was examined by western blot and immunohistochemistry. Signal transduction was studied by direct examination and use of specific inhibitors. RESULTS: During colitis, the level of NR1 phospho-Ser(896) was increased in the dorsal horn region of the L1 and S1 spinal cord; this increase was attenuated by injection of BDNF neutralizing antibody to colitic animals (36 µg/kg, intravenous (i.v.)) and was also reduced in BDNF(+/-) rat treated with TNBS. Signal transduction examination showed that the extracellular signal-regulated kinase (ERK) activation was not involved in BDNF-induced NR1 phosphorylation. In contrast, the phosphatidylinositol 3-kinase (PI3K)/Akt pathway mediated BDNF-induced NR1 phosphorylation in vivo and in culture; this is an additional pathway to the phospholipase C-gamma (PLCγ) and the protein kinase C (PKC) that was widely considered to phosphorylate NR1 at Ser(896). In spinal cord culture, the inhibitors to PLC (U73122), PKC (bisindolylmaleimide I), and PI3K (LY294002), but not MEK (PD98059) blocked BDNF-induced NR1 phosphorylation. In animals with colitis, treatment with LY294002 (50 µg/kg, i.v.) blocked the Akt activity as well as NR1 phosphorylation at Ser(896) in the spinal cord. CONCLUSION: BDNF participates in colitis-induced spinal central sensitization by up-regulating NR1 phosphorylation at Ser(896). The PI3K/Akt pathway, in addition to PLCγ and PKC, mediates BDNF action in the spinal cord during colitis.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Colitis/patología , Receptores de N-Metil-D-Aspartato/metabolismo , Transducción de Señal/fisiología , Médula Espinal/metabolismo , Animales , Anticuerpos/uso terapéutico , Factor Neurotrófico Derivado del Encéfalo/inmunología , Factor Neurotrófico Derivado del Encéfalo/farmacología , Cromonas/uso terapéutico , Colitis/tratamiento farmacológico , Colitis/etiología , Modelos Animales de Enfermedad , Inhibidores Enzimáticos , Masculino , Morfolinas/uso terapéutico , Técnicas de Cultivo de Órganos , Fosfatidilinositol 3-Quinasa/metabolismo , Fosforilación/efectos de los fármacos , Proteína Quinasa C/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética , Transducción de Señal/efectos de los fármacos , Médula Espinal/efectos de los fármacos , Factores de Tiempo , Ácido Trinitrobencenosulfónico/toxicidad , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiologíaRESUMEN
PURPOSE: We examined the role of NMDAR in the regulation of bladder hypertrophy and function in a rat model of cyclophosphamide induced cystitis. MATERIALS AND METHODS: Cystitis was induced by intraperitoneal injection of cyclophosphamide (150 mg/kg body weight). NMDAR phosphorylation (activity) and signal transduction pathways were examined by direct measurement and by specific inhibitors in vivo. Bladder hypertrophy was measured by bladder weight/body weight and type I collagen expression. Bladder function was examined by metabolic recording, conscious cystometry and detrusor muscle strip contractility in response to carbachol. RESULTS: NMDAR activity measured by the phosphorylation level of the NMDAR1 (NR1) subunit was expressed in the spinal cord but not in the bladder at 48 hours of cystitis. NMDAR inhibition with dizocilpine (MK-801) reduced the cystitis induced increment of bladder weight and type I collagen up-regulation in the bladder. NMDAR regulated type I collagen up-regulation was mediated by the PI3K/Akt pathway. NMDAR inhibition also attenuated cystitis induced urinary frequency measured by metabolic cage and cystometry. Cystitis decreased the responsiveness of detrusor muscle strips to carbachol, which was reversed by MK-801 in vivo. Unlike MK-801 the NMDAR antagonist D-AP5, which could not block central NMDAR activity, had no effect on bladder hypertrophy, type I collagen up-regulation or Akt activation caused by cystitis in the bladder. CONCLUSIONS: Findings suggest that NMDAR activity has a role in cystitis induced bladder hypertrophy and overactivity. NMDAR mediated Akt activation may underlie the mechanism of bladder dysfunction.
Asunto(s)
Cistitis/tratamiento farmacológico , Cistitis/fisiopatología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Vejiga Urinaria/patología , Vejiga Urinaria/fisiopatología , Animales , Ciclofosfamida/administración & dosificación , Cistitis/inducido químicamente , Hipertrofia/tratamiento farmacológico , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/fisiología , Vejiga Urinaria/efectos de los fármacosRESUMEN
AIMS: The present study aims to systemically characterize the factors that are associated with urinary bladder organ enlargement in spontaneously hypertensive rats (SHR). MAIN METHODS: We compared the SHR to age-matched normotensive Wistar-Kyoto (WKY) control rats in the levels of bladder pro-inflammatory factors, collagen expression (type I), and detrusor smooth muscle growth. KEY FINDINGS: Our results showed that enhanced inflammatory responses and fibrosis were key factors that were closely associated with bladder wall thickening in SHR. Specifically the mRNA levels of inflammatory factors interleukin (IL)-1α, IL-6 and TNFα were significantly higher in SHR than those in WKY rats. The SHR also had a higher number of mast cells in the suburothelium space. Type I collagen production was also significantly higher in SHR when compared to that in control rats. However, the smooth muscle content stayed the same in SHR and WKY rats. This was shown by the results that the ratio of α-smooth muscle actin (SMA) to the nuclear protein histone H3 had no difference between these two rat strains. The mRNA and protein levels of proliferating cell nuclear antigen (PCNA) also showed no change in the urinary bladder of SHR and WKY rats. Further study showed that the phosphorylation level of Akt in the urinary bladder was not changed in SHR when compared to WKY rats. In contrast, the phosphorylation level of ERK1/2 was significantly higher in SHR bladder when compared to that of WKY rats. SIGNIFICANCE: These results suggest that inflammation and fibrosis are primary factors that may lead to urinary bladder hypertrophy in SHR.
Asunto(s)
Hipertensión/patología , Vejiga Urinaria/patología , Actinas/metabolismo , Animales , Colágeno Tipo I/metabolismo , Citocinas/metabolismo , Fibrosis/patología , Histonas/metabolismo , Hiperplasia/patología , Hipertrofia/patología , Inflamación/patología , Masculino , Mastocitos/efectos de los fármacos , Antígeno Nuclear de Célula en Proliferación/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKYRESUMEN
Neurotrophin family are traditionally recognized for their nerve growth promoting function and are recently identified as crucial factors in regulating neuronal activity in the central and peripheral nervous systems. The family members including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) are reported to have distinct roles in the development and maintenance of sensory phenotypes in normal states and in the modulation of sensory activity in disease. This paper highlights receptor tyrosine kinase (Trk) -mediated signal transduction by which neurotrophins regulate neuronal activity in the visceral sensory reflex pathways with emphasis on the distinct roles of NGF and BDNF signaling in physiologic and pathophysiological processes. Viscero-visceral cross-organ sensitization exists widely in human diseases. The role of neurotrophins in mediating neural cross talk and interaction in primary afferent neurons in the dorsal root ganglia (DRG) and neurotrophin signal transduction in the context of cross-organ sensitization are also discussed.
RESUMEN
This study utilized magnetic resonance imaging (MRI) to monitor the real-time status of the urinary bladder in normal and diseased states following cyclophosphamide (CYP)-induced cystitis, and also examined the role of the phosphoinositide 3-kinase (PI3K) pathway in the regulation of urinary bladder hypertrophy in vivo. Our results showed that under MRI visualization the urinary bladder wall was significantly thickened at 8 h and 48 h post CYP injection. The intravesical volume of the urinary bladder was also markedly reduced. Treatment of the cystitis animals with a specific PI3K inhibitor LY294002 reduced cystitis-induced bladder wall thickening and enlarged the intravesical volumes. To confirm the MRI results, we performed H&E stain postmortem and examined the levels of type I collagen by real-time PCR and western blot. Inhibition of the PI3K in vivo reduced the levels of type I collagen mRNA and protein in the urinary bladder ultimately attenuating cystitis-induced bladder hypertrophy. The bladder mass calculated according to MRI data was consistent to the bladder weight measured ex vivo under each drug treatment. MRI results also showed that the urinary bladder from animals with cystitis demonstrated high magnetic signal intensity indicating considerable inflammation of the urinary bladder when compared to normal animals. This was confirmed by examination of the pro-inflammatory factors showing that interleukin (IL)-1α, IL-6 and tumor necrosis factor (TNF)α levels in the urinary bladder were increased with cystitis. Our results suggest that MRI can be a useful technique in tracing bladder anatomy and examining bladder hypertrophy in vivo during disease development and the PI3K pathway has a critical role in regulating bladder hypertrophy during cystitis.
Asunto(s)
Cistitis/prevención & control , Hipertrofia/prevención & control , Imagen por Resonancia Magnética/métodos , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Enfermedades de la Vejiga Urinaria/prevención & control , Vejiga Urinaria/citología , Animales , Western Blotting , Células Cultivadas , Cromonas/farmacología , Ciclofosfamida/toxicidad , Cistitis/inducido químicamente , Cistitis/metabolismo , Cistitis/patología , Inhibidores Enzimáticos/farmacología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Hipertrofia/etiología , Hipertrofia/metabolismo , Hipertrofia/patología , Masculino , Morfolinas/farmacología , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/genética , Ratas , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/metabolismo , Enfermedades de la Vejiga Urinaria/etiología , Enfermedades de la Vejiga Urinaria/metabolismo , Enfermedades de la Vejiga Urinaria/patologíaRESUMEN
The role of brain-derived neurotrophic factor (BDNF) in sensory hypersensitivity has been suggested; however the molecular mechanisms and signal transduction that regulate BDNF expression in primary afferent neurons during visceral inflammation are not clear. Here we used a rat model of cystitis and found that the mRNA and protein levels of BDNF were increased in the L6 dorsal root ganglia (DRG) in response to bladder inflammation. BDNF up-regulation in the L6 DRG was triggered by endogenous nerve growth factor (NGF) because neutralization of NGF with a specific NGF antibody reduced BDNF levels during cystitis. The neutralizing NGF antibody also subsequently reduced cystitis-induced up-regulation of the serine/threonine kinase Akt activity in L6 DRG. To examine whether the NGF-induced Akt activation led to BDNF up-regulation in DRG in cystitis, we found that in cystitis the phospho-Akt immunoreactivity was co-localized with BDNF in L6 DRG, and prevention of the endogenous Akt activity in the L6 DRG by inhibition of phosphoinositide 3-kinase (PI3K) with a potent inhibitor LY294002 reversed cystitis-induced BDNF up-regulation. Further study showed that application of NGF to the nerve terminals of the ganglion-nerve two-compartmented preparation enhanced BDNF expression in the DRG neuronal soma; which was reduced by pre-treatment of the ganglia with the PI3K inhibitor LY294002 and wortmannin. These in vivo and in vitro experiments indicated that NGF played an important role in the activation of Akt and subsequent up-regulation of BDNF in the sensory neurons in visceral inflammation such as cystitis.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cistitis/metabolismo , Ganglios Espinales/metabolismo , Factor de Crecimiento Nervioso/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Cistitis/genética , Modelos Animales de Enfermedad , Activación Enzimática , Masculino , Factor de Crecimiento Nervioso/antagonistas & inhibidores , Fosfatidilinositol 3-Quinasas , Unión Proteica , Transporte de Proteínas , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Transducción de SeñalRESUMEN
BACKGROUND: Optical Quality Analysis System II (OQAS, Visiometrics, Terrassa, Spain) that uses double-pass (DP) technique is the only commercially available device that allows objective measurement of ocular retinal image quality. This study aimed to evaluate the impact of spectacle lenses on the ocular optical quality parameters and the validity of the optometer within OQAS. METHODS: Seventy eyes of healthy volunteers were enrolled. Optical quality measurements were performed using OQAS with an artificial pupil diameter of 4.0 mm. Three consecutive measurements were obtained from spectacle correction corresponding to subjective refraction and from the OQAS built-in optometer separately. The modulation transfer function cutoff frequency, the Strehl ratio, the width of the point spread function (PSF) at 10% of its maximal height (PSF10), and the width of the PSF at 50% of its maximal height (PSF50) were analyzed. RESULTS: There was no significant difference in any of the parameters between the spectacle correction and the optometer correction (all P > 0.05, paired t-test). A good agreement was found between both the methods and a good intraobserver repeatability in both the correction methods. Difference in best focus between two methods was the only parameter associated significantly with optical quality parameter differences. Best focus difference, built-in optometer correction with or without external cylindrical lens, and age were associated significantly with PSF10 difference. No linear correlation between refractive status and optical quality measurement difference was observed. A hyperopic bias (best focus difference of (0.50 ± 0.44) D) and a relatively better optical quality using spectacle correction in high myopia group were found. CONCLUSIONS: OQAS based on DP system is a clinically reliable instrument. In patients with high myopia, measurements using built-in optometer correction should be considered and interpreted with caution.
Asunto(s)
Refracción Ocular , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Agudeza Visual/fisiología , Adulto JovenRESUMEN
The integral interaction of signaling components in the regulation of visceral inflammation-induced central sensitization in the spinal cord has not been well studied. Here we report that phosphoinositide 3-kinase (PI3K)-dependent Akt activation and N-methyl-d-aspartic acid receptor (NMDAR) in lumbosacral spinal cord independently regulate the activation of cAMP response element-binding protein (CREB) in vivo in a rat visceral pain model of cystitis induced by intraperitoneal injection of cyclophosphamide (CYP). We demonstrate that suppression of endogenous PI3K/Akt activity with a potent PI3K inhibitor LY294002 reverses CYP-induced phosphorylation of CREB, however, it has no effect on CYP-induced phosphorylation of NR1 at Ser(897) and Ser(896); conversely, inhibition of NMDAR in vivo with MK801 fails to block CYP-induced Akt activation but significantly attenuates CYP-induced CREB phosphorylation in lumbosacral spinal cord. This novel interrelationship of PI3K/Akt, NMDAR, and CREB activation in lumbosacral spinal cord is further confirmed in an ex vivo spinal slice culture system exposed to an excitatory neurotransmitter calcitonin gene-related peptide (CGRP). Consistently we found that CGRP-triggered CREB activation can be blocked by both PI3K inhibitor LY294002 and NMDAR antagonists MK801 and D-AP5. However, CGRP-triggered Akt activation cannot be blocked by MK801 or D-AP5; vice versa, LY294002 pretreatment that suppresses the Akt activity fails to reverse CGRP-elicited NR1 phosphorylation. These results suggest that PI3K/Akt and NMDAR independently regulate spinal plasticity in visceral pain model, and target of a single pathway is necessary but not sufficient in treatment of visceral hypersensitivity.
Asunto(s)
Sensibilización del Sistema Nervioso Central/fisiología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Cistitis/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Médula Espinal/metabolismo , Animales , Western Blotting , Cistitis/fisiopatología , Modelos Animales de Enfermedad , Inmunohistoquímica , Región Lumbosacra , Masculino , Fosforilación , Ratas , Ratas Sprague-Dawley , Transducción de Señal/fisiologíaRESUMEN
PURPOSE: To investigate the relationship between parental refractive error and the nearwork-induced transient myopia (NITM) characteristics of their children. METHODS: Three hundred sixty children (173 boys and 187 girls) aged 6 to 17 years were tested. Initial NITM and its decay time (DT) were assessed objectively (WAM-5500, Grand-Seiko) immediately after binocularly viewing and performing a sustained near task (5 diopters [D]) for 5 minutes, incorporating a cognitive demand with full distance refractive correction in place. The NITM was classified into three categories: low (< 0.15 D), moderate (0.15 to 0.30 D), or high (≥0.30 D), whereas its decay was classified into two categories, namely, complete or incomplete. In addition, the children were divided into three groups based on the number of myopic parents (none, one, or two) and into four groups based on the level of parental myopia (no, low, moderate, or high). RESULTS: Neither paternal nor maternal refractive error was associated with either their children's initial NITM magnitude or its DT in the myopic, emmetropic, or hyperopic groups or the combined group. No significant differences (p > 0.05) in the NITM magnitude, DT, or decay time constant were found as related to the number of myopic parents or level of parental myopia. Multiple odds ratio for incomplete decay of NITM did not change significantly (p > 0.05) with either an increase in number of myopic parents or level of parental myopia. CONCLUSIONS: There was no association between parental refractive error and their children's NITM characteristics. This suggests a primary environmental basis for the NITM characteristics in the children.
Asunto(s)
Acomodación Ocular/fisiología , Miopía/etiología , Padres , Refracción Ocular , Visión Binocular/fisiología , Adolescente , Niño , Femenino , Estudios de Seguimiento , Humanos , Masculino , Miopía/diagnóstico , Miopía/fisiopatología , Errores de Refracción/fisiopatología , Estudios RetrospectivosRESUMEN
PURPOSE: The purpose of the present study was to describe the baseline refractive and nearwork-induced transient myopia (NITM) characteristics of the Beijing Myopia Progression Study, a 3-year cohort study, that has three overall specific aims: to investigate the natural history of NITM in schoolchildren living in the inner city of Beijing aged between 7 and 17 years; to investigate the possible relation between NITM and permanent myopia; and to determine the possible associations with NITM (eg, parental history). METHODS: Three hundred eighty-six students (187 males and 199 females) were enrolled. The mean ages were 8.4 ± 1.1 years and 14.2 ± 1.6 years for the primary school and secondary school students, respectively. Baseline refractive aspects were determined clinically. Initial NITM and its decay were assessed objectively immediately after binocularly viewing and performing a sustained near task (5 minutes; 5 diopters [D]), incorporating a cognitive demand with full distance refractive correction in place. RESULTS: Initial NITM (mean ± SD) / decay time (median, first quartile, and third quartile) was 0.18 ± 0.16 D / 50 (20, 90) seconds, 0.09 ± 0.13 D / 30 (10, 40) seconds, and 0.10 ± 0.19 D / 20 (10, 40) seconds among the myopic, emmetropic, and hyperopic students, respectively, for the combined school levels. Initial NITM and decay time were significantly larger/longer in the myopic versus the other two refractive groups. CONCLUSIONS: The present findings demonstrate that in a large sample of school-aged children with myopia, the initial NITM magnitude was significantly larger and the decay duration was significantly longer than that observed in age-matched children with either emmetropia or hyperopia. Follow-up for the next 3 years will provide insight into the possible role of NITM in the development of permanent myopia.
Asunto(s)
Acomodación Ocular , Miopía/fisiopatología , Refracción Ocular , Adolescente , Niño , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Miopía/diagnósticoRESUMEN
OBJECTIVE: To compare the refractive results between open-field auto ref/keratometer and conventional autorefractor, and to investigate the effect of cycloplegic to this difference. METHODS: Three hundred and four primary and secondary school students were consecutively enrolled in Beijing Tongren Hospital. Non-cycloplegic and cycloplegic objective refractions were performed for each subject by conventional autorefractor (Accuref-K9001, Shin Nippon, Japan) and binocular, open-field auto ref/keratometer (Grand Seiko Co., Ltd., Hiroshima, Japan). The coincidence rate of sphere, spherical equivalent (SE) and axis (defined as difference of diopter ≤ 0.50 D, difference of axis degree ≤ 20°) were calculated; Bland-Altman and distribution analysis were performed according to mean and difference of SE. RESULTS: The coincidence rate of sphere, SE and axis were 77.3%, 78.6% and 66.0% before cycloplegic and increased to 94.4%, 95.1% and 69.5% after cycloplegic, respectively. The difference (95%CI) of SE before cycloplegic between these two refractometers was 0.12 (-1.04 to 1.29) D and was positively correlated with the mean of SE (after cycloplegic) (r(pearson) = 0.21, P < 0.001). The difference (95%CI) of SE after cycloplegic was -0.08 (-0.60 to 0.45) D. The difference (95%CI) of SE of K9001 autorefractor before and after cycloplegic was larger than that of WAM autorefractor [0.51 (-0.83 - 1.84) D and 0.31 (-0.66 to 1.28) D, P < 0.001]. Before cycloplegic, SE measured by WAM autorefractor showed myopic more than 0.25 D than K9001 (group 1) was found in 51 (16.8%) subjects; difference within 0.25 D was found in 160 (52.6%) subjects; hyperopic more than 0.25 D (group 3) was found in 93 (30.6%) subjects. After cycloplegic, 69 (22.7%) subjects were found in group 1, and subjects increased to 213 (70.1%) and decreased to 22 (7.2%) in group 2 and group 3, respectively. CONCLUSION: The binocular, open-field auto ref/keratometer provides more hyperopic readings than conventional autorefractor. It will be useful in both clinical screening and scientific research because it produces less instrument myopia than that of conventional autorefractor.