Vectors based on the adeno-associated virus (AAV) are currently the preferred tools for delivering genes to photoreceptors (PR) in small and large animals. AAVs have been applied successfully in various models of PR dystrophies. However, unknown barriers still limit AAV's efficient application in several forms of severe PR degenerations due to insufficient transgene expression and/or treated cells at the time of injection. Optimizations of PR gene therapy strategies will likely benefit from the identification of the cellular factors that influence PR transduction. Interestingly, recent studies have shown that the AAV transduction profile of PRs differs significantly between neonatal and adult mouse retinas after subretinal injection. This phenomenon may provide clues to identify host factors that influence the efficiency of AAV-mediated PR transduction. This study demonstrates that rod outer segments are critical modulators of efficient AAV-mediated rod transduction. During retinal development, rod transduction correlated temporally and spatially with the differentiation order of PRs when vectors were introduced subretinally but not when introduced intravitreally. All subretinally injected vectors had an initial preference to transduce cones in the absence of formed rod outer segments and then displayed a preference for rods as the cells matured, independently of the expression cassette or AAV serotype. Consistent with this observation, altered development of rod outer segments was associated with a strong reduction of rod transduction and an increase in the percentage of transduced cones by 2- to 2.8-fold. A similar increase of cone transduction was observed in the adult retinal degeneration 1 (rd1) retina compared to wild-type mice. These results suggest that the loss of rod outer segments in diseased retinas could markedly affect gene transfer efficiency of AAV vectors by limiting the ability of AAVs to infect dying rods efficiently. This information could be exploited for the development of more efficient AAV-based PR gene delivery procedures.
Though myasthenia gravis (MG) is a typical autoimmune disorder, there was some controversy on the treatment of the childhood-onset MG. By observing the efficacy of different therapies, the authors analyzed the affecting factors of prognosis in childhood-onset MG.The retrospective data of 155 patients with childhood-onset MG (age of MG onset was less than 15 years) were collected from Department of Neurology, Beijing Tongren Hospital (January 2000 - February 2010). The patients were non-randomly divided according to their treatment into 3 groups (glucocorticoid, thymectomy and glucocorticoid combined with thymectomy groups). Postintervention status meeting the criteria of Myasthenia Gravis Foundation of America (MGFA) "complete stable remission, CSR", "pharmacologic remission, PR", "minimal manifestations, MM", or "Improved, I" was regarded as desirable response, which was used as primary indicator of observation. The authors assessed the efficacy of three therapies and analyzed the influencing factors of prognosis by using Chi-square test and Logistic regression.At 3 months of treatment, glucocorticoid group showed the highest effective rate. At the end of 1 year or 2 years of treatment, glucocorticoid combined with thymectomy group showed the highest effective rate respectively. The generalization rate of MG at 2 years, 10 years and 20 years in childhood-onset ocular MG patients were 4.3%, 10.7%, and 41.5%, respectively. Of patients with generalization of MG, 48.1% occurred within 2 years, 92.6% within 20 years. Univariate analysis showed that in childhood-onset ocular MG patients, variables such as age at onset (> 10 years), LG-MG and with chronic fatigue were significantly associated with general MG conversion. Whereas multivariate analysis showed that patients with age at onset (> 10 years) and chronic muscle fatigue were apt to convert to generalized MG.Glucocorticoid appeared to have an effect that leads to early remission of symptoms in childhood-onset MG patients and glucocorticoid combined with thymectomy appeared to have better long-term effect. For those childhood-onset ocular MG patients with longer course of disease, older age of onset, chronic fatigue, or LG-MG, physicians should try to prevent the generalization of MG by immunosuppressive therapies.
Retinitis pigmentosa (RP) is an inherited photoreceptor degenerative disorder that results in blindness. The disease is often caused by mutations in genes that are specific to rod photoreceptors; however, blindness results from the secondary loss of cones by a still unknown mechanism. Here, we demonstrated that the mammalian target of rapamycin complex 1 (mTORC1) is required to slow the progression of cone death during disease and that constitutive activation of mTORC1 in cones is sufficient to maintain cone function and promote long-term cone survival. Activation of mTORC1 in cones enhanced glucose uptake, retention, and utilization, leading to increased levels of the key metabolite NADPH. Moreover, cone death was delayed in the absence of the NADPH-sensitive cell death protease caspase 2, supporting the contribution of reduced NADPH in promoting cone death. Constitutive activation of mTORC1 preserved cones in 2 mouse models of RP, suggesting that the secondary loss of cones is caused mainly by metabolic deficits and is independent of a specific rod-associated mutation. Together, the results of this study address a longstanding question in the field and suggest that activating mTORC1 in cones has therapeutic potential to prolong vision in RP.
Objective: The clinical differences of early-onset myasthenia gravis (EOMG) and late-onset MG (LOMG) have not been elucidated in China. In order to clarify this, a retrospective study was conducted in 985 MG patients, whose disease duration was longer than 3 years. Methods: These patients were separated into EOMG and LOMG according to the onset age of 50 years. The clinical differences including demographics, clinical features, thymus abnormalities and comorbidities of EOMG and LOMG patients were analyzed. Results: Results indicated that 485 were males and 500 were females, 714 were EOMG and 271 were LOMG. Female was more common in EOMG and male was more common in LOMG (p = 0.003). The peak onset age was 0-4 years in EOMG and 55-59 years in LOMG. Ocular MG (OMG) was more common in EOMG and generalized MG (GMG) was more common in LOMG (p = 0.004). The transformation rate of OMG to GMG was higher in LOMG (p = 0.002). The positive incidence of repetitive nerve stimulation (RNS) was higher in EOMG (p = 0.026). Thymoma was more frequent in LOMG (p = 0.017) and thymic hyperplasia was more frequent in EOMG (p < 0.001). Hyperthyroidism was more common in EOMG (p = 0.017) and diabetes was more common in LOMG (p < 0.001). Conclusion: These results have potential significance for the recognition of clinical features and the determination of management strategies in EOMG and LOMG.
Cones are the primary photoreceptor (PR) cells responsible for vision in humans. They are metabolically highly active requiring phosphoinositide 3-kinase (PI3K) activity for long-term survival. One of the downstream targets of PI3K is the kinase mammalian target of rapamycin (mTOR), which is a key regulator of cell metabolism and growth, integrating nutrient availability and growth factor signals. Both PI3K and mTOR are part of the insulin/mTOR signaling pathway, however if mTOR is required for long-term PR survival remains unknown. This is of particular interest since deregulation of this pathway in diabetes results in reduced PR function before the onset of any clinical signs of diabetic retinopathy. mTOR is found in two distinct complexes (mTORC1 & mTORC2) that are characterized by their unique accessory proteins RAPTOR and RICTOR respectively. mTORC1 regulates mainly cell metabolism in response to nutrient availability and growth factor signals, while mTORC2 regulates pro-survival mechanisms in response to growth factors. Here we analyze the effect on cones of loss of mTORC1, mTORC2 and simultaneous loss of mTORC1 & mTORC2. Interestingly, neither loss of mTORC1 nor mTORC2 affects cone function or survival at one year of age. However, outer and inner segment morphology is affected upon loss of either complex. In contrast, concurrent loss of mTORC1 and mTORC2 leads to a reduction in cone function without affecting cone viability. The data indicates that PI3K mediated pro-survival signals diverge upstream of both mTOR complexes in cones, suggesting that they are independent of mTOR activity. Furthermore, the data may help explain why PR function is reduced in diabetes, which can lead to deregulation of both mTOR complexes simultaneously. Finally, although mTOR is a key regulator of cell metabolism, and PRs are metabolically highly active, the data suggests that the role of mTOR in regulating the metabolic transcriptome in healthy cones is minimal.
Cardiac rupture (CR) and left ventricular thrombus (LVT) remain important complications of acute myocardial infarction (MI), and they are currently regarded as independent events. We explored the pathogenetic link between CR and LVT by investigating a murine model of MI with a high frequency of CR and in patients with acute MI.MI was induced in mice, the onset of CR was monitored, and the hearts of mice with or without fatal CR were histologically examined. Between 2015 and 2022, from patients admitted due to acute MI, the data of patients with CR or LVT were retrospectively collected and compared to uncomplicated patients (control).A total of 75% of mice (n = 65) with MI developed CR 2-4 days after MI. A histological examination of CR hearts revealed the existence of platelet-rich intramural thrombi in the rupture tunnel, which was connected at the endocardial site to platelet-fibrin thrombi within an LVT. In CR or non-CR mouse hearts, LV blood clots often contained a portion of platelet-fibrin thrombi that adhered to the infarct wall. In non-CR hearts, sites of incomplete CR or erosion of the infarct wall were typically coated with platelet thrombi and dense inflammatory cells. Of 8,936 patients with acute MI, CR and LVT occurred in 102 (1.14%) and 130 (1.45%) patients, respectively, with three cases having both complications. CR accounted for 32.8% of in-hospital deaths. The majority of CR (95%) or LVT (63%, early LVT) occurred within 7 days. In comparison to the control or LVT-late groups, patients with CR or early LVT reported increased levels of cellular and biochemical markers for inflammation or cardiac injury.CR and LVT after MI are potentially linked in their pathogenesis. LVT occurring early after MI may be triggered by a thrombo-inflammatory response following wall rupture or endocardial erosion.
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