Reduced Notch1 Cleavage Promotes the Development of Pulmonary Hypertension.

Clinical trials of Dll4 (Delta-like 4) neutralizing antibodies (Dll4nAbs) in cancer patients are ongoing. Surprisingly, pulmonary hypertension (PH) occurs in 14% to 18% of patients treated with Dll4nAbs, but the mechanisms have not been studied. Here, PH progression was measured in mice treated with Dll4nAbs. We detected Notch signaling in lung tissues and analyzed pulmonary vascular permeability and inflammation. Notch target gene array was performed on adult human pulmonary microvascular endothelial cells (ECs) after inhibiting Notch cleavage. Similar mechanisms were studied in PH mouse models and pulmonary arterial hypertension patients. The rescue effects of constitutively activated Notch1 in vivo were also measured. We observed that Dll4nAbs induced PH in mice as indicated by significantly increased right ventricular systolic pressure, as well as pulmonary vascular and right ventricular remodeling. Mechanistically, Dll4nAbs inhibited Notch1 cleavage and subsequently impaired lung endothelial barrier function and increased immune cell infiltration in vessel walls. In vitro, Notch targeted genes' expression related to cell growth and inflammation was decreased in human pulmonary microvascular ECs after the Notch1 inactivation. In lungs of PH mouse models and pulmonary arterial hypertension patients, Notch1 cleavage was inhibited. Consistently, EC cell-cell junction was leaky, and immune cell infiltration increased in PH mouse models. Overexpression activated Notch1-attenuated progression of PH in mice. In conclusion, Dll4nAbs led to PH development in mice by impaired EC barrier function and increased immune cell infiltration through inhibition of Notch1 cleavage in lung ECs. Reduced Notch1 cleavage in lung ECs could be an underlying mechanism of PH pathogenesis.

Electrically synchronizing and modulating the dynamics of ERK activation to regulate cell fate.

Intracellular signaling dynamics play fundamental roles in cell biology. Precise modulation of the amplitude, duration, and frequency of signaling activation will be a powerful approach to investigate molecular mechanisms as well as to engineer signaling to control cell behaviors. Here, we showed a practical approach to achieve precise amplitude modulation (AM), frequency modulation (FM), and duration modulation (DM) of MAP kinase activation. Alternating current (AC) electrical stimulation induced synchronized ERK activation. Amplitude and duration of ERK activation were controlled by varying stimulation strength and duration. ERK activation frequencies were arbitrarily modulated with trains of short AC applications with accurately defined intervals. Significantly, ERK dynamics coded by well-designed AC can rewire PC12 cell fate independent of growth factors. This technique can be used to synchronize and modulate ERK activation dynamics, thus would offer a practical way to control cell behaviors in vivo without the use of biochemical agents or genetic manipulation.

The effect of prior trabeculectomy on refractive outcomes of cataract surgery.

PURPOSE: To examine surgical and refractive outcomes of phacoemulsification with intraocular lens (IOL) implant in eyes with prior trabeculectomy. DESIGN: Retrospective observational case-control study. METHODS: The study compared eyes that underwent phacoemulsification with IOL implant at least 3 months post-trabeculectomy (n = 77) with eyes with either medically controlled glaucoma (n = 43) or no glaucoma (n = 50) at an academic institution. The main outcome measure was the difference between the expected and the actual postoperative refraction. RESULTS: Mean intraocular pressure (IOP) increased in trabeculectomy eyes from 8.7 ± 4.2 mm Hg to 10.7 ± 4.0 mm Hg (P < .0001), whereas it decreased in glaucoma control and normal control groups by 2.0 mm Hg (P = .003) and 2.1 mm Hg (P < .00001), respectively, with concurrent decrease in drops in the glaucoma control group (0.76 to 0.23, P < .0001). The difference from expected refractive outcome was -0.36 (more myopic) in trabeculectomy eyes compared with +0.23 (more hyperopic) in nonglaucoma controls and +0.40 in glaucoma controls (P < .0001). The correlation between change in IOP vs extent of refractive surprise was statistically significant (P = .01, r = -0.20). Final visual acuity was not affected by the difference in refractive error. CONCLUSIONS: The refractive surprise correlated to IOP change, with 2 mm Hg rise resulting in a -0.36 diopter shift between predicted and actual refraction. After cataract extraction, IOP decreased in controls and fewer drops were required, but IOP increased in the study group. Factors affecting refractive surprise in cataract surgery after trabeculectomy, especially IOP change and axial length, require further investigation.

Accuracy of cone-beam computed tomography and periapical radiography in detecting small periapical lesions.

INTRODUCTION: The aim of this study was to determine the diagnostic accuracy of 2 cone-beam computed tomography (CBCT) machines and periapical (PA) radiography in detecting simulated apical lesions created with the smallest dental burs available. METHODS: By using mandibles from human cadavers, simulated apical lesions were created and then progressively enlarged in 16 roots by using sizes #1/4, #1/2, #1, #2, #4, and #6 round burs. Imaging was obtained after each enlargement with a Kodak 9000 3D (Kodak) CBCT, a Veraviewpocs 3De (Morita) CBCT, and intraoral digital PA radiography. Specificity and sensitivity at variable decision thresholds were calculated and plotted on receiver operator characteristic curves. The area under the curve (AUC) served as an estimate of diagnostic accuracy. RESULTS: The overall AUCs for Kodak, Morita, and PA radiography were 0.767 (95% confidence interval [CI], 0.743-0.792), 0.753 (95% CI, 0.728-0.779), and 0.584 (95% CI, 0.554-0.615), respectively. The AUCs for Kodak and Morita were both statistically significantly larger than the AUC for all corresponding simulated lesion sizes imaged with PA radiography. Between Kodak and Morita, there were no statistically significant differences in AUCs for any of the corresponding simulated lesion sizes. CONCLUSIONS: Both CBCT devices demonstrated poor accuracy in detecting simulated lesions smaller than 0.8 mm in diameter, fair to good accuracy when simulated lesion diameter was between 0.8-1.4 mm, and excellent accuracy when simulated lesions were larger than 1.4 mm in diameter. PA radiography, at best, demonstrated poor diagnostic accuracy for all simulated lesion sizes.

Connected speech intelligibility of children with cochlear implants and children with normal hearing.

The objective of this study was to compare the connected speech intelligibility of children who use cochlear implants with that of children who have normal hearing. Previous research has shown that speech intelligibility improves from before cochlear implantation to after implantation and that the speech intelligibility of children who use cochlear implants compares favorably with that of children who use conventional hearing aids. However, no research has yet addressed the question of how the speech intelligibility of children who use cochlear implants compares to that of children with normal hearing. In the current study, archival data on connected speech intelligibility from 51 children with cochlear implants were compared with newly collected data from 47 children with normal hearing. Results showed that for children with cochlear implants, greater intelligibility was associated with both increased chronological age and increased duration of cochlear implant use. Consistent with previous studies, children with normal hearing achieved adult-like or near-adult-like intelligibility around the age of 4 years, but a similar peak in intelligibility was not observed for the children who used cochlear implants. On the whole, children with cochlear implants were significantly less intelligible than children with normal hearing, when controlling both for chronological age and for length of auditory experience. These results have implications for the socialization and education of children with cochlear implants, particularly with respect to on-time placement in mainstream educational environments with age peers.