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Inorganic phosphate is an essential molecule for all known life. Organisms have developed many mechanisms to ensure an adequate supply, even in low-phosphate conditions. In prokaryotes phosphate transport is instigated by the phosphate-binding protein (PBP), the initial receptor for the ATP-binding cassette (ABC) phosphate transporter. In the crystal structure of the PBP-phosphate complex, the phosphate is completely desolvated and sequestered in a deep cleft and is bound by 13 hydrogen bonds: 12 to protein NH and OH donor groups and one to a carboxylate acceptor group. The carboxylate plays a key recognition role by accepting a phosphate hydrogen. PBP phosphate affinity is relatively consistent across a broad pH range, indicating the capacity to bind monobasic (H2PO4−) and dibasic (HPO42−) phosphate; however, the mechanism by which it might accommodate the second hydrogen of monobasic phosphate is unclear. To answer this question, neutron diffraction studies were initiated. Large single crystals with a volume of 8 mm3 were grown and subjected to hydrogen/deuterium exchange. A 2.5 Å resolution data set was collected on the Protein Crystallography Station at the Los Alamos Neutron Science Center. Initial refinement of the neutron data shows significant nuclear density, and refinement is ongoing. This is the first report of a neutron study from this superfamily. [ABSTRACT FROM AUTHOR]

We investigated in patients with chronic venous insufficiency (CVI) and after compression therapy the fluxmotion within characteristic frequency bands, which were described earlier by Bračič and Stefanovska (Bull. Math. Biol. 60 (1998), 919–935). Therefore, the frequency spectra of laser Doppler flux data of the 36 patient's legs were compared with 41 legs of healthy subjects. In addition, 14 patients with CVI wore a compression stocking (interface pressure: 25–32 mmHg) or compression bandages and were measured after 4 weeks therapy. Data were analyzed by means of a Wavelet packet transformation (a combination of the Daubechies filter of order 4 and the Haar filter). We found significant differences between the patients and the healthy subjects in the frequency intervals of myogenic 0.06–0.16 Hz, respiratory 0.16–0.6 Hz and heart activity 0.6–1.6 Hz (p<0.05, Mann–Whitney U test). Furthermore, the main energy peak height in these frequency intervals increased with the severity of venous disease and was highest in patients with venous leg ulceration. Compression therapy had a significant influence in myogenic vessel activity, which has been proved by a positive frequency shift of 20% (p=0.007, one-sided by the exact Wilcoxon test). In venous disease fluxmotion was increased. Compression therapy over a period of 4 weeks improved myogenic vessel activity. [ABSTRACT FROM AUTHOR]

Jessica B Ciralsky, Kimberly C SippelDepartment of Ophthalmology, Weill Cornell Medical College, New York, NY, USABackground: Stevens-Johnson syndrome is often associated with blinding ocular surface cicatricial sequelae. Recent reports have described markedly improved clinical outcomes with the application of amniotic membrane to the ocular surface during the acute phase. Here we describe the clinical outcome of a patient with acute Stevens-Johnson syndrome and severe ocular surface involvement in whom the evolving medical condition and family consent resulted in amniotic membrane application to each eye at differing intervals from disease onset.Methods: We undertook a retrospective chart review of a woman with Stevens-Johnson syndrome who presented within hours of disease onset. She underwent application of amniotic membrane to the ocular surface of the left eye during the hyperacute phase (

Ana G Alzaga Fernandez,* Nathan M Radcliffe,* Kimberly C Sippel, Mark I Rosenblatt, Priyanka Sood, Christopher E Starr, Jessica B Ciralsky, Donald J D'Amico, Szilárd KissDepartment of Ophthalmology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA*These authors contributed equally to this work and both are considered principal authorsBackground: The purpose of this study was to assess whether the resolution offered by two different, recently commercially available high-resolution, spectral-domain anterior segment optical coherence tomography (AS-OCT) instruments allows for detailed anatomic characterization of the critical device-donor cornea interface in eyes implanted with the Boston type I permanent keratoprosthesis.Methods: Eighteen eyes of 17 patients implanted with the Boston type I keratoprosthesis were included in this retrospective case series. All eyes were quantitatively evaluated using the Cirrus HD-OCT while a subset (five eyes) was also qualitatively imaged using the Spectralis Anterior Segment Module. Images from these instruments were analyzed for evidence of epithelial migration onto the anterior surface of the keratoprosthesis front plate, and presence of a vertical gap between the posterior surface of the front plate and the underlying carrier donor corneal tissue. Quantitative data was obtained utilizing the caliper function on the Cirrus HD-OCT.Results: The mean duration between AS-OCT imaging and keratoprosthesis placement was 29 months. As assessed by the Cirrus HD-OCT, 83% of eyes exhibited epithelial migration over the edge of the front plate. Fifty-six percent of the keratoprosthesis devices displayed good apposition of the device with the carrier corneal donor tissue. When a vertical gap was present (44% of eyes), the mean gap was 40 (range 8–104) microns. The Spectralis Anterior Segment Module also displayed sufficient resolution to allow for similar characterization of the device-donor cornea interface.Conclusion: Spectral-domain AS-OCT permits high resolution imaging of the keratoprosthesis device-donor cornea interface. Both the Cirrus HD-OCT and the Spectralis Anterior Segment module allowed for visualization of epithelial coverage of the device-donor cornea interface, as well as identification of physical gaps. These imaging modalities, by yielding information in regard to integration of the keratoprosthesis with surrounding corneal tissue, may help identify those at risk for keratoprosthesis-related complications, such as extrusion and endophthalmitis, and hence guide clinical management.Keywords: keratoprosthesis, anterior segment optical coherence tomography, epithelialization

Purpose: To assess the effectiveness of topical and subconjunctival bevacizumab in suppressing vascularization in graft and host bed after high-risk corneal transplantation., Design: Secondary analysis of prospective, randomized, double-blind, placebo-controlled multicentric clinical trial., Participants: The study includes patients aged > 18 years who underwent high-risk penetrating keratoplasty, which was defined as corneal vascularization in ≥ 1 quadrants of the corneal graft and host bed, excluding the limbus., Methods: Patients were randomized to treatment and control groups. The patients in the treatment group received subconjunctival injection of bevacizumab (2.5 mg/0.1 ml) on the day of the procedure, followed by topical bevacizumab (10 mg/ml) 4 times per day for 4 weeks. The patients in control group received injection of vehicle (0.9% sodium chloride) on the day of procedure, followed by topical vehicle (carboxymethylcellulose sodium 1%) 4 times a day for 4 weeks., Main Outcome Measures: Vessel and invasion area of vessels in the corneal graft and host beds., Results: This study included 56 eyes of 56 patients who underwent high-risk corneal transplantation, with equal numbers in the bevacizumab and vehicle (control) treatment groups. The mean age of patients who received bevacizumab was 61.2 ± 15.9 years, and the mean age of those treated with vehicle was 60.0 ± 16.1 years. The vessel area at baseline was comparable in the bevacizumab (16.72% ± 3.19%) and control groups (15.48% ± 3.12%; P  = 0.72). Similarly, the invasion areas were also similar in the treatment (35.60% ± 2.47%) and control (34.23% ± 2.64%; P  = 0.9) groups at baseline. The reduction in vessel area was significantly higher in the bevacizumab-treated group (83.7%) over a period of 52 weeks compared with the control group (61.5%; P < 0.0001). In the bevacizumab-treated group, invasion area was reduced by 75.8% as compared with 46.5% in the control group. The vessel area was similar at 52 weeks postprocedure in cases of first (3.54% ± 1.21%) and repeat (3.80% ± 0.40%) corneal transplantation in patients who received bevacizumab treatment. In the vehicle-treated patients, the vessel area was significantly higher in repeat (9.76% ± 0.32%) compared with first (8.06% ± 1.02%; P < 0.0001) penetrating keratoplasty. In the bevacizumab treatment group, invasion areas at week 52 were comparable in first (11.70% ± 3.38%) and repeat (11.64% ± 1.74%) procedures, whereas invasion area was significantly higher in repeat (27.87% ± 2.57%) as compared with first (24.11% ± 2.17%) penetrating keratoplasty in vehicle-treated patients., Conclusions: In patients undergoing vascularized high-risk corneal transplantation, bevacizumab is efficacious in reducing vascularization of corneal graft and host bed, thereby reducing the risk of corneal graft rejection in vascularized host beds., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2024 by the American Academy of Ophthalmology.)

Background/objectives: The orexigenic peptide hormone ghrelin has been implicated in the pathophysiology of obesity and type 2 diabetes mellitus through its effects on nutrient homeostasis. Ghrelin is subject to a unique post-translational acyl modification regulating its biochemical activity., Subjects/methods: In this study we aimed to investigate the relation of acylated (AcG) as well as unacylated ghrelin (UnG) with body weight and insulin resistance in the fasting (n = 545) and post-oral glucose tolerance test (oGTT) state (n = 245) in a metabolically well characterized cohort covering a broad range of BMI (17.95 kg/m²-76.25 kg/m²)., Results: Fasting AcG (median 94.2 pg/ml) and UnG (median 175.3 pg/ml) were negatively and the AcG/UnG ratio was positively correlated with BMI (all p < 0.0001). Insulin sensitivity (ISI) correlated positively with AcG (p = 0.0014) and UnG (p = 0.0004) but not with the AcG/UnG ratio. In a multivariate analysis, including ISI and BMI, only BMI, but not ISI was independently associated with AcG and UnG concentrations. Significant changes of AcG and UnG concentrations were detectable after oGTT stimulation, with slight decreases after 30 min and increases after 90-120 min. Subject stratification into BMI-divergent groups revealed more pronounced AcG increases in the two groups with BMI < 40 kg/m²., Conclusion: Our data demonstrate lower concentrations for both AcG and UnG with increasing BMI as well as an increased proportion of the biologically active, acylated form of ghrelin giving point to pharmacologic intervention in ghrelin acylation and/or increase in UnG for treatment of obesity despite decreased absolute AcG levels., (© 2023. The Author(s).)

Background: The fetal autonomic nervous system (ANS) is believed to be negatively affected by maternal adverse emotional states. In this study, we evaluated how depression, anxiety and stress during pregnancy are related to fetal heart rate variability (HRV) as recorded with magnetocardiography (MCG). We also considered metabolic factors such as maternal adiposity and circulating levels of cortisol during gestation. Furthermore, we followed up these fetuses after birth, recording HRV and saliva levels of cortisol in these infants to establish any effects postpartum., Methods: We calculated HRV in spontaneous MCG recordings from 32 healthy fetuses between 32 and 38 weeks of gestational age. Maternal emotional state was assessed using standardized questionnaires about anxiety, depression and stress. An overall indicator of maternal well-being was calculated by z-scoring each individual questionnaire and summation. We used a median split to divide the group into high and low z-scores (HZS and LZS), respectively. Standard HRV measures were determined in the time and frequency domain. T-test analyses were performed between LZS and HZS, with the HRV and the metabolic measures as the dependent variables., Results: We found an impaired HRV in the HZS group both during pregnancy and after birth. No differences were observed between LZS and HZS for metabolic factors. Depression and anxiety symptoms seem to affect HRV differently. No relationship was found between maternal and infant cortisol levels., Conclusions: On the basis of our results on different HRV parameters, we propose that maternal emotional state might affect the development of the fetal nervous system in utero., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors.)