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Apolipoprotein J (APOJ) is a multifunctional protein with genetic evidence suggesting an association between APOJ polymorphisms and Alzheimer's disease as well as exfoliation glaucoma. Herein we conducted ocular characterizations of Apoj -/- mice and found that their retinal cholesterol levels were decreased and that this genotype had several risk factors for glaucoma: increased intraocular pressure and cup-to-disk ratio and impaired retinal ganglion cell (RGC) function. The latter was not due to RGC degeneration or activation of retinal Muller cells and microglia/macrophages. There was also a decrease in retinal levels of 24-hydroxycholesterol, a suggested neuroprotectant under glaucomatous conditions and a positive allosteric modulator of N-methyl-D-aspartate receptors mediating the light-evoked response of the RGC. Therefore, Apoj -/- mice were treated with low-dose efavirenz, an allosteric activator of CYP46A1 which converts cholesterol into 24-hydroxycholesterol. Efavirenz treatment increased retinal cholesterol and 24-hydroxycholesterol levels, normalized intraocular pressure and cup-to-disk ratio, and rescued in part RGC function. Retinal expression of Abcg1 (a cholesterol efflux transporter), Apoa1 (a constituent of lipoprotein particles), and Scarb1 (a lipoprotein particle receptor) was increased in EVF-treated Apoj -/- mice, indicating increased retinal cholesterol transport on lipoprotein particles. Ocular characterizations of Cyp46a1 -/- mice supported the beneficial efavirenz treatment effects via CYP46A1 activation. The data obtained demonstrate an important APOJ role in retinal cholesterol homeostasis and link this apolipoprotein to the glaucoma risk factors and retinal 24-hydroxycholesterol production by CYP46A1. As the CYP46A1 activator efavirenz is an FDA-approved anti-HIV drug, our studies suggest a new therapeutic approach for treatment of glaucomatous conditions., (© 2023. The Author(s).)

A small dose of the anti-HIV drug efavirenz (EFV) was previously discovered to activate CYP46A1, a cholesterol-eliminating enzyme in the brain, and mitigate some of the manifestation of Alzheimer's disease in 5XFAD mice. Herein, we investigated the retina of these animals, which were found to have genetically determined retinal vascular lesions associated with deposits within the retinal pigment epithelium and subretinal space. We established that EFV treatment activated CYP46A1 in the retina, enhanced retinal cholesterol turnover, and diminished the lesion frequency >5-fold. In addition, the treatment mitigated fluorescein leakage from the aberrant blood vessels, deposit size, activation of retinal macrophages/microglia, and focal accumulations of amyloid β plaques, unesterified cholesterol, and Oil Red O-positive lipids. Studies of retinal transcriptomics and proteomics identified biological processes enriched with differentially expressed genes and proteins. We discuss the mechanisms of the beneficial EFV effects on the retinal phenotype of 5XFAD mice. As EFV is an FDA-approved drug, and we already tested the safety of small-dose EFV in patients with Alzheimer's disease, our data support further clinical investigation of this drug in subjects with retinal vascular lesions or neovascular age-related macular degeneration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 El-Darzi, Mast, Buchner, Saadane, Dailey, Trichonas and Pikuleva.)

Cholesterol homeostasis in the retina, a sensory organ in the back of the eye, has been studied in mice but not hamsters, despite the latter being more similar to humans than mice with respect to their whole-body cholesterol maintenance. The goal of this study was to begin to assess hamster retina and conduct initial interspecies comparisons. First, young (3-month old) and mature (6-month old) Syrian (golden) hamsters were compared with 3- and 6-month old mice for ocular biometrics and retinal appearance on optical coherence tomography and fluorescein angiography. Of the 30 evaluated hamsters, seven had retinal structural abnormalities and all had increased permeability of retinal blood vessels. However, hamsters did not carry the mutations causing retinal degenerations 1 and 8, had normal blood glucose levels, and only slightly elevated hemoglobin A1c content. Cholesterol and six other sterols were quantified in hamster retina and compared with sterol profiles in mouse and human retina. These comparisons suggested that cholesterol turnover is much higher in younger than mature hamster retina, and that mature hamster and human retinas share similarities in the ratios of cholesterol metabolites to cholesterol. This study supports further investigations of cholesterol maintenance in hamster retina.

Tucatinib is a potent tyrosine kinase inhibitor selective for human epidermal growth factor receptor 2 (HER2) approved by the US Food and Drug Administration for the treatment of HER2-positive metastatic breast cancer and in development for other HER2-positive solid tumors. Modest, reversible serum creatinine (SCr) elevations have been observed in tucatinib clinical trials. SCr is conveyed by the renal drug transporters organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) and 2-K (MATE2-K) and can increase in the presence of inhibitors of these transporters. In vitro, tucatinib inhibited OCT2-, MATE1-, and MATE2-K-mediated transport of metformin, with IC 50 values of 14.7, 0.340, and 0.135 µM, respectively. Tucatinib also inhibited OCT2- and MATE1-mediated transport of creatinine, with IC 50 values of 0.107 and 0.0855 µM, respectively. A phase 1 study with metformin administered orally in the absence and presence of tucatinib was conducted in 18 healthy subjects. Renal function was assessed by measuring glomerular filtration rate (GFR; based on iohexol plasma clearance) and endogenous markers (SCr, cystatin C-based estimated glomerular filtration rate [eGFR]) with and without tucatinib. Metformin exposure increased (1.4-fold) and renal clearance decreased (29.99-17.64 L/h) with tucatinib, with no effect on metformin maximum concentration. Creatinine clearance transiently decreased 23% with tucatinib. GFR and eGFR, which are unaffected by OCT2 and/or MATE1/2-K transport, were unchanged with tucatinib. These data demonstrate that tucatinib inhibits OCT2- and MATE1/2-K-mediated tubular secretion of creatinine, which may manifest as mild SCr elevations that are not indicative of renal impairment., (© 2020 Seattle Genetics, Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

ANITA's fourth long-duration balloon flight in 2016 detected 29 cosmic-ray (CR)-like events on a background of 0.37_{-0.17}^{+0.27} anthropogenic events. CRs are mainly seen in reflection off the Antarctic ice sheets, creating a phase-inverted waveform polarity. However, four of the below-horizon CR-like events show anomalous noninverted polarity, a p=5.3×10^{-4} chance if due to background. All anomalous events are from locations near the horizon; ANITA-IV observed no steeply upcoming anomalous events similar to the two such events seen in prior flights.

We report on an upward traveling, radio-detected cosmic-ray-like impulsive event with characteristics closely matching an extensive air shower. This event, observed in the third flight of the Antarctic Impulsive Transient Antenna (ANITA), a NASA-sponsored long-duration balloon payload, is consistent with a similar event reported in a previous flight. These events could be produced by the atmospheric decay of an upward-propagating τ lepton produced by a ν_{τ} interaction, although their relatively steep arrival angles create tension with the standard model neutrino cross section. Each of the two events have a posteriori background estimates of ≲10^{-2} events. If these are generated by τ-lepton decay, then either the charged-current ν_{τ} cross section is suppressed at EeV energies, or the events arise at moments when the peak flux of a transient neutrino source was much larger than the typical expected cosmogenic background neutrinos.

We report on four radio-detected cosmic-ray (CR) or CR-like events observed with the Antarctic Impulsive Transient Antenna (ANITA), a NASA-sponsored long-duration balloon payload. Two of the four were previously identified as stratospheric CR air showers during the ANITA-I flight. A third stratospheric CR was detected during the ANITA-II flight. Here, we report on characteristics of these three unusual CR events, which develop nearly horizontally, 20-30 km above the surface of Earth. In addition, we report on a fourth steeply upward-pointing ANITA-I CR-like radio event which has characteristics consistent with a primary that emerged from the surface of the ice. This suggests a possible τ-lepton decay as the origin of this event, but such an interpretation would require significant suppression of the standard model τ-neutrino cross section.

Purpose: The passive fit of a superstructure on implant abutments is essential to success. One source of error when using a tapered cone-screw internal connection may be the difference between the tightening torque level applied to the abutments by the laboratory technician compared to that applied by the treating clinician. The purpose of this study was to measure the axial displacement of tapered cone-screw abutments into implants and their replicas as a function of the tightening torque level., Materials and Methods: Twenty tapered cone-screw abutments were selected. Two groups were created: 10 abutments were secured into 10 implants, and 10 abutments were secured into 10 corresponding implant replicas. Each abutment was tightened in increasing increments of 5 Ncm, from 0 Ncm to 45 Ncm, with a torque controller. The length of each sample was measured repeatedly with an Electronic Digital Micrometer. The mean axial displacement for the implant group and the replica group was calculated. The data were analyzed by the Mann-Whitney and Spearman tests., Results: For both groups, there was always an axial displacement of the abutment upon each incremental application of torque. The mean axial displacement values varied between 7 and 12 microm for the implant group and between 6 and 21 microm for the replica group at each 5-Ncm increment. From 0 to 45 Ncm, the total mean axial displacement values were 89 microm for the implant group and 122 microm for the replica group., Conclusion: There was a continuous axial displacement of the abutments into implants and implant replicas when the applied torque was raised from 0 to 45 Ncm. Torque applied above the level recommended by the manufacturer increased the difference in displacement between the two groups.

Objectives: Pulsed-laser deposition (PLD) is a development process to obtain hydroxyapatite (HA) thin film. It is an alternative to hydroxyapatite deposition techniques usually employed to cover orthopaedic or dental titanium implant surfaces. The aim of this study is to find out the characteristic ratio for Ca/P (1.66) deposit on titanium implant with the PLD process., Methods: In a preliminary study, the coating parameters of pure and highly crystalline HA on Ti or Ti-6Al-4V substrates were verified by analysing the deposit by Rutherford backscattering spectroscopy (RBS). Ablation parameters to reach a stoichiometric hydroxyapatite composition (ideal Ca/P atomic ratio) and to control the growth of crystalline phases were: 575 degrees C for the substrate temperature, 0.4 mbar H2O vapour pressure in the ablation chamber, the target substrate distance was 40 mm and the deposition time was 120 min. In a second part, the film properties were analysed by means of XRD, SEM, AFM. The coating adhesion of the HA to the substrate was determined with a micro scratch tester., Results: The analysed HA thin films showed a perfect crystallized and textured deposit. Sample observation and surface quality analysis demonstrated a surface roughness and adhesion of the films to the substrates compatible with biological applications., Significance: These results suggest that pulsed-laser deposition is a suitable technique to obtain crystalline and adherent hydroxyapatite films on Ti or Ti-6Al-4V substrates. The quality of the HA deposit with the PLD process could be an interesting option for coating dental implant.

Statement of Problem: New glass ionomer cements exhibit better mechanical properties than their older counterparts. However, there is concern about their use as a core material in post-and-core applications., Purpose: This in vitro study evaluated the fatigue resistance of 2 new glass ionomer cements, Shofu Hi-Dense and Fuji IX GP, and compared their mechanical behavior as a core material under masticatory load with a silver-reinforced glass ionomer (ESPE Ketac-Silver) and a silver amalgam (Cavex Avaloy LC)., Material and Methods: A total of 100 commercial plastic teeth were divided into 4 groups of 25 specimens each. Titanium posts were placed in the prepared root canals, and cores were built up in amalgam, silver-reinforced glass ionomer cement, and the 2 new glass ionomer cements. The post-and-core specimens were prepared for full cast metal crowns, which were fabricated and cemented with glass ionomer cement. Twenty specimens from each group were placed in a mastication simulator and cyclically loaded with a 400 N force for 1.5 million cycles. The 5 remaining specimens were used as controls. The specimens were sectioned and observed macroscopically and microscopically to determine the number of defects (alterations) in each material. Observed defects were verified with the Kruskal-Wallis test, and the 4 core materials were ranked with the Tukey multiple comparisons test., Results: The mean rank sum values of the defects were as follows: Cavex Avaloy LC Amalgam (16.75), Fuji IX GP (38.50), Shofu Hi-Dense (39.53), and ESPE Ketac-Silver (67.22). The amalgam alloy was significantly different (P< .05) from the others., Conclusion: Under the conditions of this study, the 2 new glass ionomer cements used as core materials showed a higher number of defects than amalgam. These results suggest that their fatigue resistance may be inadequate for post-and-core applications.

Gold and ceramic have long been used in prosthetic dentistry. In the posterior region, it is possible to use both materials with the double-inlay technique to add the strength of metal to the esthetics of ceramic. The problem, however, remains the volume of tooth reduction required to avoid ceramic fracture. This article describes a modification of the double-inlay technique that makes use of a pin system. This modified technique permits good retention while avoiding excessive tooth reduction.

Background and Objective: The purpose of this study was to investigate the effects of low-power laser irradiation on wound healing in genetic diabetes., Study Design/materials and Methods: Female C57BL/Ksj/db/db mice received 2 dorsal 1 cm full-thickness incisions and laser irradiation (830 nm, 79 mW/cm(2), 5.0 J/cm(2)/wound). Daily low-level laser therapy (LLLT) occurred over 0-4 days, 3-7 days, or nonirradiated. On sacrifice at 11 or 23 days, wounds were excised, and tensile strengths were measured and standardized., Results: Nontreated diabetic wound tensile strength was 0.77 +/- 0.22 g/mm(2) and 1.51 +/- 0.13 g/mm(2) at 11 and 23 days. After LLLT, over 0-4 days tensile strength was 1.15 +/- 0.14 g/mm(2) and 2.45 +/- 0.29 g/mm(2) (P = 0.0019). Higher tensile strength at 23 days occurred in the 3- to 7-day group (2.72 +/- 0.56 g/mm(2) LLLT vs. 1.51 +/- 0.13 g/mm(2) nontreated; P < or = 0.01)., Conclusion: Low-power laser irradiation at 830 nm significantly enhances cutaneous wound tensile strength in a murine diabetic model. Further investigation of the mechanism of LLLT in primary wound healing is warranted., (Copyright 2001 Wiley-Liss, Inc.)

Statement of Problem: Coronoradicular reconstruction techniques of pulpless teeth include prefabricated post systems that retain a core material such as silver amalgam, composite, glass ionomer, or modified glass ionomer cement. Mechanical properties of these materials are critical to sustain masticatory forces., Purpose: This in vitro study compared the mechanical resistance of 3 core materials (silver amalgam, composite, and silver-reinforced glass ionomer) under masticatory conditions., Material and Methods: Industrially fabricated teeth were used and a total of 75 specimens were divided into 3 groups of 25 specimens. Titanium canal posts were placed, followed by core buildups in amalgam, composite, or glass ionomer. Teeth were prepared for full cast crowns and the crowns were fabricated and cemented with glass ionomer cement. Twenty specimens from each group were placed in a mastication simulator cyclically loading the teeth with a 400 N force for 1.5 million cycles. The 5 remaining specimens were used as controls. Teeth were sectioned and observed macroscopically and microscopically to determine the rate of defects for each material. Observed defects were verified with the Kruskal-Wallis test. The 3 core materials were ranked with the Tukey multiple comparison test., Results: Significant differences of mechanical behavior were found for the 3 materials. At P <.01, silver amalgam was significantly superior to composite and glass ionomer. Composite was significantly superior to glass ionomer., Conclusion: Cores fabricated with amalgam had the lowest rate of defects when tested under artificial crowns. Glass ionomer, when used as a core material under artificial crowns, showed the highest rate of defects after an instantaneous load of 400 N for a 1,500,000 repetition cycle.

A rare case of rectosigmoid compression by an enormous obscure pelvic mass after cystectomy is reported. Pelvic collections in the form of abscess, hematoma, lymphocele, and urinoma are not uncommon in the early postoperative period following pelvic surgery. However, delayed appearance of a benign pelvic mass as a late complication of surgery is very rare. Localized pelvic masses discovered years after cystectomy for bladder tumor may lead to an erroneous clinical impression of local recurrence of the primary neoplasm. Differential diagnosis of common pelvic masses, diagnostic studies, and treatment are discussed.

The nutritive value of lunches in forty-eight high schools was assessed using alternate methods of menu planning. Using Type A, Basic 4, and free-choice patterns, the nutrient levels in lunches consumed were not significantly different from those of lunches using the Type A "offer vs. serve" pattern. For boys, lunches as consumed were significantly below the goals for calories, thiamin, and iron in all groups. For girls, lunches as consumed were significantly below the goal only for iron.

Numerous cases of intraurethral foreign bodies of great variety and unusual nature have been reported. Such foreign bodies are usually introduced for sexual stimulation and/or during an intoxicated or confused state. Resulting symptoms usually involve the urinary frequency, dysuria, nocturia, hematuria, gross bleeding per urethra, difficulty in voiding, or complete urinary retention. Depending on the type of foreign body and its location, various methods of removal have been described, including meatotomy, cystoscopy, internal or external urethrotomy, suprapubic cystostomy, Fogarty catheterization, and injection of solvents. The most frequent complications are urethritis, urethral tear with periurethral abscess and/or fistula, hemorrhage, and urethral diverticuli. We report a case of an intraurethral fishhook with its complications and treatment. The diagnosis should be considered in high-risk patients with lower and urinary tract signs and symptoms.