Anterior talofibular ligament footprint dimension measured using three-dimensional magnetic resonance imaging.

OBJECTIVE: Knowledge of footprint anatomy is essential for ankle anterior talofibular ligament repair and reconstruction. We aimed to determine the intra- and inter-rater measurement reliability of the anterior talofibular ligament footprint dimension using three-dimensional MRI. METHODS: MRI images of 20 ankles with intact ligaments, including 11 with a single bundle and nine with double-bundle ligaments, were analyzed. Imaging was performed using a 3.0-Tesla MRI. Isotropic three-dimensional proton density-weighted images with a voxel size of 0.6 mm were obtained. The fibular and talar footprints were manually segmented using image processing software to create three-dimensional ligament footprints. The lengths, widths, and areas of each sample were measured. A certified orthopedic surgeon and a senior orthopedic fellow performed the measurements twice at 6-week intervals. The intra- and inter-rater differences in the measurements were calculated. RESULTS: The length, width, and area of the single-bundle fibular footprint were 8.7 mm, 5.4 mm, and 37.4 mm2, respectively. Those of the talar footprint were 8.4 mm, 4.3 mm, and 30.1 mm2, respectively. The inferior bundle of the double-bundle ligament was significantly smaller than the single and superior bundles (p < 0.001). No differences were observed between intra-rater measurements by either rater, with maximum differences of 0.7 mm, 0.5, and 1.7 mm2, in length, width, and area, respectively. The maximum inter-rater measurement differences were 1.9 mm, 0.5, and 2.4 mm2, respectively. CONCLUSION: Measurements of the anterior talofibular ligament dimensions using three-dimensional MRI were sufficiently reliable. This measurement method provides in vivo quantitative data on ligament footprint anatomy.

Maternal heated tobacco product use during pregnancy and allergy in offspring.

BACKGROUND: Little is known about the association between maternal use of heated tobacco products (HTPs) during pregnancy and the onset of allergy among offspring. This study aimed to determine whether maternal HTP smoking is associated with allergy in their offspring and to evaluate the potential dose-response association. METHODS: In this web-based, cross-sectional survey conducted in July and August 2021 in Japan, we investigated 5688 pairs of postpartum women and infants (<3 years). Clinical diagnoses of infant asthma, rhinitis, conjunctivitis, or atopic dermatitis were reported. Using multilevel Poisson regression, we estimated the prevalence ratios (PRs) and 95% confidence intervals (CIs) of allergy in infants with HTP smoking categories cross-classified by pregnancy periods, and adjusted for potential covariates including maternal cigarette smoking and partner's smoking status. Non-smokers served as the reference group. RESULTS: In total, 2.4% women smoked HTPs during pregnancy. Allergy occurred in 7.8% of the infants. The prevalence of allergy increased among the offspring of current HTP smokers during pregnancy at 15.2% (PR = 1.98, 95% CI 1.28-3.05); this association was the most pronounced during the first trimester but attenuated before pregnancy and postpartum. Dose-response associations were observed, for example a one-unit increase in daily maternal HTP use during pregnancy was associated with a 5% increase in allergy onset. Sub-group analyses excluding cigarette smokers during pregnancy and sensitivity analyses using the International Study of Asthma and Allergies in Childhood questionnaire showed a similar pattern. CONCLUSIONS: Maternal HTP smoking during pregnancy is associated with allergy in the offspring.

Hydrolase Activity of the Genetic Variants of Human Alpha-1-Acid Glycoprotein.

In human plasma, the main agent of hydrolysis of the ester-type prodrug of levodopa, designated ONO-2160, is alpha-1-acid glycoprotein (AGP), which is a mixture of the F1*S and A variants at molar ratios of 3:1 to 2:1. In this study, the mechanism of AGP esterase-like activity was investigated by evaluating the contribution of the F1*S and A variants to ONO-2160 hydrolysis and identifying the AGP hydrolase active site. We found that although both variants hydrolyzed ONO-2160, their hydrolase activities were different. The intrinsic plasma clearance of the F1*S variant (0.441 mL/h/mg protein) was approximately 30 times higher than that of the A variant (0.0148 mL/h/mg protein), indicating that the F1*S variant contributed the most to AGP esterase-like activity. To identify the hydrolase active site of AGP, we performed inhibition studies of ONO-2160 hydrolysis using 12 AGP-binding drugs with various ligand-binding constants and binding selectivities to the two AGP variants. Inhibition of activity was positively correlated with the constant of ligand binding to the F1*S variant. In addition, compounds with high affinity to the F1*S variant inhibited ONO-2160 hydrolysis the most. Together, our data indicate that ONO-2160 is predominantly hydrolyzed by the F1*S variant at its ligand-binding site.

HomotopicLI: Rationale, characteristics, and implications of a new threshold-free lateralization index of functional magnetic resonance imaging.

The reliable preoperative estimation of brain hemispheric asymmetry may be achieved through multiple lateralization indices using functional magnetic resonance imaging. Adding to our previously developed AveLI, we devised a novel threshold-free lateralization index, HomotopicLI, which computes a basic formula, (Left - Right) / (Left + Right), using voxel values of pairs located symmetrically in relation to the midsagittal line as the terms Left and Right, and averages them within the regions-of-interest. The study aimed to evaluate HomotopicLI before clinical applications. Data were collected from 56 healthy participants who performed four language tasks. We compared seven index types, including HomotopicLI, AveLI, and BaseLI; BaseLI was calculated using the sums of voxel values as the terms. Contrary to our expectations, HomotopicLI performed similarly to AveLI but better than BaseLI in detecting right dominance. A detailed analysis of unilaterally activated voxels of the homotopic pairs revealed that unilateral activation occurred more frequently on the right than on the left when HomotopicLI indicated right dominance. The voxel values during right unilateral activation were smaller than those in the left, causing right dominances in the homotopic pairs by HomotopicLI. These unique features provide an advantage in detecting residual, compensative functions spreading weakly in the non-dominant hemisphere.

Species Difference in Hydrolysis of an Ester-type Prodrug of Levodopa in Human and Animal Plasma: Different Contributions of Alpha-1 Acid Glycoprotein.

Previously, we found that ONO-2160, an ester-type prodrug of levodopa (3-hydroxy-l-tyrosine), was mainly hydrolyzed in human plasma by α1-acid glycoprotein (AGP) with a partial contribution of albumin. In this study, we investigated whether ONO-2160 was hydrolyzed in the plasma of preclinical species (dog, rabbit, rat, and mouse) and humans and whether AGP and albumin are involved in its hydrolysis. ONO-2160 was hydrolyzed to some extent in the plasma of all tested species with the order of magnitude mouse > human > rabbit > rat > dog. Except for dogs, ONO-2160 was partially hydrolyzed by animal AGP and albumin. This indicated that, similar to albumin, AGP possesses esterase-like activity in mice, rats, and rabbits, as well as humans. A comparison of the values of intrinsic clearance per milliliter of plasma demonstrated that AGP was the major contributor to the hydrolysis of ONO-2160 in rabbit plasma, whereas albumin was primarily responsible for the hydrolysis of ONO-2160 in mouse plasma. This was confirmed by experiments using AGP-knockout mouse plasma. This study reports the first evidence for the existence of species differences in the hydrolysis of ONO-2160 in plasma related to the different contributions of AGP and albumin.

Unique Hydrolysis of an Ester-Type Prodrug of Levodopa in Human Plasma: Relay-Type Role Sharing between Alpha-1 Acid Glycoprotein and Human Serum Albumin.

ONO-2160 is a newly developed oral ester-type prodrug of levodopa for removing the problems in use of levodopa. It has a structure in which two of the same substituents are bound to levodopa. It is important to understand the pharmacokinetics and metabolic pathway for new drug candidate compounds. The aim of this study was to identify the major enzymes that contribute to the metabolism of ONO-2160 in human plasma. ONO-2160 was hydrolyzed by human serum albumin (HSA) and α1-acid glycoprotein (AGP) in human plasma, although the hydrolysis was not inhibited by various reported esterase inhibitors. The value of the intrinsic clearance per milliliter of plasma of ONO-2160 in AGP solution was greater than that in HSA solution and was comparable to that in human plasma. Therefore, AGP is responsible for the hydrolysis of ONO-2160 in human plasma. ONO-M, which is an intermediate metabolite of ONO-2160, has a structure in which one substituent is removed from ONO-2160 and was mainly generated in AGP solution, but not in human plasma or HSA solution. The hydrolysis of ONO-M by HSA was much greater than by AGP. These results indicate that ONO-M, which is mainly generated from ONO-2160 by AGP, is rapidly hydrolyzed by HSA, and that ONO-2160 generates levodopa via ONO-M in a relay-type reaction through AGP and HSA in human plasma. It has not been reported that AGP has esterase-like activity. These findings could be useful information for drug development of the ester-type prodrug.

Posterior Decompression and Fusion for Cervical Spondylodiscitis due to Osteoradionecrosis after Head-and-Neck Cancer Radiotherapy: Two Case Reports.

Introduction: Cervical spondylodiscitis due to osteoradionecrosis (ORN) after head-and-neck cancer radiotherapy is a severe complication. However, there are few reports on the surgical treatment of this condition. Case Report: We report two cases of cervical spondylodiscitis due to ORN, which were successfully treated with posterior decompression and fusion. The first case was in a 73-year-old male patient with spondylodiscitis at C3-C5, due to ORN. A posterior fusion of the spine (C2-T1) was performed, and a biopsy was conducted at a site separate from the incision for fusion. The second case was in a 76-year-old female patient with spondylodiscitis due to C4-C7 ORN. Cervical posterior decompression and fusion (C2-Th2) were performed, and decompression (C5-6) was conducted through an incision separate from that for the fusion.An anterior approach was avoided in both cases because of radiation-induced tissue changes. For these two patients with cervical spondylodiscitis due to ORN, surgery resulted in an improvement of infection and neurological deficits by posterior spinal fusion, isolation from decompression or biopsy of the infected area, and antibiotic treatment. Conclusion: Posterior decompression and fusion are effective for spondylodiscitis in the cervical spine after head-and-neck radiotherapy, treating both infection and neurological deficits. Spinal fusion that avoids the level of the infected vertebral body and decompression from separate skin incision sites may prevent the spread of infection. An anterior approach should be avoided because the risk of esophageal perforation and posterior pharyngeal wall defects is high.

IL-22 induces Reg3γ and inhibits allergic inflammation in house dust mite-induced asthma models.

Previous studies have shown that IL-22, one of the Th17 cell-related cytokines, plays multiple roles in regulating allergic airway inflammation caused by antigen-specific Th2 cells; however, the underlying mechanism remains unclear. Here, we show that allergic airway inflammation and Th2 and Th17 cytokine production upon intratracheal administration of house dust mite (HDM) extract, a representative allergen, were exacerbated in IL-22-deficient mice. We also found that IL-22 induces Reg3γ production from lung epithelial cells through STAT3 activation and that neutralization of Reg3γ significantly exacerbates HDM-induced eosinophilic airway inflammation and Th2 cytokine induction. Moreover, exostatin-like 3 (EXTL3), a functional Reg3γ binding protein, is expressed in lung epithelial cells, and intratracheal administration of recombinant Reg3γ suppresses HDM-induced thymic stromal lymphopoietin and IL-33 expression and accumulation of type 2 innate lymphoid cells in the lung. Collectively, these results suggest that IL-22 induces Reg3γ production from lung epithelial cells and inhibits the development of HDM-induced allergic airway inflammation, possibly by inhibiting cytokine production from lung epithelial cells.