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Valsartan is an antihypertensive drug that was developed using common marmosets (Callithrix jacchus) in pivotal toxicity studies as a non-rodent species. The aim of the present study was to investigate the utility of marmosets in the candidate selection of this drug from a pharmacokinetic and metabolic viewpoint. Valsartan, as well as three other angiotensin II type-I receptor blockers, assumed as competitive candidates, were administered to common marmosets. Human pharmacokinetic parameters predicted by single-species allometric scaling and Wajima superposition suggested that valsartan may exhibit promising pharmacokinetic properties in humans. In vitro metabolic studies of valsartan using isolated rat, dog, marmoset, cynomolgus monkey, and human hepatocytes revealed that the marmoset was the most relevant animal species to humans presenting with the most abundant human metabolite, 4-hydroxyvalsartan. Oral administration of an elevated dose of valsartan to a common marmoset demonstrated that the level of 4-hydroxyvalsartan in the plasma was comparable to that in clinical practice and suggested that safety of the human metabolite might have been confirmed in the toxicity studies using common marmosets. These results suggest that common marmosets, the small, non-human primates, had been a suitable species for the development of valsartan. [ABSTRACT FROM AUTHOR]

Common marmosets (Callithrix jacchus) are small non-human primates that genetically lack cytochrome P450 2C9 (CYP2C9). Polymorphic marmoset CYP2C19 compensates by mediating oxidations of typical human CYP2C9/19 substrates. Twenty-four probe substrates were intravenously administered in combinations to marmosets assigned to extensive or poor metaboliser (PM) groups by CYP2C19 genotyping. Eliminations from plasma of cilomilast, phenytoin, repaglinide, tolbutamide, and S-warfarin in the CYP2C19 PM group were significantly slow; these drugs are known substrates of human CYP2C8/9/19. Human total clearance values and volumes of distribution of the 24 test compounds were extrapolated using single-species allometric scaling with experimental data from marmosets and found to be mostly comparable with the reported values. Human total clearance values and volumes of distribution of 15 of the 24 test compounds similarly extrapolated using reported data sets from cynomolgus or rhesus monkeys were comparable to the present predicted results, especially to those based on data from PM marmosets. These results suggest that single-species allometric scaling using marmosets, being small, has advantages over multiple-species-based allometry and could be applicable for pharmacokinetic predictions at the discovery stage of drug development. [ABSTRACT FROM AUTHOR]

Development of an accurate reservoir model and prediction of reservoir behaviour associated with geothermal exploitation using that model are fundamentally important for sustainable geothermal utilisation. Gravity observation for a few tens of days after a field-wide shut-in of geothermal wells potentially provides valuable constraints to improve reservoir models. We investigated the applicability of superconducting gravimeters (SGs) to short-term observations after shut-ins, as a first step towards the development of a method for reservoir model improvement using short-term gravity data. Results from a reservoir simulation of a shut-in at a geothermal field in Japan showed that gravity change at 20 days after the shut-in was 10 nm/s2. To detect such changes with SGs, locations of SG stations should be chosen to minimise noise sufficient to resolve the signal. Considering that field operations and traffic in geothermal fields can make SG data noisy, laboratory gravity measurements were carried out with a SG to investigate the influence of noise level on signal detection. Test masses, which produced a gravity change (7.7–9.0 nm/s2) comparable to the simulation result, were repeatedly placed and removed above the SG during both day and night times with different ambient noise levels. Test results showed that noise level greatly affected signal detection. The signal was only detected twice, under low-noise conditions with the standard deviations of 1.1 and 5.3 nm/s2. In addition, tests in which the SG was operated without a cryogenic refrigerator revealed that the absence of the refrigerator did not increase the noise level. Enhancing the portability of a SG by reducing its weight can make multi-location noise surveys feasible. Our method, of combining reservoir simulations and preliminary noise surveys, would enable successful SG observations to be made in relatively short periods after shut-ins, which would possibly contribute to the development of a method to obtain additional constraints to be used for reservoir model calibration. [ABSTRACT FROM AUTHOR]

Purpose: To immunohistochemically examine the lacrimal sac walls harvested during dacryocystorhinostomy using an immunostain for immunoglobulin G4 (IgG4).Methods: Forty-four lacrimal sac walls were evaluated. We determined "intensively positive," "sparsely positive," or "negative" staining when the specimens showed IgG4-positive lymphoplasmacytic staining with or without >50 IgG4-positive cells/high-power field, or the absence of stained IgG4-positive cells.Results: Intensively positive, sparsely positive, or negative staining was observed in 8 (18.2%), 14 (31.8%), and 22 specimens (50.0%), respectively. Stained cells infiltrated the subepithelial layer in all specimens with positive staining. Four of the 8 specimens demonstrated partial epithelial denudation with loss of goblet cells.Conclusions: IgG4-positive lymphoplasmacytic infiltration was observed in the subepithelial layer in specimens with intensively positive staining, of which some showed a partially denuded epithelium with loss of goblet cells. These may lead to narrowing of the lacrimal sac lumen and adhesions of the sac walls. [ABSTRACT FROM AUTHOR]

Objectives: Over a 11-year period, we investigated the incidence of anterior cruciate ligament (ACL) injuries and the clinical outcomes after ACL reconstruction with hamstring autografts in two homogenous cohorts of rugby players.Methods: Two teams, including those in elite (94 players) and high school (290 players) clubs, were followed.Results: Isolated ACL injuries occurred in 28 players (12 elite, 16 high school). The incidence during match play was 1.26 per 1000 player-hours (95% confidence interval [95% CI]: 0.48–2.05) among elite players and 0.97 per 1000 player-hours (95% CI: 0.30–1.64) among high school players. After ACL reconstruction, 26 players (12 elite, 14 high school) were successfully contacted for follow-up at a mean of 71.9 months. None (0%) of the elite and 4 (29%) of the high school players experienced graft ruptures. Seven (58%) elite and 10 (91%) high school players were fearful of reinjury; the mean time to overcome this fear was 6.1 ± 4.9 months among elite players and 17.5 ± 26.0 months among high school players.Conclusion: In conclusion, young rugby players experienced inferior outcomes after ACL reconstruction with hamstring autografts compared with their older counterparts. [ABSTRACT FROM PUBLISHER]

The complete mitochondrial DNA sequence of the Japanese field vole Microtus montebelli was determined using Illumina MiSeq platform. The assembled genome was 16,307 bp in length and contained 13 protein-coding genes, two ribosomal RNA genes, 22 transfer RNA genes. According to phylogenetic analysis of 13 protein-coding genes, M. montebelli and other Microtus species consist of paraphyletic clades and M. montebelli is most closely related to M. kikuchii, a species endemic to Taiwan. [ABSTRACT FROM AUTHOR]

Purpose: To show the morphological characteristics of two different types of the sinus of Maier, one with a lacrimal sac diverticulum supplied by separate canalicular openings, and the other with a terminal dilatation of the common lacrimal canaliculus. Methods:Twelve coronal specimens (6 right and 6 left) from 6 Japanese cadavers (age range, 70–90 years at death) and 15 axial specimens of 11 Japanese cadavers (8 right, 7 left; age range, 45–89 years at death), fixed in 10% buffered formalin, were used. All specimens were stained with Masson’s trichrome. Results: The sinus of Maier, with a lacrimal sac diverticulum supplied by separate canalicular openings, was shown in one coronally sectioned group, with a diameter of 1.29 mm. The mucosa between both openings (0.282 mm length) comprised stratified squamous epithelia, which was characteristic of the lacrimal canaliculi. The diverticular mucosa was lined by a stratified columnar epithelium, which corresponded to the lacrimal sac. The sinus of Maier, with a terminal dilatation of the common lacrimal canaliculus and with a diameter of 0.51 mm, was demonstrated in one axially sectioned group. Conclusions: The morphological characteristics of two types of the sinus of Maier were described in this study. One type was the lacrimal sac diverticulum supplied by separate canalicular openings, and the other was the terminal dilatation of the common lacrimal canaliculus. [ABSTRACT FROM PUBLISHER]

Purpose: To examine surgical outcomes of the posterior layer advancement of the lower eyelid retractors (LER) in patients with congenital entropion and to ascertain whether the pretarsal orbicularis oculi muscle (OOM) was hypertrophic or not. Materials and Methods: This retrospective study included three Japanese patients with congenital entropion who underwent posterior layer advancement of the LER. We reviewed the surgical outcomes and postoperative complications, such as lower eyelid ectropion and retraction for each patient. We also measured the diameters of the pretarsal OOM fibers in these patients and compared them with those measured in the previously reported 67 eyelids of 41 Japanese patients with congenital epiblepharon. Results: Congenital entropion was successfully corrected in all three patients without recurrence during 12-months of follow-up. No patient exhibited lower eyelid ectropion or lower eyelid retraction. The mean diameter of the pretarsal OOM fibers was 21.9 μm (range, 20.5-23.7 μm), which was not significantly different from that of the congenital epiblepharon (25.3 μm; range, 18.1-34.7 μm; p = 0.272, Mann-Whitney U test). Conclusions: The surgical outcomes in the present study suggest that posterior layer advancement of the LER is a useful surgical option for treatment of congenital entropion. No histological evidence of pretarsal OOM hypertrophy was shown in congenital entropion, which demonstrated that debulking of the pretarsal OOM may not be significant for correction of this entity. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to examine the length and diameter of the intra-sac portion of the lacrimal canaliculus and to propose a modified functional valve model at the common internal ostium. Methods: We examined 14 eyelid and orbital specimens from 10 cadavers (seven right, seven left; aged 45-85 years at death), fixed in 10% buffered formalin. Sliced specimens were dehydrated and embedded in paraffin, cut into 7 μm thickness sections, and stained with Masson's trichrome. We then measured the length and diameter of the intra-sac portion of the lacrimal canaliculus. Results: The average length of the intra-sac portion of the lacrimal canaliculus was 1344.9 μm (range, 920.2-1821.5 μm), and its average diameter was 287.5 μm (range, 199.1-523.3 μm). Conclusion: The intra-sac portion of the lacrimal canaliculus had an average length and diameter of 1344.9 μm and 287.5 μm, respectively. The lacrimal sac mucosa changes its thickness with autonomic stimulation, and the length and diameter of the intra-sac portion of the lacrimal canaliculus is likely changed concurrently. The long length and small diameter of the intra-sac lacrimal canaliculus presumably contribute to it acting as an autonomic functional valve at the common internal ostium. [ABSTRACT FROM AUTHOR]

The anatomy of the lateral canthus is analogous to that of the medial canthus, but with a less defined structure. Although the lateral canthal tendon occupies the major part of the lateral canthal anatomy, the lateral rectus capsulopalpebral fascia and other structures also play a significant role. Appropriate comprehension and consideration of the lateral canthal anatomy enable safe and effective performance in the lateral canthal surgeries. In this review, we present the lateral canthal anatomy along with updated topics. We discuss the lateral canthal tendon, lateral orbital thickening, lateral palpebral raphe, lateral canthal muscle, lateral rectus capsulopalpebral fascia, lateral check ligament, lateral retinaculum, and orbitomalar ligament. [ABSTRACT FROM AUTHOR]

Island ecosystems differ from mainland ecosystems in their long-term isolation. On Sado Island, Japan, cattle grazing in the past gradually changed forests into grasslands, thereby altering the diversity of indigenous insects. We compared ground-dwelling beetle diversity on Sado Island to that on the nearby mainland. Contrary to previous reports, the island isolation effect resulted in lower γ and β diversity than on the mainland, because of the low species richness of beetles with low dispersal abilities. Few flightless beetles could invade Sado Island, even when the beech forests on the island were relatively adjacent to those on the mainland. Such a history of ecosystem formation could be the general pattern for continental-island mountain forests that were never connected to those of the mainland. We did not observe low α diversity of ground-dwelling beetles, suggesting that the cattle grazing history of the island has not changed environmental conditions for ground-dwelling beetles enough to reduce their diversity. In addition, cattle grazing increases the abundance of merdivorous insects by increasing the abundance of their food resource. [ABSTRACT FROM AUTHOR]

We performed a prospective study to determine the effects of introducing low-load muscular training with moderate restriction of blood flow during the first 16 weeks after reconstruction of the anterior cruciate ligament. 44 subjects (average age 29 (18-52) years) were randomized into a group that trained restriction of blood flow (group R, n = 22) and a group that trained without restriction (group N, n = 22). Both groups followed the same training schedule. Evaluations of knee extensor and flexor torques before surgery and 16 weeks after it showed a significant increase in muscular strength in group R as compared to group N. The preoperative/16-week postoperative ratio of the crosssectional area of the knee extensor muscles showed a statistically significant enlargement in group R as compared to group N. 16 weeks after surgery, the short diameters of type 1 and type 2 fibers of M. vastus lateralis tended to be larger in group R (n = 8) than in group N (n = 8), although the differences were not significant. These findings show that low-load resistance muscular training during moderate restriction of blood flow is an effective exercise for early muscular training after reconstruction of the anterior cruciate ligament. [ABSTRACT FROM AUTHOR]

Lymphoid infiltrates in the ocular adnexa are mostly low-grade B-cell lymphoma, but their clinicopathologic characteristics and prognostic factors have not been extensively analyzed according to the Revised European-American Lymphoma (REAL) Classification. We reviewed histopathologic sections from 77 patients with primary ocular adnexal lymphoid infiltrates, and conducted univariate and multivariate analyses of possible prognostic factors. Fifty-seven of the 77 patients were confirmed to have malignant lymphoma. Histopathologic sections from 44 of the 57 patients were reclassified into the following categories; marginal zone lymphoma (MZL) in 35, mantle cell lymphoma (MCL) in two, diffuse large cell lymphoma (DLCL) in six, and lymphoplasmacytoid lymphoma (LPL) in one. In the remaining 13 patients, biopsied specimens were inadequate for further subclassification. The cause-specific survival rates of the 57 patients with primary ocular adnexal lymphoma at 5, 10, and 15 years were 90.1%, 84.8% and 84.8%, respectively. The univariate analysis showed that the clinical stage, serum lactate dehydrogenase (LDH) value and histopathologic subtype were significant. The 5-year cause-specific survival rate of the 35 patients with MZL was 100%, whereas that of the eight patients with non-MZL (DLCL and MCL) was 25% (p<0.0001). The multivariate analysis revealed that the histologic subtype (p=0.010) and serum LDH value (p=0.015) were independent significant predictors of survival. We conclude that malignant lymphomas occurring in the ocular adnexa histologically consist mostly of MZL. The histologic subtype according to the REAL Classification significantly predicts the prognosis of ocular adnexal lymphoma. [ABSTRACT FROM AUTHOR]

AbstractCynomolgus monkeys and human FcRn transgenic mice are generally used for pharmacokinetic predictions of therapeutic monoclonal antibodies (mAbs). In the present study, the application of the common marmoset, a small nonhuman primate, as a potential animal model for prediction was evaluated for the first time.Canakinumab, adalimumab, and bevacizumab, which exhibited linear pharmacokinetics in humans, were selected as the model compounds. Marmoset pharmacokinetic data were reportedly available only for canakinumab, and those for adalimumab and bevacizumab were acquired in-house.Four pharmacokinetic parameters for a two-compartment model (i.e. clearance and volume of distribution in the central and peripheral compartments) in marmosets were extrapolated to the values in humans with allometric scaling using the average exponents of the three mAbs. As a result, the observed human serum concentration–time curves of the three mAbs following intravenous administration and those of canakinumab and adalimumab following subcutaneous injections (with an assumed absorption rate constant and bioavailability) were reasonably predicted.Although further prediction studies using a sufficient number of other mAbs are necessary to evaluate the versatility of this model, the findings indicate that marmosets can be an alternative to preceding animals for human pharmacokinetic predictions of therapeutic mAbs.Cynomolgus monkeys and human FcRn transgenic mice are generally used for pharmacokinetic predictions of therapeutic monoclonal antibodies (mAbs). In the present study, the application of the common marmoset, a small nonhuman primate, as a potential animal model for prediction was evaluated for the first time.Canakinumab, adalimumab, and bevacizumab, which exhibited linear pharmacokinetics in humans, were selected as the model compounds. Marmoset pharmacokinetic data were reportedly available only for canakinumab, and those for adalimumab and bevacizumab were acquired in-house.Four pharmacokinetic parameters for a two-compartment model (i.e. clearance and volume of distribution in the central and peripheral compartments) in marmosets were extrapolated to the values in humans with allometric scaling using the average exponents of the three mAbs. As a result, the observed human serum concentration–time curves of the three mAbs following intravenous administration and those of canakinumab and adalimumab following subcutaneous injections (with an assumed absorption rate constant and bioavailability) were reasonably predicted.Although further prediction studies using a sufficient number of other mAbs are necessary to evaluate the versatility of this model, the findings indicate that marmosets can be an alternative to preceding animals for human pharmacokinetic predictions of therapeutic mAbs. [ABSTRACT FROM AUTHOR]

A right orbit was exenterated from a male cadaver that was 85 years of age at death. It was microscopically shown for the first time that the lacrimal sac septum divided the lumen into two spaces. It consisted of fibrous tissue with a cavernous structure and was lined with stratified columnar epithelium similar to the lacrimal sac wall. [ABSTRACT FROM AUTHOR]