Kinetics of hepatic transport of 4-methylumbelliferone in rats. Analysis by multiple indicator dilution method

Hepatic elimination of 4-methylumbelliferone (4MU), which has been used as a model compound for conjugative metabolism, was studied by means of a multiple indicator dilution (MID) method in the isolated perfused rat liver. Using this method, three intrinsic hepatic clearances, CL _int,inf , CL _{int,eff, and} CL _{int,seq, which represent the influx, efflux, and sequestration processes, respectively, were obtained. When the dose was increased from a low dose (50 g/rat liver) to a high dose (3000 g/rat liver), the hepatic availability of 4MU increased from 0.11 to 0.73. With increasing dose, the} CL _{int,eff value increased approximately two times, while the} CL _{int,seq value decreased to approximately one-third. The remarkable dose dependence of hepatic availability was due to nonlinearity in both} CL _{int,eff and} CL _{int,seq values. However, the} CL_int,inf value was almost independent of dose. The dose-dependent change in CL_int,seq might be explained by the saturation of conjugative metabolism of 4-MU, while the increase in the CL _{int,eff value with increasing dose might be partly explained by the nonlinear tissue binding of 4-MU, since the tissue unbound fraction determined by an ultrafiltration method using liver homogenate increased approximately 1.5 times at higher concentration of 4-MU compared to that at lower concentrations. In addition, based on a comparison of the individual intrinsic clearances, i.e.}, CL _int,inf , CL _{int,eff, and} CL _{int,seq, the major determining process of the apparent hepatic intrinsic clearance of 4MU is thought to be the sequestration process at the high dose. However, at the low dose, the membrane transport process (influx and efflux processes) as well as the sequestration process also determine the apparent hepatic intrinsic clearance}.     

Knee Flexion Angle Following Total Knee Arthroplasty Relates to a Preoperative Range of Motion of the Hip

BackgroundMany factors have been reported to affect postoperative range of knee flexion after total knee arthroplasty (TKA); however, no study has reported the impact of preoperative range of motion of the hip to the postoperative flexion angle of the knee thus far.MethodsOf 38 consecutive patients who underwent posterior-stabilized TKA, we assessed 21 patients after excluding 17 patients who met exclusion criteria. The range of motion of the knee and the hip, age, body-mass index, serum albumin level, HbA1c, Kellgren–Lawrence grade, knee extension strength and radiological femorotibial angle as well as postoperative knee flexion angle at three months were evaluated. The preoperative data and the knee flexion angle at three months after TKA were compared using Spearman''s rank correlation coefficient.ResultsKnee flexion angle at three months after TKA was positively correlated with preoperative flexion (ρ = 0.616, p = 0.007) and external rotation angle (ρ = 0.576, p = 0.012) of the hip as well as preoperative knee flexion angle (ρ = 0.797, p = 0.001). There were no correlations between postoperative knee flexion angle and other preoperative data.ConclusionsPatients with restricted flexion and/or external rotation of the hip may have contractures of Gluteus maximus, Gluteus medius and Tensor fasciae latae, which can cause hypertension of iliotibial tract. It may cause decreased internal rotation of the tibia when the knee is flexed, which affects postoperative knee flexion angle, thus limited flexion and/or external rotation of the hip might restrict knee flexion angle following TKA.     

Effects of prior osteoporosis treatment on 12-month treatment response of romosozumab in patients with postmenopausal osteoporosis

ObjectivesTo investigate the effects of prior treatment and determine the predictors of a 12-month treatment response of romosozumab (ROMO) in 148 patients with postmenopausal osteoporosis.MethodsIn this prospective, observational, and multicenter study, treatment naïve patients (Naïve; n = 50) or patients previously treated with bisphosphonates (BP; n = 37) or denosumab (DMAb; n = 45) or teriparatide (TPTD; n = 16) (mean age, 75.0 years; T-scores of the lumbar spine [LS] ?3.2 and total hip [TH] ?2.6) were switched to ROMO due to insufficient effects of prior treatment. Bone mineral density (BMD) and serum bone turnover markers were evaluated for 12 months.ResultsAt 12 months, changes in LS BMD were Naïve (18.2%), BP (10.2%), DMAb (6.4%), and TPTD (11.2%) (P < 0.001 between groups) and changes in TH BMD were Naïve (5.6%), BP (3.3%), DMAb (0.6%), and TPTD (4.4%) (P < 0.01 between groups), respectively. In all groups, the LS BMD significantly increased from baseline at 6 and 12 months, although only the DMAb group failed to obtain a significant increase in TH BMD during 12-month treatment. Mean values of N-terminal type I procollagen propeptide (PINP; μg/L) from baseline → 1 month → 12 months were Naïve (67.9 → 134.1 → 51.0), BP (32. 2 → 81.7 → 40.9), DMAb (30.4 → 56.2 → 75.3), and TPTD (97.4 → 105.1 → 37.1), and those of isoform 5b of tartrate-resistant acid phosphatase (TRACP-5b; mU/dL) were Naïve (500.4 → 283.8 → 267.1), BP (273.4 → 203.1 → 242.0), DMAb (220.3 → 246.1 → 304.8), and TPTD (446.6 → 305.1 → 235.7), respectively. Multiple regression analysis revealed that the significant predictors of BMD change at 12 months were difference of prior treatment (r = ?2.8, P < 0.001) and value of PINP at 1 month (r = 0.04, P < 0.01) for LS, and difference of prior treatment (r = ?1.3, P < 0.05) and percentage change of TRACP-5b at 1 month (r = ?0.06, P < 0.05) for TH.ConclusionsThe early effects of ROMO on LS and TH BMD increase at 12 months were significantly affected by the difference of prior treatment and are predicted by the early change in bone turnover markers.     

Novel organosilicon-containing polymers for an oxygen permselective membrane

Synthesis and gas permeation measurements of several types of polymers from methylstyrene derivatives containing mono-and bis(trialkylsilyl) group(s) were carried out. Upon radical homo-and co-polymerization of silicon-containing monomers high-molecular-weight polymers were obtained. Results from gas permeation measurements showed that these types of silicon-containing polymers exhibit fairly high oxygen permselectivity (ratio of oxygen and nitrogen permeation coefficients P/P = 3,1 ? 4,6), keeping the oxygen permeation coefficients (P) in the range of between 1,4 · 10^?9 and 4,5·10^?9 cm³ (STP) · cm · cm^?2 · s^?1 · cmHg^?1. From time lag measurements, it was found that permeation coefficients are dependent on the solubility of gases in the membranes rather than on diffusivity. Actually, the oxygen solubility coefficients increase with increasing silicon content in the polymers. Permselectivity of oxygen against nitrogen is governed by polymer constitution rather than by silicon content.     

Role of Laryngeal Movement and Effect of Aging on Swallowing Pressure in the Pharynx and Upper Esophageal Sphincter

Objectives Describe contribution of laryngeal movement to pressure changes at the upper esophageal sphincter (UES) and the effect of aging on the swallowing function. Study Design Manofluorography on 56 nondysphagic adults divided into three age groups: the 21‐ to 31‐year‐old group (n = 32), the 61‐ to 74‐year‐old group (n = 12) and the 75‐ to 89‐year‐old group (n = 12). Analyses of the bolus transit time, the amplitudes and durations of pharyngeal pressures, the timing of a pressure fall at the UES and the laryngeal movements. Methods Intraluminal strain‐gauge sensors recorded pressure changes in the oropharynx, hypopharynx and the UES. Motion pictures of the videotapes were fed into a personal computer, and movements of the hyoid bone were measured in both the horizontal and vertical directions as an indication of laryngeal movement. Results In 26‐ and 70‐year‐old men with calcification of the thyroid cartilage, it was determined that the larynx and hyoid bone moved in consonance until the end of the rapid hyoid movements in both the superior and anterior directions. In the 21‐ to 31‐year‐old group, the magnitude of the pressure fall at the UES was maximal before or almost at the same time as the bolus arrival, in preparation for smooth passage of the bolus from the pharynx to the esophagus. The rapid superior movements of the hyoid bone started significantly early as compared with its anterior movements (P = .0001). The rapid anterior movements of the hyoid bone started simultaneously with the pressure fall at the UES. In the elderly, all segmental transit times were significantly increased. The timing of the pressure fall at the UES was significantly delayed and the UES pressure reached its minimum value after arrival of the bolus at the UES. The minimum pressure at the UES increased to a significantly positive value. The rapid anterior movements of the hyoid were significantly delayed, suggesting that this delay causes the delay in the pressure fall at the UES. Conclusions The rapid superior and anterior movements of the hyoid bone are considered to start at the same time as those of the larynx. In the young group, it is suggested that superior laryngeal movement protects the lower airway prior to the anterior laryngeal movement, causing the pressure fall at the UES to enable the passage of a bolus into the UES. In the elderly, smooth passage of the bolus from the pharynx to the esophagus is hindered and the system that prevents aspiration is rendered inefficient by changes in the swallowing pressures and laryngeal movements with aging.     

Inhibition of nociceptin-induced allodynia in conscious mice by prostaglandin D2

1. We recently showed that intrathecal administration of nociceptin induced allodynia by innocuous tactile stimuli and hyperalgesia by noxious thermal stimuli in conscious mice. In the present study, we examined the effect of prostaglandins on nociceptin-induced allodynia and hyperalgesia.
2. Prostaglandin D₂ (PGD₂) blocked the allodynia induced by nociceptin in a dose-dependent manner with an IC₅₀ of 26 ng kg⁻¹, but did not affect the nociceptin-induced hyperalgesia at doses up to 500 ng kg⁻¹. BW 245C (an agonist for PGD (DP) receptor) blocked the allodynia with an IC₅₀ of 83 ng kg⁻¹.
3. The blockade of nociceptin-induced allodynia by PGD₂ was reversed by the potent and selective DP-receptor antagonist BW A868C in a dose-dependent manner with an ED₅₀ of 42.8 ng kg⁻¹.
4. Glycine (500 ng kg⁻¹) almost completely blocked the nociceptin-induced allodynia. A synergistic effect on the inhibition of nociceptin-evoked allodynia was observed between glycine and PGD₂ at below effective doses.
5. Dibutyryl cyclic AMP, but not dibutyryl cyclic GMP, blocked the nociceptin-induced allodynia with an IC₅₀ of 2.9 μg kg⁻¹.
6. PGE₂, PGF_2α, butaprost (an EP₂ agonist) and cicaprost (a PGI receptor agonist) did not affect the nociceptin-induced allodynia.
7. These results demonstrate that PGD₂ inhibits the nociceptin-evoked allodynia through DP receptors in the spinal cord and that glycine may be involved in this inhibition.

     

Bone scan of hemodialysis patients with secondary hyperparathyroidism before and after parathyroidectomy

Renal osteodystrophy (ROD) accompanied by long-term hemodialysis patients with chronic renal failure includes several forms of disorders of mineral and skeletal metabolism such as osteitis fibrosa attributed to secondary hyperparathyroidism, osteomalasia and adynamic bone disease. Bone scan is performed to detect of the mainly pathophysiology of ROD. We investigated bone scan of 25 hemodialysis patients with secondary hyperparathyroidism diagnosed clinically before and after parathyroidectomy (PTX). Before PTX an diffusely high accumulation of bone seeking agent in the whole skeleton especially skull in all patients (100%), vertebra in 24 out of 25 (96%), patella in 24/25 (96%), limbs in 23/25 (92%), sternum in 19/25 (76%), sacrum in 18/25 (72%) and costochondral junctions in 14/25 (56%) was noted in these patients. The radionuclide activity of the calvaria, maxilla and mandible in the skull was prominently high. Fourteen patients had an equally high activity in the calvaria, maxilla and mandible, 6 patients had higher activity in the maxilla and mandible than that of calvaria and 5 patients had higher in the calvaria than that of maxilla and mandible. After PTX the changes in the skull were obvious in 19 patients who showed a more markedly decreased in activity of the maxilla and mandible than that of the calvaria. In 3 patients showed a more markedly decreased in activity of the calvaria than that of the maxilla and mandible. Another 3 demonstrated equally decreased in activity in the calvaria, maxilla and mandible. It became clear that the highest activity of the skull was shown in all patients and the therapeutic changes of the skull are the most pronounced in maxilla and mandible in this study.     

Ocular findings in Japanese women with nevus of Ota

Background: Nevus of Ota is common in Japanese women, but most patients are not examined ophthalmologically. Methods: We performed ophthalmologic examinations on 16 Japanese women who had had bluish pigmentation in the periorbital region, sclera, and conjunctiva since birth. Results: Fifteen patients had unilateral involvement, and one had bilateral lesions. The visual acuities were good, and the intraocular pressures were within normal range. All patients had a negative family history. Three patients had light pigmentation in the optic disc in the affected eye. Conclusion: We believe that optic disc pigmentation associated with nevus of Ota, as found in these three patients, may be common but have been rarely described.