Disposition and metabolism of F6-1alpha,25(OH)2 vitamin D3 and 1alpha,25(OH)2 vitamin D3 in the parathyroid glands of rats dosed with tritium-labeled compounds.

26,26,26,27,27,27-Hexafluoro-1alpha,25(OH)2 vitamin D3, a hexafluorinated analog of 1alpha,25(OH)2 vitamin D3, has been reported to be several times more potent than the parent compound with respect to some vitamin D actions. The reason for enhanced biological activity in the bones, kidneys, and small intestine appears to be related to F6-1alpha,25(OH)2 vitamin D3 metabolism to ST-232 (26,26,26,27,27,27-hexafluoro-1alpha,23S,25-trihydroxyvitamin D3), a bioactive 23S-hydroxylated form that is resistant to further metabolism. We compared the disposition and metabolism of [1beta-3H]F6-1alpha,25(OH)2 vitamin D3 and [1beta-3H]1alpha,25(OH)2 vitamin D3 in parathyroid glands of rats intravenously administered with labeled compounds at a dose of 10 microg/kg. In the [1beta-3H]F6-1alpha,25(OH)2 vitamin D3-dosed group, radioactivity was highly detected in the kidneys, parathyroid glands, and the small intestine. The radioactivity in the parathyroid glands remained high until 48 h postdosing, with values of 2.5, 8.4, and 14.6 times higher at 6, 24, and 48 h postdosing than after dosing with [1beta-3H] 1alpha,25(OH)2 vitamin D3. In the group given [1beta-3H]F6-1alpha,25(OH)2 vitamin D3, the unchanged compound was mainly detected with a small amount of ST-232 at 6 h postdosing. At the 24- and 48-h time points, over half of the radioactivity was observed as ST-232, and additionally, ST-233, the 23-oxo form, accounted for a small amount at the 48-h time point. The present study demonstrated local retention of [1beta-3H]F6-1alpha,25(OH)2 vitamin D3 and the bioactive metabolite ST-232 in parathyroid glands after intravenous administration. The findings may indicate one of the reasons for the higher potency of F6-1alpha,25(OH)2 vitamin D3 than 1alpha,25(OH)2 vitamin D3 in parathyroid.     

Fas-Fas ligand system in the peripheral blood of patients with renal diseases

To clarify the role of the Fas-Fas ligand (FasL) system in the peripheral blood from patients with various renal diseases, the Fas and FasL expression on mononuclear cells (MNCs) and serum levels of soluble Fas (sFas) and soluble FasL were investigated. Patients were selected from those with various types of glomerular diseases showing various degrees of renal function. Fas expression on MNCs was analyzed by a FACScan, sFas and soluble FasL were measured with an ELISA kit, and FasL expression on MNCs was counted using a FACScan after a bioassay. Fas-positive MNCs and sFas increased with statistical significance concomitantly with deterioration in renal function. Moreover, there was a significant correlation between them. sFas- and FasL-positive MNCs were significantly correlated with proteinuria. However, the Fas expression percentage on MNCs and/or serum levels of sFas did not correlate with the number of TUNEL-positive cells in the glomeruli. Also, there was no disease specificity in the activation of Fas. These results indicate that Fas expression on MNCs is activated in accordance with the deterioration in renal function without disease specificity, corresponding to the elevation of serum sFas levels to protect against Fas-mediated apoptosis.     

Calpain inhibitor inhibits secretory granule maturation and secretion of GH

Clathrin- and AP-1-coated buds are present on immature secretory granules of endocrine cells that mature into clathrin-uncoated granules. The mechanism of clathrin and adaptor protein uncoating has remained obscure. Benzyloxycarbonyl-L-leucyl-L-leucinal (ZLLal), a calpain inhibitor, reduced growth hormone (GH) secretion with intracellular accumulation, in a GH-secreting rat pituitary tumor cell. Pulse and chase demonstrated that ZLLal retarded the turnover of clathrin (Clt.H) and adaptins. ZLLal-treatment co-immunoprecipitated the increased amounts of GH with Clt.H and adaptins compared to control cells, suggesting the intracellular accumulation of immature secretory granules. Clt.H and adaptins were limited-proteolyzed by m-calpain in vitro, indicating that calpain may be involved partly in the maturation of secretory granules in endocrine cells via the process of clathrin uncoating.     

Double stapling method for closure of intraoperative alveolar air leakage adjacent to the staple line: a randomized experimental study on ex vivo porcine lungs

BackgroundAlveolar air leakage from a pleural defect around the staple line is one of the complications after wedge resection of the lung. An intraoperative closure of the pleural defect by suturing can cause additional pleural rupture due to tension of the pleura adjacent to staple lines. Therefore, we have introduced a novel closure method for pleural defect adjacent to the staple line, named the double stapling method. This study compared the efficacy of two closure methods; the double stapling method and conventional suturing method with pledgets using ex vivo porcine lungs.MethodsThe double stapling method involves closing the pleural defect by suturing the two parallel staple lines at both sides of the pleural defect. This method was developed to distribute the pleural tension around the needle holes of suturing. As a model of pleural defect adjacent to the staple line after wedge resection, wedge resection of the caudal lobe of left porcine lungs was performed, and a superficial square pleural defect (10 mm × 10 mm) adjacent to the staple line was made by scalpel. The defect was closed using the following two methods: (I) suturing with pledgets (n=10); and (II) double stapling method (n=10). The lobe was inflated in water at an airway pressure of 20, 25, and 30 cmH₂O; closure success or failure was judged by the absence or presence of air leakage.ResultsThe closure success was confirmed in 2 (20%) out of 10 cases in the suturing with pledgets group and 9 (90%) out of 10 in the double stapling method group (P=0.007). In 4 out of 10 cases in the suturing with pledgets group, new pleural clefts longer than 3 mm were created around the needle holes of suturing.ConclusionsEx vivo experiments have suggested the superiority of the double stapling method for the intraoperative closure of alveolar air leakage adjacent to the staple line after wedge resection, compared to conventional suturing with the pledget method.     

Simple and rapid analysis of aristolochic acid contained in crude drugs and Kampo formulations with solid-phase extraction and HPLC photodiode-array detection

Simple and rapid analysis of aristolochic acid (AA) in crude drugs and Kampo extracts using a solid-phase extraction method and HPLC-PDA analysis was investigated. Extraction of AA from samples was accomplished by adding methanol containing 1% ammonia. The addition of ammonia ionized the AA of acidic substances so that they adhered to an acrylamide copolymer of a strong anion exchange resin (Sep-Pak QMA) coupled to diol silica easily. Furthermore, a mixture of acetonitrile–water–phosphoric acid (75:25:2, v/v) was effective in isolating AA from its carrier. Since almost all interfering peaks originating from contaminants in crude drugs and Kampo extract formulations could be removed, a satisfactory HPLC chromatogram of AA was obtained. A good result was also obtained when Aristolochiaceae and crude drugs containing AA were tested. Particularly in the case of the medicinal parts of Asarum, several interfering peaks and a ghost peak detected near the AA peak were eliminated. The AA contents of two Kampo extract formulations, tokishigyakukagoshuyushokyoto and ryutanshakanto, were calculated by HPLC analysis. The AA content (the sum of AA-I and AA-II) was 1.25–6.13 mg per daily dose. From an additional recovery experiment for Kampo formulations, high recovery rates of AA were obtained. Neither LC/MS nor special instrumentation was necessary. Our results suggest that this simple, quick, and sensitive analytical method to detect AA in crude drugs and Kampo extract formulations would be valuable in safety inspections of AA in crude drugs and their products.     

Total arch replacement using frozen elephant trunk technique with Frozenix for distal aortic arch aneurysms

Open in a separate window OBJECTIVESTotal arch replacement (TAR) using an endovascular approach has been initially introduced as the frozen elephant trunk technique (FET). In our institute, TAR using the FET with Frozenix has been used as the first-line treatment for distal aortic arch aneurysms since 2014. This study aimed to evaluate the early and long-term outcomes and demonstrate the efficacy of this procedure.METHODSBetween 2014 and 2021, 121 consecutive patients were treated with TAR using the FET with Frozenix for distal aortic arch aneurysms. Early and long-term outcomes were retrospectively analysed.RESULTSThe 30-day mortality rate was 2.5% (3/121). Of postoperative complications, paraplegia due to spinal cord injury occurred in 2 (1.7%) patients, stroke in 12 (9.9%) and acute renal failure in 10 (8.3%). At follow-up, 23 secondary aortic interventions were required and 8 (6.6%) patients underwent intended secondary thoracic endovascular aortic repair for residual descending aortic aneurysm. Late and aortic-related deaths occurred in 16 (13.2%) and 4 (3.3%) patients, respectively. The overall long-term survival rates at 1, 3 and 5 years were 87.6%, 83.1% and 65.4%, respectively, while the rates of freedom from aortic-related death at 1, 3 and 5 years were 95.7%, 95.7% and 84.8%, respectively.CONCLUSIONSTAR using the FET with Frozenix for distal aortic arch aneurysms has acceptable early mortality and morbidity. Spinal cord injury and paraplegia occur less frequently than previously reported. The technique has satisfactory long-term survival and freedom from aortic-related death.     

Usefulness of gastroesophageal reflux scintigraphy using the knee-chest position for the diagnosis of gastroesophageal reflux disease

OBJECTIVES: The aim of this study is to evaluate the usefulness of gastroesophageal reflux (GER) scintigraphy using the knee-chest (KC) position for the diagnosis of gastroesophageal reflux disease (GERD). METHODS: The study subjects were 37 patients with GERD and 8 healthy volunteers (control group). Endoscopically observed esophageal mucosal breaks were evaluated with the Los Angeles classification. For GER scintigraphy, the subjects ingested liquid yogurt labeled with 99mTc-diethylene triamine pentaacetic acid (99mTc-DTPA) and water. Imaging was performed in the supine and KC position, and GER was graded as 1-4 according to the extent of GER assessed by scintigraphy. RESULTS: GER scintigraphy revealed no reflux in the control group (specificity: 100%). In the supine position, gastroesophageal reflux was observed in 49% of the patients with GERD, compared to 76% in the KC position. 21 of 23 (91%) patients with erosive esophagitis were shown to have GER with scintigraphy. GER scintigraphy revealed severe reflux (grade 3 or 4) (83%, 10/12) in the patients who had severe mucosal breaks (LA grade C or D). GER scintigraphy detected grade 1 or 2 reflux in 7 of the 14 patients who were endoscopically negative. There was a correlation between the endoscopically determined severity of mucosa and the reflux grade which was determined with GER scintigraphy. CONCLUSION: GER scintigraphy can detect gastroesophageal reflux with a high sensitivity in the KC position and might be a useful method in the screening and assessment of the severity of this disease. This method would be useful for the diagnosis of GERD in endoscopically negative patients.     

Prevalence of primary aldosteronism without hypertension in the general population: Results in Shika study

Objective: Recent studies have reported a high prevalence of primary aldosteronism (PA) among hypertensive patients. However, few data exist regarding the prevalence of PA in the general population. Therefore, we examined the prevalence of PA in the general population including normotensive subjects. Methods: Plasma renin activity (ng/mL/hr), plasma aldosterone concentration (pg/mL) and aldosterone renin ratio (ARR) were determined in 309 subjects aged >40 years in Horimatsu and Higashi-Matsuho district, Shika-machi, Ishikawa, Japan. Results: Among them, 195 subjects (78 males, mean age: 62 ± 11 years) did not take antihypertensive agents: 113 normotensive subjects and 82 hypertensive subjects. Under these conditions, 68 subjects (13 males, age 62 ± 10 years) had an ARR >200. In 14 subjects who underwent captopril suppression test, PA was documented in 5 subjects, yielding a minimum prevalence of 2.6% in total subjects (1.8% in normotensive subjects and 3.7% in hypertensive subjects). Interestingly, females subjects demonstrated significant differences in ARR between subjects with age <50 (172 ± 105) and those with age 51–60 (388 ± 531), although there were no differences in male subjects. Conclusions: These results demonstrate that PA including normotensive subjects exists more commonly than that expected in the general population. We suggest further investigation about the cause and progression of PA associated with sex and aging.     

Lessons on health promotion from Japanese early childhood development

Early childhood development (ECD) has received increasing attention in both developed and developing countries since the 1990s. In Japan, ECD facilities have pursued integrated practices of education and health care to provide appropriate services to promote children’s welfare. This ECD approach appears to embody objectives of health promotion in young children. Therefore, information about Japanese practices may help to support ECD in other countries, especially developing countries. In this context, the present study discussed the potential application of health‐related ECD practices in Japan for developing countries by reviewing an outline of Japanese ECD, along with a case study describing practices in ECD facilities in Japan. We identified four main points: (i) distinct legal grounds including a legal basis for allocating health specialists; (ii) outlines of activities based on national standards and flexible practices at the facility level; (iii) teachers’ attitudes that respect children’s initiative, and explicit and independent activities embedded in children’s daily lives that reflect the child’s developmental status; and (iv) various useful practices to enhance the effect of health‐related activities, such as cooperation with parents, lesson study and hoiku‐ (teachers) conference. As these practices are based on the Japanese context, it is essential to consider both the Japanese context and potential risks of transplanting such concepts, to enable optimum use of these lessons in other countries.     

An Exploratory Study of Dapagliflozin for the Attenuation of Albuminuria in Patients with Heart Failure and Type 2 Diabetes Mellitus (DAPPER)

Background and Aims

Sodium-dependent glucose transporter-2 (SGLT-2) inhibitors, which are anti-diabetic drugs, reportedly decrease the incidence of cardiovascular events in high-risk patients with cardiovascular diseases, and thus chronic heart failure (CHF). SGLT-2 inhibitors also decrease albuminuria in patients with type 2 diabetes mellitus (T2D). Since albuminuria is a biomarker of not only chronic kidney disease but also cardiovascular events, we hypothesized that, among T2D patients with CHF, SGLT-2 inhibitors will decrease the extent of albuminuria and also improve CHF concomitantly.

Methods

DAPPER (UMIN000025102) is a multicenter, randomized, open-labeled, parallel-group, standard treatment-controlled study, which is designed to evaluate whether dapagliflozin, one of the SGLT-2 inhibitors, decreases albuminuria in T2D patients with CHF and exerts cardioprotective effects on the failing heart. The patients are randomized to either of the dapagliflozin (5 or 10 mg, once daily orally) or control group (administration of anti-diabetic drugs administered other than SGLT 2 inhibitors). The estimated number of patients that need to be enrolled is 446 in total (223 in each group). The primary objective is the changes in the urinary albumin-to-creatinine ratio from the baseline after 2-year treatment. The key secondary objectives are (1) the safety of dapagliflozin and (2) the cardiovascular and renal efficacies of dapagliflozin.

Conclusion and Perspectives

DAPPER study investigates whether dapagliflozin decreases albuminuria and exerts beneficial effects on the failing heart in T2D patients. (UMIN000025102).