Studies on the inhibition of methanogenesis and dechlorination by (4-hydroxyphenyl) chloromethanesulfonate.

The purpose of this study was to demonstrate the inhibitory effect of chemicals on methane emissions in paddy soil. We found that (4-hydroxyphenyl) chloromethanesulfonate (C-1) has a methanogenic inhibition activity, and we studied its inhibition mechanism using laboratory tests. The study found that C-1 treatment of flooded soil did not significantly affect the bacterial community but rather the archaeal community; particularly, Methanosarcina spp. C-1 strongly inhibited the aceticlastic methanogenesis route. It was suggested that the inhibitory target of C-1 was different from the well-known methanogenic inhibitor 2-bromoethanesulfonate, which targets methyl-coenzyme M reductase of methanogen. In addition, C-1 had a secondary effect of inhibiting the dechlorination of chlorophenols. Although field trials are required as the next development step, C-1 can be used to reduce methane emissions from paddy fields, one of the largest sources in the agricultural sector.

Laparoscopic approach as a safe and effective option for incarcerated femoral hernias.

INTRODUCTION: The laparoscopic approach for elective femoral herniorrhaphy is well established. However, femoral hernias often present as incarcerations and require emergency repair surgery, mainly using the open approach. This study aimed to retrospectively analyze the efficacy of the laparoscopic approach for incarcerated femoral hernias. METHODS: Data of patients who underwent emergency surgery for incarcerated femoral hernia between April 2016 and August 2021 were retrospectively analyzed. Laparoscopy was performed whenever possible; however, conversion to an open approach remained a fallback option for when laparoscopic repair was not possible. In laparoscopic repair, incarcerated femoral hernias reduced using traction, water pressure, and preperitoneal methods. Data of patients who underwent open repair and laparoscopy were then compared. RESULTS: During the observation period, 20 patients underwent emergency surgery for incarcerated femoral hernia. Eleven patients subsequently underwent repair using a laparoscopic approach, and eight underwent repair using an open approach. Only one patient underwent intestinal resection without hernia repair due to perforated bowel. Operative time for laparoscopic repair was longer. Mesh repair was performed in 18 patients. Four patients each in the laparoscopic repair and open group required intestinal resection. CONCLUSION: Incarcerated femoral hernias can be safely repaired using the laparoscopic approach.

Clinical performance of a novel chemiluminescent enzyme immunoassay for FGF23.

INTRODUCTION: Measurement of fibroblast growth factor 23 (FGF23) has been reported to be clinically useful for the differential diagnosis of chronic hypophosphatemia. However, assays for research use only are available in Japan. Thus, the objective of this study was to examine the clinical utility of a novel and automated chemiluminescent enzyme immunoassay for the measurement of FGF23. MATERIALS AND METHODS: Participants were recruited from July 2015 to January 2017 at six facilities in Japan. Thirty-eight patients with X-linked hypophosphatemic rickets (XLH 15 males, 23 females, age 0-66 years), five patients with tumour-induced osteomalacia (TIO 3 males, 2 females, age 60-73 years), and twenty-two patients with hypophosphatemia (11 males, 11 females, age 1-75 years) caused due to other factors participated in this study. RESULTS: With the clinical cut-off value of FGF23 at 30.0 pg/mL indicated in the Diagnostic Guideline of Rickets/Osteomalacia in Japan, the sensitivity and specificity of FGF23-related hypophosphatemic rickets/osteomalacia without vitamin D deficiency (disease group-1) were 100% and 81.8%, respectively, which distinguished it from non-FGF23-related hypophosphatemia (disease group-2). Furthermore, the diagnostic sensitivity of FGF23-related hypophosphatemia with vitamin D deficiency remained at 100%. Among the four patients with FGF23 levels ≥ 30.0 pg/mL in disease group-2, two patients with relatively higher FGF23 values were suspected to have genuine FGF23-related hypophosphatemia, due to the ectopic production of FGF23 in pulmonary and prostate small cell carcinomas. CONCLUSION: The novel FGF23 assay tested in this study is useful for the differential diagnosis of hypophosphatemic rickets/osteomalacia in a clinical setting.

Changes in quality of life in patients with postmenopausal osteoporosis receiving weekly bisphosphonate treatment: a 2-year multicenter study in Japan.

We investigated changes in quality of life (QOL), including pain, in Japanese women aged ≥ 55 years who were diagnosed as having osteoporosis at 265 centers across Japan and treated continuously with once-weekly bisphosphonates for 24 months. In 2650 evaluable patients, a significant improvement in QOL was observed from 3 months after enrollment onward and maintained throughout the 2-year observation period. A significant improvement in scores was observed for all domains of the Euro QOL 5 Dimension (EQ-5D), and the "pain", "health perception", and "posture, figure" domains of the Japanese Osteoporosis QOL Questionnaire (JOQOL). Factors identified as significantly contributing to QOL change were "fractures within the year before enrollment", "presence of spondylosis deformans", "presence of osteoarthritis", "use of activated vitamin D3", and "age" based on the JOQOL, and "presence of spondylosis deformans", "use of activated vitamin D3", and "age" based on the EQ-5D. The results suggested that the patients' perception of treatment effects, such as improvement in pain, contributes to treatment continuation. Osteoporosis patients should be informed that continuous treatment with once-weekly bisphosphonates can lead to a significant improvement in QOL regardless of concomitant locomotor diseases, to encourage them to remain on treatment. In conclusion, continuous bisphosphonate treatment improved the QOL even in patients with locomotor diseases, and the concomitant use of activated vitamin D3 may also facilitate further improvement in QOL.

Factors associated with inadequate responses to risedronate in Japanese patients with osteoporosis.

Factors associated with an inadequate response (IR) to bisphosphonates have been reported in many countries, but not in Japan, where the approved dose is half the global dose. We analyzed factors associated with IR to risedronate in Japanese patients with osteoporosis. This was a post hoc analysis of 1261 Japanese osteoporosis patients who received risedronate for 1 year in phase III trials. IR was defined as more than one new vertebral fracture (VF) and/or negative change in lumbar spine bone mineral density (BMD) at 1 year. Various baseline and follow-up variables were examined for potential contribution to IR. Of the 1261 subjects, 118 exhibited an IR. At baseline, IR was associated with a higher BMD, lower levels of bone turnover markers (BTM) (serum bone-specific alkaline phosphatase, urinary N-terminal telopeptide of type 1 collagen and C-terminal telopeptide of type 1 collagen), and serum 25-hydroxyvitamin D [25(OH)D] below 16 ng/mL. BTM changes were blunted at 6 months in subjects with IR. On simple regression analysis, all the above variables and poor drug adherence were associated with an IR. On multivariate regression analysis, factors associated with IR were high BMD, vitamin D deficiency at baseline and low BTM at baseline, or a decreased BTM response at 6 months. Low serum 25(OH)D and BTM as well as high BMD at baseline were independent predictors of an IR to risedronate in Japan. These results emphasize the importance of the assessment of serum 25(OH)D and BTM in the management of osteoporosis with bisphosphonates.

[Body weight and bone/calcium metabolism. Obesity and vitamin D.]

Obesity is associated with lower serum 25(OH)D level via several mechanisms including sequestration of fat soluble vitamin D in increased fat mass. Since obesity is the major cause of insulin resistance and type 2 diabetes, lower serum 25(OH)D level is also associated with these conditions. Non-surgical weight reduction, especially that results in decreased visceral fat mass, is associated with an improvement in insulin resistance and a small but significant increase in serum 25(OH)D level. Whether the latter is independently associated with the former is not known. Plural meta-analyses reported that vitamin D supplementation per se without life-style intervention is not associated with a significant weight reduction. However, recent meta-analyses of randomized controlled trials in which large doses vitamin D over 2,000 IU/day supplemented to type 2 diabetes patients revealed a small but significant improvement in indices of insulin resistance and glycemic control. The beneficial effects of vitamin D supplementation on glucose metabolism appeared to be more prominent in non-obese subjects in whom higher serum 25(OH)D level were attained, suggesting potential benefits of vitamin D on glucose metabolism is not mediated by weight or fat mass control.

[Update on recent progress in vitamin D research. Vitamin D insufficiency/deficiency.]

Serum 25(OH)D level reflects bodily vitamin D store. Recently published "Assessment criteria for vitamin D deficiency/insufficiency in Japan" defines vitamin D sufficiency as 25(OH)D level of 30 ng/mL or more, vitamin D insufficiency as that of 20 to 30 ng/mL, vitamin D deficiency as that of less than 20 ng/mL. The lower the serum 25(OH)D level is, the higher the risks are, of secondary hyperparathyroidism, low bone mineral density, fall, fracture, rickets/osteomalacia, and hypocalcemia, as well as lower response to anti-osteoporosis medications. Beyond musculoskeletal disorders, vitamin D insufficiency/deficiency has been shown to be associated with various immunological, metabolic, and malignant disorders mainly by basic and epidemiological studies.

[Combination and sequential therapy using bisphosphonates.]

Bisphosphonates have been explored possible combination and/or sequential use with other anti-osteoporotic medications including PTH. Besides with vitamin D(metabolites), combination treatment had been uncommon mainly because there had not been enough anti-fracture evidence. PTH, which can only be used for a certain period over lifetime, requires other anti-osteoporotic medications after and/or before its use. Bisphosphonates have been tried with PTH in various sequential and/or combination ways. Various combination and/or sequential therapy using bisphosphonates will be reviewed in this article.

Assessment criteria for vitamin D deficiency/insufficiency in Japan - proposal by an expert panel supported by Research Program of Intractable Diseases, Ministry of Health, Labour and Welfare, Japan, The Japanese Society for Bone and Mineral Research and The Japan Endocrine Society [Opinion].

Vitamin D is indispensable for the maintenance of bone and mineral health. Inadequate vitamin D action increases the risk for various musculoskeletal/mineral events including fracture, fall, secondary hyperparathyroidism, diminished response to antiresorptives, rickets/osteomalacia, and hypocalcemia. Its most common cause in recent years is vitamin D deficiency/insufficiency, clinically defined by low serum 25-hydroxyvitamin D [25(OH)D] level. Guidelines for vitamin D insufficiency/deficiency defined by serum 25(OH)D concentrations have been published all over the world. In Japan, however, the information on the associations between serum 25(OH)D and bone and mineral disorders has not been widely shared among healthcare providers, partly because its measurement had not been reimbursed with national medical insurance policy until August 2016. We have set out to collect and analyze Japanese data on the relationship between serum 25(OH)D concentration and bone and mineral events. Integrating these domestic data and published guidelines worldwide, here we present the following assessment criteria for vitamin D sufficiency/insufficiency/deficiency using serum 25(OH)D level in Japan. 1) Serum 25(OH)D level equal to or above 30 ng/mL is considered to be vitamin D sufficient. 2) Serum 25(OH)D level less than 30 ng/mL but not less than 20 ng/mL is considered to be vitamin D insufficient. 3) Serum 25(OH)D level less than 20 ng/mL is considered to be vitamin D deficient. We believe that these criteria will be clinically helpful in the assessment of serum 25(OH)D concentrations and further expect that they will form a basis for the future development of guidelines for the management of vitamin D deficiency/insufficiency.

Assessment criteria for vitamin D deficiency/insufficiency in Japan: proposal by an expert panel supported by the Research Program of Intractable Diseases, Ministry of Health, Labour and Welfare, Japan, the Japanese Society for Bone and Mineral Research and the Japan Endocrine Society [Opinion].

Vitamin D is indispensable for the maintenance of bone and mineral health. Inadequate vitamin D action increases the risk for various musculoskeletal/mineral events including fracture, fall, secondary hyperparathyroidism, diminished response to antiresorptives, rickets/osteomalacia, and hypocalcemia. Its most common cause in recent years is vitamin D deficiency/insufficiency, clinically defined by a low serum 25-hydroxyvitamin D [25(OH)D] level. Guidelines for vitamin D insufficiency/deficiency defined by serum 25(OH)D concentrations have been published all over the world. In Japan, however, the information on the associations between serum 25(OH)D and bone and mineral disorders has not been widely shared among healthcare providers, partly because its measurement had not been reimbursed with national medical insurance policy until August 2016. We have set out to collect and analyze Japanese data on the relationship between serum 25(OH)D concentration and bone and mineral events. Integrating these domestic data and published guidelines worldwide, here, we present the following assessment criteria for vitamin D sufficiency/insufficiency/deficiency using serum 25(OH)D level in Japan. (1) Serum 25(OH)D level equal to or above 30 ng/ml is considered to be vitamin D sufficient. (2) Serum 25(OH)D level less than 30 ng/ml but not less than 20 ng/ml is considered to be vitamin D insufficient. (3) Serum 25(OH)D level less than 20 ng/ml is considered to be vitamin D deficient. We believe that these criteria will be clinically helpful in the assessment of serum 25(OH)D concentrations and further expect that they will form a basis for the future development of guidelines for the management of vitamin D deficiency/insufficiency.

Osteoporosis Associated with Chronic Obstructive Pulmonary Disease.

Recent epidemiological studies have revealed that osteoporosis is closely associated with common chronic diseases including diabetes, hypertension, chronic kidney disorders, and chronic obstructive pulmonary disease (COPD). COPD is a chronic inflammatory airway disease but now well known to be associated with various systemic comorbidities including osteoporosis. Osteoporosis and osteoporotic fractures are extremely common in COPD patients, which have significant impacts on their quality of life (QOL), activities of daily life (ADL), respiratory function, and possibly their prognosis. COPD-associated osteoporosis is however extremely under-recognized, hence undertreated. Recent studies have suggested that both decreased bone mineral density (BMD) and impaired bone quality compromise bone strength causing fractures in COPD. In COPD patients, various general clinical risk factors for osteoporosis are present including smoking, older age, low body weight, and physical inactivity. In addition, disease-related risk factors such as decreased pulmonary function, inflammation, glucocorticoid use and vitamin D deficiency/insufficiency have been linked to the development of osteoporosis in COPD. Increased awareness of osteoporosis in COPD, especially that of high prevalence of vertebral fractures is called upon among general physicians as well as pulmonologists. Routine screening for osteoporosis and risk assessment of fractures will enable physicians to diagnose COPD patients with comorbid osteoporosis at an early stage. Timely prevention of developing osteoporosis together with appropriate treatment of established osteoporosis may improve QOL and ADL of the COPD patients, preserve their lung function and eventually result in better prognosis in these patients.

[COPD and bone].

Chronic obstructive pulmonary disease(COPD)is a chronic inflammatory airway disease associated with various systemic comorbidities including osteoporosis. Osteoporosis is extremely common in COPD patients;up to 80%prevalence of vertebral fracture has been reported. However, its low awareness has left many patients untreated. Although pathophysiology of COPD-associated osteoporosis is largely unknown, multiple risk factors for osteoporosis are present, such as smoking, low body weight, systemic inflammation, vitamin D insufficiency, hypoxia. Further research to elucidate its pathophysiology is needed. But, more importantly, increased awareness of its significance is urgently called upon.

COPD and osteoporosis: links, risks, and treatment challenges.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory airway disease associated with various systemic comorbidities including osteoporosis. Osteoporosis and its related fractures are common and have significant impacts on quality of life and even respiratory function in patients with COPD. COPD-associated osteoporosis is however extremely undertreated. Recent studies have suggested that both decreased bone mineral density (BMD) and impaired bone quality contribute to bone fragility, causing fractures in COPD patients. Various clinical risk factors of osteoporosis in COPD patients, including older age, emaciation, physical inactivity, and vitamin D deficiency, have also been described. It is critically important for pulmonologists to be aware of the high prevalence of osteoporosis in COPD patients and evaluate them for such fracture risks. Routine screening for osteoporosis will enable physicians to diagnose COPD patients with comorbid osteoporosis at an early stage and give them appropriate treatment to prevent fracture, which may lead to improved quality of life as well as better long-term prognosis.

[Vitamin D insufficiency/deficiency:its clinical significance and treatment].

Vitamin D insufficiency/deficiency, a medical condition in which vitamin D store is decreased, is the most frequent cause of decreased action of vitamin D. Severer form vitamin D deficiency can cause hypocalcemia and rickets/osteomalacia. Milder form vitamin D insufficiency also harms bone health via secondary hyperparathyroidism, the increase in fracture risk, and poor responses to anti-osteoporotic medications. Diagnosis can only be made by measuring serum 25(OH)D, which is not currently covered by the Japanese health insurance policy. In Japan, the guideline for the diagnosis vitamin D insufficiency/deficiency is in the process of drafting. According to the current provisional guideline draft that was made in public, vitamin D deficiency would be defined by serum 25(OH)D level less than 20 ng/mL whereas vitamin D insufficiency would refer to the state in which serum 25(OH)D level is between 20 and 30 ng/mL.

Efficacy and Safety of Risedronate in Osteoporosis Subjects with Comorbid Diabetes, Hypertension, and/or Dyslipidemia: A Post Hoc Analysis of Phase III Trials Conducted in Japan.

Many osteoporotics have comorbid diabetes mellitus (DM), hypertension (HT), and dyslipidemia (DL). However, whether such comorbidities alter response to anti-osteoporotic treatment is unknown. We did post hoc analyses of combined data from three risedronate Japanese phase III trials to determine whether the presence of DM, HT, or DL affects its efficacy and safety. Data from 885 subjects who received 48-week treatment with risedronate were collected and combined from the three phase III trials. They were divided into two groups by the presence or absence of comorbidities: DM (n = 53) versus non-DM (n = 832); HT (n = 278) versus non-HT (n = 607); and DL (n = 292) versus non-DL (n = 593). Bone mineral density (BMD), urinary type 1 collagen N-telopeptide (uNTX), and serum bone-specific alkaline phosphatase (BAP) were measured at baseline and sequentially until 48 weeks. BMD or bone markers were not different between any of the two groups. Overall, BMD was increased by 5.52%, and uNTX and BAP were decreased by 35.4 and 33.8%, respectively. Some bone markers were slightly lower in DM and DL subjects, but the responses to risedronate were not significantly different. Statin users had lower uNTX and BAP, but showed no difference in the treatment response. All the other medications had no apparent effect. Adverse event incidence was marginally higher in DL compared with non-DL (Relative risk 1.06; 95% confidence interval 1.01-1.11), but was not related to increase in any specific events. Risedronate shows consistent safety and efficacy in suppressing bone turnover and increasing BMD in osteoporosis patients with comorbid DM, HT, and/or DL.

[Pharmacological treatment of other types of secondary osteoporosis].

This article reviews the treatment strategy for the secondary osteoporosis excluding those caused by diabetes, CKD, endocrine disorders, or glucocorticoid, which proceeding articles deal with. Among numerous possible causes for such secondary osteoporosis, the author has selected osteogenesis imperfecta (OI), osteoporosis associated with gastrectomy or bariatric surgery, inflammatory bowel diseases (IBD), and chronic obstructive pulmonary disease (COPD). For OI, current standard treatment is bisphosphonates (BPs), of which efficacy for fracture inhibition has recently been of issue. Other treatment modalities, e.g. PTH, have just been explored. Osteoporosis associated with gastrectomy, bariatric surgery or IBD, have been treated with vitamin D, calcium, and BPs. Despite high fracture rates, there are almost no treatment data for osteoporosis associated with COPD.

Pathogenesis and diagnostic criteria for rickets and osteomalacia--proposal by an expert panel supported by the Ministry of Health, Labour and Welfare, Japan, the Japanese Society for Bone and Mineral Research, and the Japan Endocrine Society.

Rickets and osteomalacia are diseases characterized by impaired mineralization of bone matrix. Recent investigations have revealed that the causes of rickets and osteomalacia are quite variable. Although these diseases can severely impair the quality of life of affected patients, rickets and osteomalacia can be completely cured or at least respond to treatment when properly diagnosed and treated according to the specific causes. On the other hand, there are no standard criteria to diagnose rickets or osteomalacia nationally and internationally. Therefore, we summarize the definition and pathogenesis of rickets and osteomalacia, and propose diagnostic criteria and a flowchart for the differential diagnosis of various causes of these diseases. We hope that these criteria and the flowchart are clinically useful for the proper diagnosis and management of these diseases.

Nationwide survey of fibroblast growth factor 23 (FGF23)-related hypophosphatemic diseases in Japan: prevalence, biochemical data and treatment.

A nationwide epidemiologic survey of fibroblast growth factor 23 (FGF23)-related hypophosphatemic diseases was conducted in 2010 to clarify the prevalence and the clinical presentations of the disorders. A questionnaire inquiring the experience of patients with these diseases was sent to randomly selected hospitals throughout Japan. The estimated annual incidence of the diseases was 117 cases (95% CI 75 - 160), 55 males (95% CI 30 - 81) and 62 females (95% CI 40 - 84). Tumor-induced osteomalacia (TIO) and X-linked hypophosphatemic rickets (XLH) were the most prevalent causes of acquired and genetic FGF23-related hypophosphatemic diseases, respectively. The estimated incidence of XLH was about 1 in 20,000. We have also collected clinical data of the patients by a secondary survey. These patients showed FGF23 levels of above 30 pg/mL by intact assay in the presence of hypophosphatemia. While complete resection of responsible tumors improved biochemical abnormalities in patients with TIO, treatment with phosphate and/or active vitamin D3 did not normalize serum phosphate and tubular maximum transport of phosphate in patients with XLH. Our results suggest that there is no racial difference in the incidence of XLH. While FGF23 measurement is useful for the diagnosis of FGF23-related hypophosphatemic diseases, the better management is necessary especially for patients with genetic hypophosphatemic rickets caused by excessive actions of FGF23.

Pathogenesis and diagnostic criteria for rickets and osteomalacia - proposal by an expert panel supported by Ministry of Health, Labour and Welfare, Japan, The Japanese Society for Bone and Mineral Research and The Japan Endocrine Society.

Rickets and osteomalacia are diseases characterized by impaired mineralization of bone matrix. Recent investigations revealed that the causes for rickets and osteomalacia are quite variable. While these diseases can severely impair the quality of life of the affected patients, rickets and osteomalacia can be completely cured or at least respond to treatment when properly diagnosed and treated according to the specific causes. On the other hand, there are no standard criteria to diagnose rickets or osteomalacia nationally and internationally. Therefore, we summarize the definition and pathogenesis of rickets and osteomalacia, and propose the diagnostic criteria and a flowchart for the differential diagnosis of various causes for these diseases. We hope that these criteria and flowchart are clinically useful for the proper diagnosis and management of patients with these diseases.

Osteoporosis is highly prevalent in Japanese males with chronic obstructive pulmonary disease and is associated with deteriorated pulmonary function.

Osteoporosis has recently been recognized as a major comorbidity in chronic obstructive pulmonary disease (COPD). We conducted a cross-sectional study in a cohort of 136 Japanese males with COPD to evaluate the prevalence of vertebral fracture (VF) and to explore its relationship with pulmonary function parameters. VFs were present in 108 (79.4%); multiple and severe (SQ grade 2 or 3) VFs were found in 77 (56.6%) and 25 (18.4%), respectively. Multivariate logistic regression analyses revealed that decrease in forced expiratory volume in one second (FEV1.0)/forced vital capacity (FVC) [odds ratio (OR) 0.963, 95% confidence interval (CI) 0.929-998, p = 0.036] was associated with the presence of VF after adjustment for age and that FVC (OR 0.462, 95% CI 0.220-0.968, p = 0.041) and current smoking (OR 2.992, 95% CI 1.128-7.940, p = 0.028) were associated with VF severity (grade 2-3 vs. 1). We also found that FEV1.0 was the sole independent determinant of the number of VFs by stepwise multivariate linear regression (p < 0.001). Bone mineral density (BMD) values were available in 49 subjects. Mean T scores were -2.0 ± 1.2 in femoral neck, -1.4 ± 1.2 in total hip and -1.1 ± 1.4 in lumbar spine. Nineteen patients (38.8%) had a BMD T score less than -2.5. BMD Z scores of all the sites showed a progressive decrease as GOLD stage of COPD advanced (p < 0.05). Our results indicate a high prevalence of osteoporosis in Japanese male COPD patients and a strong inter-relationship between the two diseases, re-emphasizing the urgent need for appropriate intervention to maintain both bone and lung health.