Targeting neurotrophin and nitric oxide signaling to promote recovery and ameliorate neurogenic bladder dysfunction following spinal cord injury - Mechanistic concepts and clinical implications.

This review summarizes the presentations made to a workshop entitled "Targeting Neurotrophin and Nitric Oxide Signaling to Promote Recovery and Ameliorate Neurogenic Bladder Dysfunction following Spinal Cord Injury - Mechanistic Concepts and Clinical Implications" at the International Continence Society (ICS) 2022 Vienna Meeting. Spinal cord injury (SCI; T8-T9 contusion/transection) causes impaired mobility, neurogenic detrusor overactivity (NDO), detrusor sphincter dyssynergia (DSD) and subsequent decreased quality of life. This workshop discussed the potential of future therapeutic agents that manage the lesion and its consequences, in particular possibilities to reduce the lesion itself and manage pathophysiological changes to the lower urinary tract (LUT). Attenuation of the spinal cord lesion itself was discussed with respect to the potential of a trio of agents: LM11A-3, a p75 neurotrophin receptor modulator to counter activation of local apoptotic pathways; LM22B-10 to promote neuronal growth by targeting tropomyosin-related kinase (Trk) receptors; and cinaciguat, a soluble guanylate cyclase (sGC) activator as an agent promoting angiogenesis at the injury site. The workshop also discussed targets on the bladder to block selectivity sites associated with detrusor overactivity and poor urinary filling profiles, such as purinergic pathways controlling excess contractile activity and afferent signaling, as well as excess fibrosis. Finally, the importance of increased mechanosensitive signaling as a contributor to DSD was considered, as well as potential drug targets. Overall, an emphasis was placed on targets that help restore function and reduce pathological LUT consequences, rather than downregulate normal function.

Is it time to consider population screening for fracture risk in postmenopausal women? A position paper from the International Osteoporosis Foundation Epidemiology/Quality of Life Working Group.

The IOF Epidemiology and Quality of Life Working Group has reviewed the potential role of population screening for high hip fracture risk against well-established criteria. The report concludes that such an approach should strongly be considered in many health care systems to reduce the burden of hip fractures. INTRODUCTION: The burden of long-term osteoporosis management falls on primary care in most healthcare systems. However, a wide and stable treatment gap exists in many such settings; most of which appears to be secondary to a lack of awareness of fracture risk. Screening is a public health measure for the purpose of identifying individuals who are likely to benefit from further investigations and/or treatment to reduce the risk of a disease or its complications. The purpose of this report was to review the evidence for a potential screening programme to identify postmenopausal women at increased risk of hip fracture. METHODS: The approach took well-established criteria for the development of a screening program, adapted by the UK National Screening Committee, and sought the opinion of 20 members of the International Osteoporosis Foundation's Working Group on Epidemiology and Quality of Life as to whether each criterion was met (yes, partial or no). For each criterion, the evidence base was then reviewed and summarized. RESULTS AND CONCLUSION: The report concludes that evidence supports the proposal that screening for high fracture risk in primary care should strongly be considered for incorporation into many health care systems to reduce the burden of fractures, particularly hip fractures. The key remaining hurdles to overcome are engagement with primary care healthcare professionals, and the implementation of systems that facilitate and maintain the screening program.

TRENDS IN THE PREVALENCE OF FRAILTY IN JAPAN: A META-ANALYSIS FROM THE ILSA-J.

OBJECTIVE: To examine whether age-specific prevalence of frailty in Japan changed between 2012 and 2017. DESIGN: This study performed meta-analyses of data collected from 2012 to 2017 using the Integrated Longitudinal Studies on Aging in Japan (ILSA-J), a collection of representative Japanese cohort studies. SETTING: The ILSA-J studies were conducted on community-living older adults. PARTICIPANTS: ILSA-J studies were considered eligible for analysis if they assessed physical frailty status and presence of frailty in the sample. Seven studies were analyzed for 2012 (±1 year; n = 10312) and eight studies were analyzed for 2017 (±1 year; n = 7010). Five studies were analyzed for both 2012 and 2017. MEASUREMENTS: The study assessed the prevalence of frailty and frailty status according to 5 criteria: slowness, weakness, low activity, exhaustion, and weight loss. RESULTS: The overall prevalence of physical frailty was 7.0% in 2012 and 5.3% in 2017. The prevalence of frailty, especially in people 70 years and older, tended to decrease in 2017 compared to 2012. Slight decreases were found in the prevalence of frailty subitems including weight loss, slowness, exhaustion, and low activity between 2012 and 2017, but change in the prevalence of weakness was weaker than other components. CONCLUSIONS: The prevalence of physical frailty decreased from 2012 to 2017. There are age- and gender-related variations in the decrease of each component of frailty.

Incidence rate and risk factors for radiographic hip osteoarthritis in Japanese men and women: a 10-year follow-up of the ROAD study.

OBJECTIVE: To investigate the incidence and progression rate of radiographic hip osteoarthritis (OA) and its risk factors in Japanese men and women using a large-scale population of a nationwide cohort study, Research on Osteoarthritis/osteoporosis Against Disability (ROAD). METHODS: From the baseline survey of the ROAD study, 2,975 participants (1,043 men and 1,932 women) aged 23-94 years (mean, 70.2 years) living in urban, mountainous, and coastal communities were followed up with hip radiography at 3, 7, and 10 years (mean follow-up, 7.1 years). Radiographs were scored using the Kellgren/Lawrence (K/L) grading system, and radiographic hip OA was defined as K/L ≥ 2. The incidence and progression rate of hip OA were examined. Acetabular dysplasia was defined as a central-edge angle <20°. Cox's proportional hazard model was used to assess risk factors for incident and progressive radiographic hip OA. RESULTS: The incidence rate of radiographic hip OA was 5.6/1,000 person-years and 8.4/1,000 person-years in men and women, respectively. The progression rate of hip OA was 2.2/1,000 person-years and 6.0/1,000 person-years in men and women, respectively. The significant risk factors for incident hip OA were age, obesity, and acetabular dysplasia at baseline (hazard risk [HR] 1.05, 95% confidence interval [CI] 1.03-1.08; 1.78, 1.10-2.75; 2.06, 1.30-3.17, respectively). The significant risk factors for progressive hip OA were baseline hip pain and acetabular dysplasia (HR 5.68, 95%CI 1.07-22.61; 14.78, 3.66-56.06, respectively). CONCLUSION: Continued longitudinal surveys of the ROAD study will contribute to knowledge about and potential prevention of incident and progressive hip OA.

A population-based study identifies an association of THBS2 with intervertebral disc degeneration.

OBJECTIVE: To clarify the genetic mechanisms underlying intervertebral disc degeneration (IDD), we examined the associations between single-nucleotide polymorphisms (SNPs) and indicated as coefficient of interaction term (IDD) in a general population in Japan. METHODS: This was a cross-sectional study. In 1,605 participants, C2-3 to L5/S1 in the total spine magnetic resonance imaging (MRI) were evaluated using the Pfirrmann's scoring system. Disc scores of 4 and 5 were defined as IDD. Eight SNPs in eight genes associated with IDD were examined at each disc level, considering the non-genetic risk factors of age, sex, and body mass index (BMI). RESULTS: The highest odds ratio was found for rs9406328 in the THBS2 gene at disc level T12-L1 (OR 1.27, 95%CI 1.05 to 1.53), and this association was strengthened after adjustment for age using logistic regression (OR 1.37, 95%CI 1.12 to 1.67). Among participants aged <50 years and 50-59, the average IDD score in those with 2 risk alleles of rs9406328 was markedly higher than in those with 0 or 1 risk allele, and the difference is much wider than the elderly participants. It indicates the genetic effect of rs9406328 is stronger in the younger age groups. Finally, multiple linear regression analyses of the association between rs9406328 and IDD, adjusted for age, sex, and BMI at each disc level, showed a statistical interaction between age and the number of risk alleles at C7-T1, T3-4 and T4-T5 as well as T12-L1. CONCLUSION: CONCLUSION: The association between rs9406328 in THBS2 and IDD was replicated. The contributions of genetic and environmental factors to IDD differed by disc level.

Graft Immunocomplex Capture Fluorescence Analysis Can Detect Intragraft Anti-Major Histocompatibility Complex Antibodies in Mice Cardiac Transplant.

BACKGROUND: Immunocomplex capture fluorescence analysis has recently been applied as a method for detection of intragraft donor-specific anti-major histocompatibility complex (MHC) antibodies (DSA) in humans. Although intragraft DSA in humans is an intense topic of investigation, there is no report to assess intragraft DSA in murine organ transplantation. METHODS: A model of presensitized mouse cardiac transplantation by donor splenocytes was used. To capture mouse MHC, anti-MHC class I/II antibodies were immobilized on Luminex beads. The MHC/DSA complexes were captured by the Luminex beads followed by detection of phycoerythrin-conjugated antimouse IgG antibodies where DSA had already reacted with the allograft in vivo. RESULTS: Luminex beads were capable of detecting class I DSA in the cardiac allograft, though results for class II DSA were negative. Immunohistochemical investigation revealed that cardiac allografts had abundant MHC class I expression but only minor expression of MHC class II. Furthermore, MHC/class II DSA complexes were successfully detected in splenocytes and serum from a presensitized recipient. CONCLUSIONS: These data suggested that graft immunocomplex capture fluorescence analysis can be also applied in murine cardiac transplantation. This novel application in mice would accelerate our comprehension of DSA through mechanistic studies.

Short- and Long-Term Outcomes of Live Donor Renal Allografts From Older and Younger Donors.

BACKGROUND: The rising demand for living renal donors has led to the recruitment of older donors. Findings vary, but these grafts appear to survive as long as grafts from standard criteria deceased and expanded criteria deceased donors. We investigated the effects of donor age ≥65 years and the presence or absence of donor antihypertensive therapy on patient condition 1 year after transplantation, and retrospectively examined 1-year (273 patients), 3-year (217 patients), and 5-year (140 patients) patient and graft survival. METHODS: We divided 273 donor-recipient pairs into Group Y (donor age <65 years, n = 224) and Group O (donor age ≥65 years, n = 49). Group O was subdivided into donors receiving treatment for hypertension (subgroup O-1, n = 16) and those not receiving treatment for hypertension (subgroup O-2, n = 33). We compared results of 1 hour post-transplant biopsies and looked at a small number of 1 year post-transplant biopsies. RESULTS: Although a significantly larger percentage of recipients from younger donors were undergoing preemptive transplantation, and the incidence of arteriosclerosis was significantly higher in the Group O kidneys, there were no significant differences between the 2 groups in terms of patient or graft survival at 1, 3, or 5 years; serum creatinine levels; or number of episodes of acute rejection. The presence or absence of donor antihypertensive treatment had no effect. CONCLUSIONS: We found that donor age ≥65, with or without antihypertensive treatment, had no effect on graft or patient survival.

Do sarcopenia and/or osteoporosis increase the risk of frailty? A 4-year observation of the second and third ROAD study surveys.

In this 4-year follow-up study including 1083 subjects (≥ 60 years), the prevalence of frailty was estimated to be 5.6%; osteoporosis was found to be significantly associated with frailty. Moreover, the presence of both osteoporosis and sarcopenia increased the risk of frailty compared to the presence of osteoporosis or sarcopenia alone. INTRODUCTION: This study aims to examine the contribution of sarcopenia and osteoporosis to the occurrence of frailty using 4-year follow-up information of a population-based cohort study. METHODS: The second survey of the Research on Osteoarthritis/Osteoporosis Against Disability (ROAD) study was conducted between 2008 and 2010; 1083 subjects (aged ≥ 60 years, 372 men, 711 women) completed all examinations on frailty, sarcopenia, and osteoporosis, which were defined using Fried's definition, Asian Working Group for Sarcopenia criteria, and WHO criteria, respectively. The third survey was conducted between 2012 and 2013; 749 of 1083 individuals enrolled from the second survey (69.2%, 248 men, 501 women) completed assessments identical to those in the second survey. RESULTS: The prevalence of frailty in the second survey was 5.6% (men, 3.8%; women, 6.6%). The cumulative incidence of frailty was 1.2%/year (men, 0.8%/year; women, 1.3%/year). After adjustment for confounding factors, logistic regression analysis indicated that osteoporosis was significantly associated with the occurrence of frailty (odds ratio, 3.07; 95% confidence interval, 1.26-7.36; p = 0.012). Moreover, the occurrence of frailty significantly increased according to the presence of osteoporosis and sarcopenia (odds ratio vs. neither osteoporosis nor sarcopenia: osteoporosis alone, 2.50; osteoporosis and sarcopenia, 5.80). CONCLUSIONS: Preventing osteoporosis and coexistence of osteoporosis and sarcopenia may help reduce the risk of frailty.

Harmonising measures of knee and hip osteoarthritis in population-based cohort studies: an international study.

OBJECTIVE: Population-based osteoarthritis (OA) cohorts provide vital data on risk factors and outcomes of OA, however the methods to define OA vary between cohorts. We aimed to provide recommendations for combining knee and hip OA data in extant and future population cohort studies, in order to facilitate informative individual participant level analyses. METHOD: International OA experts met to make recommendations on: 1) defining OA by X-ray and/or pain; 2) compare The National Health and Nutrition Examination Survey (NHANES)-type OA pain questions; 3) the comparability of the Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) scale to NHANES-type OA pain questions; 4) the best radiographic scoring method; 5) the usefulness of other OA outcome measures. Key issues were explored using new analyses in two population-based OA cohorts (Multicenter Osteoarthritis Study; MOST and Osteoarthritis Initiative OAI). RESULTS: OA should be defined by both symptoms and radiographs, with symptoms alone as a secondary definition. Kellgren and Lawrence (K/L) grade ≥2 should be used to define radiographic OA (ROA). The variable wording of pain questions can result in varying prevalence between 41.0% and 75.4%, however questions where the time anchor is similar have high sensitivity and specificity (91.2% and 89.9% respectively). A threshold of 3 on a 0-20 scale (95% CI 2.1, 3.9) in the WOMAC pain subscale demonstrated equivalence with the preferred NHANES-type question. CONCLUSION: This research provides recommendations, based on expert agreement, for harmonising and combining OA data in existing and future population-based cohorts.

Dexamethasone Prolongs Cardiac Allograft Survival in a Murine Model Through Myeloid-derived Suppressor Cells.

BACKGROUND: Recently, myeloid-derived suppressor cells (MDSCs) have attracted considerable attention because of their cancer-promoting and immunosuppressive effects. The glucocorticoid dexamethasone (Dex) is an important immunosuppressive agent used to treat autoimmune diseases and organ transplant rejection. However, the mechanism by which it modulates the immune system is not completely understood. MATERIAL AND METHODS: In this study, we investigated the mechanisms by which Dex modulated the immune response in mice given an allogeneic cardiac transplant. RESULTS: Dex injection significantly prolonged heart graft survival compared with phosphate-buffered saline-injected controls. Dex treatment increased the number of splenic MDSCs. Moreover, Gr-1high/CD11b+ MDSCs and CD3+/CD4+/Foxp3+ regulatory T cells (Tregs) were significantly increased in the Dex group compared with controls. Administration of anti-Gr-1 antibody (Ab) to the Dex group significantly shortened mouse heart graft survival. In addition, anti-Gr-1 Ab treatment significantly reduced Tregs in the Dex + anti-Gr-1 co-treatment group compared with the Dex group. These observations suggest that Dex treatment increased both MDSCs and Tregs, and that MDSCs regulated the incidence of Tregs in this immunosuppressive pathway. CONCLUSION: An important role of Dex in the prevention of the rejection of cardiac grafts in mice is to expand MDSCs and Tregs.

Effects of herpes simplex virus vectors encoding poreless TRPV1 or protein phosphatase 1α in a rat cystitis model induced by hydrogen peroxide.

Enhanced afferent excitability is considered to be an important pathophysiological basis of interstitial cystitis/bladder pain syndrome (IC/BPS). In addition, transient receptor potential vanilloid-1 (TRPV1) receptors are known to be involved in afferent sensitization. Animals with hydrogen peroxide (HP)-induced cystitis have been used as a model exhibiting pathologic characteristics of chronic inflammatory condition of the bladder. This study investigated the effect of gene therapy with replication-defective herpes simplex virus (HSV) vectors encoding poreless TRPV1 (PL) or protein phosphatase 1 α (PP1α), a negative regulator of TRPV1, using a HP-induced rat model of cystitis. HSV vectors encoding green fluorescent protein, PL or PP1α were inoculated into the bladder wall of female rats. After 1 week, 1% HP or normal saline was administered into the bladder, and the evaluations were performed 2 weeks after viral inoculation. In HP-induced cystitis rats, gene delivery of PL or PP1α decreased pain behavior as well as a reduction in the intercontraction interval. Also, both treatments reduced nerve growth factor expression in the bladder mucosa, reduced bladder inflammation characterized by infiltration of inflammatory cells and increased bladder weight. Taken together, HSV-mediated gene therapy targeting TRPV1 receptors could be effective for the treatment of IC/BPS.

Significance of measurement of serum trough level and anti-drug antibody of adalimumab as personalised pharmacokinetics in patients with Crohn's disease: a subanalysis of the DIAMOND trial.

BACKGROUND: Significance of monitoring adalimumab trough levels and anti-adalimumab antibodies (AAA) for disease outcome in Crohn's disease (CD) patients remained unclear. AIM: To evaluate the association of adalimumab trough levels and AAA at week 26 with clinical remission at week 52, the effect of azathiopurine on AAA and factors influencing trough levels in CD patients in the DIAMOND trial. METHODS: We performed this study using adalimumab trough levels, AAA at week 26 and 6-thioguanine nucleotide (TGN) in red blood cells at week 12. A multiple regression model and receiver operating analysis was performed to identify factors influencing adalimumab trough levels and AAA, and adalimumab thresholds for predicting disease activity. RESULTS: There was a significant difference of adalimumab trough level at week 26 between patients with disease remission and without at week 52 (7.7 ± 3.3 µg/mL vs 5.4 ± 4.3 µg/mL: P <.001). Adalimumab trough level of 5.0 µg/mL yielded optimal sensitivity and specificity for remission prediction (80.2% and 55.6%, respectively). AAA development at week 26 significantly affected remission at week 52 (P = .021), which was strongly associated with adalimumab trough levels. Female gender and increasing body weight were independently associated with low adalimumab trough levels, and female gender was associated with AAA development. A cut-off 6TGN level of >222.5 p mol/8 ×108 RBCs yielded sensitivity (100%) and specificity (60.6%) for AAA negativity. CONCLUSION: Adalimumab trough levels and AAA occurrence were significantly associated with clinical remission. Higher 6TGN affected AAA negativity. The combination therapy is beneficial in some relevant aspects for CD patients. (UMIN Registration No. 000005146).

Radiographic measurements of the hip joint and their associations with hip pain in Japanese men and women: the Research on Osteoarthritis/osteoporosis Against Disability (ROAD) study.

OBJECTIVE: To investigate radiographic measurements of the hip joint and their associations with hip pain, and the prevalence of acetabular dysplasia defined by radiographic measurements of the hip joint in Japanese men and women using the large-scale population-based cohort of the Research on Osteoarthritis/osteoporosis Against Disability (ROAD) study. METHODS: From the baseline survey of the ROAD study (cross-sectional study), 2963 participants (1040 men, 1923 women; mean age, 70.2 years) were analyzed. All participants underwent radiographic examinations of both hips using an anteroposterior view under weight-bearing. Minimum joint space width (mJSW), central-edge (CE) angle, acetabular depth-to-width ratio (ADR), and acetabular head index (AHI) were measured. Associations between these radiographic measurements and hip pain were assessed by calculating odds ratios (ORs) using multivariable logistic-regression analysis. Acetabular dysplasia was defined as a CE angle <20°. RESULTS: Mean radiographic measurements of the hip joint for men were: mJSW, 3.8 mm; CE angle, 30.6°; ADR, 262.1 per 1000; and AHI, 81.4%. For women, these values were: mJSW, 3.4 mm; CE angle, 29.9°; ADR, 262.7 per 1000; and AHI, 81.2%. Associations were seen between hip pain and each of mJSW, CE angle, ADR, and AHI (OR 4.52, 95% confidence interval 3.45-5.97; 1.14, 1.11-1.18; 1.31, 1.24-1.40; and 1.15, 1.12-1.18, respectively). Acetabular dysplasia showed an overall prevalence of 13.9%, and was significantly more prevalent in women than in men (P = 0.012). CONCLUSION: The present study of radiographic measurements of the hip joint showed that mJSW, CE angle, ADR, and AHI were associated with hip pain.

Effective Treatment With Daclatasvir and Asunaprevir in Kidney Transplant Patients Infected With Hepatitis C Virus: A Report of Two Cases.

BACKGROUND: Hepatitis C virus (HCV) infection is known to affect long-term patient and graft survivals after kidney transplantation (KT). Recently, combination therapy with the use of 2 oral direct-acting antivirals, daclatasvir (DCV) and asunaprevir (ASV) reportedly showed a high rate of HCV eradication. We report the safety and efficacy of DCV and ASV therapy in 2 KT patients. METHODS: The safety and viral responses were investigated in a prospective study of KT patients infected with HCV genotype 1. Two patients received 60 mg DCV once daily plus 100 mg ASV twice daily for 24 weeks. RESULTS: A 69-year-old woman and a 57-year-old man underwent DCV and ASV therapy for 24 weeks. In both cases, the HCV genotype was 1b. Case 1 had undergone KT twice and had received treatment with pegylated interferon and ribavirin. She received DCV and ASV therapy 12 years after the 2nd KT, and had undetectable virus after only 6 weeks of treatment and at 24 weeks after the end of treatment (SVR24). The post-transplantation immunosuppressive therapy at that time comprised tacrolimus, mycophenolate mofetil, and prednisolone. The other case, after failure of interferon treatment, received DCV and ASV therapy 27 years after his KT and achieved SVR24. His immunosuppressive regimen at that time was mizoribine and prednisolone. DCV and ASV therapy did not affect renal graft function or tacrolimus blood concentrations. CONCLUSIONS: DCV and ASV therapy had high antiviral effect and a low rate of adverse events in KT patients.

Living Donor Kidney Transplantation After Brachytherapy for Prostate Cancer: Case Report.

INTRODUCTION: There is no obvious criterion about kidney transplantation for patients with pretransplant malignancy. Minimum tumor-free waiting periods differ according to type of cancer, staging, site of occurrence, response to therapy, and risk of cancer recurrence. We report a case of living donor kidney transplantation (LDKT) in a patient after brachytherapy for prostate cancer. CASE REPORT: The patient was a 65-year-old man with chronic kidney disease due to chronic glomerular nephritis. He received hemodialysis 3 times a week. His prostate-specific antigen level (PSA) was high (6.57 ng/mL), and he was diagnosed with prostate cancer (T1cN0M0, Gleason Score 3 + 4 = 7, 3/10) by needle biopsy in urology. He was treated with maximum androgen blockade (MAB) therapy and brachytherapy in May 2014. He underwent LDKT from a spousal donor at our department in December 2015, because urologists concluded that the prostate cancer was completely cured. Immunosuppression consisted of induction with basiliximab and maintenance with tacrolimus, mizoribine, and steroids. The postoperative course was uneventful. He discharged at postoperative day 29 with a serum creatinine level of 1.30 mg/dL. Three months after LDKT, his PSA level was 0.477 ng/mL, and there was no evidence of prostate cancer recurrence. CONCLUSION: This is the first case of LDKT for patients with prostate cancer after brachytherapy in combination with MAB. There is no recurrence of prostate cancer so far; however, careful follow-up including PSA is necessary and important.

Influences of Pre-formed Donor-Specific Anti-Human Leukocyte Antigen Antibodies in Living-Donor Renal Transplantation: Results With Graft Immunocomplex Capture Fluorescence Analysis.

BACKGROUND: Advances in immunosuppressants enable organ transplantation for sensitized patients. However, influences of pre-formed donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) have not been fully understood in renal transplantation (RT). On the other hand, immunocomplex capture fluorescence analysis (ICFA) is a reliable method to detect donor-specific anti-HLA antibodies and HLA antigen complexes. Graft ICFA can detect DSA in an allograft (g-DSA). METHODS: To elucidate the consequences of pre-formed DSA, 198 patients who underwent living-donor RT were enrolled for this study (observation period: 57.8 ± 34.9 months); 187 patients in the DSA- group (excluding ABO-incompatible cases) and 11 patients in the DSA+ group. Before RT, all DSA+ patients had undergone rituximab administration and plasmapheresis. For a graft ICFA, the biopsy specimen (1 × 105 cells) was dissolved, and HLA antigens were captured by anti-HLA beads. Finally, DSA-HLA complexes were detected by means of PE-conjugated anti-human IgG antibodies and analyzed by use of a Luminex system. A ratio (sample/blank beads, mean of fluorescence intensity) was calculated: ≥1.0 was determined as positive g-DSA. RESULTS: There were no significant differences in 5-year graft survival (87.9%/100% in the DSA-/DSA+ groups, respectively). In terms of antibody-mediated rejection (AMR), within 1 month after RT, pathologically determined AMR occurred 3.2% and 63.4% in the DSA- and DSA+ groups, respectively (P < .0001). However, interestingly, more than half of them (57.1%) indicated only subclinical AMR, that is, no fluctuation of S-Cr. As representative of 2 cases of subclinical AMR, g-DSA deposition could be confirmed (1.15 ± 0.04) at 1 hour after reperfusion by graft ICFA. Furthermore, g-DSA shifted to 2.20 ± 0.98 at 3 weeks after transplantation, along with a decline in s-DSA mean of fluorescence intensity (1718-506.5). CONCLUSIONS: Although pathologically determined AMR occurred more frequently in pre-formed DSA+ recipients, it can be argued that a successful de-sensitization protocol inhibits further production of DSA and graft destruction.

Beneficial Effects of High-Dose Mizoribine on ABO-Incompatible Living-Related Kidney Transplantation: Two-Year Results by a Japanese Multicenter Study.

BACKGROUND: Mizoribine (MZ) has been developed as an immunosuppressive agent in Japan, but it has a less-potent immunosuppressive effect up to 3 mg/kg/d. In the previous study, a Japanese multicenter study, we reported that high-dose MZ, at 6 mg/kg/d, with a calcineurin inhibitor was effective and safe in reducing the frequency of cytomegalovirus (CMV)-related events in ABO-incompatible (ABO-i) living-related kidney transplantation (LKT). In the present study, therefore, we investigated the effects of high-dose MZ with a CNI in ABO-i LKT recipients in a Japanese multicenter study. METHODS: A total of 37 patients were treated with high-dose MZ (6 mg/kg), a CNI (cyclosporine [CsA] or tacrolimus [Tac]), basiliximab (Bas), rituximab (Rit), and corticosteroids. CsA was started at a dose of 7 mg/kg to maintain blood levels [200 ng/mL (C0), 6000 ng-h/mL (AUC 0-9)]. Tac was started at a dose of 0.2 mg/kg to maintain blood levels [8-10 ng/mL (C0), 100 ng-h/mL (AUC 0-9)]. Bas (20 mg/body) was administrated on day 0 and day 4 after transplantation. Rit (100-200 mg/body) was administrated on day -14 and day -7 before transplantation. MZ was adjusted to maintain target C0 levels of 1.5 to 2.0 µg/mL. RESULTS: Patient and graft survival rates for 2 years were 100% in the CsA group (n = 22) and 93.3% in the Tac group (n = 15) (not significant, NS). Overall incidence of acute rejection for 2 years was 22.7% in the CsA group and 26.7% in the Tac group. Mean serum creatinine levels at 2 years were 1.29 ± 0.2 mg/dL in the CsA group and 1.21 ± 0.34 mg/dL in the Tac group (NS). The incidence of CMV disease was 0% in both groups, and positive rates of CMV antigenemia were 50.0% and 26.7% in the CsA and Tac groups, respectively (NS). Mean serum uric acid levels were 5.5 ± 1.3 mg/dL and 6.4 ± 1.2 mg/dL at 2 years (NS) in the CsA and Tac groups, respectively. CONCLUSIONS: A high-dose MZ regimen including calcineurin inhibitor (CsA or Tac), Bas, Rit, and steroids was effective and safe in reducing the frequency of CMV-related events in ABO-i LKT.

Progression, incidence, and risk factors for intervertebral disc degeneration in a longitudinal population-based cohort: the Wakayama Spine Study.

OBJECTIVE: The present study examined the progression, incidence, and risk factors for intervertebral disc degeneration (DD) throughout the lumbar spine using magnetic resonance imaging (MRI) in a large population-based cohort. METHODS: We followed up 617 subjects for more than 4 years as part of the Wakayama Spine Study. 1) "Progression of DD" in each of the entire, upper (L1/2 to L3/4) and lower (L4/5 and L5/S1) lumbar spine was defined as Pfirrmann grade progression at follow-up in at least one disc in the affected region. 2) "Incidence of DD" in each of these regions was defined if all discs were grade 3 or lower (white disc) at baseline, and at least one disc had progressed to grade 4 or higher (black disc) at follow-up. Logistic regression analyses were used to determine the risk factors for progression and incidence of DD. RESULTS: DD progression and incidence in the entire lumbar spine were 52.0% and 31.6% in men, and 60.4% and 44.7% in women, respectively. Women was associated with DD progression in the upper lumbar spine (odds ratio [OR] = 1.68, 95% confidence interval [CI] = 1.18-2.42). Aging was associated with the incidence of DD in each region (entire: OR = 1.14, CI = 1.06-1.14; upper: OR = 1.10, CI = 1.05-1.15; lower: OR = 1.11, CI = 1.05-1.19). Diabetes mellitus (DM) was associated with the incidence of DD in the upper lumbar spine (OR = 6.83, CI = 1.07-133.7). CONCLUSION: This 4-year longitudinal study is the first to demonstrate DD progression and incidence in the lumbar spine and their risk factors in a large population-based cohort.

Prediction of hypotension during spinal anesthesia for elective cesarean section by altered heart rate variability induced by postural change.

BACKGROUND: Maternal hypotension is a common complication during cesarean section performed under spinal anesthesia. Changes in maternal heart rate with postural changes or values of heart rate variability have been reported to predict hypotension. Therefore, we hypothesized that changes in heart rate variability due to postural changes can predict hypotension. METHODS: A total of 45 women scheduled to undergo cesarean section under spinal anesthesia were enrolled. A postural change test was performed the day before cesarean section. The ratio of the power of low and high frequency components contributing to heart rate variability was assessed in the order of supine, left lateral, and supine. Patients who exhibited a ⩾two-fold increase in the low-to-high frequency ratio when moving to supine from the lateral position were assigned to the postural change test-positive group. RESULTS: According to the findings of the postural change test, patients were assigned to the positive (n=22) and negative (n=23) groups, respectively. Hypotension occurred in 35/45 patients, of whom 21 (60%) were in the positive group and 14 (40%) were in the negative group. The incidence of hypotension was greater in the positive group (P<0.01). The total dose of ephedrine was greater in the positive group (15±11 vs. 7±7mg, P=0.005). The area under the receiver operating characteristic curve was 0.76 for the postural change test as a predictor of hypotension. CONCLUSION: The postural change test with heart rate variability analysis may be used to predict the risk of hypotension during spinal anesthesia for cesarean section.

Is osteoporosis a predictor for future sarcopenia or vice versa? Four-year observations between the second and third ROAD study surveys.

In a 4-year follow-up study that enrolled 1099 subjects aged ≥60 years, sarcopenia prevalence was estimated at 8.2%. Moreover, the presence of osteoporosis was significantly associated with short-term sarcopenia occurrence, but the reciprocal relationship was not observed, suggesting that osteoporosis would increase the risk of osteoporotic fracture and sarcopenia occurrence. INTRODUCTION: The present 4-year follow-up study was performed to clarify the prevalence, incidence, and relationships between sarcopenia (SP) and osteoporosis (OP) in older Japanese men and women. METHODS: We enrolled 1099 participants (aged, ≥60 years; 377 men) from the second survey of the Research on Osteoarthritis/Osteoporosis against Disability (ROAD) study (2008-2010) and followed them up for 4 years. Handgrip strength, gait speed, skeletal muscle mass, and bone mineral density were assessed. SP was defined according to the Asian Working Group for Sarcopenia. OP was defined based on the World Health Organization criteria. RESULTS: SP prevalence was 8.2% (men, 8.5%; women, 8.0%) in the second survey. In those with SP, 57.8% (21.9%; 77.6%) had OP at the lumbar spine L2-4 and/or femoral neck. SP cumulative incidence was 2.0%/year (2.2%/year; 1.9%/year). Multivariate regression analysis revealed that OP was significantly associated with SP occurrence within 4 years (odds ratio, 2.99; 95% confidence interval, 1.46-6.12; p < 0.01), but the reciprocal relationship was not significantly observed (2.11; 0.59-7.59; p = 0.25). CONCLUSIONS: OP might raise the short-term risk of SP incidence. Therefore, OP would not only increase the risk for osteoporotic fracture but may also increase the risk for SP occurrence.