IL-27 regulates the differentiation of follicular helper NKT cells via metabolic adaptation of mitochondria.

Invariant natural killer T (iNKT) cells are innate-like T lymphocytes that express an invariant T cell receptor α chain and contribute to bridging innate and acquired immunity with rapid production of large amounts of cytokines after stimulation. Among effecter subsets of iNKT cells, follicular helper NKT (NKTFH) cells are specialized to help B cells. However, the mechanisms of NKTFH cell differentiation remain to be elucidated. In this report, we studied the mechanism of NKTFH cell differentiation induced by pneumococcal surface protein A and α-galactosylceramide (P/A) vaccination. We found that Gr-1+ cells helped iNKT cell proliferation and NKTFH cell differentiation in the spleen by producing interleukin-27 (IL-27) in the early phase after vaccination. The neutralization of IL-27 impaired NKTFH cell differentiation, which resulted in compromised antibody production and diminished protection against Streptococcus pneumoniae infection by the P/A vaccine. Our data indicated that Gr-1+ cell-derived IL-27 stimulated mitochondrial metabolism, meeting the energic demand required for iNKT cells to differentiate into NKTFH cells. Interestingly, Gr-1+ cell-derived IL-27 was induced by iNKT cells via interferon-γ production. Collectively, our findings suggest that optimizing the metabolism of iNKT cells was essential for acquiring specific effector functions, and they provide beneficial knowledge on iNKT cell-mediated vaccination-mediated therapeutic strategies.

Aging in females has minimal effect on changes in celiac artery blood flow during dynamic light-intensity exercise.

Blood flow to the active muscles and arterial blood pressure (ABP) increase during dynamic exercise, whereas blood flow to inactive organs (e.g., splanchnic organs and inactive limbs) declines. Aging leads to exaggerated ABP responses to exercise in females, but whether this is related to greater splanchnic vasoconstriction is unknown. This study sought to clarify the effect of aging in females on celiac artery blood flow during dynamic light-intensity exercise. Twelve healthy young females (YF: 20 ± 2 yr, mean ± SD) and 12 healthy older females (OF: 71 ± 4 yr) performed dynamic knee-extension and knee-flexion exercises at 30% of heart rate reserve for 4 min. The absolute changes from baseline (Δ) for mean arterial blood pressure (MAP), celiac artery mean blood flow (celMBF), and celiac vascular conductance (celVC) during exercise were calculated. ABP was measured using an automated sphygmomanometer, and celMBF was recorded by Doppler ultrasonography. The increase in MAP during exercise was greater in OF than in YF (YF: +14 ± 7 mmHg, OF: +24 ± 13 mmHg, P = 0.028). The celMBF decreased during exercise in both groups, but there was no significant difference in the response between YF and OF (YF: -93.0 ± 66.1 mL/min, OF: -89.6 ± 64.0 mL/min, P = 0.951). The celVC also decreased during exercise and remained lower than baseline during exercise. However, the response was not different between YF and OF (YF: -1.8 ± 1.0 mL/min/mmHg, OF: -1.5 ± 0.6 mL/min/mmHg, P = 0.517). These results demonstrate that aging in females has minimal influence on splanchnic artery hemodynamic responses during dynamic light-intensity exercise, suggesting that exaggerated ABP responses during exercise in OF are not due to greater splanchnic vasoconstriction.NEW & NOTEWORTHY During exercise, the splanchnic arteries vasoconstrict, contributing to blood flow redistribution and the blood pressure response. Blood pressure responses to exercise are exaggerated with aging in females; however, the physiological mechanism responsible has not been clarified. We show that celiac artery blood flow changes during light-intensity dynamic exercise do not differ with age in females. This indicates the exaggerated blood pressure to exercise with aging is likely not due to a difference in splanchnic vasoconstriction.

Association of chronic liver disease with bone diseases and muscle weakness.

The liver is a vital organ involved in nutrient metabolism, hormone regulation, immunity, cytokine production, and gut homeostasis. Impairment in liver function can result in malnutrition, chronic inflammation, decreased anabolic hormone levels, and dysbiosis. These conditions eventually cause an imbalance in osteoblast and osteoclast activities, resulting in bone loss. Osteoporosis is a frequent complication of chronic liver disease (CLD) that adversely affects quality of life and increases early mortality. Sarcopenia is another common complication of CLD characterized by progressive loss of skeletal muscle mass and function. Assessment criteria for sarcopenia specific to liver disease have been established, and sarcopenia has been reported to be associated with an increase in the risk of liver disease-related events and mortality in patients with CLD. Owing to their similar risk factors and underlying pathophysiological mechanisms, osteoporosis and sarcopenia often coexist (termed osteosarcopenia), progress in parallel, and further exacerbate the conditions mentioned above. Therefore, comprehensive management of these musculoskeletal disorders is imperative. This review summarizes the clinical implications and characteristics of osteoporosis, extending to sarcopenia and osteosarcopenia, in patients with CLD caused by different etiologies.

Coffee and caffeine intake reduces risk of ulcerative colitis: a case-control study in Japan.

BACKGROUND AND AIM: Although diet is one of the potential environmental factors affecting ulcerative colitis (UC), evidence is not sufficient to draw definitive conclusions. This Japanese case-control study examined the association between the consumption of coffee, other caffeine-containing beverages and food, and total caffeine and the risk of UC. METHODS: The study involved 384 UC cases and 665 control subjects. Intake of coffee, decaffeinated coffee, black tea, green tea, oolong tea, carbonated soft drinks, and chocolate snacks was measured with a semiquantitative food-frequency questionnaire. Adjustments were made for sex, age, pack-years of smoking, alcohol consumption, history of appendicitis, family history of UC, education level, body mass index, and intake of vitamin C, retinol, and total energy. RESULTS: Higher consumption of coffee and carbonated soft drinks was associated with a reduced risk of UC with a significant dose-response relationship (P for trend for coffee and carbonated soft drinks were <0.0001 and 0.01, respectively), whereas higher consumption of chocolate snacks was significantly associated with an increased risk of UC. No association was observed between consumption of decaffeinated coffee, black tea, green tea, or oolong tea and the risk of UC. Total caffeine intake was inversely associated with the risk of UC; the adjusted odds ratio between extreme quartiles was 0.44 (95% confidence interval: 0.29-0.67; P for trend <0.0001). CONCLUSIONS: We confirmed that intake of coffee and caffeine is also associated with a reduced risk of UC in Japan where people consume relatively low quantities of coffee compared with Western countries.

The lymphocyte-to-monocyte ratio as a significant inflammatory marker associated with survival of patients with metastatic renal cell carcinoma treated using nivolumab plus ipilimumab therapy.

BACKGROUND: Nivolumab plus ipilimumab (NIVO + IPI) is the first-line treatment for patients with metastatic renal cell carcinoma (mRCC). While approximately 40% of patients treated with NIVO + IPI achieve a durable response, 20% develop primary resistance with severe consequences. Therefore, there is a clinical need for criteria to select patients suitable for NIVO + IPI therapy to optimize its therapeutic efficacy. Accordingly, our aim was to evaluate the association between candidate biomarkers measured before treatment initiation and survival. METHODS: This was a multi-institutional, retrospective, cohort study of 183 patients with mRCC treated with systematic therapies between August 2015 and July 2023. Of these, 112 received NIVO + IPI as first-line therapy: mean age, 68 years; men, 83.0% (n = 93), and clear cell histology, 80.4% (n = 90). Univariable and multivariable analyses were used to evaluate associations between biomarkers and survival. RESULTS: On univariate analysis, high C-reactive protein and systemic index, a high neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio, and a low lymphocyte-to-monocyte ratio (LMR) were associated with shorter overall survival (OS). On multivariable analysis, a LMR ≤ 3 was retained as an independent factor associated to shorter OS with the highest accuracy (C-index, 0.656; hazard ratio, 7.042; 95% confidence interval, 2.0-25.0; p = 0.002). CONCLUSION: A low LMR may identify patients who would be candidate for NIVO + IPI therapy for mRCC.

First ray mobility in hallux rigidus, hallux valgus, and normal feet based on weightbearing computed tomography and three-dimensional analysis: A case-control study.

BACKGROUND: Hallux valgus and hallux rigidus are disorders affecting the first ray and are associated with hypermobility of this structure. This study aimed to investigate the three-dimensional mobility of each joint of the first ray between feet with hallux valgus or hallux rigidus and healthy feet using weightbearing and nonweightbearing computed tomography (CT). METHODS: This case-control study analyzed 17 feet of 11 healthy volunteers (control group), 16 feet of 16 patients with hallux valgus (HV group), and 16 feet of 11 patients with hallux rigidus (HR group). First, nonweightbearing foot CT imaging was performed in the supine position on a loading device with no load applied, with the legs extended and the ankle in the neutral position. Next, a load equivalent to body weight was applied for weightbearing CT imaging. Distal bone displacement relative to the proximal bone was quantified three-dimensionally under both conditions. RESULTS: In the HV group, the talonavicular joint showed significantly greater eversion (P = 00.011) compared with the control group and significantly greater dorsiflexion (P = 00.027) and eversion (P < 00.01) compared with the HR group. In the medial cuneiform joint, the HV group showed significantly greater eversion (P < 00.01) and abduction (P = 00.011) than the control group. For the first tarsometatarsal joint, the HV group showed significantly greater dorsiflexion (P = 00.014), inversion (P = 00.028), and adduction (P < 00.01) than the control group, and greater inversion (P < 00.01) and adduction (P < 00.01) than the HR group. Dorsiflexion of the first tarsometatarsal joint was significantly greater in the HR group compared with the control group (P = 00.026). CONCLUSION: Hypermobility of the first ray appears to be three-dimensional: in hallux valgus, it is centered at the first tarsometatarsal joint, while in hallux rigidus it is mainly in the sagittal plane at the first tarsometatarsal joint only. This difference may explain the different deformities ultimately observed in each condition.

Molecular, Morphological and Electrophysiological Differences between Alpha and Gamma Motoneurons with Special Reference to the Trigeminal Motor Nucleus of Rat.

The muscle contraction during voluntary movement is controlled by activities of alpha- and gamma-motoneurons (αMNs and γMNs, respectively). In spite of the recent advances in research on molecular markers that can distinguish between αMNs and γMNs, electrophysiological membrane properties and firing patterns of γMNs have remained unknown, while those of αMNs have been clarified in detail. Because of the larger size of αMNs compared to γMNs, blindly or even visually recorded MNs were mostly αMNs, as demonstrated with molecular markers recently. Subsequently, the research on αMNs has made great progress in classifying their subtypes based on the molecular markers and electrophysiological membrane properties, whereas only a few studies demonstrated the electrophysiological membrane properties of γMNs. In this review article, we provide an overview of the recent advances in research on the classification of αMNs and γMNs based on molecular markers and electrophysiological membrane properties, and discuss their functional implication and significance in motor control.

Long-term course of developmental dysplasia of the hip: follow-up of the non-operated hips of patients undergoing unilateral rotational acetabular osteotomy for twenty-four years.

PURPOSE: To follow-up the non-operated hips of patients who underwent unilateral rotational acetabular osteotomy (RAO) for bilateral developmental dysplasia of the hip (DDH) for a minimum of 20 years to clarify (1) the timing of onset of hip osteoarthritis (OA) in DDH, and (2) factors associated with the development of OA. METHODS: This study included 92 non-operated hips of patients who underwent unilateral RAO for bilateral DDH. We examined the timing of OA onset and total hip arthroplasty (THA) and the joint survival rate in the studied hips. Furthermore, the patients were divided into those with OA onset (progression group) and those without OA onset and compared in terms of lateral center-edge angle (LCEA), sharp angle, acetabular head index (AHI), acetabular roof obliquity (ARO), joint congruity, and the presence or absence of OA progression on the RAO side. RESULTS: The progression group experienced OA onset 12 years after RAO and underwent THA 6 years after OA onset. The 20-year joint survival rate was 73% with the endpoint of OA onset and 81% with the endpoint of THA. The progression group had significantly smaller LCEA and AHI and larger ARO. The risk of developing OA was 8.2 times greater in patients with LCEA ≤ 7° than in those with LCEA > 7°. CONCLUSION: The patients with OA progression group experienced OA onset at an average age of 55 years. A small LCEA (≤ 7°) was identified as a risk factor for the development of OA.

The mechanism for regulating the isometric contraction of masseter muscles is involved in determining the vertical dimension of occlusion.

We previously demonstrated that accurate regulation of isometric contraction (IC) of jaw-closing muscles to counteract the ramp load applied to the jaw in the jaw-opening direction is achieved through the calibration between the two sensations arising from muscle spindles (MSs) and periodontal mechanoreceptors (PMRs). However, it remains unclear whether this calibration mechanism accurately works at any jaw positions, i.e., any vertical dimensions of occlusion (VDO). In the present study, we examined the effects of altering VDO on the IC of the masseter muscles in complete dentulous and edentulous subjects. At a VDO higher than the original VDO (O-VDO), the root mean square (RMS) of masseter EMG activity increased more steeply with a load increase, resulting in an over-counteraction. The regression coefficient of the load-RMS relationship significantly increased as the VDO was increased, suggesting that the overestimation became more pronounced with the VDO increases. Consistently also in the edentulous subjects, at a higher VDO than the O-VDO, a steeper increase in the RMS emerged with a delay in response to the same ramp load whereas a similar steeper increase was seen surprisingly even at a lower VDO. Thus, the edentulous subjects displayed a delayed overestimation of the ramp load presumably due to less and slowly sensitive mucous membrane mechanoreceptor (MMR) in alveolar ridge compared with the PMR. Taken together, the accurate calibration between the two sensations arising from MSs and PMRs/MMRs can be done only at the O-VDO, suggesting that the O-VDO is the best calibration point for performing accurate IC.NEW & NOTEWORTHY Since 1934, the vertical dimension of occlusion (VDO) in edentulous individuals has been anatomically determined mostly by referring to the resting jaw position. However, such a static method is not always accurate. Considering the dynamic nature of clenching/mastication, it is desirable to determine VDO dynamically. We demonstrate that VDO can be accurately determined by measuring masseter EMG during the voluntary isometric contraction of jaw-closing muscles exerted against the ramp load in the jaw-opening direction.

Determination of a Serum 25-Hydroxyvitamin D Reference Ranges in Japanese Adults Using Fully Automated Liquid Chromatography-Tandem Mass Spectrometry.

BACKGROUND: Despite an increasing interest in vitamin D status, a reference range of the nutrient has not been fully established. This is partly due to a paucity of standardized measuring systems with high throughput. In addition, the range may vary by populations and may change with modernization of lifestyles. OBJECTIVES: This study aims to calculate the current reference concentration of 25-hydroxyvitamin D (25(OH)D) among healthy people living in an urban area in Japan. METHODS: A newly developed fully automated liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) system was used to measure serum 25(OH)D concentrations. Reproducibility was assessed by measuring standardized samples. Accuracy was validated by comparing with commercially available immunoassays. Then, mass screening was conducted targeting participants who received medical checkups in Tokyo from April 2019 to March 2020, and the reference ranges were calculated. RESULTS: The coefficients of variations of interoperator and interday reproducibility were 4.1%-8.5% and 3.7%-8.0% for 25-hydroxyvitamin D2 (25(OH)D2) and 4.7%-7.0% and 4.0%-6.9% for 25-hydroxyvitamine D3, respectively. The measured total 25(OH)D concentrations correlated well with those measured by immunoassays. In total, 5518 participants were measured for 25(OH)D concentrations, among whom 98% showed inadequate concentrations (<30 ng/mL). The reference ranges of total 25(OH)D for female, male, and total participants were 7-30 ng/mL, 5-27 ng/mL, and 6-29 ng/mL, respectively. After excluding those with abnormal renal and liver function, the range was 6-30 ng/mL. CONCLUSIONS: The high prevalence of vitamin D insufficiency among seemingly healthy population may be attributed to lifestyle characteristics of people living in urban areas of Japan, including spending less time outdoors and lower intake of traditional foods. Longitudinal follow-up and mass screenings targeting different population will help elucidate reasons for discrepancies between official guidelines and the observed concentrations, to which the well-validated measurement system is essential.

Impact of trough abiraterone level on adverse events in patients with prostate cancer treated with abiraterone acetate.

PURPOSE: We assessed the impact of plasma trough concentrations of abiraterone (ABI) and its metabolite Δ4-abiraterone (D4A) and related polymorphisms on adverse events (AEs) in patients with metastatic prostate cancer who received abiraterone acetate (AA). METHODS: This prospective study enrolled patients with advanced prostate cancer treated with AA between 2016 and 2021. Plasma trough concentrations of ABI and D4A were measured using high-performance liquid chromatography. The impact of HSD3B1 rs1047303, SRD5A2 rs523349, and cytochrome P450 family 3A member 4 rs2242480 polymorphisms on plasma concentrations of ABI and D4A and the incidence of AEs were also assessed. RESULTS: In 68 patients treated with AA, the median ABI and D4A concentrations were 18.1 and 0.94 ng/mL, respectively. The high plasma trough concentration of ABI (≥ 20.6 ng/mL) was significantly associated with the presence of any AE and its independent risk factor based on multivariable analysis (odds ratio, 7.20; 95% confidence interval (CI): 2.20-23.49). Additionally, a high plasma trough concentration of ABI was an independent risk factor of time to withdraw AA (hazard ratio, 4.89; 95% CI: 1.66-14.38). The risk alleles of three polymorphisms were not statistically associated with the ABI and D4A concentrations and the incidence of AEs. CONCLUSIONS: The plasma trough concentration of ABI is associated with the presence of AEs and treatment failure after AA administration. ABI concentration monitoring may be useful in patients with prostate cancer who received AA.

Immunological risk and complement genetic evaluations in early onset de novo thrombotic microangiopathy after living donor kidney transplantation: A Japanese multicenter registry.

BACKGROUND: Thrombotic microangiopathy (TMA) after kidney transplantation (KTx), particularly early onset de novo (dn) TMA, requires immediate interventions to prevent irreversible organ damage. This multicenter study was performed to investigate the allogeneic clinical factors and complement genetic background of dnTMA after KTx. METHODS: Perioperative dnTMA after KTx within 1 week after KTx were diagnosed based on pathological or/and hematological criteria at each center, and their immunological backgrounds were researched. Twelve aHUS-related gene variants were examined in dnTMA cases. RESULTS: Seventeen recipients (15 donors) were enrolled, and all dnTMA cases were onset within 72-h of KTx, and 16 of 17 cases were ABO incompatible. The implementation rate of pre-transplant plasmaphereses therapies were low, including cases with high titers of anti-A/anti-B antibodies. Examination of aHUS-related gene variants revealed some deletions and variants with minor allele frequency (MAF) in Japan or East Asian genome databases in genes encoding alternative pathways and complement regulatory factors. These variants was positive in 8 cases, 6 of which were positive in both recipient and donor, but only in one graft loss case. CONCLUSIONS: Although some immunological risks were found for dnTMA after KTx, only a few cases developed into TMA. The characteristic variations revealed in the present study may be novel candidates related to dnTMA in Japanese or Asian patients, but not pathogenic variants of aHUS. Future studies on genetic and antigenic factors are needed to identify factors contributing to dnTMA after KTx.

Real clinical outcomes of nivolumab plus ipilimumab for renal cell carcinoma in patients over 75 years old.

BACKGROUND: Although nivolumab plus ipilimumab is the standard treatment for metastatic renal cell carcinoma (RCC), its efficacy and safety in older patients remain unclear. Therefore, this study aimed to assess the clinical outcomes of nivolumab plus ipilimumab for metastatic RCC in patients aged ≥ 75 years. METHODS: We enrolled 120 patients with metastatic RCC treated with nivolumab plus ipilimumab from August 2015 to January 2023. Objective response rates (ORRs) were compared between patients aged < 75 and ≥ 75 years. Progression-free survival (PFS), overall survival (OS), and adverse events were compared between the groups. Adverse events were evaluated according to the Response Evaluation Criteria in Solid Tumors 1.1. RESULTS: Among the patients, 57 and 63 were classified as intermediate and poor risk, respectively, and one could not be classified. The median follow-up duration after the initiation of treatment was 16 months. The patient characteristics between the groups, except for age, were not significantly different. Intergroup differences in ORR (42% vs. 40%; p = 0.818), PFS (HR: 0.820, 95% CI 0.455-1.479; p = 0.510), and median OS (HR: 1.492, 95% CI 0.737-3.020; p = 0.267) were not significant. The incidence of adverse events (50% vs. 67%; p = 0.111) and nivolumab plus ipilimumab discontinuation due to adverse events was not significantly different between the groups (14% vs. 13%; p = 0.877). CONCLUSIONS: The effectiveness of nivolumab plus ipilimumab was comparable between patients with metastatic RCC aged < 75 and those ≥ 75 years with respect to their ORRs, PFS, OS, and adverse event rates.

Advanced Tertiary Lymphoid Tissues in Protocol Biopsies are Associated with Progressive Graft Dysfunction in Kidney Transplant Recipients.

BACKGROUND: Tertiary lymphoid tissues (TLTs) are ectopic lymphoid tissues found in chronically inflamed organs. Although studies have documented TLT formation in transplanted kidneys, the clinical relevance of these TLTs remains controversial. We examined the effects of TLTs on future graft function using our histologic TLT maturity stages and the association between TLTs and Banff pathologic scores. We also analyzed the risk factors for the development of TLTs. METHODS: Serial protocol biopsy samples (0 hour, 1, 6, and 12 months) without rejection were retrospectively analyzed from 214 patients who underwent living donor kidney transplantation. TLTs were defined as lymphocyte aggregates with signs of proliferation and their stages were determined by the absence (stage I) or presence (stage II) of follicular dendritic cells. RESULTS: Only 4% of patients exhibited TLTs at the 0-hour biopsy. Prevalence increased to almost 50% at the 1-month biopsy, and then slightly further for 12 months. The proportion of advanced stage II TLTs increased gradually, reaching 19% at the 12-month biopsy. Presence of stage II TLTs was associated with higher risk of renal function decline after transplantation compared with patients with no TLT or stage I TLTs. Stage II TLTs were associated with more severe tubulitis and interstitial fibrosis/tubular atrophy at 12 months and predicted poorer graft function independently from the degree of interstitial inflammation. Pretransplantation rituximab treatment dramatically attenuated the development of stage II TLTs. CONCLUSIONS: TLTs are commonly found in clinically stable transplanted kidneys. Advanced stage II TLTs are associated with progressive graft dysfunction, independent of interstitial inflammation.

Chronological changes in the rate of surgical field contamination in the shoulder joint.

BACKGROUND: In shoulder surgery, low-virulence bacteria such as Cutibacterium acnes and coagulase-negative staphylococci can cause postoperative infection. However, the degree of sterility during surgery after disinfection is not known, and the efficacy of double skin preparation for such bacteria is unclear. This study aimed to evaluate chronological changes in the surgical field contamination rate in the shoulder joint and to compare single and double skin preparation. METHODS: In total, 126 shoulders in 121 patients undergoing shoulder surgery (64 men, 62 women; mean age 64 years) were enrolled. Patients were divided into two groups: single skin preparation, where the site was painted with 10% povidone iodine, and double skin preparation, where the site was treated with 1% chlorhexidine gluconate/83% isopropyl alcohol and painted 10% povidone iodine. Swab samples from the axillary and proximal areas in the surgical field were collected chronologically before starting surgery and at 30, 60, and 120 min after starting surgery (MAS). The contamination rate of each sample was compared and detected species were evaluated. RESULTS: The contamination rate for the axillary area was 48.4%, 85.9%, 95.3%, and 97.1% in the single-preparation group and 32.3%, 72.6%, 87.1%, and 91.2% in the double-preparation group before starting surgery and 30, 60, and 120 MAS, respectively, and that the proximal area was 12.5%, 26.6%, 29.7%, and 35.3% in the single-preparation group and 16.1%, 19.4%, 27.4%, and 38.2% in the double-preparation group, respectively. Significant differences were not seen between the groups by area or time point. Most detected species were Cutibacterium acnes and coagulase-negative staphylococci. CONCLUSIONS: The incidence of surgical field contamination in shoulder joint was high from immediately after starting surgery. In the axillary area, the contamination rates exceeded 70% from 30 MAS in both groups. Measures against infection should be instituted considering these findings when performing shoulder surgery.

Clinical study of preoperative skeletal muscle mass as a predictor of physical performance recovery following palliative surgery for spinal metastases.

BACKGROUND: Surgical treatment of spinal metastases has been associated with high morbidity and mortality in patients with sarcopenia based on low skeletal muscle mass. We assessed physical performance using the Eastern Cooperative Oncology Group performance status scale and the Barthel Index on the 30th day after palliative surgery for spinal metastases and investigated the effectiveness of surgery according to sarcopenia assessed by skeletal muscle mass. METHODS: We retrospectively analyzed 78 consecutive patients with thoracic and lumbar spinal metastases who underwent palliative surgery. The value of the area of the psoas major muscle at the L3 level normalized by the vertebral area was divided into first, middle, and third tertiles. Clinical variables were compared by tertile. Variables affecting the 30-day good performance status were investigated with univariate and multivariate analyses. RESULTS: The 30-day morbidity rates were 50%, 38.5%, and 15.4% by tertile. The 30-day mortality rate was 2%; all were in the first tertile. Good preoperative performance status scores were seen in 15.4% of first and 50% of third tertile patients. Postoperatively, the performance status improved in all groups, with 30.8%, 65.4%, and 92.3% by tertile. Multivariate regression analysis revealed that a good preoperative performance status (OR: 15.50, 95% CI: 1.610-149.00, P < 0.05) and the value of the area of the psoas major muscle at the L3 level normalized by the vertebral area not in the first tertile (OR: 0.22, 95% CI: 0.06-0.82, P < 0.05) were significant predictors of a good postoperative 30-day performance status. CONCLUSIONS: A good preoperative performance status and exclusion from the first tertile were clinical factors predicting a good postoperative 30-day performance status. In patients with large psoas muscle mass (third tertile), a good 30-day performance status can be expected after surgery, suggesting that surgery in this population should be pursued aggressively.

Impact of germline HLA genotypes on clinical outcomes in patients with urothelial cancer treated with pembrolizumab.

Human leukocyte antigen class I (HLA-I) genotypes are suggested to influence the cancer response to checkpoint blockade immunotherapy. This study assessed the impact of germline HLA genotypes on clinical outcomes in patients with chemoresistant advanced urothelial cancer (UC) treated with pembrolizumab. Zygosity, supertypes, evolutionary divergency, and specific alleles of germline HLA-I and -II were evaluated using the Luminex technique in 108 patients with chemoresistant metastatic or locally advanced UC treated with pembrolizumab. Among the 108 patients, 69 died and 83 showed radiographic progression during follow-up. Homozygous for at least one HLA-I locus, absence of the HLA-A03 supertype, and high HLA-I evolutionary divergence were associated with a radiographic response, but were not associated with survival outcomes. Patients with the HLA-DQB1*03:01 allele had significantly lower disease control rates than patients without the allele (17.4% vs. 53.8%, p = 0.002); its presence was also an independent risk factor for progressive disease (hazard ratio 4.35, 95% confidence interval 1.03-18.46). Furthermore, patients with the HLA-DQB1*03:01 allele had significantly worse progression-free survival than patients without the allele (median progression-free survival 3.1 vs. 4.8 months, p = 0.035). There was no significant relationship between any HLA status and the incidence of severe adverse events. Several germline HLA genotypes, especially HLA-DQB1*03:01, may be associated with radiographic progression. However, their impact on treatment response is limited, and germline HLA genotypes was not independently associated with survival outcomes. Further prospective studies are needed to confirm the relationship between germline HLA genotypes and clinical outcomes in patients with chemoresistant advanced UC treated with pembrolizumab.

IL12B rs6887695 polymorphism and interaction with alcohol intake in the risk of ulcerative colitis in Japan.

BACKGROUND: The interleukin (IL)-23/Th17 pathway plays a critical role in ulcerative colitis (UC). The IL-12p40 subunit, which is shared by IL-23 and IL-12, is encoded by the IL12B gene. The current case-control study investigated the association between IL12B SNP rs6887695 and the UC risk. METHODS: There were 384 cases within 4 years of UC diagnosis and 661 controls who were enrolled. Adjustments were made for sex, age, pack-years of smoking, alcohol consumption, history of appendicitis, family history of UC, education level, and body mass index. RESULTS: Subjects with the GG IL12B SNP rs6887695 genotype had a significantly increased risk of UC compared with those with the CC genotype (adjusted odds ratio [AOR], 1.60; 95% confidence interval [CI], 1.08-2.36). This positive association was also significant using the additive and recessive models (AOR, 1.25; 95% CI, 1.03-1.52; AOR, 1.50; 95% CI, 1.08-2.09, respectively). An independent inverse relationship was observed between ever alcohol consumption and the UC risk in those with the CC genotype while no significant association was found in those with at least one G allele (P for interaction = 0.0008). CONCLUSIONS: IL12B SNP rs6887695 was significantly associated with UC. The influence of alcohol consumption might rely on rs6887695.

Ibandronate Suppresses Changes in Apatite Orientation and Young's Modulus Caused by Estrogen Deficiency in Rat Vertebrae.

Bone material quality is important for evaluating the mechanical integrity of diseased and/or medically treated bones. However, compared to the knowledge accumulated regarding changes in bone mass, our understanding of the quality of bone material is lacking. In this study, we clarified the changes in bone material quality mainly characterized by the preferential orientation of the apatite c-axis associated with estrogen deficiency-induced osteoporosis, and their prevention using ibandronate (IBN), a nitrogen-containing bisphosphonate. IBN effectively prevented bone loss and degradation of whole bone strength in a dose-dependent manner. The estrogen-deficient condition abnormally increased the degree of apatite orientation along the craniocaudal axis in which principal stress is applied; IBN at higher doses played a role in maintaining the normal orientation of apatite but not at lower doses. The bone size-independent Young's modulus along the craniocaudal axis of the anterior cortical shell of the vertebra showed a significant and positive correlation with apatite orientation; therefore, the craniocaudal Young's modulus abnormally increased under estrogen-deficient conditions, despite a significant decrease in volumetric bone mineral density. However, the abnormal increase in craniocaudal Young's modulus did not compensate for the degradation of whole bone mechanical properties due to the bone loss. In conclusion, it was clarified that changes in the material quality, which are hidden in bone mass evaluation, occur with estrogen deficiency-induced osteoporosis and IBN treatment. Here, IBN was shown to be a beneficial drug that suppresses abnormal changes in bone mechanical integrity caused by estrogen deficiency at both the whole bone and material levels.

Sympathetic vasomotor outflow during low-intensity leg cycling in healthy older males.

NEW FINDINGS: What is the central question of this study? Sympathetic vasomotor outflow is reduced during low-intensity dynamic leg exercise in younger individuals: does ageing influence the sympathoinhibitory effect during low-intensity leg cycling? What is the main finding and its importance? Muscle sympathetic nerve activity during low-intensity cycling decreased in older males, as seen in young males. It is possible that cardiopulmonary baroreflex-mediated inhibition of sympathetic vasomotor outflow during dynamic leg exercise is preserved in healthy older males. ABSTRACT: Muscle sympathetic nerve activity (MSNA) is reduced during low-intensity dynamic leg exercise in young males. It is suggested that this inhibition is mediated by loading of the cardiopulmonary baroreceptors. The purpose of this study was to clarify the impact of age on MSNA during dynamic leg exercise. Nine younger males (YM, mean ± SD, 20 ± 1 years) and nine older males (OM, 72 ± 3 years) completed the study. The subjects performed two 4-min cycling exercises at 10% of their heart rate reserve using a cycle ergometer in a semirecumbent position (MSNA and estimated central venous pressure (eCVP) trials). MSNA was recorded via microneurography of the left radial nerve. The CVP was estimated based on peripheral venous pressure, which was monitored using a cannula in the right large antecubital vein. The magnitude of the increase in mean arterial blood pressure during leg cycling was larger in OM (+9.3 ± 5.5 mmHg) compared with YM (+2.8 ± 4.7 mmHg). MSNA burst frequency was decreased during cycling in both YM (-8.1 ± 3.8 bursts/min) and OM (-10.6 ± 3.3 bursts/min), but no significant difference was found between the two groups. The eCVP increased during exercise in both groups, and there was no difference in the changes in eCVP between YM (+1.1 ± 0.4 mmHg) and OM (+1.2 ± 0.7 mmHg). These data indicate that inhibition of sympathetic vasomotor outflow during low-intensity cycling appears in OM as seen in YM. It is possible that the muscle pump-induced loading of the cardiopulmonary baroreflex is preserved during cycling in healthy older males.