Transcription factor Zbtb1 interacts with bridging factor Lmo2 and maintains the T-lineage differentiation capacity of lymphoid progenitor cells.

Hematopoietic stem and progenitor cells can differentiate into all types of blood cells. Regulatory mechanisms underlying pluripotency in progenitors, such as the ability of lymphoid progenitor cells to differentiate into T-lineage, remain unclear. We have previously reported that LIM domain only 2 (Lmo2), a bridging factor in large transcriptional complexes, is essential to retain the ability of lymphoid progenitors to differentiate into T-lineage. However, biochemical characterization of Lmo2 protein complexes in physiological hematopoietic progenitors remains obscure. Here, we identified approximately 600 Lmo2-interacting molecules in a lymphoid progenitor cell line by two-step affinity purification with LC-MS/MS analysis. Zinc finger and BTB domain containing 1 (Zbtb1) and CBFA2/RUNX1 partner transcriptional corepressor 3 (Cbfa2t3) were found to be the functionally important binding partners of Lmo2. We determined CRISPR/Cas9-mediated acute disruption of Zbtb1 or Cbfa2t3 in the lymphoid progenitor or bone marrow-derived primary hematopoietic progenitor cells causes significant defects in the initiation of T-cell development when Notch signaling is activated. Our transcriptome analysis of Zbtb1- or Cbfa2t3-deficient lymphoid progenitors revealed that Tcf7 was a common target for both factors. Additionally, ChIP-seq analysis showed that Lmo2, Zbtb1, and Cbfa2t3 cobind to the Tcf7 upstream enhancer region, which is occupied by the Notch intracellular domain/RBPJ transcriptional complex after Notch stimulation, in lymphoid progenitors. Moreover, transduction with Tcf7 restored the defect in the T-lineage potential of Zbtb1-deficient lymphoid progenitors. Thus, in lymphoid progenitors, the Lmo2/Zbtb1/Cbfa2t3 complex directly binds to the Tcf7 locus and maintains responsiveness to the Notch-mediated inductive signaling to facilitate T-lineage differentiation.

Clinical significance of 123I-BMIPP washout rate in patients with uncertain chronic heart failure.

BACKGROUND: Recently, triglyceride deposit cardiomyovasculopathy (TGCV) with defective intracellular lipolysis was found to be a disease that causes heart failure. As a diagnostic criterion for TGCV, an Iodaine-123-ß-methyl iodophenyl-pentadecanoic acid washout rate (BMIPP WOR) of < 10% is used, but its clinical significance in patients with heart failure remains to be clarified. METHODS: In 62 hospitalized patients with chronic heart failure, 123I-BMIPP myocardial single-photon emission computed tomography (SPECT) was performed predischarge state. The prevalence of TGCV was investigated. Subsequently, follow-up was conducted for ≥ 90 days (mean: 724.6 ± 392.7 days), and the association between the BMIPP WOR and cardiac events was examined, establishing all-cause mortality and admission due to heart failure as endpoints. RESULTS: Of the 62 patients, the WOR was < 10% in 41 (66.1%). Of these, 26 (41.9%) were diagnosed with definite TGCV. Furthermore, cardiac events were noted in 12 patients (19.4%). Analysis with Cox proportional hazards models showed that the BMIPP WOR < 4.5% was a significant event-predicting factor [HR 4.29, 95% CI: 1.20-16.87; p = 0.0245]. On a Kaplan-Meier curve, the WOR was 4.5%; there was a significant difference in the incidence of events (p = 0.0298). CONCLUSION: In the predischarge state of heart failure, 123I-BMIPP myocardial SPECT was performed. In approximately 40% of the patients, a diagnosis of TGCV was made. The results suggested that the BMIPP WOR is useful for predicting the prognosis of chronic heart failure patients regardless of TGCV.

Notch signaling supports the appearance of follicular helper T cells in the Peyer's patches concomitantly with the reduction of regulatory T cells.

The intracellular fragment of Notch1, a mediator of Notch signaling that is frequently detected in thymic immigrants, is critical for specifying T-cell fate in the thymus, where Delta-like 4 (Dll4) functions as a Notch ligand on the epithelium. However, as such Notch signaling has not been detected in mature T cells, how Notch signaling contributes to their response in secondary lymphoid organs has not yet been fully defined. Here, we detected the marked expression of Dll4 on the stromal cells and the active fragment of Notch1 (Notch1 intracellular domain, N1ICD) in CD4+ T cells in the follicles of Peyer's patches (PPs). In addition, N1ICD-bearing T cells were found in the T-cell zone of PPs, especially in the transcription factor Foxp3+ regulatory T (Treg) cells, with slight expression of Dll4 on the stromal cells. These fragments disappeared in Dll4-deficient conditions. It was also found that Notch1- and Notch2-deficient T cells preferentially differentiated into Treg cells in PPs, but not CXCR5+PD-1+ follicular helper T (Tfh) cells. Moreover, these phenotypes were also observed in chimeric mice reconstituted with the control and T-cell-specific Notch1/2-deficient bone marrow or Treg cells. These results demonstrated that Dll4-mediated Notch signaling in PPs is required for the efficient appearance of Tfh cells in a Treg cell-prone environment, which is common among the gut-associated lymphoid tissues, and is critical for the generation of Tfh-mediated germinal center B cells.

A near-infrared fluorescent long-chain fatty acid toward optical imaging of cardiac metabolism in living mice.

Non-invasive fatty acid (FA) metabolic imaging is crucial for the evaluation of cardiac function in the heart. Currently, single-photon emission computed tomography (SPECT) and positron emission tomography (PET) are widely employed for cardiac metabolic imaging both in pre-clinical and clinical studies. Although SPECT and PET enable highly sensitive cardiac metabolic imaging, there are several disadvantages such as the high cost of instruments and radioactive tracer synthesis. In contrast, near-infrared (NIR) optical imaging using fluorescent FAs provides a simple and useful platform for in vivo imaging of cardiac metabolism. In this work, we synthesized a NIR fluorescence labelled long-chain fatty acid (LCFA) for real-time imaging of cardiac metabolism in vivo. A NIR fluorescence labelled LCFA was designed as an analogue of ß-methyl [123I] iodophenyl-pentanedecanoic acid (123I-BMIPP), which is widely used for the diagnosis of heart diseases in clinical practice. As a NIR fluorescent label, we used an Alexa 680 fluorophore that emits over 700 nm. By conjugation of Alexa 680 to Amino-BMPP (15-(4-(3-aminopropyl)phenyl)-3-methylpentadecanoic acid), we prepared a NIR fluorescent BMIPP analogue, Alexa680-BMPP. NIR fluorescence imaging showed that Alexa680-BMPP is taken up by the mouse heart tissue after intravenous injection, showing that Alexa680-BMPP can act as a fluorescent LCFA analogue. Among Alexa680 conjugated FA analogues including short and middle chain NIR fluorescent FAs, Alexa680-BMPP was most efficiently taken up by heart tissues. For fasted and fed mice, the difference in the degree of the uptake of Alexa680-BMPP in their heart tissues was clearly observed by in vivo and ex vivo NIR fluorescence imaging. Herein, we present the synthesis of a NIR fluorescent LCFA, Alexa680-BMPP, and its capability for real-time optical imaging of cardiac metabolism in living mice.

Usefulness of rapid MR angiography using two-point Dixon for evaluating carotid and aortic plaques.

PURPOSE: Recently, various magnetic resonance imaging (MRI) modalities have been developed to easily detect carotid and aortic plaques, but these techniques are time-consuming and vulnerable to motion artifacts. We investigated the utility of a gradient echo MRI technique known as liver acquisition with volume acceleration flexible (LAVA-Flex) to detect carotid and aortic atherosclerotic plaques. METHODS: Ten patients who underwent carotid endarterectomy (CEA) were assessed regarding the correspondence between LAVA-Flex findings and the histopathology of excised carotid plaques. In addition, 47 patients with cryptogenic ischemic stroke underwent LAVA-Flex and transesophageal echocardiography (TEE) for detection of embolic sources in the thoracic aorta. We analyzed the relationship between the thickness of the aortic plaque measured by TEE and the presence of high-intensity lesions on LAVA-Flex. RESULTS: Nine of 10 patients (90.0%) who underwent CEA showed a high-intensity carotid lesion on LAVA-Flex, which corresponded pathologically to plaques containing large lipid cores and hemorrhage. Twenty-four (51.1%) of 47 cryptogenic stroke patients showed a high-intensity lesion in the thoracic aorta on LAVA-Flex; of these, 21 (87.5%) also demonstrated a large plaque (thickness ≥4 mm) on TEE. Twenty-two (95.7%) of 23 patients without a high-intensity lesion on LAVA-Flex demonstrated no large plaque on TEE. LAVA-Flex had a sensitivity of 95.5% and a specificity of 88.0% in patients with large plaques. CONCLUSION: This study showed that LAVA-Flex successfully detected carotid and aortic plaques. This imaging technique may be useful to rapidly diagnose and evaluate carotid and aortic plaques, which are critical risk factors for aortogenic stroke.

Targeting of plasminogen activator inhibitor-1 activity promotes elimination of chronic myeloid leukemia stem cells.

Therapeutic strategies that target leukemic stem cells (LSCs) provide potential advantages in the treatment of chronic myeloid leukemia (CML). Here, we show that selective blockade of plasminogen activator inhibitor-1 (PAI-1) enhances the susceptibility of CML-LSCs to tyrosine kinase inhibitor (TKI), which facilitates the eradication of CML-LSCs and leads to sustained remission of the disease. We demonstrated for the first time that TGF-ß-PAI-1 axis was selectively augmented in CML-LSCs in the bone marrow (BM), whereby protecting CML-LSCs from TKI treatment. Furthermore, the combined administration of TKI plus a PAI-1 inhibitor, in a mouse model of CML, significantly enhanced the eradication of CML cells in the BM and prolonged the survival of CML mice. The combined therapy of imatinib and a PAI-1 inhibitor prevented the recurrence of CML-like disease in serially transplanted recipients, indicating the elimination of CML-LSCs. Interestingly, PAI-1 inhibitor treatment augmented membrane-type matrix metalloprotease-1 (MT1-MMP)-dependent motility of CML-LSCs, and the anti-CML effect of PAI-1 inhibitor was extinguished by the neutralizing antibody for MT1-MMP, underlining the mechanistic importance of MT1-MMP. Our findings provide evidence of, and a rationale for, a novel therapeutic tactic, based on the blockade of PAI-1 activity, for CML patients.

Aortic insufficiency associated with Impella that required surgical intervention upon implantation of the durable left ventricular assist device.

The Impella is an axial-flow percutaneous ventricular assist device for cardiogenic shock. In this report, we describe two patients who developed aortic insufficiency (AI) associated with Impella and required surgical intervention upon implantation of the durable left ventricular assist device (LVAD). Both patients presented with cardiogenic shock and underwent insertion of Impella 5.0 as a bridge to decision. The cardiac function in these patients did not improve and obtaining approval for heart transplantation required time. They were managed with Impella for 91 and 98 days, respectively. In both cases, moderate AI that was not present before Impella insertion was observed when the Impella was removed. Therefore, we performed aortic valve closure to control the AI during durable LVAD implantation. In patients with durable LVAD implantation, AI may occur and progress after the operation in several cases. Aortic valve surgery is often performed to prevent deterioration of AI, especially in patients with AI before the surgery. Hence, AI is an important complication following Impella device implantation as a bridge to decision. Careful observation of AI is essential when the Impella is removed as the evaluation of AI by echocardiogram during Impella management is cumbersome because of device-generated artifacts.

Reference values for the locomotive syndrome risk test quantifying mobility of 8681 adults aged 20-89 years: A cross-sectional nationwide study in Japan.

BACKGROUND: The locomotive syndrome risk test was developed to quantify the decrease in mobility among adults, which could eventually lead to disability. The purpose of this study was to establish reference values for the locomotive syndrome risk test for adults and investigate the influence of age and sex. METHODS: We analyzed 8681 independent community dwellers (3607 men, 5074 women). Data pertaining to locomotive syndrome risk test (the two-step test, the stand-up test, and the 25-question geriatric locomotive function scale [GLFS-25]) scores were collected from seven administrative areas of Japan. RESULTS: The reference values of the three test scores were generated and all three test scores gradually decreased among young-to-middle-aged individuals and rapidly decreased in individuals aged over 60 years. The stand-up test score began decreasing significantly from the age of 30 years. The trajectories of decrease in the two-step test score with age was slightly different between men and women especially among the middle-aged individuals. The two physical test scores were more sensitive to aging than the self-reported test score. CONCLUSION: The reference values generated in this study could be employed to determine whether an individual has mobility comparable to independent community dwellers of the same age and sex.

Newly developed selective immunoinactivation assay revealed reduction in adipose triglyceride lipase activity in peripheral leucocytes from patients with idiopathic triglyceride deposit cardiomyovasculopathy.

Triglyceride deposit cardiomyovasculopathy (TGCV) is a rare and newly identified disease among patients requiring cardiac transplantation. TGCV is characterized by cardiomyocyte steatosis and triglyceride (TG)-deposit atherosclerosis, resulting from the abnormal intracellular metabolism of TG. TGCV is classified into primary and idiopathic types. Primary TGCV carries ultra-rare genetic mutations in the adipose triglyceride lipase (ATGL), a rate-liming enzyme that hydrolyzes intracellular TG in adipose and non-adipose tissues. Idiopathic TGCV, first identified among autopsied individuals with diabetes mellitus (DM) with severe heart diseases, shows no ATGL mutations and its causes and underlying mechanisms are still unknown. TGCV is difficult to diagnose in daily clinics, thereby demanding feasible diagnostic procedures. We aimed to develop an assay to measure ATGL activity using peripheral leucocytes. Human his6-ATGL was expressed in COS1 cells, purified to homogeneity, and used to raise a polyclonal antibody neutralizing TG-hydrolyzing activity of ATGL. We developed a selective immunoinactivation assay (SIIA) for the quantitation of ATGL activity in cell lysates of leucocytes by the antibody neutralizing ATGL activities. ATGL activity was measured in 13 idiopathic TGCV patients, with two patients with primary TGCV as the negative control. Healthy (non-DM) and DM controls without heart diseases were also subjected. The developed SIIA assay revealed significant reduction in ATGL activity in leucocytes from patients with idiopathic TGCV who did not carry ATGL mutations as compared with non-DM and DM controls. Thus, ATGL in leucocytes may be an important biomarker for the diagnosis of TGCV and our assay may provide insights into pathophysiology and elucidate the underlying mechanism of TGCV and related disorders.

Effect of lipid metabolism on male fertility.

Cholesterol and lipid homeostasis is important for male fecundity. However, the plasma total cholesterol level does not reflect sperm concentration and motility. Adipose tissue in mammals is the main tissue contributing to the dynamic equilibrium of lipid synthesis and catabolism. However, recent studies suggested that local lipolysis has an important role in male fertility. If so, which plasma lipid metabolism parameter reflects sperm concentration and motility? Leptin receptor-deficient db/db mice show hyperphagia, hyperglycemia, hypercholesterolemia, hypertriglyceridemia, morbid obesity and are reported to be infertile. Impairment of spermatogenesis and sperm motility in db/db mice was observed in our experiments. Medium-chain triglycerides (MCTs) are more quickly metabolized as fuel compared to long-chain triglycerides (LCTs). If the LCTs are replaced with MCTs in the diet, even in hyperphagia, does it affect spermatogenesis and sperm motility? In this study, we investigated the effect of a MCT replacement diet on sperm parameters using db/db mice. Six weeks of MCT replacement diet improved not only spermatogenesis but also the maturation processes in the epididymis for sperm to acquire the ability to move forward. Plasma chylomicron and large VLDL levels showed positive correlation with total and motile sperm concentrations. The MCT replacement diet could be an effective treatment for idiopathic non-obstructive oligozoospermia or asthenozoospermia men with low levels of chylomicron and large VLDL.

Long-chain fatty acid triglyceride (TG) metabolism disorder impairs male fertility: a study using adipose triglyceride lipase deficient mice.

STUDY QUESTION: Does the deletion of adipose triglyceride lipase (Atgl) gene impair male fertility? SUMMARY ANSWER: The deletion of Atgl gene impaired male fertility but the effect was partially reversed by a low long-chain triglyceride (TG) diet. WHAT IS KNOWN ALREADY: ATGL specifically hydrolyses long-chain fatty acid TG to diacylglycerol and a high level of expression of ATGL in testes has been reported. However, the role of ATGL in male fertility is unknown. STUDY DESIGN, SIZE, DURATION: To investigate the effect of deletion of Atgl gene on male fertility, cauda epididymides and testes were collected from wild-type, heterozygous and homozygous Atgl-deficient mice at 10 weeks of age and epididymal sperm analysis and histological analysis of the testes were performed. To investigate whether a medium-chain triglycerides (MCTs) replacement diet mitigated the impaired male fertility by deletion of Atgl gene, homozygous Atgl-deficient mice were fed a MCT replacement diet, or a standard diet including long-chain triglycerides (LCTs) in a control group, for 6 weeks from 5 weeks of age (n = 22). The systematic and local effects of the MCT replacement diet on spermatogenesis and sperm maturation in the epididymis were analyzed at 10 weeks of age. PARTICIPANTS/MATERIALS, SETTING, METHODS: Hematoxylin and eosin staining in paraffin-embedded sections of testes and Oil Red O staining in frozen sections of testes were performed. The epididymal sperm concentrations were analyzed. Statistical analyses were performed using the Student's t-test or Mann-Whitney U test with Shapiro-Wilk Normality test. MAIN RESULTS AND THE ROLE OF CHANCE: Although heterozygous mice were fertile and showed a similar number of epididymal total and motile sperm concentrations to wild-type mice, the deletion of Atgl gene in homozygous mice led to accumulation of TG deposits in testes and impaired spermatogenesis. The deletion of Atgl gene also impaired the sperm maturation process required for sperm to acquire the ability to move forward in the epididymis. The MCT replacement diet for 6 weeks increased the plasma level of non-esterified fatty acid (NEFA) (1.5-fold, P = 0.005), but not the plasma total cholesterol (T-Cho) and TG levels. In testes, the MCT replacement diet decreased the number of Oil Red O stain positive vacuoles (-40%, P < 0.001) and increased testis tissue weight (1.1-fold, P = 0.012), total sperm concentration (1.5-fold, P = 0.011) and motile sperm concentration (2.1-fold, P < 0.001) compared to the control group. However, there was no significant change in the sperm survival rate between the two groups. LARGE SCALE DATA: None. LIMITATIONS REASONS FOR CAUTION: One previous study reported that Atgl-deficient male mice were fertile. In most studies heterozygous Atgl(+/-) mice were used to generate homozygous Atgl-deficient Atgl(-/-) mice. Although the same gene targeting mice were used in this study and the formation of vaginal plugs were observed after mating with Atgl(-/-) male mice, there were no pregnant wild-type mice observed after mating with Atgl(-/-) male mice. WIDER IMPLICATIONS OF THE FINDINGS: Local TG metabolism in the male reproductive system could affect spermatogenesis and sperm motility in men. The MCT replacement diet could be an effective therapy for idiopathic non-obstructive oligozoospermia or asthenozoospermia in men with low levels of serum NEFA. STUDY FUNDING AND COMPETING INTEREST(S): This study was supported in part by the Japan Society for the Promotion of Science JSPS KAKENHI Grant (Nos. JP24249080, JP25462557, JP16K11086). The authors declare no conflict of interest.

Comparison between a novel and conventional artificial pancreas for perioperative glycemic control using a closed-loop system.

This clinical study aimed to compare a novel and conventional artificial pancreas (AP) used in surgical patients for perioperative glycemic control, with respect to usability, blood glucose measurements, and glycemic control characteristics. From July in 2010 to March in 2015, 177 patients underwent perioperative glycemic control using a novel AP. Among them, 166 patients were eligible for inclusion in this study. Intensive insulin therapy (IIT) targeting a blood glucose range of 80-110 mg/dL was implemented in 82 patients (49 %), and the remaining 84 patients (51 %) received a less-intensive regime of insulin therapy. Data were collected prospectively and were reviewed or analyzed retrospectively. A comparison study of 324 patients undergoing IIT for glycemic control using a novel (n = 82) or conventional AP (n = 242) was conducted retrospectively. All patients had no hypoglycemia. The comparison study revealed no significant differences in perioperative mean blood glucose level, achievement rates for target blood glucose range, and variability in blood glucose level achieved with IIT between the novel AP and conventional AP groups. The usability, performance with respect to blood glucose measurement, and glycemic control characteristics of IIT were comparable between novel and conventional AP systems. However, the novel AP was easier to manipulate than the conventional AP due to its smaller size, lower weight, and shorter time for preparation. In the near future, this novel AP system might be accepted worldwide as a safe and useful device for use in perioperative glycemic control.

Hepatic aberrant glycosylation by N-acetylglucosaminyltransferase V accelerates HDL assembly.

Glycosylation is involved in various pathophysiological conditions. N-Acetylglucosaminyltransferase V (GnT-V), catalyzing ß1-6 branching in asparagine-linked oligosaccharides, is one of the most important glycosyltransferases involved in cancer and the immune system. Recent findings indicate that aberrant N-glycan structure can modify lipid metabolism. In this study, we investigated the effects of aberrant glycosylation by GnT-V on high-density lipoprotein cholesterol (HDL) assembly. We used GnT-V transgenic (Tg) mice and GnT-V Hep3B cell (human hepatoma cell line) transfectants. The study also included 96 patients who underwent medical health check-ups. Total serum cholesterol levels, particularly HDL-cholesterol (HDL-C) levels, were significantly increased in Tg vs. wild-type (WT) mice. Hepatic expression of apolipoprotein AI (ApoAI) and ATP-binding cassette subfamily A member 1 (ABCA1), two important factors in HDL assembly, were higher in Tg mice compared with WT mice. ApoAI and ABCA1 were also significantly elevated in GnT-V transfectants compared with mock-transfected cells. Moreover, ApoAI protein in the cultured media of GnT-V transfectants was significantly increased. Finally, we found a strong correlation between serum GnT-V activity and HDL-C concentration in human subjects. Multivariate logistic analyses demonstrated that GnT-V activity was an independent and significant determinant for serum HDL-C levels even adjusted with age and gender differences. Further analyses represented that serum GnT-V activity had strong correlation especially with the large-size HDL particle concentration. These findings indicate that enhanced hepatic GnT-V activity accelerated HDL assembly and could be a novel mechanism for HDL synthesis.

Delta-like 4-mediated Notch signaling is required for early T-cell development in a three-dimensional thymic structure.

Delta-like 4 (Dll4)-mediated Notch signaling is critical for specifying T-cell fate, but how Dll4-mediated Notch signaling actually contributes to T-cell development in the thymus remains unclear. To explore this mechanism in the thymic three-dimensional structure, we performed fetal thymus organ culture using Dll4-deficient mice. DN1a/b+DN2mt cells, which had not yet committed to either the αß T or γδ T/NK cell lineage, did not differentiate into the αß T-cell lineage in Dll4-deficient thymus despite the lack of cell fate conversion into other lineages. However, DN3 cells efficiently differentiated into a later developmental stage of αß T cells, the double-positive (DP) stage, although the proliferation was significantly impaired during the differentiation process. These findings suggest that the requirement for Notch signaling differs between the earliest and pre-TCR-bearing precursors and that continued Notch signaling is required for proper differentiation with active proliferation of αß T lineage cells. Furthermore, we showed that Notch signaling increased the c-Myc expression in DN3 cells in the thymus and that its overexpression rescued the proliferation and differentiation of DN3 cells in the Dll4-null thymus. Therefore, c-Myc plays a central role in the transition from stage DN3 to DP as a downstream target of Notch signaling.

Spinal sagittal balance substantially influences locomotive syndrome and physical performance in community-living middle-aged and elderly women.

OBJECTIVES: Spinal sagittal imbalance has been well known risk factor of decreased quality of life in the field of adult spinal deformity. However, the impact of spinal sagittal balance on locomotive syndrome and physical performance in community-living elderly has not yet been clarified. The present study investigated the influence of spinal sagittal alignment on locomotive syndrome (LS) and physical performance in community-living middle-aged and elderly women. METHODS: A total of 125 women between the age of 40-88 years (mean 66.2 ± 9.7 years) who completed the questionnaires, spinal mouse test, physical examination and physical performance tests in Yakumo study were enrolled in this study. Participants answered the 25-Question Geriatric Locomotive Function Scale (GLFS-25), the visual analog scale (VAS) for low back pain (LBP), knee pain. LS was defined as having a score of >16 points on the GLFS-25. Using spinal mouse, spinal inclination angle (SIA), thoracic kyphosis angle (TKA), lumbar lordosis angle (LLA), sacral slope angle (SSA), thoracic spinal range of motion (TSROM), lumbar spinal range of motion (LSROM) were measured. Timed-up-and-go test (TUG), one-leg standing time with eyes open (OLS), and maximum stride, back muscle strength were also measured. The relationship between spinal sagittal parameters and GLFS-25, VAS and physical performance tests were analyzed. RESULTS: 26 people were diagnosed as LS and 99 were diagnosed as non-LS. LBP and knee pain were greater, physical performance tests were poorer, SIA were greater, LLA were smaller in LS group compared to non-LS group even after adjustment by age. SIA significantly correlated with GLFS-25, TUG, OLS and maximum stride even after adjustment by age. The cutoff value of SIA for locomotive syndrome was 6°. People with a SIA of 6° or greater were grouped as "Inclined" and people with a SIA of less than 6° were grouped as "Non-inclined". 21 people were "Inclined" and 104 were "Non-inclined". Odds ratio to fall in LS of Inclined group compared to Non-inclined group is 5.0. GLFS-25 were significantly higher, VAS for LBP were greater, TUG, OLS and maximum stride were poorer in Inclined group compared to Non-inclined group even after adjustment by age. CONCLUSIONS: The present study demonstrated that spinal sagittal balance influences the LS and physical performance in community-living middle-aged and elderly women. SIA is a useful spinal parameter to evaluate the risk of LS, and its cutoff value is 6°.

Anti-fibrotic effects of a novel small compound on the regulation of cytokine production in a mouse model of colorectal fibrosis.

Intestinal fibrotic stricture is a major complication of inflammatory bowel disease. Despite its clinical importance, anti-fibrotic therapy has not been implemented. Transforming growth factor-ß (TGF-ß) is considered to be a major factor contributing to tissue fibrosis. We have previously shown that the administration of a small compound, HSc025, which promotes the nuclear translocation of YB-1 as a downstream effector of IFN-γ and antagonizes TGF-ß/Smad signaling, improves fibrosis in several murine tissues. In this study, we evaluated the anti-fibrotic effect of HSc025 on colorectal fibrosis in TNBS-induced murine chronic colitis. Daily oral administration of HSc025 (3, 15 and 75 mg/kg) suppressed collagen production and decreased the severity of colorectal fibrosis in a dose-dependent manner. In addition, the local production of TGF-ß was decreased after HSc025 treatment, whereas that of IL-13 and TNF-α was not affected. HSc025 administration maintained the level of IFN-γ production, even at a late stage when IFN-γ production was lost without the drug treatment. These results demonstrate that HSc025 could be a therapeutic candidate for intestinal fibrosis in inflammatory bowel disease that acts by altering the local production of cytokines, as well as by directly suppressing collagen production.

Surgically treated cases of lumbar spondylolysis and isthmic spondylolisthesis: a multicenter study.

STUDY DESIGN: Prospective database study. OBJECTIVES: To grasp the characteristics of surgically treated cases with lumbar spondylolysis or isthmic spondylolisthesis. SUMMARY OF BACKGROUND DATA: A detailed analysis of surgically treated cases with spondylolysis or isthmic spondylolisthesis has never been reported. An epidemiological study in Japan conducted on 2000 subjects found the incidence of lumbar spondylolysis in the Japanese general population (population-based study) to be 5.9% (males: 7.9%, females: 3.9%). Among 124 vertebrae with spondylolysis, there were 0.8% L2 lesions, 3.2% L3 lesions, 5.6% L4 lesions, and 90.3% L5 lesions, including 5 cases (4.3%) with multiple-level lesions. METHODS: We have been registering surgically treated spine cases in our database since 2000. From this database, we prospectively collected cases with lumbar spondylolysis or isthmic spondylolisthesis that were treated surgically between January 2000 and December 2009. We determined the age at surgery, sex, and vertebral level of spondylolysis. RESULTS: Of the 564 spondylolysis patients treated surgically, 66.8% were male and 33.2% were female. The mean age at surgery was 52.5 years (range, 13-84 y). There were 585 vertebrae with spondylolysis including 21 cases (3.7%) with multiple-level lesions. L5 spondylolysis affected 432 vertebrae and was the most common location (73.8%), followed by 125 L4 lesions (21.4%), 24 L3 lesions (4.1%), and 2 L2 lesions (0.7%). CONCLUSIONS: The percentage of L4 lesions in our study was significantly higher and of L5 lesions was significantly lower than those lesions' percentages in the population-based study. L4 spondylolysis may be more unstable or cause clinical symptoms more frequently leading to more surgical intervention. The percentage of multiple-level spondylolysis was similar between the 2 studies, suggesting these patients respond relatively well to conservative treatment. The male/female ratio was 2:1 in both studies, indicating that males and females require surgery at a similar frequency.

Appropriate timing of surgical intervention for the proximal type of cervical spondylotic amyotrophy.

PURPOSE: The purposes of this study were to evaluate the clinical outcome after surgical treatment of patients with the proximal type of cervical spondylotic amyotrophy (CSA) and to explore the appropriate timing for surgical intervention. MATERIALS AND METHODS: A retrospective review was performed on a consecutive cohort of 41 patients who underwent surgical treatment for the proximal type of CSA between 1995 and 2011 at the Nagoya Spine Group Hospitals. We collected information regarding age, type of muscle atrophy, preoperative and final manual muscle test, duration of symptoms, high-intensity areas on T2-weighted MRI images, low-intensity areas on T1-weighted MRI images, levels of spinal canal stenosis, the compression lesion site, cervical kyphosis and surgical procedures (laminoplasty, anterior spinal fusion and posterior spinal fusion). Univariate analyses and multivariate logistic regression analysis were performed to identify correlates of a poor outcome. To explore the appropriate timing for performing surgery, we analyzed the data using receiver operating characteristic (ROC) analysis. RESULTS: The duration of CSA symptoms was 11.6 months on average. The surgical results were excellent for 25 patients, good for six, fair for nine and poor for one. On multivariate logistic regression analysis, the duration of symptoms was statistically associated with a poor surgical outcome (OR 1.393, p = 0.011). ROC analysis demonstrated that 4.3 months from the onset of CSA symptoms was the appropriate time to undergo surgery. CONCLUSIONS: Our results indicate that we should recommend surgical intervention to patients with the proximal type of CSA within about 4 months after the onset of symptoms if conservative treatment has not been successful.