Preliminary results of stabilization of far distal tibia fractures with the distal tibial nail: A prospective, multicenter case series study.

INTRODUCTION: The distal tibial nail (DTN) is a novel retrograde intramedullary nail used for distal tibial fracture stabilization. We investigated the clinical results of DTN use for distal tibial fractures and compared them with those reported in the literature on locking plates and antegrade intramedullary nails. MATERIALS AND METHODS: This multicenter, prospective, observational cohort study examined distal tibial fractures with AO/OTA classification 43 types: A1, A2, A3 or C1. The primary outcomes included bone union rate, soft tissue problems, and surgical complications. Secondary outcomes were EuroQol-5 Dimension-5 Level (EQ-5D-5L), Self-Administered Foot Evaluation Questionnaire (SAFE-Q), and American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot clinical scores 1 year postoperatively. Incidence of varus or valgus/anterior-posterior flexion deformity with a difference of ≥5° and postoperative reduction loss rate were evaluated. RESULTS: Five men and five women were enrolled (mean age, 69 years [range, 30-77 years]), including one open-fracture-type Gustilo type IIIB case. Bone union was observed in all patients at 6 months postoperatively. Delayed union, leg edema, and guide pin breakage were observed in three, one, and one cases, respectively. No soft tissue or surgical complications were observed. During the final follow-up, the EQ-5D-5L, SAFE-Q, and AOFAS hindfoot scores were 0.876 (0.665-1.0), 83-92, and AOFAS 92.6 (76-100), respectively. Varus and retroflexion deformities were observed in one case each. DISCUSSION: DTN has been reported to have biomechanically equivalent or stronger fixation strength than locking plates or antegrade intramedullary nails. In addition, while DTN was thought to be less invasive for soft tissue and can avoid injury to the knee, it was thought that care should be taken to avoid medial malleolus fractures and posterior tibialis tendon injuries. Comparisons with literature treatment results for locking plates and antegrade intramedullary nails showed comparable to advantageous results. CONCLUSIONS: DTN treatment results for distal tibial fractures were as good as those for locking plates and antegrade intramedullary nails. DTN is useful for stabilization and does not compromise the surrounding soft tissues.

Publisher Correction: Malaria predictions based on seasonal climate forecasts in South Africa: A time series distributed lag nonlinear model.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Malaria predictions based on seasonal climate forecasts in South Africa: A time series distributed lag nonlinear model.

Although there have been enormous demands and efforts to develop an early warning system for malaria, no sustainable system has remained. Well-organized malaria surveillance and high-quality climate forecasts are required to sustain a malaria early warning system in conjunction with an effective malaria prediction model. We aimed to develop a weather-based malaria prediction model using a weekly time-series data including temperature, precipitation, and malaria cases from 1998 to 2015 in Vhembe, Limpopo, South Africa and apply it to seasonal climate forecasts. The malaria prediction model performed well for short-term predictions (correlation coefficient, r > 0.8 for 1- and 2-week ahead forecasts). The prediction accuracy decreased as the lead time increased but retained fairly good performance (r > 0.7) up to the 16-week ahead prediction. The demonstration of the malaria prediction process based on the seasonal climate forecasts showed the short-term predictions coincided closely with the observed malaria cases. The weather-based malaria prediction model we developed could be applicable in practice together with skillful seasonal climate forecasts and existing malaria surveillance data. Establishing an automated operating system based on real-time data inputs will be beneficial for the malaria early warning system, and can be an instructive example for other malaria-endemic areas.

Identification of U11snRNA as an endogenous agonist of TLR7-mediated immune pathogenesis.

The activation of innate immune receptors by pathogen-associated molecular patterns (PAMPs) is central to host defense against infections. On the other hand, these receptors are also activated by immunogenic damage-associated molecular patterns (DAMPs), typically released from dying cells, and the activation can evoke chronic inflammatory or autoimmune disorders. One of the best known receptors involved in the immune pathogenesis is Toll-like receptor 7 (TLR7), which recognizes RNA with single-stranded structure. However, the causative DAMP RNA(s) in the pathogenesis has yet to be identified. Here, we first developed a chemical compound, termed KN69, that suppresses autoimmunity in several established mouse models. A subsequent search for KN69-binding partners led to the identification of U11 small nuclear RNA (U11snRNA) as a candidate DAMP RNA involved in TLR7-induced autoimmunity. We then showed that U11snRNA robustly activated the TLR7 pathway in vitro and induced arthritis disease in vivo. We also found a correlation between high serum level of U11snRNA and autoimmune diseases in human subjects and established mouse models. Finally, by revealing the structural basis for U11snRNA's ability to activate TLR7, we developed more potent TLR7 agonists and TLR7 antagonists, which may offer new therapeutic approaches for autoimmunity or other immune-driven diseases. Thus, our study has revealed a hitherto unknown immune function of U11snRNA, providing insight into TLR7-mediated autoimmunity and its potential for further therapeutic applications.

Improving seasonal forecasts of air temperature using a genetic algorithm.

Seasonal forecasts of air-temperature generated by numerical models provide guidance to the planners and to the society as a whole. However, generating accurate seasonal forecasts is challenging mainly due to the stochastic nature of the atmospheric internal variability. Therefore, an array of ensemble members is often used to capture the prediction signals. With large spread in the prediction plumes, it becomes important to employ techniques to reduce the effects of unrealistic members. One such technique is to create a weighted average of the ensemble members of seasonal forecasts. In this study, we applied a machine learning technique, viz. a genetic algorithm, to derive optimum weights for the 24-ensemble members of the coupled general circulation model; the Scale Interaction Experiment-Frontier research center for global change version 2 (SINTEX-F2) boreal summer forecasts. Our analysis showed the technique to have significantly improved the 2m-air temperature anomalies over several regions of South America, North America, Australia and Russia compared to the unweighted ensemble mean. The spatial distribution of air temperature anomalies is improved by the GA technique leading to better representation of anomalies in the predictions. Hence, machine learning techniques could help in improving the regional air temperature forecasts over the mid- and high-latitude regions where the model skills are relatively modest.

Role of sea-ice initialization in climate predictability over the Weddell Sea.

Potential impact of sea-ice initialization on the interannual climate predictability over the Weddell Sea is investigated using a coupled general circulation model. Climate variability in the Weddell Sea is generally believed to have association with remote forcing such as El Niño-Southern Oscillation and the Southern Annual Mode. However, sea-ice variability in the Weddell Sea has been recently suggested to play additional roles in modulating local atmospheric variability through changes in surface air temperature and near-surface baroclinicity. Reforecast experiments from September 1st, in which the model's sea-surface temperature (SST) and sea-ice concentration (SIC) are initialized with observations using nudging schemes, show improvements in predicting the observed SIC anomalies in the Weddell Sea up to four months ahead, compared to the other experiments in which only the model's SST is initialized. During austral spring (Oct-Dec) of lower-than-normal sea-ice years in the Weddell Sea, reforecast experiments with the SST and SIC initializations reasonably predict high surface air temperature anomalies in the Weddell Sea and high sea-level pressure anomalies over the Atlantic sector of the Southern Ocean. These results suggest that accurate initialization of sea-ice conditions during austral winter is necessary for skillful prediction of climate variability over the Weddell Sea during austral spring.

Role of subsurface ocean in decadal climate predictability over the South Atlantic.

Decadal climate predictability in the South Atlantic is explored by performing reforecast experiments using a coupled general circulation model with two initialization schemes; one is assimilated with observed sea surface temperature (SST) only, and the other is additionally assimilated with observed subsurface ocean temperature and salinity. The South Atlantic is known to undergo decadal variability exhibiting a meridional dipole of SST anomalies through variations in the subtropical high and ocean heat transport. Decadal reforecast experiments in which only the model SST is initialized with the observation do not predict well the observed decadal SST variability in the South Atlantic, while the other experiments in which the model SST and subsurface ocean are initialized with the observation skillfully predict the observed decadal SST variability, particularly in the Southeast Atlantic. In-depth analysis of upper-ocean heat content reveals that a significant improvement of zonal heat transport in the Southeast Atlantic leads to skillful prediction of decadal SST variability there. These results demonstrate potential roles of subsurface ocean assimilation in the skillful prediction of decadal climate variability over the South Atlantic.

Decadal climate predictability in the southern Indian Ocean captured by SINTEX-F using a simple SST-nudging scheme.

Decadal climate variability in the southern Indian Ocean has great influences on southern African climate through modulation of atmospheric circulation. Although many efforts have been made to understanding physical mechanisms, predictability of the decadal climate variability, in particular, the internally generated variability independent from external atmospheric forcing, remains poorly understood. This study investigates predictability of the decadal climate variability in the southern Indian Ocean using a coupled general circulation model, called SINTEX-F. The ensemble members of the decadal reforecast experiments were initialized with a simple sea surface temperature (SST) nudging scheme. The observed positive and negative peaks during late 1990s and late 2000s are well reproduced in the reforecast experiments initiated from 1994 and 1999, respectively. The experiments initiated from 1994 successfully capture warm SST and high sea level pressure anomalies propagating from the South Atlantic to the southern Indian Ocean. Also, the other experiments initiated from 1999 skillfully predict phase change from a positive to negative peak. These results suggest that the SST-nudging initialization has the essence to capture the predictability of the internally generated decadal climate variability in the southern Indian Ocean.

Involvement of Irreversible Vacuolar Membrane Fragmentation in the Lethality of Food Emulsifier Diglycerol Monolaurate against Budding Yeast.

Diglycerol monolaurate (DGL) has been manufactured as a novel type of food emulsifier and is being considered for further application as a food preservative. DGL lethality was thus examined against Saccharomyces cerevisiae as a model of a yeast that causes food spoilage. In spite of its molecular structure as a nonionic surfactant, DGL could exhibit lethality at a concentration lower than that which caused disruptive damage to the yeast plasma membrane. DGL lethality was rather accompanied by a dynamic intracellular event such as a marked vacuolar membrane fragmentation. In DGL-treated cells, the tiny dots or particles of fragmented vacuolar membranes failed to fuse into the original large rounded architecture after its removal from medium, which were distinguished from those generated as a result of vacuolar fission normally accelerated under hyperosmotic conditions. Such an irreversible structural damage of the organelle membrane was considered a cause of DGL lethality.

Direct evidence for pitavastatin induced chromatin structure change in the KLF4 gene in endothelial cells.

Statins exert atheroprotective effects through the induction of specific transcriptional factors in multiple organs. In endothelial cells, statin-dependent atheroprotective gene up-regulation is mediated by Kruppel-like factor (KLF) family transcription factors. To dissect the mechanism of gene regulation, we sought to determine molecular targets by performing microarray analyses of human umbilical vein endothelial cells (HUVECs) treated with pitavastatin, and KLF4 was determined to be the most highly induced gene. In addition, it was revealed that the atheroprotective genes induced with pitavastatin, such as nitric oxide synthase 3 (NOS3) and thrombomodulin (THBD), were suppressed by KLF4 knockdown. Myocyte enhancer factor-2 (MEF2) family activation is reported to be involved in pitavastatin-dependent KLF4 induction. We focused on MEF2C among the MEF2 family members and identified a novel functional MEF2C binding site 148 kb upstream of the KLF4 gene by chromatin immunoprecipitation along with deep sequencing (ChIP-seq) followed by luciferase assay. By applying whole genome and quantitative chromatin conformation analysis {chromatin interaction analysis with paired end tag sequencing (ChIA-PET), and real time chromosome conformation capture (3C) assay}, we observed that the MEF2C-bound enhancer and transcription start site (TSS) of KLF4 came into closer spatial proximity by pitavastatin treatment. 3D-Fluorescence in situ hybridization (FISH) imaging supported the conformational change in individual cells. Taken together, dynamic chromatin conformation change was shown to mediate pitavastatin-responsive gene induction in endothelial cells.

Predictability of the Ningaloo Niño/Niña.

The seasonal prediction of the coastal oceanic warm event off West Australia, recently named the Ningaloo Niño, is explored by use of a state-of-the-art ocean-atmosphere coupled general circulation model. The Ningaloo Niño/Niña, which generally matures in austral summer, is found to be predictable two seasons ahead. In particular, the unprecedented extreme warm event in February 2011 was successfully predicted 9 months in advance. The successful prediction of the Ningaloo Niño is mainly due to the high prediction skill of La Niña in the Pacific. However, the model deficiency to underestimate its early evolution and peak amplitude needs to be improved. Since the Ningaloo Niño/Niña has potential impacts on regional societies and industries through extreme events, the present success of its prediction may encourage development of its early warning system.

[Strategy for the treatment of Stage IV gastric cancer with preoperative chemotherapy].

In 2007, we began using neoadjuvant chemotherapy for the treatment of Stage IV gastric cancer and then performing R0/1 surgery in patients in whom chemotherapy was effective. Here, we evaluate the use of this therapeutic strategy combining chemotherapy and surgery for the treatment of Stage IV gastric cancer. The subjects of our investigation were 46 patients with Stage IV gastric cancer treated from 2007 through 2012. We divided these patients into the NAC group (19 patients), in whom we performed R0/1 surgery after chemotherapy, and the Cx group (27 patients), who continued chemotherapy. We also included 79 patients with Stage IV gastric cancer treated from 2001 to 2006, divided into the OPE group (36 patients), in whom we performed R0/1 surgery without neoadjuvant chemotherapy, and the NC group (43 patients), in whom we performed R2 surgery. We plotted the survival curves of these 4 groups. The chemotherapy protocols used were S-1+cisplatin( CDDP) and S-1+docetaxel( DOC). The disease control rate of these chemotherapies was 72%, and R0/1 surgery was performed in 53.8% of patients with liver metastasis, 62.5% of those with paraaortic lymph node (PALN) metastasis, 29.4% of those with peritoneal metastasis, 100% of patients with T4N2 disease, and 0% of patients with distant metastasis. The 2-year survival rates of the NAC, OPE, Cx, and NC groups were 69%, 55%, 0%, and 20%, respectively. The 5-year survival rates of the NAC, OPE, Cx, and NC groups were 35%, 30%, 0%, and 5%, respectively.

Pitavastatin increases ABCA1 expression by dual mechanisms: SREBP2-driven transcriptional activation and PPARα-dependent protein stabilization but without activating LXR in rat hepatoma McARH7777 cells.

Hepatic ATP-binding cassette transporter A1 (ABCA1) plays a key role in high-density lipoprotein (HDL) production by apolipoprotein A-I (ApoA-I) lipidation. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, increase ABCA1 mRNA levels in hepatoma cell lines, but their mechanism of action is not yet clear. We investigated how statins increase ABCA1 in rat hepatoma McARH7777 cells. Pitavastatin, atorvastatin, and simvastatin increased total ABCA1 mRNA levels, whereas pravastatin had no effect. Pitavastatin also increased ABCA1 protein. Hepatic ABCA1 expression in rats is regulated by both liver X receptor (LXR) and sterol regulatory element-binding protein (SREBP2) pathways. Pitavastatin repressed peripheral type ABCA1 mRNA levels and its LXR-driven promoter, but activated the liver-type SREBP-driven promoter, and eventually increased total ABCA1 mRNA expression. Furthermore, pitavastatin increased peroxisome proliferator-activated receptor α (PPARα) and its downstream gene expression. Knockdown of PPARα attenuated the increase in ABCA1 protein, indicating that pitavastatin increased ABCA1 protein via PPARα activation, although it repressed LXR activation. Furthermore, the degradation of ABCA1 protein was retarded in pitavastatin-treated cells. These data suggest that pitavastatin increases ABCA1 protein expression by dual mechanisms: SREBP2-mediated mRNA transcription and PPARα-mediated ABCA1 protein stabilization, but not by the PPAR-LXR-ABCA1 pathway. [Supplementary Figures: available only at http://dx.doi.org/10.1254/jphs.10241FP].

Computed tomography fluoroscopy-guided placement of iliosacral screws in patients with unstable posterior pelvic fractures.

OBJECTIVE: The purpose of this study was to evaluate retrospectively the safety and effectiveness of the computed tomography (CT) fluoroscopy-guided placement of iliosacral screws in patients with unstable posterior pelvic fractures. MATERIALS AND METHODS: Six patients (four women and two men; mean age 55.8 years; range 35-77 years) with unstable posterior pelvic fractures underwent iliosacral screw placement under CT fluoroscopy guidance between November 2007 and August 2008. Unstable pelvic ring injury (AO types B and C) was the indication for this procedure. RESULTS: In all the six patients except one, CT fluoroscopy-guided placement had been technically successful. In one patient, a second screw had been inserted, with a tilt to the caudal site, and slightly advanced into the extrasacral body; afterward, it could be exchanged safely for a shorter screw. Five patients and one patient underwent placement of two screws and one screw, respectively. The mean duration of the procedure was 15.0 min (range 9-30 min) per screw; the duration was 12.3 min and 18.2 min for the first and second screws, respectively. No complications requiring treatment occurred during or after the procedure. The mean clinical and radiologic follow-up period was 14 months (range 6-21 months). All pelvic injuries had healed satisfactorily, without complication, and all patients are now doing well clinically and can walk. CONCLUSION: CT fluoroscopy-guided placement of iliosacral screws is a safe and effective treatment in patients with unstable posterior pelvic fractures.

Identification of GATA3 binding sites in Jurkat cells.

Determining binding sites of transcription factors is important for understanding the transcriptional control of target genes. Although a transcription factor GATA3 plays a pivotal role in Th2 lymphocyte development, its physiological role is not clearly defined because the target genes remain largely unknown. In this study, we modified chromatin immunoprecipitation (ChIP), and isolated 121 GATA3 binding sites and 83 different annotated target genes. Re-ChIP analysis using anti-GATA3 and anti-RNA polymerase II mAbs and chromosome conformation capture assay demonstrate that GATA3-bound fragments interact with basal transcriptional units of target genes. GATA3 regulation of target genes under the control of binding fragments was confirmed by reporter assay and quantification of target gene mRNA expression in the presence of GATA inhibitor or short interfering RNA against GATA3. These data demonstrate that GATA3 binds to regulatory elements and controls target gene expression through physical interaction with core promoter regions.

The role of fractalkine as an accelerating factor on the autoimmune exocrinopathy in mice.

PURPOSE: Sjögren's syndrome (SS) is an organ-specific autoimmune disease caused by the progressive loss of exocrine glands and is associated with several autoimmune phenomena. Various research studies have been performed, and many molecules have been suggested as responsible for the pathogenesis of SS. Here the authors show the increased expression of fractalkine (CX(3)CL1) in lacrimal glands of SS model mice. Among more than 50 known chemokines, fractalkine is the sole member of the CX(3)C family and has unique structural and functional attributes. The purpose of this study was to analyze the role of fractalkine in exocrine glands. METHODS: The expression of fractalkine in the lacrimal glands of thymectomized NFS/sld mice was investigated by immunohistochemistry and RT-PCR. To confirm the effects of fractalkine in exocrine glands, tissue-specific fractalkine transgenic mice were generated using the salivary amylase promoter. RESULTS: The results demonstrated the upregulated fractalkine expression in thymectomized NFS/sld mice. Furthermore, the lacrimal and salivary gland-specific fractalkine transgenic mice showed the expression of fragmented fractalkine and lymphocytic infiltration in their lacrimal and submandibular glands. Interestingly, the dominant population was B cells in the lacrimal glands, whereas B cells and CD4(+) T cells were infiltrated in the submandibular glands. These mice also demonstrated slightly decreased tear and salivary secretion compared with wild-type mice. CONCLUSIONS: Based on these results, it may be that fractalkine contributes to the development of SS, especially in lymphocyte migration to exocrine glands, and that it accelerates the disease in association with other molecules.

Establishment and functional characterization of a tracheal epithelial cell line RTEC11 from transgenic rats harboring temperature-sensitive simian virus 40 large T-antigen.

A tracheal epithelial cell line RTEC11 was established from transgenic rats harboring temperature-sensitive simian virus 40 large T-antigen. The cells grew continuously at a permissive temperature of 33 degrees C but not at a non-permissive temperature of 39 degrees C. Morphological and functional investigations demonstrated that the cells were polarized epithelial cells maintaining a regulated permeability barrier function. Interestingly, the expression levels of Muc1 (mucin 1) and Scgb1a1 (uteroglobin), non-ciliated secretory cell markers, and Tubb4 (tubulin beta 4), a ciliated cell marker, were significantly increased under the cell growth-restricted condition. Global gene expression and computational network analyses demonstrated a significant genetic network associated with cellular development and differentiation in cells cultured at the non-permissive temperature. The tracheal epithelial cell line RTEC11 with unique characteristics should be useful as an in vitro model for studies of the physiological functions and gene expression of tracheal epithelial cells.

Investigation of binding proteins for anti-platelet agent K-134 by Drug-Western method.

K-134 ((-)-6-[3-[3-cyclopropyl-3-[(1R, 2R)-2-hydroxycyclohexyl]ureido]-propoxy]-2(1H)-quinolinone) is a novel anti-platelet agent with anti-hyperplastic activities. We found previously that K-134 is a potent phosphodiesterase-3 (PDE3) inhibitor. In the present study, we found other K-134-binding proteins by Drug-Western method. We isolated two clones that can bind directly to K-134, cofilin-2, and CD36 in vitro. Comparison of their amino acid sequences showed similarity over a short stretch [KxxxxVxIxWxxE] in part in the collagen-binding region of CD36. K-134 inhibited binding between CD36 and collagen type-I; however, other PDE3 inhibitors, cilostazol, amrinone, and an inactive derivative of K-134, 4S-OH-K-134, showed little or no effect on binding. It was strongly suggested that the direct binding between K-134 and CD36 is a characteristic effect of K-134, and the homologous stretch may be necessary for binding to K-134. These results also suggested that these interactions are involved in the mechanisms of the anti-platelet and anti-hyperplastic effects of K-134.

Essential role of GATA transcriptional factors in the activation of mast cells.

Mast cells are pivotal effector cells in IgE-mediated allergic reactions. GATA transcriptional factors such as GATA-1 and GATA-2 are expressed in mast cells, and recent studies have revealed that both GATA-1 and GATA-2 are required for mast cell development. However, the role of GATA transcriptional factors in differentiated mast cells has remained largely unknown. In this study, we repressed the activity of GATA-1 and GATA-2 by using three different approaches (inducible overexpression of a dominant-negative form of GATA, pharmacological inactivation, or small interfering RNA technology), and analyzed the molecular mechanisms of GATA transcriptional factors in the activation of mast cells. Surprisingly, the repression of GATA activity in differentiated mast cells led to the impairment of cell survival, IgE-induced degranulation, and cytokine production. Signal transduction and histone modification in the chromatin related to protein kinase Cbeta were defective in these cells. These results identify that GATA has a critical role in the activation of mast cell.

Overexpression of heat shock protein 70 restores the structural stability and functional defects of temperature-sensitive mutant of large T antigen at nonpermissive temperature.

The effects of heat shock protein 70 (Hsp70), a molecular chaperone, on the degradation and functional alterations of a mutant large T antigen induced by a nonpermissive temperature were examined. In this study, mouse tracheal epithelial TM02-3 cells harboring temperature-sensitive simian virus 40 large T antigen and stable TM02-3 cells overexpressing human Hsp70 and/or Hsp40 were used. Although the temperature shift from 33 degrees C (permissive temperature) to 39 degrees C (nonpermissive temperature) induced increases in the endogenous chaperones including Hsp70 and Hsp40, degradation of the T antigen, activation of the p53-p21(waf1) pathway, and an arrest of cell growth were observed in the mock cells. In contrast, these changes induced by the temperature shift were partially but significantly prevented in stable cells overexpressing human Hsp70 and/or Hsp40. A combination of Hsp70 and Hsp40 was the most effective, suggesting that Hsp40 may cooperate with Hsp70. Moreover, immunocytochemical observation indicated that human Hsp70 was expressed in the cytoplasm at 33 degrees C, but it colocalized with T antigen in the nucleus at 39 degrees C. These results suggest that overexpressed Hsp70 translocates from the cytoplasm to nucleus, and significantly restores the structural stability and functional defects of mutant large T antigen in the cells.