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Synovial sarcoma (SS) is an aggressive soft-tissue cancer with a poor prognosis and a propensity for local recurrence and distant metastasis. In this study, we investigated whether S phase kinase-associated protein (Skp2) plays an oncogenic role in tumor initiation, progression, and metastasis of SS. Our study revealed that Skp2 is frequently overexpressed in SS specimens and SS18-SSX transgenic mouse tumors, as well as correlated with clinical stages. Next, we identified that genetic depletion of Skp2 reduced mesenchymal and stemness markers, and inhibited the invasive and proliferative capacities of SS cell lines. Furthermore, Skp2 depletion markedly suppressed the growth of SS xenografts tumors. Treatment of SS cell lines with the skp2 inhibitor flavokawain A (FKA) reduced Skp2 expression in a dose-dependent manner and resulted in cell cycle arrest and apoptosis. FKA also suppressed the invasion and tumor-initiating properties in SS, similar to the effects of Skp2 knockdown. In addition, a combination of FKA and conventional chemotherapy showed a synergistic therapeutic efficacy. Taken together, our results suggest that Skp2 plays an essential role in the biology of SS by promoting the mesenchymal state and cancer stemness. Given that chemotherapy resistance is often associated with cancer stemness, strategies of combining Skp2 inhibitors with conventional chemotherapy in SS may be desirable.

Previous reports document expression of low-density lipoprotein receptor-related protein 5 (LRP5) in osteosarcoma (OS) tissue. Expression of this Wnt receptor correlated with metastatic disease and poor disease-free survival. Forced expression of dominant-negative LRP5 (dnLRP5), which lacks the membrane binding domain of the native protein and therefore functions as a soluble receptor-sponge for Wnt ligands, reduced in vitro cellular invasion and in vivo xenograft tumor growth for osteosarcoma cell lines. Here, we use a genetically engineered mouse model of osteosarcomagenesis with and without expression of dnLRP5 to assess to what degree tumorigenesis is affected and whether Wnt/β-catenin signaling is circumvented or maintained. Each cohort of mice developed osteosarcoma at a similar ultimate prevalence, but after a slightly increased latency in those also expressing dnLRP5. On histology, there was no difference between groups, despite previous reports that the dnLRP5 osteosarcoma cells specifically undergo a mesenchymal-to-epithelial transition in vitro. Finally, immunohistochemistry showed the presence of cytosolic and nuclear β-catenin and nuclear Cyclin D1, markers consistent with preserved Wnt/β-catenin signaling despite constitutive blockade of the cell surface receipt of Wnt signaling ligand. These data suggest that canonical Wnt signaling plays a role in OS progression and that while blockade of singular nodes in signaling pathways can have dramatic effects on individual cell lines, real tumors readily evade such focused attacks.

Flavokawain A (FKA), a major chalcone in the Kava plant, has recently demonstrated promising anti-cancer activities. A systematic evaluation of FKA's safety profile has not been reported before. In this study, male FVB/N mice were fed with an AIN-76A diet or AIN-76A diet supplemented with 0.6% (6 g/kg food) FKA or 0.6% commercial kava root extract (KRE) for three weeks. Dietary feeding of FKA did not affect food consumption and body weight. Histopathological examination of liver, kidney, colon, lung, heart, spleen, and thymus revealed no signs of FKA-induced toxicity. Biochemical serum analysis and histological examination confirmed normal organ function in FKA-treated mice. The cytotoxicity profile showed FKA had minimal side effects on bone marrow and small intestinal epithelial cells compared with Adriamycin. In addition, oral feeding of FKA increased activities of both glutathione S-transferase and quinone reductase in the liver, lung, prostate and bladder tissues of mice. In comparison, dietary feeding of 0.6% KRE increased liver/body weight ratio and decreased spleen, thymus, and testis/body weight ratios, as well as induced nodular proliferation in liver tissues. Therefore, dietary feeding FKA showed no adverse effects on major organ function and homeostasis in mice, suggesting the potential of FKA for chemoprevention study of human cancers.

Background: Accumulating research substantiated that tumor-associated macrophages (TAMs) have a significant impact on the tumorigenesis, progression, and distant metastasis, representing a novel target for various cancers. However, the underlying dynamic changes and interactions between TAMs and tumor cells remain largely elusive in colorectal cancer (CRC). Methods: We depicted the dynamic changes of macrophages using sing-cell RNA-seq data and extracted TAM differentiation-related genes. Next, we utilized the weighted gene co-expression network analysis (WGCNA) to acquire CMS-related modular genes using bulk RNA-seq data. Finally, we utilized univariate Cox and Lasso Cox regression analyses to identify TAM differentiation-related biomarkers and established a novel risk signature model. We employed quantitative real-time polymerase chain reaction (qRT-PCR) on CRC tissue samples and used immunohistochemistry (IHC) data frome the HPA database to validate the mRNA and protein expression of prognostic genes. The interaction of TAMs and each consensus molecular subtype (CMS) subpopulation was analyzed at the cellular level. Results: A total of 47,285 cells from single-cell dataset and 1197 CRC patients from bulk dataset were obtained. Among those, 6400 myeloid cells were re-clustered and annotated. RNASE1, F13A1, DAPK1, CLEC10A, RPN2, REG4 and RGS19 were identified as prognostic genes and the risk signature model was established based on the above genes. The qRT-PCR analysis indicated that the expression of RNASE1 and DAPK1 were significantly up-regulated in CRC tumor tissues. The cell-cell communication analysis demonstrated complex interactions between TAMs and CMS malignant cell subpopulations. Conclusion: This study presents an in-depth dissection of the dynamic features of TAMs in the tumor microenvironment and provides promising therapeutic targets for CRC.

Summary: Background: Postoperative complications and recurrence are major diffficulties in the flap techniques for the treatment of pilonidal sinus (PS), however, the risk factors remain unclear. While magnetic resonance imaging (MRI) offers the highest soft tissue resolution, few studies have applied MRI to investigate the basic parameters of PS. Methods: A total of 100 patients receiving Limberg flap (LF) or Karydakis flap (KF) surgery at the Sixth Affiliated Hospital of Sun Yat-Sen University were retrospectively analyzed, and the median follow-up period was 42 (range, 20–90) months. We performed a multivariate logistic analysis on the clinicopathological parameters and MRI data to identify risk factors for complications and recurrence. Results: The basic parameters of PS were obtained by MRI analysis. The multivariate analysis revealed a large longitudinal sinus diameter (OR = 1.020, 95%CI = 1.000–1.041) and sacrococcygeal dermal thickness (OR = 1.680, 95%CI = 1.142–2.472) to be independent risk factors for early complications. Meanwhile, a small sacrococcygeal fat thickness (OR = 0.923, 95%CI = 0.864–0.987) and a high BMI (OR = 1.291, 95%CI = 1.067–1.563) are independent risk factors for late complications and recurrence, respectively. Conclusion: We used MRI to measure the basic parameters of PS accurately, including size, volume, location and some key points of the surrounding tissues, and identified, besides the selection of surgical approach, some specific basic parameters of PS might be the risk factors for complications and recurrence after flap techniques.

Introduction: Breast cancer is the most common malignancy in women of reproductive age and chemotherapy protocols impair fertility, frequently necessitating fertility preservation (FP) referral. Embryo, oocyte, or ovarian tissue cryopreservation are established FP modalities in women with breast cancer but there are few data on their uptake over time. In this study our aim was to determine the regional time trends and utility differences for fertility preservation methods of reproductive tissue cryopreservation., Methods: This multicenter study included 1623 women diagnosed with breast cancer from 7 tertiary centers in 6 countries (Brazil, Italy, Scotland, South Korea, Turkey, USA). Participant centers provided the details of FP cryopreservation approaches broken down annually from 2012 to 2021. Women with newly diagnosed breast cancer, aged 18-45 years who were referred for FP at participating centers and had normal ovarian function at the time were included., Results: We found a mean increase of 7% per year (P = .002, adjusting for centers) in the number of women referred for FP. Of those who were referred (n = 1623), a mean 38.7% underwent FP (n = 629), with a range of 12% in South Korea) to 95% in Brazil. The number of women undergoing ovarian stimulation for FP continually increased until 2021, with oocyte cryopreservation being the most common procedure throughout the study period (P = .014 for time trend). The proportion of random start ovarian stimulation cycles increased each year from 58.3% in 2012 to 86.8% in 2021, (P = .005 for time trend, and P = .04 for 2012 vs. 2021)., Conclusions: The utility of FP has steadily increased for young women with breast cancer over the last decade, although regional differences significantly influence FP practices. The findings of our study could have value for policy making in FP care for young women with breast cancer at the local, regional, or global level., Competing Interests: Disclosure Dr. Lambertini reports advisory role for Roche, Lilly, Novartis, Astrazeneca, Pfizer, Seagen, Gilead, MSD, and Exact Sciences; speaker honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Libbs, Daiichi Sankyo, Takeda, Knight, Ipsen, and AstraZeneca; travel Grants from Gilead, Daiichi Sankyo, Roche and a research grant (to his Institution) from Gilead, all outside the submitted work. All other authors state that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Lipoprotein(a) [Lp(a)] contributes to cardiovascular disease risk. A genetically determined size polymorphism in apolipoprotein(a) [apo(a)], determined by the number of Kringle (K) repeats, inversely regulates Lp(a) levels. Nongenetic factors including dietary saturated fat influence Lp(a) levels. However, less is known about the effects of carbohydrates including dietary sugars. In this double-blind, parallel arm study among 32 overweight/obese adults, we investigated the effect of consuming glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 weeks on Lp(a) level and assessed the role of the apo(a) size polymorphism. The mean (±SD) age of participants was 54 ± 8 years, 50% were women, and 75% were of European descent. Following the 10-week intervention, Lp(a) level was reduced by an average (±SEM) of -13.2% ± 4.3% in all participants (P = 0.005); -15.3% ± 7.8% in the 15 participants who consumed glucose (P = 0.07); and -11.3% ± 4.5% in the 17 participants who consumed fructose (P = 0.02), without any significant difference in the effect between the two sugar groups. Relative changes in Lp(a) levels were similar across subgroups of lower versus higher baseline Lp(a) level or carrier versus noncarrier of an atherogenic small (≤22K) apo(a) size. In contrast, LDL-C increased. In conclusion, in older, overweight/obese adults, consuming sugar-sweetened beverages reduced Lp(a) levels by ∼13% independently of apo(a) size variability and the type of sugar consumed. The Lp(a) response was opposite to that of LDL-C and triglyceride concentrations. These findings suggest that metabolic pathways might impact Lp(a) levels., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Reducing dietary saturated fatty acids (SFA) intake results in a clinically significant lowering of low-density lipoprotein cholesterol (LDL-C) across ethnicities. In contrast, dietary SFA's role in modulating emerging cardiovascular risk factors in different ethnicities remains poorly understood. Elevated levels of lipoprotein(a) [Lp(a)], an independent cardiovascular risk factor, disproportionally affect individuals of African descent. Here, we assessed the responses in Lp(a) levels to dietary SFA reduction in 166 African Americans enrolled in GET-READI (The Gene-Environment Trial on Response in African Americans to Dietary Intervention), a randomized controlled feeding trial. Participants were fed two diets in random order for 5 weeks each: 1) an average American diet (AAD) (37% total fat: 16% SFA), and 2) a diet similar to the Dietary Approaches to Stop Hypertension (DASH) diet (25% total fat: 6% SFA). The participants' mean age was 35 years, 70% were women, the mean BMI was 28 kg/m 2 , and the mean LDL-C was 116 mg/dl. Compared to the AAD diet, LDL-C was reduced by the DASH-type diet (mean change: -12 mg/dl) as were total cholesterol (-16 mg/dl), HDL-C (-5 mg/dl), apoA-1 (-9 mg/dl) and apoB-100 (-5 mg/dl) (all P < 0.0001). In contrast, Lp(a) levels increased following the DASH-type diet compared with AAD (median: 58 vs. 44 mg/dl, P < 0.0001). In conclusion, in a large cohort of African Americans, reductions in SFA intake significantly increased Lp(a) levels while reducing LDL-C. Future studies are warranted to elucidate the mechanism(s) underlying the SFA reduction-induced increase in Lp(a) levels and its role in cardiovascular risk across populations., Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Autoimmune diseases (AIDs) are caused by the loss of self-tolerance and destruction of tissues by the host's immune system. Several antigen-specific immunotherapies, focused on arresting the autoimmune attack, have been tested in clinical trials with discouraging results. Therefore, there is a need for innovative strategies to restore self-tolerance safely and definitively in AIDs. We previously demonstrated the therapeutic efficacy of phosphatidylserine (PS)-liposomes encapsulating autoantigens in experimental type 1 diabetes and multiple sclerosis. Here, we show that PS-liposomes can be adapted to other autoimmune diseases by simply replacing the encapsulated autoantigen. After administration, they are distributed to target organs, captured by phagocytes and interact with several immune cells, thus exerting a tolerogenic and immunoregulatory effect. Specific PS-liposomes demonstrate great preventive and therapeutic efficacy in rheumatoid arthritis and myasthenia gravis. Thus, this work highlights the therapeutic potential of a platform for several autoimmunity settings, which is specific, safe, and with long-term effects., Competing Interests: Declaration of competing interest M.V.-P. is co-founder and CSO of Ahead Therapeutics SL. L.A.-F., S.R.-F., B.B. and S.R.-V., M.S., and M.D. are employees by this company. J.V. and M.V.-P. hold a patent that relate to liposome immunotherapy for autoimmune diseases, licensed to Ahead Therapeuthics SL. This work was partially funded by Ahead Therapeutics SL. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Breastfeeding (BF) provides optimal nutrition during the first 6 mo of life and is associated with reduced infant mortality and several health benefits for children and mothers. However, not all infants in the United States are breastfed, and sociodemographic disparities exist in BF rates. Experiencing more BF-friendly maternity care practices at the hospital is associated with better BF outcomes, but limited research has examined this association among mothers enrolled in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC), a population at risk of low BF rates., Objectives: We assessed the association between BF-related hospital practices (rooming-in, support from hospital staff, and provision of a pro-formula gift pack) and the odds of any or exclusive BF through 5 mo among infants and mothers enrolled in WIC., Methods: We analyzed data from the WIC Infant and Toddler Feeding Practices Study II, a nationally representative cohort of children and caregivers enrolled in WIC. Exposures included maternal experience of hospital practices reported at 1 mo postpartum, and BF outcomes were surveyed at 1, 3, and 5 mo. ORs and 95% CIs were obtained using survey-weighted logistic regression, adjusting for covariates., Results: Rooming-in and strong hospital staff support were associated with higher odds of any BF at 1, 3, and 5 mo postpartum. Provision of a pro-formula gift pack was negatively associated with any BF at all time points and with exclusive BF at 1 mo. Each additional BF-friendly hospital practice experienced was associated with 47% to 85% higher odds of any BF over the first 5 mo and 31% to 36% higher odds of exclusive BF over the first 3 mo., Conclusions: Exposure to BF-friendly hospital practices was associated with BF beyond the hospital stay. Expanding BF-friendly policies at the hospital could increase BF rates in the United States WIC-served population., (Copyright © 2022 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

During the COVID-19 pandemic, concerns about hospital capacity in the United States led to a demand for models that forecast COVID-19 hospital admissions. These short-term forecasts were needed to support planning efforts by providing decision-makers with insight about future demands for health care capacity and resources. We present a SARIMA time-series model called Gecko developed for this purpose. We evaluate its historical performance using metrics such as mean absolute error, predictive interval coverage, and weighted interval scores, and compare to alternative hospital admission forecasting models. We find that Gecko outperformed baseline approaches and was among the most accurate models for forecasting hospital admissions at the state and national levels from January-May 2021. This work suggests that simple statistical methods can provide a viable alternative to traditional epidemic models for short-term forecasting., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Targeting oncogenic genomic aberrations is an established therapeutic strategy in multiple tumor types. Molecular classification has uncovered a number of novel targets, and rapamycin-insensitive companion of mTOR (RICTOR) amplification has been identified in lung cancer. Further investigation assessing the therapeutic potential of RICTOR amplification as a novel target across advanced cancers is needed., Patients and Methods: Tumor samples from 640 patients with metastatic solid tumors, primarily gastrointestinal and lung cancers were prospectively subjected to a next-generation sequencing (NGS) assay to identify molecular targets. Samples with NGS-detected RICTOR amplification were confirmed with FISH. A RICTOR-amplified patient-derived cell (PDC) line was generated and used to investigate the effectiveness of selective AKT, mTORC1, and mTORC1/2 inhibition., Results: NGS identified 13 (2%) of 640 patients with RICTOR-amplified tumors (6 gastric, 3 NSCLC, 1 SCLC, 1 CRC, 1 sarcoma, 1 MUO). Of the 13 patients, seven patients had RICTOR protein overexpression by IHC. The prevalence of RICTOR amplification in gastric cancer by NGS was 3.8% (6/160). FISH testing confirmed amplification (RICTOR/control >2) in 5/13 (38%) of samples, including four gastric cancers and one lung cancer. Treatment of a RICTOR amplified PDC with a selective AKT (AZD5363), selective mTORC1 (everolimus), dual mTORC1/2 (AZD2014), and the multi-target kinase inhibitor pazopanib demonstrated preferential sensitivity to the mTORC1/2 inhibitor (AZD2014). Knockdown of RICTOR reversed PDC sensitivity to AZD2014, validating the importance of RICTOR amplification to the PDC line., Conclusions: RICTOR amplification is a rare but therapeutically relevant genomic alteration across solid tumors. Our results support further pre-clinical and clinical investigation with AZD2014 in RICTOR amplified gastric cancer and highlights the importance of genomic profiling., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aim: To investigate patterns of and factors associated with help-seeking behaviors among individuals with diabetes mellitus (DM) and/or serious psychological distress (SPD)., Methods: The analysis was conducted with the California Health Interview Survey (CHIS) 2011-2012 of 40,803 adults. Logistic regression was used to examine the associations between the multiple facilitating/preventing factors and outcome, guided by the Andersen's Health Care Utilization Model., Results: The prevalence of DM and SPD were 10.9% and 3.4%, respectively, among participants in the survey. The participants with DM were more likely to experience SPD than those without DM (OR 1.46, 95% CI=1.11-1.91, p=0.006). Participants with combined DM and SPD, the most underserved, were less likely to perceive the need for mental health services and less likely to seek help, compared to those with only SPD. Need factors (SPD status and perceived need) were significantly associated with help-seeking behaviors for mental health, along with predisposing factors (age, gender, obesity, race, and employment), and enabling factors (insurance, English proficiency)., Conclusions: Perceptions about need for seeking help seem to play an important role in receiving mental health services in addition to other predisposing or enabling factors. Identification of these factors may improve clinical outcomes related to DM and SPD., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2016 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

This study was conducted to investigate the effects of providing oxygenated and hydrogenated water on the growth performance, blood biochemical parameters, and immunoglobulin concentrations and antioxidant enzyme activity of broiler chickens. In our investigation, 144 Ross × Ross broiler chicks were randomly allotted to three different treatment groups with four replicates (treatment × replicate × bird = 3 × 4 × 12). All chicks were given one of the following types of water for five weeks: tap water (CON), hydrogenated water (HNW), and oxygenated water (ONW). ONW supplementation increased the final body weight and weight gain and also improved both feed intake and feed conversion of broiler chickens as compared to those of CON broiler chickens (P < 0.05). The abdominal fat and its ratio to the final body weight showed that fat accumulation in the broiler chicken abdomen was reduced when broiler chickens drank only ONW for five weeks (P < 0.05). ONW supplementation improved blood parameters, including triacylglyceride, total cholesterol, and low-density lipoprotein-cholesterol. Additionally, in accordance with a globulin increase in broiler chickens, both IgG and IgM generation were significantly enhanced when ONW was supplied to broiler chickens (P < 0.05) but only a numerical advance was observed in the HNW group (P > 0.05). Both oxygenated and hydrogenated water supplementation significantly improved the antioxidant effects (P < 0.05), and it seems that superoxide dismutase refinement was completed due to oxygen and/or hydrogen enhancement of drinking water. These results indicate that oxygen enhancement of drinking water may be recommended to improve growth performance by increasing immunoglobulins mainly IgG and IgM., (© Crown copyright 2016.)

We evaluated the hepatoprotective activity of allyl isothiocyanate (AITC) against carbon tetrachloride (CCl4)-induced liver injury in rats. Sprague Dawley rats were orally administered AITC at doses of 5 (AITC 5) and 50 (AITC 50) mg/kg body weight once daily for 3 days, with or without intraperitoneal injection of CCl4. Serum chemistry was assessed for changes in alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The enzyme activities of superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) were examined in liver tissues, while pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) mRNA expression were analyzed using real-time polymerase chain reaction. And heme oxygenase-1 (HO-1) and ionized calcium binding protein-1 (Iba-1) immunoreactivities were evaluated by Western blot analysis and immunohistochemistry, respectively. In serum chemistry, the oral administration of AITC itself did not affect the serum levels of ALT or AST, furthermore pretreatment with AITC 5 and AITC 50 significantly reduced the ALT and AST activity levels that were elevated in CCl4-intoxicated rats. In addition, AITC significantly suppressed the reduction of SOD and CAT, and the elevation of MDA, TNF-α mRNA expression, on the other hands, induced the expression of HO-1 compared with those of the vehicle-treated CCl4 group. The histopathological evaluation and Iba-1 immunoreactivity also supported the hepatoprotective effects of AITC against CCl4-induced liver injury. These results suggest that AITC ameliorates oxidative liver injury, possibly through reducing lipid peroxidation, enhancing antioxidant enzymes, and suppressing Kupffer cells and macrophages., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: This study was conducted to determine whether there is additive benefit of dual-antiplatelet therapy (DAPT) with aspirin (acetylsalicylic acid [ASA]) and clopidogrel compared with ASA monotherapy among patients with symptomatic peripheral arterial disease., Methods: This was an observational cohort analysis that included 629 patients with claudication or critical limb ischemia. The prevalence of patients taking ASA monotherapy vs DAPT was assessed monthly for up to 3 years. A propensity model was constructed to adjust for baseline demographic characteristics and to assess the effect of DAPT on major adverse cardiovascular events (MACEs) and major adverse limb events., Results: At baseline, 348 patients were taking DAPT and 281 were taking ASA monotherapy. During 3 years of follow-up, 50 events (20%) occurred in the DAPT group vs 59 (29%) in the ASA monotherapy group. After propensity weighting, DAPT use was associated with a decreased risk of MACEs (adjusted hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.44-0.96) and overall mortality (adjusted HR, 0.55; 95% CI, 0.35-0.89). No association was found between DAPT use and the risk of major amputation (adjusted HR, 0.69; 95% CI, 0.37-1.29). In a subgroup of 94 patients who underwent point-of-care platelet function testing, 21% had decreased response to ASA and 55% had a decreased response to clopidogrel. No association was found between a reduced response to ASA or clopidogrel and adverse events at 1 year., Conclusions: DAPT may be associated with reduced rates of MACEs and death among patients with symptomatic peripheral arterial disease., (Published by Elsevier Inc.)

The authors report dualplate fixation technique for providing stable fixation in comminuted proximal humerus fractures. This technique has been used for proximal humerus fractures with metaphyseal comminution and provides excellent anatomical reduction and neck shaft angle (NSA). The recently locking plate is clinically more widely used due to its small size, low rigidity, high elasticity, and biomechanical properties such as fixed initial angle and rotational stability. However, in severely comminuted complex type proximal metaphyseal humerus fractures, the use of locking plate alone does not provide stable fixation, leading to complications such as varus collapse, anterior-posterior angulation, screw cutout, nonunion, malunion, and metal failure. Therefore, a more robust and enhanced fixation method, the dual plating technique using the locking compression plate (Proximal Humeral Internal Locking System and Variable Angle Locking Compression Plate) was developed., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Corporate community initiatives (CCI) are often established via cross-sector partnerships with nonprofit agencies to address critical social problems. While there is a growing body of literature exploring the effectiveness and social impact of these partnerships, there is a limited evaluative research on the implementation and execution processes of CCIs. In this paper, we examined the implementation and operational processes in the delivery of a professional sport organization's CCI initiative using program theory evaluation. The findings showed discrepancies between the associate organization and the implementers regarding understanding and fulfilling responsibilities with performing certain aspects (maintaining accurate records and program marketing) of the service delivery protocol. Despite program stakeholders being satisfied overall with the program delivery, contradictions between program stakeholders' satisfaction in the quality of program delivery was found in critical components (marketing and communications) of the service delivery. We conclude that ongoing evaluations are necessary to pinpoint the catalyst of the discrepancies along with all partners valuing process evaluation in addition to outcome evaluation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Ischemic preconditioning (IPC) is a powerful mechanism for limiting myocardial infarction during or after ischemia-reperfusion (IR) injury. However, effective target genes and proteins for IPC are unknown. We characterized global changes in gene expression in the heart during IR, and identified effective target genes for IPC., Methods: Hearts were isolated from Sprague-Dawley rats under control, IR, and IPC conditions. We generated expressed-sequence-tags (ESTs) for each group and investigated their functions and the major biological processes in which they are involved using the eukaryotic clusters of orthologous groups (KOG) database and bioinformatics analysis tools., Results: IR modified the expression of 126 genes. Of these, 62 were upregulated, 64 were downregulated, and 77 were found to be effective target genes for IPC. In KOG analysis, most of the genes whose expression was modified were involved in energy production and conversion and the cytoskeleton. A gene-to-gene interaction map revealed that IR modified the expression of genes in four major functional modules: electron transport chain/oxidative phosphorylation; tricarboxylic acid cycle/glucose metabolism/amino acid metabolism; cellular structure and contraction; and gene transcription, translation, and protein folding. At the individual gene level, the genes encoding mitochondrial cytochrome c oxidase subunits 2 and 3 were downregulated, and those encoding the major cytoskeleton components tropomyosin, myosin light chain, myomesin 2, and myosin regulatory light chain 2, as well as the gene encoding the iron-storage protein ferritin, were upregulated, and thus were identified as potential target genes. Real time PCR evaluated expression patterns of three mitochondrial IPC effective genes. Two-dimensional electrophoresis proteomic analyses revealed altered expression of 14 target proteins. The expression patterns of six proteins matched the corresponding EST expression patterns., Conclusion: The global profiling of cardiac ischemia-related genes provides the possible mechanisms of IR and IPC and ways of treating IR injury., (Copyright © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

(-)-Epigallocatechin-3-gallate (EGCG) induces apoptosis in cancer cells without adversely affecting normal cells. Understanding the cancer-specific cytotoxic activity of EGCG is very important in defining the mechanism of tumorigenesis and identifying superb chemotherapeutic agents against cancer. We comparatively assayed human telomerase reverse transcriptase (hTERT)-mediated apoptosis by EGCG-induced reactive oxygen species (ROS) in normal cells and cancer cells. EGCG showed differential levels of ROS induction between the cell types; ROS, especially hydrogen peroxide, was highly induced in cancer cells, while it was not in normal cells. In addition, the higher level of ROS down-regulated hTERT via binding of CCCTC binding factor (CTCF) to the core promoter region of hTERT, which repressed hTERT expression. CTCF binding was epigenetically controlled by the demethylation of the previously hypermethylated site for CTCF, which was induced by down-regulation of DNA methyltransferase 1 (DNMT1). In contrast, hTERT down-regulation was not observed in normal cells. These results suggest that preferential death of cancer cells by EGCG could be caused by the cancer-specific induction of ROS and epigenetic modulation of expression of apoptosis-related genes, such as hTERT., (Copyright © 2012 Elsevier Inc. All rights reserved.)

A geothermal heat pump (GHP) is a potential heat source for the economic heating of broiler houses with optimum production performance. An investigation was conducted to evaluate the effect of a heating system using a GHP on production performance and housing environment of broiler chickens. A comparative analysis was also performed between the GHP system and a conventional heating system that used diesel for fuel. In total, 34,000 one-day-old straight run broiler chicks were assigned to 2 broiler houses with 5 replicates in each (3,400 birds/replicate pen) for 35 d. Oxygen(,) CO(2), and NH(3) concentrations in the broiler house, energy consumption and cost of heating, and production performance of broilers were evaluated. Results showed that the final BW gain significantly (P < 0.05) increased when chicks were reared in the GHP broiler house compared with that of chicks reared in the conventional broiler house (1.73 vs. 1.62 kg/bird). The heating system did not affect the mortality of chicks during the first 4 wk of the experimental period, but the mortality markedly increased in the conventional broiler house during the last wk of the experiment. Oxygen content in the broiler house during the experimental period was not affected by the heating system, but the CO(2) and NH(3) contents significantly increased (P < 0.05) in the conventional broiler house compared with those in the GHP house. Fuel consumption was significantly reduced (P < 0.05) and electricity consumption significantly increased (P < 0.05) in the GHP house compared with the consumption in the conventional house during the experiment. The total energy cost of heating the GHP house was significantly lower (P < 0.05) compared with that of the conventional house. It is concluded that a GHP system could increase the production performance of broiler chicks due to increased inside air quality of the broiler house. The GHP system had lower CO(2) and NH(3) emissions with lower energy cost than the conventional heating system for broiler chickens.

Objectives: This study aimed to determine whether a non-penetrating sham needle can serve as an adequate sham control., Design: We conducted a randomised, subject-blind, sham-controlled trial in both acupuncture-naïve and experienced healthy volunteers., Setting and Interventions: Participants were randomly allocated to receive either real acupuncture (n=39) or non-penetrating sham acupuncture (n=40) on the hand (LI4), abdomen (CV12) and leg (ST36). The procedures were standardised and identical for both groups., Main Outcome Measures: Participants rated acupuncture sensations on a 10-point scale. A blinding index was calculated based on the participants' guesses on the type of acupuncture they had received (real, sham or do not know) for each acupuncture point. The association of knowledge about and experience in acupuncture with correct guessing was also examined., Results: The subjects in both groups were similar with respect to age, gender, experience or knowledge about acupuncture. The sham needle tended to produce less penetration, pain and soreness only at LI4. Blinding appeared to be successfully achieved for ST36. Although 41% of participants in the real acupuncture group made correct guesses for LI4, 31% guessed incorrectly for CV12, beyond chance level. People with more experience and knowledge about acupuncture were more likely to correctly guess the type of needle they received at ST36 only, compared to that at the other points., Conclusions: A non-penetrating sham needle may successfully blind participants and thus, may be a credible sham control. However, the small sample size, the different needle sensations, and the degree and direction of unblinding across acupuncture points warrant further studies in Korea as well as other countries to confirm our finding. Our results also justify the incorporation of formal testing of the use of sham controls in clinical trials of acupuncture., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels are widely distributed in cellular membranes of various tissues, but have not previously been found in cardiomyocytes. In this study, we cloned a gene encoding the mouse cardiac BK(Ca) channel alpha-subunit (mCardBKa). Sequence analysis of the cDNA revealed an open reading frame encoding 1154 amino acids. Another cDNA variant, identical in amino acid sequence, was also identified by sequence analysis. The nucleotide sequences of the two mCardBKa cDNAs, type 1 (mCardBKa1) and type 2 (mCardBKa2), differed by three nucleotide insertions and one nucleotide substitution in the N-terminal sequence. The amino acid sequence demonstrated that mCardBKa was a unique BK(Ca) channel alpha-subunit in mouse cardiomyocytes, with amino acids 41-1153 being identical to calcium-activated potassium channel SLO1 and amino acids 1-40 corresponding to BK(Ca) channel subfamily M alpha member 1. These findings suggest that a unique BK(Ca) channel alpha-subunit is expressed in mouse cardiomyocytes.

Background: Measles persists in Europe despite the incorporation of the measles vaccine into routine childhood vaccination programmes more than 20 years ago. Our aim was therefore to review the epidemiology of measles in relation to the goal of elimination by 2010., Methods: National surveillance institutions from 32 European countries submitted data for 2006-07. Data for age-group, diagnosis confirmation, vaccination, hospital treatment, the presence of acute encephalitis as a complication of disease, and death were obtained. 30 countries also supplied data about importation of disease. Clinical, laboratory-confirmed, and epidemiologically linked cases that met the requirements for national surveillance were analysed. Cases were separated by age: younger than 1 year, 1-4 years, 5-9 years, 10-14 years, 15-19 years, and older than 20 years. Countries with indigenous measles incidence per 100 000 inhabitants per year of 0, less than 0.1, 0.1-1, and more than 1 were grouped into categories of zero, low, moderate, and high incidence, respectively., Findings: For the 2 years of the study, 12 132 cases of measles were recorded with most cases (n=10 329; 85%) from five countries: Romania, Germany, UK, Switzerland, and Italy. Most cases were unvaccinated or incompletely vaccinated children; however, almost a fifth were aged 20 years or older. For the same 2 years, seven measles-related deaths were recorded. High measles incidence in some European countries revealed suboptimum vaccination coverage. Of the 210 cases that were reported as being imported, 117 (56%) came from another country within Europe and 43 (20%) from Asia., Interpretation: The suboptimum vaccination coverage raises serious doubts that the goal of elimination by 2010 can be attained. Achievement and maintenance of optimum vaccination coverage and improved surveillance are the cornerstones of the measles elimination plan for Europe.

Methionine (Met) loading increases total plasma homocysteine (tHcy) and assesses homocysteine metabolism. We tested the hypothesis that pre- or post-Met tHcy will predict recurrent stroke or coronary artery disease (CAD) in a subgroup analysis of the Vitamin Intervention for Stroke Prevention (VISP) trial. VISP subjects with non-disabling stroke underwent measurement of tHcy at baseline (fasting pre- and post-Met load) and were randomized to high/low-dose B-vitamin therapy for prevention of recurrent stroke or CAD. In the sample cohort of 2124 subjects, mean+/-S.D. tHcy levels in micromol/l were pre-Met 13.2+/-4.3, post-Met 30.4+/-9.76, and pre/post-Met Delta 17.1+/-8.3. The hazard ratio (HR) for recurrent stroke was 1.16 (p=0.026) for 1 S.D. higher pre-Met tHcy and 1.15 (p=0.054) for 1 S.D. higher post-Met tHcy. For CAD, the HR for 1 S.D. higher pre-Met tHcy was 1.27 (p=0.001) and was 1.00 (p=0.99) for post-Met tHcy. In survival analyses using pre- or post-Met as covariates, the coefficient of pre/post-Met Delta was not significant for stroke and was only marginally significant for CAD (p<0.08), but was negative. We conclude that fasting, pre-Met tHcy is as effective as post-Met tHcy or pre/post-Met Delta in predicting the risk for stroke and CAD.

Purpose: The validity of parental occupation recalled by adult children is not established, yet it is commonly used to measure childhood socioeconomic status (SES). We investigated the feasibility of using data from historical records to validate recalled parental SES., Methods: Data from death certificates and applications for Social Security numbers (parents' names, date and place of birth) were used to locate birth certificates and 1930 census records of 416 decedents in Forsyth County, NC, to verify parental occupation and childhood residence., Results: Birth certificates and/or census records were located for 85% of decedents. Of 257 for whom both records were searched, both were found for 60%, only a census record for 10%, and only a birth certificate for 24%. Among those with father's occupation recorded on both records (n = 138), occupational category matched on 89% of records (kappa = 0.86). Place of residence/birth, which can be linked with census-based county socioeconomic indicators, was also highly concordant across records., Conclusions: These results demonstrate that birth and census records can be located for most decedents and that the childhood SES data contained therein is highly concordant. Thus they are an alternative to recalled childhood SES and a source of validation data in life course studies.

Incompleteness is a key feature of most survival data. Numerous well established statistical methodologies and algorithms exist for analyzing life or failure time data. However, induced censorship invalidates the use of those standard analytic tools for some survival-type data such as medical costs. In this paper, some valid methods currently available for analyzing censored medical cost data are reviewed. Some cautionary findings under different assumptions are envisioned through application to medical costs from colorectal cancer patients. Cost analysis should be suitably planned and carefully interpreted under various meaningful scenarios even with judiciously selected statistical methods. This approach would be greatly helpful to policy makers who seek to prioritize health care expenditures and to assess the elements of resource use.

The neuropeptide Y (NPY) gene in rat chromosome 4 has been shown to play an important role in alcohol-seeking behavior. NPY knockout mice drink more alcohol than wild-type mice, implicating a link between NPY deficiency and high alcohol intake. This is supported by recent studies showing that intracerebroventricular injections of NPY reduce alcohol intake in both alcohol-preferring (P) and high alcohol-drinking rats. However, it is unknown which anatomical NPY systems are involved in alcohol preference. This study was designed to investigate whether there are innate differences in NPY mRNA in cerebral cortical areas, dentate gyrus (DG) of the hippocampus and medial habenular nucleus (MHb) between P and alcohol-nonpreferring (NP) rats, as these discrete brain regions are rich in NPY mRNA. [(33)P]-labeled 28-mer oligodeoxynucleotide probe was applied for the in situ hybridization study to detect the NPY mRNA, measured using quantitative autoradiography. This study revealed an absence of NPY mRNA in the MHb of P rats. We found that NPY mRNA was significantly lower in the DG of P rats than NP rats. This innate difference of NPY mRNA expression in the DG between P and NP rats is region specific. For example, in most of the cerebral cortical areas examined, an innate difference was not seen. Our study suggests that lower NPY gene expression in the DG and MHb of P rats may be factors contributing to some of the phenotypic differences observed between the P and NP lines of rats.

Success of blinding is a fundamental issue in many clinical trials. The validity of a trial may be questioned if this important assumption is violated. Although thousands of ostensibly double-blind trials are conducted annually and investigators acknowledge the importance of blinding, attempts to measure the effectiveness of blinding are rarely discussed. Several published papers proposed ways to evaluate the success of blinding, but none of the methods are commonly used or regarded as standard. This paper investigates a new approach to assess the success of blinding in clinical trials. The blinding index proposed is scaled to an interval of -1 to 1, 1 being complete lack of blinding, 0 being consistent with perfect blinding and -1 indicating opposite guessing which may be related to unblinding. It has the ability to detect a relatively low degree of blinding, response bias and different behaviors in two arms. The proposed method is applied to a clinical trial of cholesterol-lowering medication in a group of elderly people.

The affinity capillary electrophoretic separation of the complex of the enzyme cyclophilin (Cyp) with the immunosuppressive drug cyclosporin A (CsA) from uncomplexed Cyp and CsA in phosphate buffer (pH 8) under non-denaturing conditions by equilibrium-mixture analysis is reported. Using a new approach combining mobility-shift analysis and electrophoretically mediated microanalysis the binding constant of rhCyp18 to CsA and derivatives was estimated.

The trigger factor is associated with bacterial ribosomes and catalyzes proline-limited protein folding reactions. Its folding activity is very high and conserved in evolution, as shown for the homologous enzymes from Escherichia coli and Mycoplasma genitalium. The folding protein substrate (a variant of ribonuclease T1) binds with high affinity to the trigger factors, and permanently unfolded proteins are strong, competitive inhibitors. We used this inhibition to characterize the substrate binding sites of the trigger factors. Unfolded alpha-lactalbumin binds very tightly and inhibits the trigger factor from M. genitalium with a KI value of 50 nM. The binding of inhibitory proteins is independent of proline residues, as shown for unfolded tendamistat, which binds to the trigger factor with equal affinity in the presence and in the absence of its three proline residues. The good inhibition by a non-folding variant of ribonuclease T1 that lacks Pro39 showed that this proline, at which the catalysis of folding occurs, is dispensable for substrate binding. The trigger factors cannot catalyze prolyl isomerization when proteins are partially folded already. They preferentially recognize unstructured protein chains, which bind with high affinity to a site distinct from the catalytic prolyl isomerase center in the FKBP domain., (Copyright 1998 Academic Press Limited.)

We report a novel mutation in a case of ichthyosis bullosa of Siemens that results in a threonine --> proline substitution in a novel location, codon 485 in a highly conserved residue position of the IATYRKLLEGE consensus motif at the end of the 2B rod domain segment of the keratin 2e chain. The disease phenotype is consistent with the inappropriate substitution of a proline near the end of the rod domain, because it lies near the predicted molecular overlap region of coiled-coil molecules, which is critical for the maintenance of the structural integrity of keratin intermediate filaments.

The palmar advancement flap with V-Y closure was used in two patients with thumb tip injuries. This technique allows more distal advancement of the flap than does a conventional palmar advancement flap and does not require skin graft coverage.

Death from cardiovascular disease is rare among Eskimos. Haemostasis was investigated in twenty-one Greeland Eskimos and twenty-one age and sex matched Danish controls. Platelet lipid analysis demonstrated that a high consumption of omega-3 polyunsaturated fatty acids (such as cis 5, 8, 11, 14, 17-eicosapentaenoic acid [C20:5]) by Eskimos increased the proportion of omega-3 polyunsaturated fatty acids in the platelets. The Eskimos had a significantly longer bleeding-time due to a reduction in platelet aggregation. It is suggested that C20:5 in the platelets is converted by the vascular-wall tissue to an anti-aggregatory prostacyclin. Partial dietary substitution of arachidonic acid by eicosapentaenoic acid may reduce the incidence of thrombotic disorders, including myocardial infarction.

Gas-liquid chromatography analyses have been carried out to investigate the composition of esterified fatty acids in the plasma lipids in 130 Greenland Eskimos, compared with those of 32 Greenland Eskimos living in Denmark and of 31 Caucasian Danes in Denmark. While the Eskimos living in Denmark did not differ substantially from other persons living in Denmark and, from what is found in other studies in Western communities, the Greenland Eskimos showed a completely different pattern. They demonstrated a much higher proportion of palmitic, palmitoleic, and timnodonic acids, while they had a markedly lower concentration of linoleic acid. The total concentration of polyunsaturated fatty acids was lower in Greenland Eskimos than in the other groups. These findings are discussed in the light of the generally accepted opinion of the beneficial effect on plasma lipid levels and on the morbidity of coronary atherosclerosis of a high dietary intake of polyunsaturated fatty acids. As plasma lipid and lipoprotein levels in Greenland Eskimos in a previous study were found markedly lower than those found in Western populations, and as coronary atherosclerosis seems to occur far less commonly among Eskimos in Greenland than among peoples in industrialized countries, it was found difficult to combine these observations with the results from the present study. If dietary differences are the main reason for the differences in plasma lipid concentrations, the results from the present study point more toward qualitative than toward quantitative differences in respect of fatty acid composition of the food.

Unlike arachidonic acid (eicosatetraenoic acid, C20:4omega-6, A.A.), eicosapentaenoic acid (C20:5omega-3, E.P.A.) does not induce platelet aggregation in human platelet-rich plasma (P.R.P.), probably because of the formation of thromboxane A3 (T.X.A3) which does not have platelet aggregating properties. Moreover, E.P.A., like A.A., can be utilised by the vessel wall to make an anti-aggregating substance, probably a delta17-prostacyclin (P.G.I3). This finding suggests that, in vivo, high levels of E.P.A. and low levels of A.A. could lead to an antithrombotic state in which an active P.G.I3 and a non-active T.X.A3 are formed. Eskimos have high levels of E.P.A. and low levels of A.A. and they also have a low incidence of myocardial infarction and a tendency to bleed. It is possible that dietary enrichment with E.P.A. will protect against thrombosis.

In the winter of 1976 an examination of the composition of Eskimo food was carried out in north western Greenland. Duplicate specimens of diets collected from 50 adults, equal numbers of males and females, were analyzed for water, ash, protein, fat, individual fatty acids, cholesterol, and carbohydrate. The results are compared with those of typical Danish diets. Seal and the fish are predominant Eskimo food. Marked differences between Eskimo and Danish food were found. The Eskimo diets were richer in polyunsaturated fatty acids, the ratio to saturated fatty acids was 0.84 as compared with 0.24 in Danes. The polyunsaturated fatty acids were predominantly of the linolenic class (n-3) in Eskimos and the linoleic class (n-6) in Danes. Monoenes other than palmitoleic and oleic acids were high in Eskimo diets, but negligible in Danish. The results are related to previous examinations of the plasma lipids in Eskimos. The rarity of ischemic heart disease in Greenland Eskimos may partly be explained by the antithrombotic effect of the long-chained polyunsaturated fatty acids, especially eicosapentaenoic acid prevalent in diets rich in marine oils.