Quantifying the High-Speed Running and Sprinting Profiles of Elite Female Soccer Players During Competitive Matches Using an Optical Player Tracking System.
The aim of this study was to determine the high-speed running and sprinting profiles of elite female soccer players during competitive matches using a new Optical Player Tracking system. Eight stationary video cameras were positioned at vantage points surrounding the soccer field so that when each camera view was combined, the entire field could be viewed simultaneously. After each match, an optical player tracking system detected the coordinates (x, y) of each player for every video frame. Algorithms applied to the x and y coordinates were used to determine activity variables for 12 elite female players across 7 competitive matches. Players covered 9,220-10,581 m of total distance, 1,772-2,917 m of high-speed running (3.4-5.3 m·s) distance, and 417-850 m of sprinting (>5.4 m·s) distance, with variations between positional groups (p < 0.001; partial η = 0.444-0.488). Similarly, the number of high-speed runs differed between positional groups (p = 0.002; partial η = 0.342), and a large proportion of high-speed runs (81-84%) and sprints (71-78%) were performed over distances less than 10 m. Mean time between high-speed runs (13.9 ± 4.4 seconds) and sprints (86.5 ± 38.0 seconds) varied according to playing position (p < 0.001; partial η = 0.409) and time of the match (p < 0.001; partial η = 0.113-0.310). The results of this study can be used to design match-specific conditioning drills and shows that coaches should take an individualized approach to training load monitoring according to position.


Ball milling in organic synthesis: solutions and challenges.
During the last decade numerous protocols have been published using the method of ball milling for synthesis all over the field of organic chemistry. However, compared to other methods leaving their marks on the road to sustainable synthesis (e.g. microwave, ultrasound, ionic liquids) chemistry in ball mills is rather underrepresented in the knowledge of organic chemists. Especially, in the last three years the interest in this technique raised continuously, culminating in several high-quality synthetic procedures covering the whole range of organic synthesis. Thus, the present tutorial review will be focused on the highlights using this method of energy transfer and energy dissipation. The central aim is to motivate researchers to take notice of ball mills as chemical reactors, implementing this technique in everyday laboratory use and thus, pave the ground for future activities in this interdisciplinary field of research.


Essential newborn care practice and its predictors among mother who delivered within the past six months in Chencha District, Southern Ethiopia, 2017.
Components of essential newborn care and neonatal resuscitation are proven interventions for reducing neonatal mortality rate and stillbirth rates. Various studies have been conducted, but they failed in assessing health workers that delivered essential newborn care, facets of the health care system, and different traditional beliefs. As such, the primary aim of this study is to fill the gaps of the aforementioned previous studies, assess mothers' current practice of essential newborn care and identify factors affecting newborn care practices in Chencha District, Southern Ethiopia. A mixed type, community-based cross sectional study was conducted among 630 study participants by using one-stage cluster sampling method. Three focus group discussions (FGD) with purposively selected 18 mothers were involved for qualitative study. Data entry was carried out by Epi data version 3.1 and analysis was done by SPSS window version 22. Binary logistic regression was used to identify predictors. Qualitative data were analyzed deductively by using thematic framework analysis approach by using Open Code version 4.02. This study found that 38.4% of mothers had good practices in essential newborn care. Of the neonates, 52.9% received safe cord care, 71.0% received optimal thermal care and 74.8% had good neonatal feeding. Factors such as mothers receiving antenatal care, attending pregnant mothers meetings, receiving immediate postnatal care, wealth index, whether a complication was faced during delivery and overall knowledge of mothers were statistically significantly associated with practice. This study indicated that the current rate of essential newborn care practice was low. As such, strengthening the provision of antenatal and postnatal care services, information communication education and behavioral change communications on essential newborn care are recommended.


Dissecting and Reconstructing Matrix in Malignant Mesothelioma Through Histocell-Histochemistry Gradients for Clinical Applications.
Malignant pleural mesotheliomas (MM) are known for their heterogenous histology and clinical behavior. MM histology reveals three major tumor cell populations: epithelioid, sarcomatoid, and biphasic. Using a dissecting approach, we showed that histochemical gradients help us better understand tumor heterogeneity and reconsider its histologic classifications. We also showed that this method to characterize MM tumor cell populations provides a better understanding of the underlying mechanisms for invasion and disease progression. In a cohort of 87 patients with surgically excised MM, we used hematoxylin and eosin to characterize tumor cell populations and Movat's pentachrome staining to dissect the ECM matrisome. Next, we developed a computerized semi-assisted protocol to quantify and reconstruct the ECM in 3D and examined the clinical association between the matricellular factors and patient outcome. Epithelioid cells had a higher matrix composition of elastin and fibrin, whereas, in the sarcomatoid type, hyaluronic acid and total collagen were most prevalent. The 3D reconstruction exposed the collagen I and III that form channels surrounding the neoplastic cell blocks. The estimated volume of the two collagen fractions was 14% of the total volume, consistent with the median estimated area of total collagen (12.05 mm2) for epithelioid MM. Differential patterns in matricellular phenotypes in MM could be used in translational studies to improve patient outcome. More importantly, our data raise the possibility that cancer cells can use the matrisome for disease expansion and could be effectively targeted by anti-collagen, anti-elastin, and/or anti-hyaluronic acid therapies.


The male reproductive pattern and histology of the testes of the lesser yellow house bat, Scotophilus borbonicus (E Geoffroy, 1803) (Chiroptera: Vespertilionidae).
Monthly samples of the testes of the vespertilionid bat, Scotophilus borbonicus were collected, sectioned and examined by light microscopy. Spermatogenesis was prolonged and extended over 8 months, coinciding with spring, summer and autumn. During any particular month only certain spermatogenic cells are present in the seminiferous tubules. The mediastinum is, unlike that of most other mammals, situated towards the caudal border of the testis. This species is eminently suited for the study of the process of spermatocytogenesis.


E1A physically interacts with RUNX3 and inhibits its transactivation activity.
The adenoviral gene, termed early region 1A (E1A), is crucial for transformation and has been used very effectively as a tool to determine the molecular mechanisms that underlie the basis of cellular transformation. pRb, p107, p130, p300/CBP, p400, TRRAP, and CtBP were identified to be E1A-binding proteins and their roles in cellular transformation have been established. Although the major function of E1A is considered to be the regulation of gene expression that is critical for differentiation and cell cycle exit, one of the most significant questions relating to E1A transformation is how E1A mediates this regulation. RUNX3 is a transcription factor that was first described as a gastric cancer tumor suppressor but is now known to be involved in many different cancers. Exogenous expression of RUNX3 strongly inhibits the growth of cells. Here, we show that the adenovirus oncoprotein E1A interacts with RUNX3 in vitro and in vivo. RUNX3 interacts with the N-terminus (amino acids 2-29) of E1A, which is known to interact with p300/CBP, p400, and TRRAP. E1A interacts directly with the Runt domain of RUNX3 but does not interfere with CBFbeta-RUNX3 interactions. In addition, E1A inhibits the transactivation activity of RUNX3 on the p21(WAF1/CIP1) promoter. Consistent with these observations, the growth inhibition induced by RUNX3 is reduced by E1A. These results demonstrate that E1A specifically binds to RUNX3 and inactivates its transactivation activity. We propose that one of the mechanisms for the oncogenic activity of E1A is the inhibition of RUNX3, similar to that of RB and p300/CBP.


Clip migration causes choledocholithiasis after laparoscopic cholecystectomy.
The migration of surgical clips after laparoscopic procedures was first reported in 1992, but such instances are extremely rare. We herein demonstrate a case of a migrated metal clip, which had been applied originally to the cystic duct, but thereafter had moved to the common bile duct. This clip caused choledocholithiasis in a patient 1 year after a laparoscopic cholecystectomy. A 63-year-old man underwent a laparoscopic cholecystectomy. During the operation, the inflamed cystic duct was divided accidentally, and three clips were applied immediately. The patient complained of upper abdominal pain from postoperative day 8. Endoscopic retrograde cholangiography demonstrated bile leakage from the cystic duct, but showed no clips or choledochal stones. The patient complained of severe upper abdominal and back pain 1 year after the operation. Endoscopic retrograde cholangiography showed a metal clip in the common bile duct and choledochal stones above the clip. The clip and the cholesterol stones were removed using a basket catheter. Three clips applied to the cystic duct should have been removed because of the necrosis in the remaining cystic duct. Thereafter, the clip may have migrated through the stump of the cystic duct into the lower part of the common bile duct. This clip seems to have later caused choledocholithiasis resulting from stagnation of the bile flow. Bile leakage after an operation seems to increase the risk of clip migration. Regardless of the primary lesion, a careful follow-up evaluation is necessary for patients demonstrating complications.


The role of Rac2 in regulating neutrophil production in the bone marrow and circulating neutrophil counts.
Circulating neutrophils are persistently higher in mice deficient in the small GTPase Rac2 than in wild-type (WT) mice. Therefore, we examined the mechanisms through which the small GTPase Rac2 regulates neutrophil production and release. Lethally irradiated WT mice reconstituted with a 50:50 mixture of WT and Rac2(-/-) fetal liver cells were protected from neutrophilia, suggesting that neutrophilia is primarily because of extrinsic defects that can be corrected by WT leukocytes. However, the differential counts and numbers of leukocyte subtypes differed between Rac2(-/-) and WT cells, suggesting that Rac2 modulates leukocyte lineage distribution. Kinetic studies suggest Rac2 modulates the release of neutrophils into the circulation and does not prolong their circulating half life. The percentage of bone marrow cells that expressed the neutrophil marker Gr-1 in lethally irradiated WT or Rac2(-/-) recipients of Rac2(-/-) stem cells was greater than in recipients of WT stem cells; however, circulating neutrophil counts were higher only in Rac2(-/-) recipients of Rac2(-/-) stem cells. Rac2 mRNA was expressed in the bone marrow of WT recipients of Rac2(-/-) stem cells and in human mesenchymal stem cells. The data presented here suggest that Rac2 in hematopoietic cells regulates leukocyte lineage distribution and Rac2 in nonhematopoietic cells might contribute to regulating circulating neutrophil counts.


A formal assessment of gene flow and selection in the fire ant Solenopsis invicta.
Recent studies of the introduced fire ant Solenopsis invicta suggest that introduced polygyne (with multiple queens per nest) populations are strongly influenced by male-mediated gene flow from neighboring monogyne (single queen per nest) populations and selection acting on a single locus, general protein-9 (Gp-9). This investigation formally tests this hypothesis and determines if these processes can account for the genotypic structure of polygyne S. invicta. To increase the statistical power of this test, we considered the genotypes of polygyne queens and workers at both Gp-9 and the closely linked, selectively neutral locus Pgm-3. We then constructed and analyzed a novel mathematical model to delimit the effects of monogyne male gene flow and selection on the joint genotypes at the Pgm-3/Gp-9 superlocus. Using this framework, a hierarchical maximum-likelihood method was developed to estimate the best-fitting gene flow and selection parameters based on the fit of our model to data from both the current study and an earlier one of the same population. In each case, selection on polygyne queens and workers alone, with no monogyne male gene flow, provides the most parsimonious explanation for the observed genotype frequencies. The apparent discrepancy between this result and the empirical evidence for monogype male gene flow indicates that undocumented factors, such as other forms of selection in polygyne males or workers, are operating in introduced polygyne S. invicta.


CPEB4 and IRF4 expression in peripheral mononuclear cells are potential prognostic factors for advanced lung cancer.
Lung cancer is a heterogeneous disease with varied outcomes. Molecular markers are eagerly investigated to predict a patient's treatment response or outcome. Previous studies used frozen biopsy tissues to identify crucial genes as prognostic markers. We explored the prognostic value of peripheral blood (PB) molecular signatures in patients with advanced non-small cell lung cancer (NSCLC). Peripheral blood mononuclear cell (PBMC) fractions from patients with advanced NSCLC were applied for RNA extraction, cDNA synthesis, and real-time polymerase chain reaction (PCR) for the expression profiling of eight genes: DUSP6, MMD, CPEB4, RNF4, STAT2, NF1, IRF4, and ZNF264. Proportional hazard (PH) models were constructed to evaluate the association of the eight expressing genes and multiple clinical factors [e.g., sex, smoking status, and Charlson comorbidity index (CCI)] with overall survival. One hundred and forty-one patients with advanced NSCLC were enrolled. They included 109 (77.30%) patients with adenocarcinoma, 12 (8.51%) patients with squamous cell carcinoma, and 20 (14.18%) patients with other pathological lung cancer types. A PH model containing two significant survival-associated genes, CPEB4 and IRF4, could help in predicting the overall survival of patients with advanced stage NSCLC [hazard ratio (HR) = 0.48, p < 0.0001). Adding multiple clinical factors further improved the prediction power of prognosis (HR = 0.33; p < 0.0001). Molecular signatures in PB can stratify the prognosis in patients with advanced NSCLC. Further prospective, interventional clinical trials should be performed to test if gene profiling also predicts resistance to chemotherapy.


Do statins really cause diabetes? A meta-analysis of major randomized controlled clinical trials.
To investigate and establish the relationship between the use of statin therapy and the risk of development of diabetes. PubMed and the Cochrane Central Register of Controlled Trials was searched for randomized controlled end-point trials of statins, with more than 1000 subjects and a minimum of one-year follow-up period, published until August 2015. The odds ratio (OR) of diabetes incidence with overall statin therapy as well as with different statins in question was calculated through random effect meta-analysis model. Fourteen studies were included in the analysis with a total of 94,943 participants. Of these, 2392 subjects developed incident diabetes in the statin and 2167 in the placebo groups during a 4-year follow-up. The OR of diabetes incidence with statin therapy was significantly higher as compared with the placebo group (OR=1.11; 95% confidence interval = 1.0 to 1.2; p=0.007). There was an insignificant level of heterogeneity between the included trials (Cochran Q= 19.463, p=0.109, I2=33.20). Subgroup analysis showed that only 2 statins namely, atorvastatin (OR= 1.29; p=0.042) and rosuvastatin (OR = 1.17; p=0.01) were significantly associated. Statin therapy can slightly increase risk of incident diabetes in subjects with hypercholesterolemia.


Effect of primary drying temperature on process efficiency and product performance of lyophilized Ertapenam sodium.
The present work aimed to investigate the impact of primary drying temperature on lyophilization process efficiency and product performance of lyophilized Ertapenam sodium (EPM). Phase behavior of EPM formulation (200 mg/mL) using differential scanning calorimetry (DSC) and freeze drying microscopy (FDM) showed Tg' at -28.3 °C (onset) and Tc at -25.0 °C (onset), respectively. The formulation was freeze dried at different product temperature (Tp) during primary drying, using (a) conservative cycle (CC) where the maximum Tp (-31.9 °C) <Tg', (b) aggressive cycle 01 (AC01) where the maximum Tp (-24.8 °C) >Tg', and (c) AC02 where the maximum Tp (-21.0 °C) >Tc. The drying kinetics revealed that the sublimation rate was increased from 0.128 g/h/vial in CC to 0.159 and 0.182 g/h/vial in AC01 and AC02, respectively. This ultimately reduced the primary drying time of 208 min in CC to 145 min in AC01 and to 103 minutes in AC02. Morphological evaluation of cake using scanning electron microscopy (SEM) and texture analysis revealed that AC01 lead to induction of microcollapse, whereas AC02 resulted in collapsed cake. Furthermore, the microcollapsed formulations showed similar physicochemical stability to CC formulation, whereas collapsed cake showed significant degradation of EPM and increased degradation on stress stability. The study highlights that primary drying with microcollapse can be utilized to improve the process efficiency without compromising product quality of amorphous EPM.


Outpatient care programs of mental health organizations, United States, 1988.
In 1988, 2,989 (60 percent) of the 4,961 mental health organizations in the United States (including the territories) offered outpatient care programs. A total of 5.8 million patient care episodes were generated by these organized outpatient programs. These episodes included 3.1 million outpatient additions, produced 54 million outpatient visits, and represented 67 percent of all patient care episodes in mental health organizations in 1988. Although the number of mental health organizations with outpatient care programs increased by less than one percent between 1986 and 1988, the number of outpatient additions showed an 11 percent gain during this period. Multiservice mental health organizations were the primary locus of outpatient care in 1988, accounting for 41 percent of the 2,989 mental health organizations providing this care. Ranking next in this respect, were free-standing psychiatric outpatient clinics, and the separate psychiatric outpatient services in non-Federal general hospitals, with 25 and 16 percent, respectively, of the total outpatient care programs. In general, these three organization types had similar rankings with respect to the volume of the outpatient caseload. By definition, all of the freestanding psychiatric outpatient clinics provided outpatient care, and almost all of the VA mental health programs and multiservice mental health organizations also offered this care (99 and 92 percent, respectively). In contrast, psychiatric outpatient care was available in only 37 percent of non-Federal general hospitals with separate psychiatric services, 36 percent of private psychiatric hospitals, 29 percent of State mental hospitals, and 22 percent of RTCs for emotionally disturbed children. Outpatient care was available in mental health organizations in all States in 1988, with every State having at least two or more organization types providing this service. In general, the most populous States had the largest number and the greatest variety of mental health organizations with outpatient care programs. Of the 2.87 million clients receiving outpatient care in mental health organizations at the end of 1988, 23 percent were under 18 years of age, 68 percent were 18 to 64, and 9 percent were 65 and older. Male outpatient clients slightly outnumbered female clients. The majority (77 percent) of the outpatient clients were white, with blacks representing 21 percent; native Americans and Asians/Pacific Islanders, the remaining two percent. Eleven percent of the total client population were reported to be of Hispanic origin.(ABSTRACT TRUNCATED AT 400 WORDS)


Lifestyle effects on aging and CVD: A spotlight on the nutrient-sensing network.
Aging is widespread worldwide and a significant risk factor for cardiovascular disease (CVD). Mechanisms underlying aging have attracted considerable attention in recent years. Remarkably, aging and CVD overlap in numerous ways, with deregulated nutrient sensing as a common mechanism and lifestyle as a communal modifier. Interestingly, lifestyle triggers or suppresses multiple nutrient-related signaling pathways. In this review, we first present the composition of the nutrient-sensing network (NSN) and its metabolic impact on aging and CVD. Secondly, we review how risk factors closely associated with CVD, including adverse life states such as sedentary behavior, sleep disorders, high-fat diet, and psychosocial stress, contribute to aging and CVD, with a focus on the bridging role of the NSN. Finally, we focus on the positive effects of beneficial dietary interventions, specifically dietary restriction and the Mediterranean diet, on the regulation of nutrient metabolism and the delayed effects of aging and CVD that depend on the balance of the NSN. In summary, we expound on the interaction between lifestyle, NSN, aging, and CVD.


SnapHiC: a computational pipeline to identify chromatin loops from single-cell Hi-C data.
Single-cell Hi-C (scHi-C) analysis has been increasingly used to map chromatin architecture in diverse tissue contexts, but computational tools to define chromatin loops at high resolution from scHi-C data are still lacking. Here, we describe Single-Nucleus Analysis Pipeline for Hi-C (SnapHiC), a method that can identify chromatin loops at high resolution and accuracy from scHi-C data. Using scHi-C data from 742 mouse embryonic stem cells, we benchmark SnapHiC against a number of computational tools developed for mapping chromatin loops and interactions from bulk Hi-C. We further demonstrate its use by analyzing single-nucleus methyl-3C-seq data from 2,869 human prefrontal cortical cells, which uncovers cell type-specific chromatin loops and predicts putative target genes for noncoding sequence variants associated with neuropsychiatric disorders. Our results indicate that SnapHiC could facilitate the analysis of cell type-specific chromatin architecture and gene regulatory programs in complex tissues.


Adenoma of the posterior urethra: 131 case report.
A case-report on adenoma of the posterior urethra. In 131 cases of adenoma of the posterior urethra, aged 17-79 (mean: 36.4) years, a detailed medical history was taken and urinalysis, urethroscopy, and prostatic specific antigen (PSA) immunohistochemical staining were performed. They were then treated with transurethral resection (TUR) or transurethral electric coagulation (TUEC). Hemospermia occurred in 51% of the cases, hematuria in 38%, blood overflow from the urethral orifice in 6%, and dysuria in 5%. The position of the tumor was at or around the verumontanum. The appearance of the tumor was similar to those of a papilla, a villus, a dactyl or polyp, or simply an engorgement. The tumor contained glandular alveoli and adeno-epithelial cells. PSA immunohistochemistry was positive in the cytoplasm and nucleus of the adeno-epithelial cell. One hundred and tweenty-nine cases were cured after TUR or TUEC, while 2 patients recurred and were operated again. Adenoma of the posterior urethra is a common cause of hemospermia and hematuria in young men. Urethroscopic examination and biopsy are the principal diagnostic measures. TUR or TUEC are believed to be the treatment of choice with a short-term recurrence rate of around 1. 5%.


'Melanoma? It can't be melanoma!' A subset of melanomas that defies clinical recognition.
We diagnosed histologically 178 cases of malignant melanoma in 1990. Thirteen cases were recorded in which the diagnosis of malignant melanoma was not considered by the clinician prior to biopsy or, in retrospect, following pathologic diagnosis. Eight of the 13 lesions were amelanotic. The majority were deeply invasive at the time of biopsy, implying poor prognosis. Despite improvements in early detection of malignant melanoma, a significant subcategory of melanomas escapes clinical diagnosis.


Drug-induced hepatic steatosis.
Several drugs have been associated with the potential for drug-induced hepatic steatosis (DIHS) and/or phospholipidosis (DIPL), a lysosomal storage disorder. Drug-induced hepatic steatosis is generally a chronic but reversible affliction and may involve drug accumulation in the liver. Fat accumulation may be either macrovesicular or microvesicular in nature. Commonly used medications associated with DIHS include amiodarone, valproate, tamoxifen, methotrexate, and some chemotherapeutic and antiretroviral agents. Two recently approved medications for the treatment of hereditary homozygous hypercholesterolemia have also been noted to cause hepatic steatosis. For some compounds such as methotrexate and tamoxifen, the underlying metabolic risk factors such as obesity and metabolic syndrome may exacerbate their potential to cause DIHS and its progression. In this article, the authors discuss the preclinical screening and mechanisms of DIHS and DIPL, and review specific examples of drugs commonly used in clinical practice that are known to cause DIHS.


Pain assessment and management in critically ill intubated patients: a retrospective study.
Little research has been done on pain assessment in critical care, especially in patients who cannot communicate verbally. To describe (1) pain indicators used by nurses and physicians for pain assessment, (2) pain management (pharmacological and nonpharmacological interventions) undertaken by nurses to relieve pain, and (3) pain indicators used for pain reassessment by nurses to verify the effectiveness of pain management in patients who are intubated. Medical files from 2 specialized healthcare centers in Quebec City, Quebec, were reviewed. A data collection instrument based on Melzack's theory was developed from existing tools. Pain-related indicators were clustered into nonobservable/subjective (patients' self-reports of pain) and observable/objective (physiological and behavioral) categories. A total of 183 pain episodes in 52 patients who received mechanical ventilation were analyzed. Observable indicators were recorded 97% of the time. Patients' self-reports of pain were recorded only 29% of the time, a practice contradictory to recommendations for pain assessment. Pharmacological interventions were used more often (89% of the time) than nonpharmacological interventions (<25%) for managing pain. Almost 40% of the time, pain was not reassessed after an intervention. For reassessments, observable indicators were recorded 66% of the time; patients self-reports were recorded only 8% of the time. Pain documentation in medical files is incomplete or inadequate. The lack of a pain assessment tool may contribute to this situation. Research is still needed in the development of tools to enhance pain assessment in critically ill intubated patients.


Late-Onset Inflammation in Asian Rhinoplasty Using Alloplastic Implants.
Late-onset inflammation is a rare complication that may occur several months to years after undergoing an uneventful rhinoplasty using alloplastic implants and an uneventful postoperative course. Studies to determine the pathophysiological mechanisms of late-onset inflammation related to implants used in rhinoplasty are limited. The purpose of the study was to analyze differences between non-healthy capsules (NHC) with late-onset inflammation and healthy capsules (HC) without inflammation as controls to determine the possible cause of the inflammation. Between April 2009 and May 2018, 39 patients who underwent rhinoplasty with alloplastic implants underwent histological studies. Twenty-one patients in the NHC group showed late-onset inflammation, while 18 patients in the HC group did not display late-onset inflammation. Capsules around the alloplastic implants were harvested, and histological studies using hematoxylin and eosin, Masson's trichrome, colloidal iron, and CD31 staining were performed and compared between the NHC and HC groups. In hematoxylin and eosin and Masson's trichrome staining, edematous granulation tissues, inflammatory cellular contents, and a disorganized collagen layer were increased in the NHC group compared to the HC group. The colloidal iron staining revealed mucin deposition in the NHC group. CD31-positive cells were observed lining the capsule in both groups; however, the lining cells were damaged in the NHC group. Granulation tissues, inflammatory reaction, collagen degeneration, mucin deposition, and endothelial lining cell damage were greater in the NHC group compared to the HC group. Damaged capsules may play a crucial role in late-onset inflammation. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


Knockdown of circ_0060745 alleviates acute myocardial infarction by suppressing NF-κB activation.
It has been shown that circRNAs are involved in the development of heart diseases. However, few studies explored the role of circRNAs in acute myocardial infarction (AMI). The present study aims to investigate the role of circ_0060745 in the pathogenesis of AMI. We found that the expression of circ_0060745 was significantly increased in the myocardium of AMI mice and was mainly expressed in myocardial fibroblasts. The knockdown of circ_0060745 decreased myocardial infarct size and improved systolic cardiac functions after AMI. The knockdown of circ_0060745 in cardiac fibroblasts inhibited the migration of peritoneal macrophage, the apoptosis of cardiomyocytes and the expressions of IL-6, IL-12, IL-1β, TNF-α and NF-κB under hypoxia. Overexpression of circ_0060745 caused an increase in infarct size and worsened cardiac functions after AMI. In summary, our findings showed that knockdown of circ_0060745 mitigates AMI by suppressing cardiomyocyte apoptosis and inflammation. These protective effects could be attributed to inhibition of NF-κB activation.


Sensitization to stress and psychostimulants. Involvement of dopamine transmission versus the HPA axis.
Rats exposed to chronic stress demonstrate an enhanced motor response to psychostimulants, such as cocaine. This behavioral cross-sensitization between stress (repeated mild footshock) and cocaine (15 mg/kg, ip) is associated with an increase in extracellular dopamine in the nucleus accumbens, but a decrease in the prefrontal cortex. To determine a role for the hypothalamic-pituitary-adrenal axis in sensitization, rats were adrenalectomized prior to administering repeated cocaine injections. One and twelve days after discontinuing repeated cocaine, rats were challenged with acute cocaine. Adrenalectomy blocked the cocaine-induced sensitization observed in sham animals, but both the sham and adrenalectomized rats demonstrated behavioral sensitization to cocaine after twelve days of withdrawal. These data argue that while long-term alterations in dopamine transmission may be an important neurochemical substrate of stress and psychostimulant-induced sensitization, the hypothalamic-pituitary-adrenal axis may not have a necessary role.


Practices in dioxin emission reduction by special regulatory enforcement and utilizing advanced control technologies for incinerators in Korea.
This study strives to estimate the emission of dioxin and furthermore attempts to find the best technological control methods available for waste incinerators by investigating the emission status thereof. In order to incorporate the Stockholm Convention, a particular stringent law was promulgated in Korea and in recent years incinerators were forced to utilize better technological control. After the enforcement of special dioxin emission regulation in 2003, the average concentration of dioxin emitted from municipal and industrial waste incinerators decreased from 15.25 and 12.86 ng TEQ Nm(-3) to 5.53 and 4.96 ng TEQ Nm(-3) in 2001 and 2004, respectively. Based on test results at commercial plants, several best arranged sets of air pollution control devices (APCDs) were suggested in order to provide guidelines to help operators. These sets included combinations of spray dry absorbers, bag type filters, wet scrubbers, selective catalytic reductions and electrostatic precipitators. Different suggestions and real installations of APCD arrangement were investigated during the years around the regulation in effective. The results were presented depending on the capacity of the incinerators and different waste streams to observe the efforts to reduce dioxin emission by operators of incineration plants. The annual amount of dioxin emission from the incinerators is expected to be 212.5 g-TEQ in 2011 and 234.3g-TEQ in 2015, respectively, compared to 891.6g-TEQ recorded in 2001. The enforcement of new regulation and the installation of better APCDs showed the significant effect on such reduction. This reduction in dioxin emission from incinerators confirmed the nation's commitment to the regulatory requirement set by the Stockholm Convention.


[Nursing managerial approach: a study based on general management theories].
The purpose of this study was to identify nurses managerial conduct in a private maternity hospital located in the interior of the São Paulo state, Brazil. In order to collect data, authors used a questionnaire with 20 propositions related to the work of nurses in the different units of the hospital. Following, authors performed a descriptive statistical analysis of the data. Results showed a tendency toward democratization in the conduct of the nurses investigated as the majority of the responses privileged questions on team work, workers' participation and group development. Also, authors evidenced that great part of the responses did not agree with the propositions about the principles of the Classical Administration Theory.


Random Versus Blocked Practice to Enhance Mental Representation in Golf Putting.
The purpose of this study was to investigate changes in mental representation from either random or blocked practice when engaged in golf putting. Thirty participants were randomly assigned to random practice, blocked practice, and no-practice groups. First, we measured novice golfers' initial mental representation levels and required them to perform 18 putting trials as a pre-test. We then asked random and blocked groups to practice in accordance with their group assignment for six consecutive days (10 blocks each day, 18 trials each). A week after the last practice session, we re-measured all participants' final mental representation levels and required them to perform 18 putting trials to evaluate learning retention through practice. While those engaged in the random practice method putted more poorly during acquisition (i.e., practice) than those in blocked practice, the random practice group experienced more accurate retention during the final putting trials, and they showed a more structured mental representation than those in blocked practice, one that was more similar to that of skilled golfers. These results support the acquisition of a rich mental representation through random versus blocked practice.


Discovery of transcription factors and regulatory regions driving in vivo tumor development by ATAC-seq and FAIRE-seq open chromatin profiling.
Genomic enhancers regulate spatio-temporal gene expression by recruiting specific combinations of transcription factors (TFs). When TFs are bound to active regulatory regions, they displace canonical nucleosomes, making these regions biochemically detectable as nucleosome-depleted regions or accessible/open chromatin. Here we ask whether open chromatin profiling can be used to identify the entire repertoire of active promoters and enhancers underlying tissue-specific gene expression during normal development and oncogenesis in vivo. To this end, we first compare two different approaches to detect open chromatin in vivo using the Drosophila eye primordium as a model system: FAIRE-seq, based on physical separation of open versus closed chromatin; and ATAC-seq, based on preferential integration of a transposon into open chromatin. We find that both methods reproducibly capture the tissue-specific chromatin activity of regulatory regions, including promoters, enhancers, and insulators. Using both techniques, we screened for regulatory regions that become ectopically active during Ras-dependent oncogenesis, and identified 3778 regions that become (over-)activated during tumor development. Next, we applied motif discovery to search for candidate transcription factors that could bind these regions and identified AP-1 and Stat92E as key regulators. We validated the importance of Stat92E in the development of the tumors by introducing a loss of function Stat92E mutant, which was sufficient to rescue the tumor phenotype. Additionally we tested if the predicted Stat92E responsive regulatory regions are genuine, using ectopic induction of JAK/STAT signaling in developing eye discs, and observed that similar chromatin changes indeed occurred. Finally, we determine that these are functionally significant regulatory changes, as nearby target genes are up- or down-regulated. In conclusion, we show that FAIRE-seq and ATAC-seq based open chromatin profiling, combined with motif discovery, is a straightforward approach to identify functional genomic regulatory regions, master regulators, and gene regulatory networks controlling complex in vivo processes.


Pain in the assessment of total knee replacement.
The results of total knee replacement (TKR) are commonly assessed by survival analysis using revision as the endpoint. We have used the assessment of pain by a patient-based questionnaire as an alternative. In one hospital, 1429 TKRs were inserted by 66 surgeons between 1987 and 1993. The survival at seven years, with revision as the endpoint, was 97.5% (CI 94 to 100). There were no significant differences between the three different types of implant used, the AGC, the IB2 and the Nuffield Knee. When the endpoint was the development of moderate pain, the survival at seven years for the AGC knee was 72% and that for the IB2 was similar. Significantly more patients (p = 0.007) with the Nuffield Knee, however, had developed moderate pain. Using revision as the endpoint, it is difficult to discriminate between the various types of TKR, but this can be achieved using pain. In this investigation 30% of the patients reported moderate pain at some stage by seven years from operation.


Sex-specific differences in pain localization in female patients with endometriosis: A comparison of sexless and female human body outlines.
This study explores sex-specific differences in pain localization using pain drawings in female patients with endometriosis. Traditional human body outlines (HBOs) used for pain drawings are often viewed as male, making accurate pain assessment difficult. The study aims to compare pain localization and extent between patients presented with sexless and female HBOs. A total of 49 female patients with endometriosis completed questionnaires and pain drawings (n = 24 and n = 26 with individually designed sexless and female HBOs, respectively). The Ruzika similarity index was used to investigate potential differences in pain drawings between sexless and female HBOs. Hypothesis testing was applied to compare the number of pixels marked in the pain extents and to investigate the suitability of the presented body outline. Sex of HBOs used in pain drawings had no effect on pain area, and no statistically significant differences were found in pain localization or area between female and sexless outlines. Most, but not all participants found the body outlines suitable. The findings suggest that differences in the resulting areas marked in the pain drawings were negligible and the preferences for sexless pain drawings were not significant, so that a sexless body outline for pain drawings could be a good choice, especially when a study does not focus on one specific sex.


Diurnal rhythmicity in breast-milk glucocorticoids, and infant behavior and sleep at age 3 months.
In previous studies, associations between breast-milk cortisol levels obtained on one occasion and infant neurodevelopment were demonstrated. However, more recent evidence indicates that breast-milk cortisol and cortisone concentrations follow the diurnal rhythm of maternal hypothalamus-pituitary-adrenal axis, peaking in the early morning and with a nadir at midnight. We studied associations between breast-milk glucocorticoid (GC) rhythmicity, and infant behavior and sleep. We included 59 mothers, and their infants, of whom 17 had consulted an expert center during pregnancy for an increased risk of psychological distress. At 1 month postpartum, breast milk was sampled (on average six times) over a 24 h period for assessment of cortisol and cortisone using LC-MS/MS, and experienced maternal distress was assessed using the Hospital Anxiety and Depression Scale questionnaire. Three months after birth, infant behavior was assessed with the Infant Behavior Questionnaire, and infant sleep pattern was quantified by questionnaire. Associations between breast-milk GC rhythm parameters (maximum, delta, and Area Under the Curve increase and ground) and infant behavior and sleep were tested with linear regression analyses. No consistent associations between breast-milk GC rhythm parameters and infant behavior or sleep were found. Breast-milk GC rhythmicity at 1 month postpartum was not associated with infant behavior or sleep at the age of 3 months. Findings from previous studies linking breast-milk cortisol to infant neurodevelopment might be biased by the lack of GC measurements across the full diurnal cycle, and should therefore be interpreted with caution.


Genetic effects on physical activity: results from the Swedish Twin Registry.
The aim of this study was to investigate the genetic effects on leisure-time physical activity using data from the Swedish Twin Registry. We investigated 13,362 twin pairs (5334 monozygotic and 8028 dizygotic pairs) aged 14-46 yr. Information on leisure-time physical activity was obtained by questionnaire. Correlations and odds ratios of physical activity were calculated for males, females, and monozygotic and dizygotic twins, respectively. Structural equation modeling was used to estimate the contribution of genetic effects as well as common and nonshared environmental factors on leisure-time physical activity. About one third of the twins reported that they exercised regularly (26% in females and 39% in males). The correlations of physical activity were twice as high in monozygotic compared with dizygotic twins, suggesting the presence of genetic effects. The variation in physical activity due to heritage was 57% (95% confidence interval (CI) = 0.49-0.63) in males and 50% (95% CI = 0.49-0.55) in females. The common environmental influence on physical activity was very small compared with the influence from environmental factors unique to the individual. Our study establishes heredity as an important component behind individual differences in physical activity in adult men and women. This may be one reason behind difficulties in convincing people to adopt an active lifestyle. Still, this study shows that there is a substantial influence on physical activity from environmental factors unique to the individual.


Toxicity and immunogenicity of a verotoxin 1 mutant with reduced globotriaosylceramide receptor binding in rabbits.
The verotoxins (VT1 and VT2), produced by strains of enterohemorrhagic Escherichia coli, have been implicated in the pathogenesis of hemorrhagic colitis and the hemolytic uremic syndrome. To better understand the role of globotriaosylceramide (Gb3) receptor binding by the verotoxins in disease production, we examined the clinicopathologic effects of an intravenously (i.v.) administered verotoxin 1 mutant holotoxin (Phe30Ala) in rabbits. The substitution of alanine for phenylalanine 30 in the VT1 B subunit has been shown previously to reduce both Gb3 binding affinity and capacity in vitro. This reduction in receptor binding corresponded to a 10(5)-fold reduction in the toxic activity of VT1 on a Vero cell monolayer. In this study, purified 125I-labeled Phe30Ala was administered i.v. to rabbits to determine its specific distribution in rabbit tissues. In contrast to the rapid elimination of i.v. administered 125I-VT1 from the bloodstream, 125I-Phe30Ala had a 52-fold-longer half-life in serum and failed to localize preferentially in the gastrointestinal tract and central nervous system (CNS). Rabbits challenged with Phe30Ala at a dose equivalent to 10 times the 50% lethal dose (LD50) of VT1 showed no visible clinical symptoms typical of VT effect after 7 days. Administration of Phe30Ala at a dose equivalent to 100 times the LD50 of VT1, however, caused both clinical and histopathologic features indistinguishable from VT1 toxemia in rabbits, although the onset of symptoms was delayed. Rabbits were immunized with Phe30Ala and challenged i.v. with either 125I-VT1 or 125I-VT2. The specific uptake of 125I-VT1 in the gastrointestinal tract and CNS was totally inhibited in Phe30Ala immune rabbits. Only a partial decrease in target organ uptake was observed in Phe30Ala immune rabbits challenged with 125I-VT2. From this study, we conclude that Gb3 binding is responsible for target organ localization of VT1 and disease production in the rabbit. The ability of Phe30Ala to induce both strong antibody and protective responses against VT1 suggests that VT mutants with reduced receptor binding properties may be useful in vaccine strategies. A further reduction in the toxicity of Phe30Ala would be required for its use as a natural toxoid to protect against human verotoxigenic E. coli infections.


Effect of Saturated Stearic Acid on MAP Kinase and ER Stress Signaling Pathways during Apoptosis Induction in Human Pancreatic β-Cells Is Inhibited by Unsaturated Oleic Acid.
It has been shown that saturated fatty acids (FAs) have a detrimental effect on pancreatic β-cells function and survival, leading to apoptosis, whereas unsaturated FAs are well tolerated and are even capable of inhibiting the pro-apoptotic effect of saturated FAs. Molecular mechanisms of apoptosis induction and regulation by FAs in β-cells remain unclear; however, mitogen-activated protein (MAP) kinase and endoplasmic reticulum (ER) stress signaling pathways may be involved. In this study, we tested how unsaturated oleic acid (OA) affects the effect of saturated stearic acid (SA) on the p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) pathways as well as the ER stress signaling pathways during apoptosis induction in the human pancreatic β-cells NES2Y. We demonstrated that OA is able to inhibit all effects of SA. OA alone has only minimal or no effects on tested signaling in NES2Y cells. The point of OA inhibitory intervention in SA-induced apoptotic signaling thus seems to be located upstream of the discussed signaling pathways.


What do Clinicians Perceive as a Successful "Trial of Fluids"?: A Secondary Assessment of a Randomized Controlled Trial.
The aim of the study was to explore physician perceptions of the amount of fluid that demonstrates a successful "trial of fluids" (adequate fluid intake) in the emergency department in children who have had insufficient fluid intake at home. This is a secondary analysis of a randomized placebo-controlled trial of viscous lidocaine versus placebo in children aged 6 months to 8 years with acute infectious ulcerative mouth conditions (gingivostomatitis, ulcerative pharyngitis, or hand foot and mouth disease) and poor oral fluid intake. We measured the amount of fluid ingested in 60 minutes after administration of the intervention and related physician perception of adequate intake to measured intake. Given that there was little difference in oral intake between the treatment groups, the 2 arms were pooled for this analysis. One hundred participants were recruited (50 per treatment group), all of whom completed the 60-minute trial period. At baseline, 72% were mildly dehydrated, 21% were not dehydrated, and 5% were moderately dehydrated. The participants drank a median of 8.6 mL/kg (interquartile range [IQR], 3.7-14). Clinicians perceived 58% of the participants to have an adequate intake within the first hour after intervention. The median consumption of those whose oral intake was deemed as adequate was 12.6 mL/kg (IQR, 9.4-18.4); for those whose oral intake was not deemed adequate, the median consumption was 2.7 mL/kg (IQR, 0.7-5.3) (rank sum, P < 0.001). In children undergoing trial of fluids, we found that most clinicians perceived a fluid intake greater than 9 mL/kg as adequate and lower than 5 mL/kg as inadequate.


Calibrating GESPECOR model of computing the full-energy peak efficiency of coaxial high-purity germanium detectors by Monte Carlo simulation.
In this work, a classical approach was used for calibrating the GESPECOR detector model for computing the full-energy peak efficiency of p-type coaxial HPGe detectors that is based on the use of linear least squares optimization. The key element of the work is the multiplicative model developed for approximating the values of the full-energy peak efficiency provided by GESPECOR code. It was linearized using the logarithmic transformation to allow an easy use of the linear least squares optimization. A procedure was also developed to estimate the optimal values of the parameters, describing the p-type coaxial HPGe detectors. Its application to a Canberra detector GC3018 showed that it is possible to determine accurate values of the full-energy peak efficiency computed by GESPECOR code using the optimized parameter values.


Critical issues in mucosal immunity for HIV-1 vaccine development.
Development of a safe and effective vaccine for HIV-1 infection is a critical global priority. However, the nature of host-virus interactions that lead to early immunosuppression and CD4 depletion, HIV-1 diversity, and the inability of the immune system to eliminate the latently infected CD4 pool of cells has to date thwarted successful vaccine development. Moreover, both the initial antibody-inducing vaccine (protein envelope gp120) and cell-mediated vaccine (recombinant adenovirus containing HIV-1 genes) strategies have failed in efficacy trials, and the latter cell-mediated vaccine appeared to have caused enhanced HIV-1 acquisition. Thus basic and translational research to understand why current vaccines have failed and elucidation of new mechanisms of virus control at mucosal surfaces is essential for eventual successful development of a preventive HIV-1 vaccine.


Fatty liver hemorrhagic syndrome in the backyard chicken: a retrospective histopathologic case series.
Fatty liver hemorrhagic syndrome, characterized by sudden death in overconditioned hens due to hepatic rupture and hemorrhage, is one of the leading noninfectious idiopathic causes of mortality in backyard chickens. Nutritional, genetic, environmental, and hormonal factors, or combinations of these, have been proposed yet not proven as the underlying cause. In an attempt to characterize the hepatic changes leading to the syndrome, this retrospective case study examined 76 backyard chickens that were diagnosed with fatty liver hemorrhagic syndrome between January 2007 and September 2012 and presented for necropsy to the diagnostic laboratory of the California Animal Health and Food Safety Laboratory System. A majority of the birds were female (99%), obese (97.5%), and in active lay (69.7%). Livers were examined histologically, and the degree of hepatocellular vacuolation (lipidosis), the reticular stromal architecture, the presence of collagenous connective tissue, and vascular wall changes were evaluated and graded using hematoxylin and eosin, Gomori's reticulin, oil red O, Masson's trichrome, and Verhoeff-Van Gieson stains. Interestingly, there was no correlation between lipidosis and reticulin grades; hepatocellular lipidosis was absent in 22% of the cases and mild in 26% of the cases. Additionally, there was evidence of repeated bouts of intraparenchymal hemorrhage before the acute "bleed-out" in 35.5% of the cases. These data are not supportive of the previously proposed causes and provide a framework for future studies to elucidate the pathogenesis of this condition. Furthermore, the data shown in this study support hemorrhagic liver syndrome as a more accurate name, as hepatic lipidosis is absent in a significant proportion of ruptured livers.


Acellular vaccines for preventing whooping cough in children.
Routine use of whole cell pertussis vaccines was suspended in some countries in the late 1970s and early 1980s, leading to a resurgence of whooping cough. Acellular pertussis vaccines containing purified or recombinant Bordetella pertussis antigens were developed in the hope that they would be as effective but less toxic than the whole cell vaccines. The objective of this review was to assess the effects of acellular pertussis vaccines in children. The Cochrane Controlled Trials Register and Medline were searched up to January 1998. Double-blind randomised efficacy and safety trials of acellular pertussis vaccines in children, with active follow-up of participants and laboratory verification of pertussis cases. One reviewer assessed trial quality and extracted data. Six efficacy trials and 45 safety trials were included. Acellular pertussis vaccines with three or more pertussis vaccines were more effective than those with one or two antigens. They were also more effective than one type of whole cell pertussis vaccine, but less effective than two other types of whole cell vaccines. Differences in trial design precluded pooling of the efficacy data and results should be interpreted with caution. Most systemic and local adverse events were significantly less common with acellular than with whole cell pertussis vaccines. Multi-component acellular pertussis vaccines are effective, and show less adverse effects than whole cell pertussis vaccines. However in areas where whooping cough is more likely to be fatal, the higher toxicity of some whole cell vaccines may be offset by their increased effectiveness.


Involvement of c-src in beta-casein expression by mammary epithelial cells.
HC11 mouse mammary epithelial cells were stably transfected with c-src or a dominant negative mutant of c-src driven by a MMLV promoter. Prolactin increased c-src activity in control and c-src transfected cells, while dominant negative c-src reduced the prolactin-induced increase in c-src activity. Dominant negative c-src also reduced the ability of insulin, hydrocortisone, and prolactin to induce beta-casein accumulation to levels one-half to one-third that of control cells. This effect was uncorrelated with any change in cell proliferation or laminin accumulation and was observed both in cultures grown to confluency in the presence of EGF and in cultures grown on laminin.


Electrophysiologic effects of papillary muscle traction in the intact heart.
In this study we used transmural multipolar electrodes, sonomicrometers implanted within the left ventricular wall, and cardiac electrical stimulation techniques to examine the effect of transient mechanical posterior papillary muscle traction on local myocardial electrophysiologic characteristics. Nine open-chest dogs were atrially paced (cycle length 400 msec) followed by insertion of timed premature extrastimuli at left ventricular epicardial pacing sites either in the vicinity of (traction zone) or remote from (nontraction zone) the site of papillary muscle traction. Electrophysiologic recordings were made before and during periods of intermittent papillary muscle traction of predetermined timing, application rate (25 cm/sec), and duration (170 msec). Papillary muscle traction was applied in late diastole just before the last beat of each atrial drive train. In seven of nine dogs application of transient papillary muscle traction resulted in significantly earlier local ventricular activation (mean activation advancement 30 +/- 13 msec), altered QRS morphology of the last conducted atrial drive-train beat, and relative prolongation of ventricular functional refractory period in the traction zone. Conversely, in nontraction zones in these seven dogs, early activation did not occur and refractoriness remained unchanged as tested by a locally placed extrastimulus. In two of nine dogs traction failed to induce early activation and changes in refractoriness did not occur. Alterations in regional myocardial blood flow (assessed by radioactive microsphere technique) did not appear responsible for the observed changes, since there was no demonstrable traction-induced difference in regional blood flow between the traction and nontraction zones.(ABSTRACT TRUNCATED AT 250 WORDS)


A protocol for concurrent high-quality immunohistochemical and biochemical analyses in adult mouse central nervous system.
Biochemical analysis of central nervous system proteins and nucleic acids requires fresh-tissue homogenates, whereas immunohistochemistry usually is performed in sections prepared from perfusion-fixed tissue. Post-mortem immersion-fixation is possible, but largely impairs morphological preservation and protein antigenicity. Here, we present a simple, fast and versatile protocol allowing concurrent biochemical and immunohistochemical analysis, including pre-embedding immunoelectron microscopy, using tissue from the same animal. The protocol includes a brief transcardiac perfusion with ice-cold, oxygenated and glucose-supplemented artificial cerebrospinal fluid to maintain brain tissue alive, prior to isolation of regions of interest, followed by homogenisation for biochemistry or immersion-fixation for immunohistochemistry. We provide several examples demonstrating that this protocol allows optimal biochemical and morphological analysis, characterised with optimal sensitivity and preservation of tissue structure, along with a reduction of artefacts typically seen in perfusion-fixed tissue. This protocol should find widespread applications for combining analytical methods in tissue from the same animal, thereby reducing the number of mice required for a given experiment.


Metformin protects against systolic overload-induced heart failure independent of AMP-activated protein kinase α2.
Activation of AMP-activated protein kinase (AMPK)-α2 protects the heart against pressure overload-induced heart failure in mice. Although metformin is a known activator of AMPK, it is unclear whether its cardioprotection acts independently of an AMPKα2-dependent pathway. Because the role of AMPKα1 stimulation on remodeling of failing hearts is poorly defined, we first studied the effects of disruption of both the AMPKα1 and AMPKα2 genes on the response to transverse aortic constriction-induced left ventricular (LV) hypertrophy and dysfunction in mice. AMPKα2 gene knockout significantly exacerbated the degree of transverse aortic constriction-induced LV hypertrophy and dysfunction, whereas AMPKα1 gene knockout had no effect on the degree of transverse aortic constriction-induced LV hypertrophy and dysfunction. Administration of metformin was equally effective in attenuating transverse aortic constriction-induced LV remodeling in both wild-type and AMPKα2 knockout mice, as evidenced by reduced LV and lung weights, a preserved LV ejection fraction, and reduced phosphorylation of mammalian target of rapamycin (p-mTOR(Ser2448)) and its downstream target p-p70S6K(Thr389). These data support the notion that activation of AMPKα1 plays a negligible role in protecting the heart against the adverse effects of chronic pressure overload, and that metformin protects against adverse remodeling through a pathway that seems independent of AMPKα2.


VirB1* promotes T-pilus formation in the vir-Type IV secretion system of Agrobacterium tumefaciens.
The vir-type IV secretion system of Agrobacterium is assembled from 12 proteins encoded by the virB operon and virD4. VirB1 is one of the least-studied proteins encoded by the virB operon. Its N terminus is a lytic transglycosylase. The C-terminal third of the protein, VirB1*, is cleaved from VirB1 and secreted to the outside of the bacterial cell, suggesting an additional function. We show that both nopaline and octopine strains produce abundant amounts of VirB1* and perform detailed studies on nopaline VirB1*. Both domains are required for wild-type virulence. We show here that the nopaline type VirB1* is essential for the formation of the T pilus, a subassembly of the vir-T4SS composed of processed and cyclized VirB2 (major subunit) and VirB5 (minor subunit). A nopaline virB1 deletion strain does not produce T pili. Complementation with full-length VirB1 or C-terminal VirB1*, but not the N-terminal lytic transglycosylase domain, restores T pili containing VirB2 and VirB5. T-pilus preparations also contain extracellular VirB1*. Protein-protein interactions between VirB1* and VirB2 and VirB5 were detected in the yeast two-hybrid assay. We propose that VirB1 is a bifunctional protein required for virT4SS assembly. The N-terminal lytic transglycosylase domain provides localized lysis of the peptidoglycan cell wall to allow insertion of the T4SS. The C-terminal VirB1* promotes T-pilus assembly through protein-protein interactions with T-pilus subunits.


Prognostic value of plasma N-terminal probrain natriuretic peptide levels in the acute respiratory distress syndrome.
Patients with acute respiratory distress syndrome suffer from profound cardiac and pulmonary derangement, including right ventricular strain and noncardiogenic pulmonary edema, which may potentially alter concentrations of cardiac natriuretic peptides. We sought to determine whether N-terminal probrain natriuretic peptide (NT-proBNP) levels are elevated in acute respiratory distress syndrome and whether they can serve as a marker of prognosis in this setting. Prospective study. Tertiary-care academic medical center. One hundred seventy-seven acute respiratory distress syndrome subjects enrolled in a prospective intensive care unit cohort. None. NT-proBNP was measured from blood taken within 48 hrs of acute respiratory distress syndrome onset. Patients were followed for the primary outcome of 60-day mortality and secondary outcomes of organ dysfunction and ventilator-free days. Seventy patients died (40%). Median NT-proBNP level was 3181 ng/L (interquartile range 723-9246 ng/L). NT-proBNP levels were significantly higher among nonsurvivors (p < .0001). Receiver operating curve analysis revealed an optimal NT-proBNP cut-point of 6813 ng/L for predicting death. Patients with levels above the cut-point had significantly higher odds of mortality on multivariable analysis (odds ratio 2.36, 95% confidence interval 1.11-4.99, p = .02) than those with levels below the cut-point. Kaplan-Meier survival analysis showed that this difference emerged early and was sustained (p < .0001). Patients with elevated NT-proBNP also had higher organ dysfunction scores (p < .0001) and fewer ventilator free days (p = .03) than those with lower NT-proBNP levels. NT-proBNP levels are elevated among acute respiratory distress syndrome patients and parallel the severity of the syndrome and likelihood for morbidity and mortality. This demonstrates the potential utility of this biomarker for prognosis in this disease.


Comparative analysis of intestinal tract models.
The human gut is a complex ecosystem occupied by a diverse microbial community. Modulation of this microbiota impacts health and disease. The definitive way to investigate the impact of dietary intervention on the gut microbiota is a human trial. However, human trials are expensive and can be difficult to control; thus, initial screening is desirable. Utilization of a range of in vitro and in vivo models means that useful information can be gathered prior to the necessity for human intervention. This review discusses the benefits and limitations of these approaches.


Elastogram quality assessment score in vibration-controlled transient elastography: Diagnostic performance compared to digital morphometric analysis of liver biopsy in chronic hepatitis C.
Vibration-controlled transient elastography (VCTE) is widely used for noninvasive fibrosis staging in chronic hepatitis C. However, internal validation is based solely on variability and success rate and lacks reproducible quality indicators. We analysed the graphic representation of shear wave propagation in comparison with morphometric results of liver biopsy, eliminating observer variability bias. Individual elastograms were classified according to two morphologic criteria: extension of wave propagation (length of the graphic representation) and shear wave dispersal (level of parallelism displayed in the elastogram). Then, a score based on these criteria stratified the elastogram in classes I through III (highest to lowest technical quality). Liver stiffness results of each measurement were compared with collagen contents in liver biopsy by morphometric analysis. A total of 3243 elastograms were studied (316 patients). Digital morphometry in liver biopsy showed significant fibrosis in 66% of samples and advanced fibrosis in 31%. Elastogram quality analysis resulted in 1438 class I measurements (44%), 1070 class II (34%) and 735 class III. Area under the receiver operating curve (AUROC) for severe fibrosis according to class (I, II and III) was 0.941, 0.887 and 0.766, respectively. For advanced fibrosis, AUROCs were 0.977, 0.883 and 0.781, respectively. Spearman's correlation testing for all classes and levels of fibrosis demonstrated significant independent association (r2 = -.95, P < .01). Our study is the first to propose measurable quality criteria for VTCE and to validate them against objective assessment of liver biopsy through digital morphometric imaging analysis. We concluded that VCTE performance is significantly influenced by quality assessment of individual measurements. Considering these criteria in clinical practice may improve accuracy.


A multi-centre, single-blinded randomised controlled clinical trial evaluating the effect of resorbable glass fibre matrix in the treatment of diabetic foot ulcers.
Diabetic foot ulcers (DFUs) are at risk for detrimental complications even with current, standard of care (SOC) treatments. The primary objective of this randomised controlled trial was to compare a unique resorbable glass microfiber matrix (Mirragen; Advanced Wound Matrix [BBGFM]; ETS Wound Care, Rolla, Missouri) compared with a standard of care group (SOC, collagen alginate dressing) at 12 weeks. Both groups received standard diabetic foot care including glucose monitoring, weekly debridements when needed and an offloading device. The primary endpoint was proportion of full-thickness, non-infected, non-ischaemic wounds healed at 12 weeks, with secondary endpoints including percent area reduction (PAR) and changes in Semmes-Weinstein monofilament testing. The result illustrated in the intent-to-treat analysis at 12 weeks showed that 70% (14/20) of the BBGFM-treated DFUs healed compared with 25% (5/20) treated with SOC alone (adjusted P = .006). Mean PAR at 12 weeks was 79% in the BBGFM group compared with 37% in the SOC group (adjusted P = .027). Mean change in neuropathic score between baseline and up to 12 weeks of treatment was 2.0 in the BBGFM group compared with -0.6 in the SOC group where positive improvement in scores are better (adjusted P = .008). The mean number of BBGFM applications was 6.0. In conclusion, adding BBGFM to SOC significantly improved wound healing with no adverse events related to treatment compared with SOC alone.


High incidence of lymph node metastasis in major salivary gland cancer.
To analyze the incidence and risk factors for clinically apparent and occult lymph node metastases in patients with major salivary gland cancers. Cohort of patients with a median follow-up of 46 months (range, 1-174 months). University-based referral center. A total of 160 consecutive patients with complete clinical and pathologic data. Neck dissection was performed in all cases. Patients were treated with surgery alone (55%); surgery and radiation therapy (43%); or a combination of surgery, radiation, and chemotherapy (2%). Incidence of apparent and occult lymph node metastases. Univariate and multivariate analyses were used to evaluate the significance of clinical and pathologic data. Histologically confirmed positive neck was found in 53% of all cases. Histologic diagnosis was significantly related to the incidence of lymph node metastasis: 89% (16/18) for undifferentiated carcinomas. However, so-called low-risk tumors had incidence rates of 22% to 47%. Twenty-one patients (13%) presented with clinically apparent cervical lymph node metastasis. Of the 139 patients with clinical N0 neck, 45% had occult neck metastasis. Neck metastasis was found in 29% (10/34) of T1, 54% (38/70) of T2, 65% (20/31) of T3, and 54% (16/25) of T4 tumors. Assessment of survival according to nodal status revealed significant correlations for overall (P<.001) and disease-free survival (P<.001). We found a high incidence of lymph node metastasis from major salivary gland cancers. Neck dissections should be considered as an integral part of the surgical approach in patients with major salivary gland cancer, especially if no postoperative radiation therapy is planned.


Developing a Modular Unmanned Aerial Vehicle (UAV) Platform for Air Pollution Profiling.
The unmanned aerial vehicle (UAV) offers great potential for collecting air quality data with high spatial and temporal resolutions. The objective of this study is to design and develop a modular UAV-based platform capable of real-time monitoring of multiple air pollutants. The system comprises five modules: the UAV, the ground station, the sensors, the data acquisition (DA) module, and the data fusion (DF) module. The hardware was constructed with off-the-shelf consumer parts and the open source software Ardupilot was used for flight control and data fusion. The prototype UAV system was tested in representative settings. Results show that this UAV platform can fly on pre-determined pathways with adequate flight time for various data collection missions. The system simultaneously collects air quality and high precision X-Y-Z data and integrates and visualizes them in a real-time manner. While the system can accommodate multiple gas sensors, UAV operations may electronically interfere with the performance of chemical-resistant sensors. Our prototype and experiments prove the feasibility of the system and show that it features a stable and high precision spatial-temporal platform for air sample collection. Future work should be focused on gas sensor development, plug-and-play interfaces, impacts of rotor wash, and all-weather designs.


Successful topical application of Ankaferd blood stopper in a patient with life-threatening fundal variceal bleeding despite cyanoacrilate injection.
Gastric variceal bleeding is a common problem in patients with cirrhosis and despite early endoscopic and/or pharmacological therapy, variceal bleeding cannot be controlled or recurs early in about 10 to 20% of patients with considerable morbidity and mortality rates. For this reason, effective control of active bleeding varices is of great importance for the prevention of late complications. Although endoscopic band ligation and sclerotherapy are the choice of endoscopic treatment modalities with various grades of success, limited data is available for the use of Ankaferd Blood Stopper (ABS) for the controlling of variceal bleeding due to gastric varices. We herein present a unique case of gastric variceal bleeding despite cyanoacrilate injection, which was successfully controlled with topical ABS application.


Induced defense by Bemisia tabaci biotype B (Hemiptera: Aleyrodidae) in tobacco against Myzus persicae (Hemiptera: Aphididae).
Myzus persicae and Bemisia tabaci are serious pests of tobacco and can occur simultaneously on the same plant. We found that tobacco plants infested by whiteflies had fewer aphids than those without whiteflies. To determine whether B. tabaci feeding could induce plant defense against aphids locally and systemically, we determined the effects of B. tabaci on several biological parameters of M. persicae on tobacco. Infestation of B. tabaci nymphs reduced survival rates of M. persicae by 30.0%. In three generations, M. persicae populations increased 1,091-fold on uninfested plants compared with 222-fold on the plants with whiteflies. On the upper leaves with systemic damage but uninfested B. tabaci, the survival rate of aphids was 9.3-fold lower than that on plants that were never been infested by whitefly. Survival rates of M. persicae on leaves with whiteflies present or with whiteflies removed were also lower than those on uninfested leaves. Fecundity of M. persicae was not different on leaves with whiteflies, with whiteflies removed or uninfested leaves; however, fecundity on leaves with systemic damage was lower than on uninfested leaves. Growth rates of M. persicae on the leaves with whiteflies, or with whiteflies removed, were higher than on uninfested leaves, whereas it was lower on systemically damaged leaves than on uninfested leaves. The development of M. persicae was approximately 1 d longer on systemic leaves with whiteflies than on uninfested leaves. These results indicate that feeding of B. tabaci induced a defense in tobacco plants against M. persicae, both locally and systemically, although other mechanisms may also be involved.


Hispidin and related herbal compounds from Alpinia zerumbet inhibit both PAK1-dependent melanogenesis in melanocytes and reactive oxygen species (ROS) production in adipocytes.
Recently several compounds from Okinawa plants including Alpinia zerumbet (alpinia) were shown to inhibit directly the oncogenic/ageing kinase PAK1 (p21-activated kinase 1). Furthermore, it was recently revealed that both PAK1 and PAK4 (p21-activated kinase 4) are equally essential for the melanogenesis in melanoma cells. Thus, in this study, we tested if several alpinia compounds inhibit the melanogenesis in melanoma (B16F10) cells, as well as the PAK1-dependent up-regulation of both reactive oxygen species (ROS) and nitric oxide (NO) in cultured adipocytes (3T3-L1) without any cytotoxicity. The effect of alpinia compounds on the melanogenesis was measured by both the melanin content and intracellular tyrosinase activity in melanoma cells treated with 3-isobutyl-1-methylxanthine (IBMX), a melanogenesis stimulating hormone. We found that (1E,3E,5E)-6-methoxyhexa-1,3,5-trien-1-yl)-2,5-dihydrofuran (MTD), 5,6-dehydrokawain (DK), labdadiene, hispidin and dihydro-5,6-dehydrokawain (DDK) at 50 μg/mL reduced the melanin content by 63-79%. The MTD, DK and hispidin, at 50 μg/mL, inhibited tyrosinase activity by 70-83% in melanoma cells. Among these compounds, labdadiene, MTD, (E)-2,2,3,3-Tetramethyl8-methylene-7-(oct-6-en-1-yl)octahydro-1H-quinolizine (TMOQ) and hispidin strongly inhibited the ROS production. Hispidin, labdadiene and MTD at 20 μg/mL inhibited NO production by over 70%. These findings altogether suggest that some of these alpinia compounds could be potentially useful for the prevention or treatment of hyperpigmentation and obesity.


The impact of sinus computed tomography on treatment decisions for chronic sinusitis.
To determine the impact of sinus computed tomography (CT) on treatment decisions by otolaryngologists and to explore the factors leading to choice of surgical treatment for patients suspected of having chronic sinusitis. Prospective cohort study. A tertiary academic medical center. Questionnaires were administered to 3 otolaryngologists in a tertiary academic institution regarding diagnosis and treatment decisions in 27 patients suspected of having chronic sinusitis, before and after they reviewed sinus CT scans. The dichotomous decisions regarding surgical or nonsurgical treatment and the agreement of treatment decisions among surgeons were evaluated. The factors strongly influencing surgeons' treatment decisions regarding patients selected for surgery were also determined. The dichotomous treatment decisions were changed in one third of patients (9 of 27) after the sinus CT scans were reviewed. The agreement of treatment decisions among the 3 surgeons was markedly improved after they reviewed sinus CT scans. The factors favorably influencing surgical treatment were obstruction of the ostiomeatal complex on CT and concordance of CT abnormality with a patient's symptoms. Lund-Mackay stage, symptoms, and corticosteroid or antibiotic use were not significant predictors. Despite the common belief that treatment decisions for chronic sinusitis should be solely based on clinical grounds, with sinus CT providing only anatomic detail before surgery, our study indicates that the decision to perform surgery was altered by CT in a substantial portion of the patients. In our preliminary study, CT increased the tendency to elect surgical treatment by all 3 surgeons.


The Escherichia coli signal transducers PII (GlnB) and GlnK form heterotrimers in vivo: fine tuning the nitrogen signal cascade.
The PII protein is Escherichia coli's cognate transducer of the nitrogen signal to the NRII (NtrB)/NRI (NtrC) two-component system and to adenylyltransferase. Through these two routes, PII regulates both amount and activity of glutamine synthetase. GlnK is the recently discovered paralogue of PII, with a similar trimeric x-ray structure. Here we show that PII and GlnK form heterotrimers, in E. coli grown in nitrogen-poor medium. In vitro, fully uridylylated heterotrimers of the two proteins stimulated the deadenylylation activity of adenylyltransferase, albeit to a lower extent than homotrimeric PII-UMP. Fully uridylylated GlnK did not stimulate, or hardly stimulated, the deadenylylation activity. We propose that uridylylated PII/GlnK heterotrimers fine-regulate the activation of glutamine synthetase. The PII/GlnK couple is a first example of prokaryotic signal transducer that can form heterotrimers. Advantages of hetero-oligomer formation as molecular mechanism for fine-regulation of signal transduction are discussed.


Morphological and molecular characterization of Giardia isolated from the straw-necked ibis (Threskiornis spinicollis) in Western Australia.
Following the first report of avian Giardia infection in Australia, isolates of the parasite recovered from naturally infected straw-necked ibis (Theskiornis spinicollis) were characterized using median body morphology, scanning electron microscopy, multilocus enzyme electrophoresis, random amplified polymorphic DNA (RAPD), and small subunit ribosomal RNA (SSU-rRNA) analyses. Results were compared with Giardia from other birds and mammals, and the extent of genetic diversity between a range of ibis isolates collected in Western Australia was determined. The ibis isolates of Giardia were genetically relatively homogeneous, which is in contrast to the extensive genetic heterogeneity often displayed by mammalian Giardia isolates. Morphologically, Giardia from ibis were similar to Giardia ardeae although they differed genetically and by the fact that the ibis isolates could not be established in in vitro culture. Sequence data of the DNA coding for the SSU-rRNA found a 96% homology between the ibis isolates from Western Australia and G. ardeae, suggesting that they represent distinct strains of the same species. In contrast, the ibis isolates were genetically and morphologically very different than Giardia duodenalis and Giardia muris from mammals.


[Role of prostacyclin and its derivatives in the treatment of pulmonary arterial hypertension].
Pulmonary arterial hypertension (PAH) is defined as a group of diseases characterised by a progressive increase of pulmonary vascular resistance leading to right ventricular failure and death. A dysregulation of prostacyclin metabolic pathways has been demonstrated in patients with PAH and in experimental models. Recently, therapy with continuous intravenous prostacyclin (epoprostenol) has been shown to improve symptoms and prognosis in New York Heart Association (NYHA) functional class III and IV patients with different types of PAH. However, epoprostenol administration requires invasive methods with a permanent intravenous catheter and is associated with several side effects and potentially serious complications. Other modes of prostacyclin therapies are being considered using stable prostacyclin analogues administered by inhalation (iloprost), subcutaneously (treprostinil) or orally (beraprost). Over the last years, different multicenter international double-blind trials have demonstrated the efficacy of those novel prostacyclin analogues in PAH compared to conventional therapy promising a better future for these patients.


[Electrophysiological and morphological study of the synaptic organization of the tonic muscle fibers in the frog].
The histochemical and electrophysiological investigation of tonic muscle fibers was performed in the frog m. cruralis. Cholinesterase activity studies in tonic fibers revealed 4 to 14 synapses aggregated in groups. A number of synapses were in positive correlation with the muscle fibers length. In MPSP recording, the distribution of amplitude, periods of growth and of half-time decay had a nonsymmetrical form. At the scatter diagrams of MPSP amplitude recorded by two intracellular microelectrodes, two to six signal groups were revealed in single synapses at different distances from the site of recording. The groups were represented by different number of signals of various duration. Similar groups of signals were also found in evoked PSP, the number of such groups depending upon the intensity of nerve stimulation. The synapses formed by a single motor axon seem to congregate in certain areas of tonic fibers and to be functionally heterogeneous. Intracellular recording revealed only a part of the tonic fibre synapses.


The concept of type-1 and type-2 helper T cells and their cytokines in humans.
In both mice and humans, functionally distinct helper T (Th)-cell subsets, known as Th1 and Th2 cells, are characterized by the patterns of cytokines they produce. These two polarized forms of the specific cellular immune response provide a useful model for explaining not only the different types of protection, but also the pathogenic mechanisms of several immunopathological disorders. The development of polarized Th1 or Th2 responses depends on either environmental factors, including dose of antigen, nature of immunogen and cytokines (IL-12 and interferons or IL-4) at the time of antigen presentation, or other undefined factors in the individual genetic background, mainly at level of the so-called "natural immunity". Th1-dominated responses are potentially effective in eradicating infectious agents, including those hidden within the host cells. When the Th1 response is poorly effective or exhaustively prolonged, it may result in host damage. In contrast, Th2 responses are apparently insufficient to protect against the majority of infectious agents, but can provide some protection against parasites. Th2 cells are able to make unpleasant the life of parasites in the host and tend to limit potentially harmful Th1-mediated responses. Thus, Th2 cells may be regarded as a part of down regulatory (or suppressor) mechanism for exaggerated and/ or inappropriate Th1 responses. The Th1/Th2 paradigm applied to the study of chronic inflammatory disorders or autoimmune diseases allowed to understand that a number of diseases are mediated by Th1 cells, the two clearest examples being multiple sclerosis and thyroid autoimmunity. In other disorders, Th1/Th2 polarization is less prominent, or rather Th2 responses tend to predominate, such as in systemic lupus erythematosus, progressive systemic sclerosis or allergic diseases. It is of note that in experimental models in animals, a number of diseases can be prevented by switching immune responses from Th1 to Th2 or from Th2 to Th1. Moreover, the Th1/Th2 concept suggests that modulation of the relative contribution of Th1- or Th2-type cytokines makes possible to regulate the balance between protection and immunopathology, as well as the development and/or the severity of some immunologic disorders.


Nutritional value of enzyme- or sodium hydroxide-treated feathers from dead hens.
Two feather digestion processes to remove the feathers from the carcasses of dead hens were evaluated for their impact on the nutritional quality of the resulting feather meal. There were three treatments: control (untreated feathers), a feather-digesting enzyme, and NaOH treatment. Both enzyme- and NaOH-treated feathers were easily separated from the hen carcasses. The CP level of enzyme-treated feathers after autoclaving (49.90%) was significantly less than the control and NaOH-treated feathers (94.48 and 87.31%, respectively) because of elevated ether extract levels resulting from skin and abdominal fat release during the 12-h enzyme incubation. Before autoclaving, pepsin digestibilities of enzyme- and NaOH-treated feathers were significantly higher than the control. However, after autoclaving, no significant difference was found in pepsin digestibility between the control and enzyme treatments or control and NaOH treatments. The typical limiting amino acids, methionine, lysine, and histidine, in feathers were present at greater levels in the resulting enzyme-feather meal (E-FM) compared with the NaOH-feather meal (N-FM) or control-feather meal (C-FM) on a percentage of CP basis. Cystine levels, however, were significantly lower in the E-FM and N-FM compared with that of the C-FM. In chick bioassays, no significant differences were found in protein efficiency ratio (PER) and net protein ratio (NPR) among C-FM, E-FM, and N-FM. The AMEn of E-FM (4.52 kcal/g) was significantly higher than the C-FM (3.58) or N-FM (2.79). These findings indicated that although enzyme treatment could improve the nutritional quality of feathers from dead hens, NaOH treatment was a more rapid means of separating feathers from the carcass.


Rapid and selective apoptosis in human leukemic cells induced by Aplidine through a Fas/CD95- and mitochondrial-mediated mechanism.
Aplidine is a promising antitumor agent derived from the Mediterranean tunicate Aplidium albicans. We have found that Aplidine at nM concentrations (10-100 nM) induced apoptosis in human leukemic cell lines and primary leukemic cell cultures from leukemic patients. Inhibition of the Fas (CD95)/Fas ligand (CD95L) signaling pathway with an antagonistic anti-Fas antibody partially inhibited Aplidine-induced apoptosis. L929 cells were resistant to Aplidine action but underwent apoptosis after transfection with human Fas cDNA. Aplidine induced a rapid and sustained c-Jun NH(2)-terminal kinase activation, and pretreatment with curcumin or SP600125 inhibited Aplidine-induced c-Jun NH(2)-terminal kinase activation and apoptosis. However, inhibition of extracellular signal-regulated kinase and p38 kinase signaling pathways did not affect Aplidine-induced apoptosis. Aplidine induced caspase-3 activation, and caspase inhibition prevented Aplidine-induced apoptosis. Aplidine failed to induce apoptosis in MCF-7 breast cancer cells, defective in caspase-3, additionally implicating caspase-3 in its proapoptotic action. Aplidine also triggered an early release of cytochrome c from mitochondria, and overexpression of bcl-2 by gene transfer abrogated mitochondrial cytochrome c release and apoptosis. Aplidine rapidly induced cleavage of Bid, a mediator that connects the Fas/CD95 cell death receptor to the mitochondrial apoptosis pathway. Primary cultures of normal human cells, including hepatocytes and resting peripheral blood lymphocytes, were spared or weakly affected after Aplidine treatment. Nevertheless, mitogen (phytohemagglutinin/interleukin-2)-activated T lymphocytes resulted sensitively to the apoptotic action of Aplidine. Thus, Aplidine is an extremely potent and rapid apoptotic inducer on leukemic cells that triggers Fas/CD95- and mitochondrial-mediated apoptotic signaling routes, and shows a rather selective apoptotic action on cancer cells and activated T cells.


Learning curve for new technology?: a nationwide register-based study of 46,363 total knee arthroplasties.
The risk of early revision is increased for the first patients operatively treated with a newly introduced knee prosthesis. In this study, we explored the learning curves associated with ten knee implant models to determine their effect on early revision risk. We studied register data from all seventy-five surgical units that performed knee arthroplasty in Finland from 1998 to 2007. Of 54,925 patients (66,098 knees), 39,528 patients (46,363 knees) underwent arthroplasty for osteoarthritis of the knee with the ten most common total knee implants and were followed with complete data until December 31, 2010, or the time of death. We used a Cox proportional-hazards regression model for calculating the hazard ratios for early revision for the first fifteen arthroplasties and subsequent increments of numbers of arthroplasties. We found large differences among knee implants at the introduction with regard to the risk of early revision, as well as for the overall risk of early revision. A learning curve was found for four implant models, while six models did not show a learning effect on the risk of early revision. The survivorship of the studied prostheses showed substantial differences. Knee implants have model-specific learning curves and early revision risks. Some models are more difficult to implement than others. The manufacturers should consider the learning effect when designing implants and instrumentation. The surgeons should thoroughly familiarize themselves with the new knee implants before use.


[Hemorrhagic complications and thrombotic phenomena in oral anticoagulation of elderly patients].
To retrospectively analyze the hemorrhagic complications and thrombotic events associated with aging and the degree of anticoagulation in a series of ambulatory patients treated with acenocumarol and controlled in a specialized anticoagulant therapy unit. A total of 1,613 ambulatory patients were studied. Patients were divided into two groups (group 1, 645 patients > 65 years old, mean age 71.7 +/- 4.5 years; INR, 2.1-2.8; group 2, 968 patients < or = 65 years, mean age 53.7 +/- 10 years; INR, 2.8-4.2) for a time period of twelve months. The prevalence of hemorrhagic complications and severity according to a validated international index (Bleeding Severity Index), as well as the thrombotic events occurred despite anticoagulation therapy. Fifty-two hemorrhagic events (8/100 patients-year) were recorded in the older group (group 1). Twenty-six cases were considered banal episodes, 24 minor hemorrhages and two major hemorrhages. Ten patients (1.5/100 patients-year) had thrombotic complications. In the younger group (group 2) 150 bleeding episodes were recorded (15 patients-year), of which 11 were banal, 39 minor hemorrhages and no major hemorrhages. Only eight patients 0.8/100 patients-year) had thrombosis. The presence of local factors predisposing to bleeding was more common in group 1 (p < 0.001). Older patients had in general more complications than younger patients (p < 0.001), but no significant differences were observed between the occurrence of hemorrhages or thrombosis independently analyzed between both groups. The rate in the therapeutic range was greater among the youngest individuals (p < 0.05). Our results support the idea that patients with advanced age can benefit from a less aggressive anticoagulation. A statistical trend was observed, although not significant, towards the presence of major hemorrhages and thrombosis in this group of patients. The presence of local or predisposing factors to hemorrhage (underlying disease and NSAIDs use) is more relevant in patients with advanced age.


Circular Order Aggregation and its Application to Cell-cycle Genes Expressions.
The aim of circular order aggregation is to find a circular order on a set of n items using angular values from p heterogeneous data sets. This problem is new in the literature and has been motivated by the biological question of finding the order among the peak expression of a group of cell cycle genes. In this paper, two very different approaches to solve the problem that use pairwise and triplewise information are proposed. Both approaches are analyzed and compared using theoretical developments and numerical studies, and applied to the cell cycle data that motivated the problem.


Increased plasma osteoprotegerin concentrations are associated with indices of bone strength of the hip.
Osteoprotegerin (OPG) is an important regulator of bone turnover through its effects on osteoclastogenesis, yet findings from previous studies of circulating OPG and commonly measured bone indices in humans have been conflicting. We conducted a cross-sectional study to evaluate the association between plasma OPG and femoral neck (FN) bone density (BMD) and geometry in a large cohort of women and men. Participants included 1379 postmenopausal women and 1165 men, aged 50-89 yr (mean, 64 yr), in the Framingham Offspring Study. Dual x-ray absorptiometry was used to evaluate FN BMD and geometry (bone width, section modulus, and cross-sectional area at the narrow neck region). Plasma OPG concentrations were measured by ELISA. Sex-specific analysis of covariance was used to calculate means and assess linear trend in BMD and geometry values across OPG quartiles, adjusted for confounders. OPG concentrations were greater in women than men, increased with age, and were greater in smokers and those with diabetes and heart disease. Multivariable-adjusted mean FN BMD in women increased from the lowest to the highest OPG quartile (trend, P < 0.01). However, no linear trend between FN BMD and OPG was observed in men (trend, P = 0.34). Section modulus and bone width increased with OPG in men (trend, P < 0.01), whereas no association between hip geometry indices and OPG was observed in women. Higher OPG concentration may indicate greater skeletal strength in women and men, possibly through reducing bone loss in women and increasing periosteal apposition in men.


Dietary recommendations in the prevention and treatment of osteoporosis.
This article presents the initial recommendations of the French Rheumatology Society (Société Française de Rhumatologie - SFR) and the Osteoporosis Research and Information Group (Groupe de Recherche et d'Informations sur les Ostéoporoses - GRIO) on the role of diet in the prevention and treatment of osteoporosis. The recommendations were produced by a working group composed of rheumatologists, physician nutrition specialists and a geriatrician. Fifteen (15) questions pertaining to "daily practices" were preselected by the working group. For the literature review, the working group focussed mainly on the effects of diet on bone mineral density (BMD) and fractures, and primarily on meta-analyses of longitudinal studies and dietary intervention studies. A Mediterranean-type diet and the daily consumption of 2 to 3 dairy products are recommended. Together, these provide the calcium and "high quality" protein required to maintain a normal calcium-phosphorus balance and bone metabolism, and are associated with lower fracture risk. Conversely, unbalanced Western diets, vegan diets, weight-loss diets in non-overweight individuals, alcohol consumption and daily consumption of sodas are advised against. In terms of the beneficial effects on bone mineral density and fracture risk, current scientific data are either insufficient or too divergent to recommend increasing or restricting the consumption of tea or coffee, vitamins other than vitamin D, vitamin D-enriched or phytoestrogen-rich foods, calcium-enriched plant-based beverages, oral nutritional supplements, or dietary sources of prebiotics and probiotics. These are the first set of recommendations addressing the role of diet in the prevention and treatment of osteoporosis. More research is necessary to direct and support guidelines.


Mesenchymal Stem Cell Therapy for Autoimmune Disease: Risks and Rewards.
Mesenchymal stem cells (MSC) possess a range of immunomodulatory properties which they exert through soluble mediators and through direct cell-cell contact. Due to these immune regulatory properties, the safety and clinical efficacy of MSC treatment has been tested in a number of autoimmune disorders. In this review we analyze the current data from early phase trials into Crohn's disease, systemic lupus erythematosus, and rheumatoid arthritis. In general, no adverse side effects were observed in patients treated with MSC; however, their clinical efficacy is difficult to interpret. Systemic or site-specific administration of MSC has been reported to exert potent immunomodulatory effects in 7 of the 11 trials discussed. Nonetheless, the mechanism(s) by which MSC exert their regulatory effects in vivo remain largely unknown. We discuss potential limitations or safety concerns associated with MSC therapy, including the heterogeneity of MSC and their potential contribution to disease pathogenesis, which need to be considered when designing future clinical trials, along with the need to standardize trial design. Although we are bridging the translational gap between scientific observations on MSC function and clinical applications for therapy, our understanding of basic MSC biology is still limited. Despite these issues, large, double-blinded, multicenter clinical trials are already underway. Further research into the endogenous function of MSC is required to elucidate the mechanism by which therapeutic MSC are acting.