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The aim of this study was to analyze the effects of dual tasking on obstacle crossing during walking by individuals with Alzheimer's disease (AD) and by healthy older people. Thirty four elderly individuals (16 healthy subjects and 18 individuals with AD) were recruited to participate in this study. Three AD individuals and one control participant were excluded due to exclusion criteria. The participants were instructed to walk barefoot at their own speed along an 8 m long pathway. Each participant performed five trials for each condition (unobstructed walking, unobstructed walking with dual tasking, and obstacle crossing during walking with dual tasking). The trials were completely randomized for each participant. The mid-pathway stride was measured in the unobstructed walking trials and the stride that occurred during the obstacle avoidance was measured in the trials that involved obstacle crossing.

Is obstacle crossing with dual tasking a danger for individuals with Alzheimer 's disease and for healthy older people?

Advances in digital imaging methods have resulted in use of telecytology in the immediate assessment of fine-needle aspiration (FNA) specimens. We retrospectively compared the nondiagnostic rate for endoscopic ultrasound-guided (EUS) FNA of pancreatic lesions in two groups: one with on-site evaluation for adequacy via telecytopathology and the other without on-site adequacy evaluation. All patients undergoing EUS-FNA of pancreatic lesions over a 2-year period were included. Direct smears were immediately wet-fixed or air-dried, and any residual material was rinsed in saline for cell block or cytospin preparation. Patients were divided into two groups: Group 1 had on-site telecytopathology evaluation for adequacy by a cytopathologist, and Group 2 had no on-site adequacy evaluation. The cytologic diagnoses were reviewed, and the nondiagnostic rates for each group were calculated. The age, sex, and characteristics of pancreatic lesions (solid versus cystic) between the two groups were compared. In total, 217 patients were included. Telecytopathology on-site evaluation was provided for 95 (43.8%) cases. There was no difference between the groups in terms of age and sex. Pancreatic lesions were predominantly solid in the group that underwent telecytopathology on-site evaluation (p<0.005). The nondiagnostic rates for solid lesions in Group 1 and Group 2 were 3.7% and 25.6%, respectively (p<0.0001). Although the nondiagnostic rate for cystic lesion was higher in Group 2, it did not reach a level of statistical significance (16.5% versus 7.1%; p=0.249). After adjusting for the effects of sex and lesion characteristics (solid versus cystic lesion) with multivariate logistic regression, the odds of having a nondiagnostic specimen in Group 2 was 6.9 times greater than in Group 1, and the result was statistically significant (p=0.0013).

Does telecytopathology for on-site adequacy evaluation decrease the nondiagnostic rate in endoscopic ultrasound-guided fine-needle aspiration of pancreatic lesions?

Serum KL-6 is a useful biomarker for the diagnosis of interstitial lung diseases (ILD). However, KL-6 has not been used to discriminate different types of ILD. Serum KL-6 concentrations can vary depending on antigen exposure levels in patients with hypersensitivity pneumonitis (HP); however, seasonal changes in serum KL-6 concentrations in ILD have not been determined. We hypothesized that seasonal variation of serum KL-6 is greater in HP than for the other ILD. The aim of this study was to determine seasonal variation of serum KL-6 concentrations in various ILD. Serum KL-6 concentrations in the summer season from June 1 to September 30 and the winter season from November 1 to February 28 were retrospectively analyzed in patients with idiopathic pulmonary fibrosis (IPF, n=16), non-specific interstitial pneumonia (NSIP, n=16), collagen vascular disease-associated interstitial pneumonia (CVD-IP, n=33), house-related HP (House-HP, n=9), bird-related HP (Bird-HP, n=9), and combined pulmonary fibrosis and emphysema (CPFE, n=13). Bird-HP and House-HP showed greater seasonal serum KL-6 variation than the other ILD. Serum KL-6 concentrations in Bird-HP were significantly increased in the winter and KL-6 concentrations in House-HP were significantly increased in the summer. Serum KL-6 variation was significantly greater in acute HP than chronic HP. Receiver operating characteristic curve analysis revealed that greater seasonal variation in serum KL-6 concentrations is diagnostic for Bird-HP.

Is seasonal variation of serum KL-6 concentrations greater in patients with hypersensitivity pneumonitis?

EEG and somatosensory evoked potential are highly predictive of poor outcome after cardiac arrest; their accuracy for good recovery is however low. We evaluated whether addition of an automated mismatch negativity-based auditory discrimination paradigm (ADP) to EEG and somatosensory evoked potential improves prediction of awakening. EEG and ADP were prospectively recorded in 30 adults during therapeutic hypothermia and in normothermia. We studied the progression of auditory discrimination on single-trial multivariate analyses from therapeutic hypothermia to normothermia, and its correlation to outcome at 3 months, assessed with cerebral performance categories. At 3 months, 18 of 30 patients (60%) survived; 5 had severe neurologic impairment (cerebral performance categories = 3) and 13 had good recovery (cerebral performance categories = 1-2). All 10 subjects showing improvements of auditory discrimination from therapeutic hypothermia to normothermia regained consciousness: ADP was 100% predictive for awakening. The addition of ADP significantly improved mortality prediction (area under the curve, 0.77 for standard model including clinical examination, EEG, somatosensory evoked potential, versus 0.86 after adding ADP, P = 0.02).

Does automated auditory mismatch negativity paradigm improve coma prognostic accuracy after cardiac arrest and therapeutic hypothermia?

Manual scoring of sleep relies on identifying certain characteristics in polysomnograph (PSG) signals. However, these characteristics are disrupted in patients with neurodegenerative diseases. This study evaluates sleep using a topic modeling and unsupervised learning approach to identify sleep topics directly from electroencephalography (EEG) and electrooculography (EOG). PSG data from control subjects were used to develop an EOG and an EEG topic model. The models were applied to PSG data from 23 control subjects, 25 patients with periodic leg movements (PLMs), 31 patients with idiopathic REM sleep behavior disorder (iRBD) and 36 patients with Parkinson's disease (PD). The data were divided into training and validation datasets and features reflecting EEG and EOG characteristics based on topics were computed. The most discriminative feature subset for separating iRBD/PD and PLM/controls was estimated using a Lasso-regularized regression model. The features with highest discriminability were the number and stability of EEG topics linked to REM and N3, respectively. Validation of the model indicated a sensitivity of 91.4% and a specificity of 68.8% when classifying iRBD/PD patients.

Does data-driven modeling of sleep EEG and EOG reveal characteristics indicative of pre-Parkinson 's and Parkinson 's disease?

To find permanent prostate implant (PPI) pre-plan dosimetric parameters that predict post-implant D90 ≥ 140 Gy. Pre-plans were evaluated for 504 patients undergoing PPI with (125)I seeds for low or intermediate risk prostate cancer. Baseline patient and disease factors, numbers of seeds, ratios of number of seeds to available positions (occupancy proportion), and distances between the 100% isodose line and edge of the prostate (margin) planned for the whole prostate (WP), superior (S), inferior (I), anterior (A), and posterior (P) halves, SA, SP, IA, and IP quarters, and superior (ST), inferior (IT), and middle (MT) thirds, and anterior (AT) and posterior (PT) middle one-sixth segments were analyzed by post-implant D90 subset (≥ 140 Gy vs. < 140 Gy). 20% had post-implant D90 < 140 Gy (mean: 128.0 Gy, range: 97.5-139.2) vs. ≥ 140 Gy (mean: 154.4 Gy, range: 140.0-193.5). The D90 ≥ 140 Gy subset had larger AT and IA segment mean numbers of seeds (p = 0.01, 0.046), larger WP, S, A, SA, ST, AT, and MT segment mean margins (p = 0.01, 0.01, 0.001, 0.0001, 0.03, 0.005, 0.02), and lower PT segment occupancy proportion (p = 0.004). On multivariate analysis, independent predictors of post-implant D90 ≥ 140 Gy were increased SA mean margin, no pre-implant 5-α-reductase inhibitor, higher pre-plan D90, decreased P occupancy proportion, no pre-implant hormone therapy, and decreased SP mean margin.

Do pre-plan parameters predict post-implant D90 ≥ 140 Gy for ( 125 ) I permanent prostate implants?

Parkinson's disease (PD) is the second most common neurodegenerative movement disorder, caused by preferential dopaminergic neuronal cell death in the substantia nigra, a process also influenced by oxidative stress. L-3,4-dihydroxyphenylalanine (L-DOPA) represents the main treatment route for motor symptoms associated with PD however, its exact mode of action remains unclear. A spectrum of conflicting data suggests that L-DOPA may damage dopaminergic neurons due to oxidative stress whilst other data suggest that L-DOPA itself may induce low levels of oxidative stress, which in turn stimulates endogenous antioxidant mechanisms and neuroprotection. In this study we performed a two-dimensional gel electrophoresis (2DE)-based proteomic study to gain further insight into the mechanism by which L-DOPA can influence the toxic effects of H2O2 in neuronal cells. We observed that oxidative stress affects metabolic pathways as well as cytoskeletal integrity and that neuronal cells respond to oxidative conditions by enhancing numerous survival pathways. Our study underlines the complex nature of L-DOPA in PD and sheds light on the interplay between oxidative stress and L-DOPA.

Does proteome analysis reveal roles of L-DOPA in response to oxidative stress in neurons?

The optimal timing of surgery for multiply injured patients with operative spinal injuries remains unknown. The purported benefits of early intervention must be weighed against the morbidity of surgery in the early post-injury period. The performance of spine surgery in the Afghanistan theater permits analysis of the morbidity of early surgery on military casualties. The objective is to compare surgical morbidity of early spinal surgery in multiply injured patients versus stable patients. Patients were retrospectively categorized as stable or borderline unstable depending on the presence of at least one of the following: ISS >40, ISS >20 and chest injury, exploratory laparotomy or thoracotomy, lactate >2.5 mEq/L, platelet <110,000/mm(3), or >10 U PRBCs transfused pre-operatively. Surgical morbidity, complications, and neurologic improvement between the two groups were compared retrospectively. 30 casualties underwent 31 spine surgeries during a 12-month period. 16 of 30 patients met criteria indicating a borderline unstable patient. Although there were no significant differences in the procedures performed for stable and borderline unstable patients as measured by the Surgical Invasiveness Index (7.5 vs. 6.9, p = 0.8), borderline unstable patients had significantly higher operative time (4.3 vs. 3.0 h, p = 0.01), blood loss (1,372 vs. 366 mL, p = 0.001), PRBCs transfused intra-op (3.88 vs. 0.14 U, p < 0.001), and total PRBCs transfused in theater (10.18 vs. 0.31 U, p < 0.001).

Do morbidity of early spine surgery in the multiply injured patient?

Lipopolysaccharide (LPS) is considered a prominent pathogenic factor in inflammatory bone diseases. LPS challenge contributes to the production of reactive oxygen species (ROS) in diverse inflammatory diseases. However, its mechanism remains to be clarified in bone. Thus, we investigated the critical mechanism of ROS in LPS-induced osteoclastogenesis and bone loss. Antioxidant prevented LPS-induced osteoclast formation via inhibition of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and c-Fos expression in preosteoclasts. Moreover, LPS-induced osteoclast formation via ROS was attenuated by treatment with c-Jun N-terminal protein kinase (JNK) inhibitor. Interestingly, LPS also activated signal transducer and activator of transcription 3 (STAT3), which is suppressed by antioxidants. We found that knockdown of STAT3 or use of a STAT3 inhibitor resulted in a significant reduction in interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and nitric oxide (NO) production, followed by decreased osteoclast formation by LPS. Peroxiredoxin II (PrxII) is a member of the antioxidant enzyme family, and it plays a protective role against oxidative damage caused by ROS. In our study, ROS production and osteoclast formation by LPS was significantly enhanced in PrxII(-/-) cells. Moreover, JNK-mediated c-Fos and NFATc1 expression was promoted in PrxII(-/-) cells. Furthermore, STAT3 activation and accompanying IL-1β, IL-6, and NO production was also increased in PrxII(-/-) cells. Consistent with the in vitro result, PrxII-deficient mice showed increased osteoclast formation and bone loss by LPS challenge compared with wild-type mice. For the first time, we showed that LPS-induced ROS signaling is dependent on the coordinated mechanism of JNK and STAT3 during osteoclastogenesis, which is negatively regulated by PrxII.

Does peroxiredoxin II negatively regulate lipopolysaccharide-induced osteoclast formation and bone loss via JNK and STAT3?

Synovial sarcoma (SS) is an aggressive soft-tissue tumor. Despite being considered as a chemosensitive disease, the real impact of perioperative chemotherapy on metastasis-free survival (MFS) is controversial. We have shown that metastatic relapse of SS is strongly associated with genomic complexity. There are no data regarding the potential correlation between genomic complexity and response to chemotherapy. The study population included 65 SS patients diagnosed between 1991 and 2013 and with available tissue material. Genomic profiling was carried out by using array-CGH. Forty-five SS out of the 65 patients were treated with neoadjuvant anthracycline/ifosfamide-based chemotherapy. Radiological response was assessed according to RECIST criteria. Histological response was defined by the percentage of recognizable tumor cells on the surgical specimen. Genomic complexity was significantly associated with MFS. However, there was no statistically significant association between radiological or histological response and genomic complexity.

Is response to chemotherapy related to chromosome instability in synovial sarcoma?

Studies on the role of labour market position and change in alcohol use during midlife are scarce and their results are inconclusive mainly due to their failure to define comprehensive and distinct labour market groups and the short periods of time studied. In this study we used different activity categories for men and women to examine alcohol use trajectories in midlife covering a period of 17 years. Using data from four sweeps of the National Child Development Study covering ages 33-50 (N=9960), we used multilevel growth models to study the association between labour market categories and longitudinal changes in weekly units of alcohol consumed. In the reference group of full-time employed men alcohol trajectory decreased over the follow-up period (β=-0.14; 95% CI -0.18 to -0.11) while in the reference group of employed women it increased (β=0.06; 95% CI 0.04 to 0.08). Men and women who were 'mainly sick' had significantly steeper declines in their alcohol consumption trajectory. Women who became employed after being homemakers had the steepest increase in alcohol use (β=0.05; 95% CI 0.01 to 0.09).

Do the relationship between labour market categories and alcohol use trajectories in midlife?

The non-neuronal acetylcholine system (NNAS) in endothelial cells participates in modulating endothelial function, vascular tone, angiogenesis and inflammation, thus plays a critical role in cardiovascular diseases. In this study, we used a proteomic approach to study potential downstream receptor-effectors of NNAS that were involved in regulating cellular function in endothelial cells. Human umbilical vein endothelial cells were incubated in the presence of acetylcholine, oxotremorine, pilocarpine or nicotine at the concentration of 10 μmol/L for 12 h, and the expressed proteins in the cells were separated and identified with two-dimensional electrophoresis (2-DE) and LC-MS. The protein spots with the largest changes were identified by LC-MS. Biowork software was used for database search of the peptide mass fingerprints. Over 1200 polypeptides were reproducibly detected in 2-DE with a pH range of 3-10. Acetylcholine, oxotremorine, pilocarpine and nicotine treatment caused 16, 9, 8 and 9 protein spots, respectively, expressed differentially. Four protein spots were identified as destrin, FK506 binding protein 1A (FKBP1A), macrophage migration inhibitory factor (MIF) and profilin-1. Western blotting analyses showed that treatment of the cells with cholinergic agonists significantly decreased the expression of destrin, FKBP1A and MIF, and increased the expression of profilin-1.

Does proteomics reveal potential non-neuronal cholinergic receptor-effectors in endothelial cells?

Among many neglected tropical diseases endemic in Honduras, soil-transmitted helminth (STH) infections are of particular importance. However, knowledge gaps remain in terms of risk factors involved in infection transmission. The aim of this study was to investigate risk factors associated with STH infections in schoolchildren living in rural Honduras. A cross-sectional study was conducted among Honduran rural schoolchildren in 2011. Demographic, socio-economic, and epidemiological data were obtained through a standardized questionnaire and STH infections were determined by the Kato-Katz method. Logistic regression models accounting for school clustering were used to assess putative risk factors for infection. A total of 320 children completed the study. Prevalences for any STH and for Ascaris lumbricoides, Trichuris trichiura and hookworms were: 72.5%, 30.3%, 66.9% and 15.9%, respectively. A number of risk factors were identified at the individual, household, and school level. Boys were at increased odds of infection with hookworms (OR 2.33, 95% CI = 1.23-4.42). Higher socio-economic status in the family had a protective effect against infections by A. lumbricoides (OR 0.80, 95% CI = 0.65-0.99) and T. trichiura (OR 0.77, 95% CI = 0.63-0.94).Low school hygiene conditions significantly increased the odds for ascariasis (OR 14.85, 95% CI = 7.29-30.24), trichuriasis (OR 7.32, 95% CI = 3.71-14.45), mixed infections (OR 9.02, 95% CI = 4.66-17.46), and ascariasis intensity of infection (OR 3.32, 95% CI = 1.05 -10.52).Children attending schools not providing deworming treatment or that had provided it only once a year were at increased odds of ascariasis (OR 10.40, 95% CI = 4.39-24.65), hookworm (OR 2.92, 95% CI = 1.09-7.85) and mixed infections (OR 10.57, 95% CI = 4.53-24.66).

Are school hygiene and deworming key protective factors for reduced transmission of soil-transmitted helminths among schoolchildren in Honduras?

Stress acclimation is an effective mechanism that plants acquired for adaption to dynamic environment. Even though generally considered to be sensitive to low temperature, Cassava, a major tropical crop, can be tolerant to much lower temperature after chilling acclimation. Improvement to chilling resistance could be beneficial to breeding. However, the underlying mechanism and the effects of chilling acclimation on chilling tolerance remain largely unexplored. In order to understand the mechanism of chilling acclimation, we profiled and analyzed the transcriptome and microRNAome of Cassava, using high-throughput deep sequencing, across the normal condition, a moderate chilling stress (14°C), a harsh stress (4°C) after chilling acclimation (14°C), and a chilling shock from 24°C to 4°C. The results revealed that moderate stress and chilling shock triggered comparable degrees of transcriptional perturbation, and more importantly, about two thirds of differentially expressed genes reversed their expression from up-regulation to down-regulation or vice versa in response to hash stress after experiencing moderate stress. In addition, microRNAs played important roles in the process of this massive genetic circuitry rewiring. Furthermore, function analysis revealed that chilling acclimation helped the plant develop immunity to further harsh stress by exclusively inducing genes with function for nutrient reservation therefore providing protection, whereas chilling shock induced genes with function for viral reproduction therefore causing damage.

Does chilling acclimation provide immunity to stress by altering regulatory networks and inducing genes with protective functions in cassava?

Long-QT syndrome (LQTS), a cardiac arrhythmia disorder with variable phenotype, often results in devastating outcomes, including sudden cardiac death. Variable expression, independently from the primary disease-causing mutation, can partly be explained by genetic modifiers. This study investigates variants in a known LQTS-causative gene, AKAP9, for potential LQTS-type 1-modifying effects. Members of a South African LQTS-type 1 founder population (181 noncarriers and 168 mutation carriers) carrying the identical-by-descent KCNQ1 p.Ala341Val (A341V) mutation were evaluated for modifying effects of AKAP9 variants on heart rate-corrected QT interval (QTc), cardiac events, and disease severity. Tag single nucleotide polymorphisms in AKAP9 rs11772585, rs7808587, rs2282972, and rs2961024 (order, 5'-3'positive strand) were genotyped. Associations between phenotypic traits and alleles, genotypes, and haplotypes were statistically assessed, adjusting for the degree of relatedness and confounding variables. The rs2961024 GG genotype, always represented by CGCG haplotype homozygotes, revealed an age-dependent heart rate-corrected QT interval increase (1% per additional 10 years) irrespective of A341V mutation status (P=0.006). The rs11772585 T allele, found uniquely in the TACT haplotype, more than doubled (218%) the risk of cardiac events (P=0.002) in the presence of A341V; additionally, it increased disease severity (P=0.025). The rs7808587 GG genotype was associated with a 74% increase in cardiac event risk (P=0.046), whereas the rs2282972 T allele, predominantly represented by the CATT haplotype, decreased risk by 53% (P=0.001).

Is aKAP9 a genetic modifier of congenital long-QT syndrome type 1?

Periodontitis is a chronic, polymicrobial inflammatory disease that degrades connective tissue and alveolar bone and results in tooth loss. Oxidative stress has been linked to the onset of periodontal tissue breakdown and systemic inflammation, and the success of antiresorptive treatments will rely on how effectively they can ameliorate periodontal disease-induced oxidative stress during oral infection. Rats were infected with polybacterial inoculum consisting of Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia, as an oral lavage every other week for 12 weeks. Daily subcutaneous injections of enoxacin, bis-enoxacin, alendronate, or doxycycline were administered for 6 weeks after 6 weeks of polybacterial infection in rats. The serum levels of oxidative stress parameters and antioxidant enzymes, including glutathione peroxidase, superoxide dismutase, and catalase, were evaluated in each of the infected, treated, and sham-infected rats. Rats infected with the periodontal pathogens displayed a five-fold increase in the oxidative stress index compared with controls as a result of increased levels of serum oxidants and decreases in total antioxidant activity. The overall decrease in antioxidant activity occurred despite increases in three important antioxidant enzymes, suggesting an imbalance between antioxidant macromolecules/small molecules production and antioxidant enzyme levels. Surprisingly, the bone-targeted antiresorptives bis-enoxacin and alendronate inhibited increases in oxidative stress caused by periodontitis. Bis-enoxacin, which has both antiresorptive and antibiotic activities, was more effective than alendronate, which acts only as an antiresorptive.

Does periodontitis in rats induce systemic oxidative stress that is controlled by bone-targeted antiresorptives?

The sagittal fibular axis serves as an intra-operative landmark during conventional total knee arthroplasty (TKA); however, only a few relevant anatomical studies have been published regarding its use as an extramedullary guide. Furthermore, the correlation between the coronal fibular and tibial mechanical axes in osteoarthritic knees has been only reported once. Here, the hypothesis of this study is that the fibula can be a reliable intra-operative landmark, in the sagittal and coronal planes, among patients with osteoarthritis who have undergone TKA. Osteoarthritic knees (n = 62) after TKA were evaluated using three-dimensional image-matching software. The angles between the tibial mechanical axis and the fibular shaft axis were measured in the sagittal and coronal planes. Moreover, correlations between the angles and patient-specific factors were evaluated. The mean angle between the tibial mechanical and fibular shaft axes was 2.6° ± 2.3° for posterior inclination in the sagittal plane and 0.9° ± 2.0° for varus inclination in the coronal plane. The percentage of subjects with the fibular shaft axis within 2° of the tibial mechanical axis was 17.7 and 69.3 % in the sagittal and coronal planes, respectively. No patient-specific factors were correlated with the angle between the tibial mechanical and fibular shaft axes.

Are fibular axes a reliable landmark for tibial mechanical axes of osteoarthritic knees that underwent total knee arthroplasty?

Patients with glioblastoma multiforme (GBM) have an overall median survival of 15 months. This catastrophic survival rate is the consequence of systematic relapses that could arise from remaining glioblastoma stem cells (GSCs) left behind after surgery. We previously demonstrated that GSCs are able to escape the tumor mass and specifically colonize the adult subventricular zones (SVZs) after transplantation. This specific localization, away from the initial injection site, therefore represents a high-quality model of a clinical obstacle to therapy and relapses because GSCs notably retain the ability to form secondary tumors. In this work, we questioned the role of the CXCL12/CXCR4 signaling in the GSC-specific invasion of the SVZs. We demonstrated that both receptor and ligand are respectively expressed by different GBM cell populations and by the SVZ itself. In vitro migration bio-assays highlighted that human U87MG GSCs isolated from the SVZs (U87MG-SVZ) display stronger migratory abilities in response to recombinant CXCL12 and/or SVZ-conditioned medium (SVZ-CM) compared with cancer cells isolated from the tumor mass (U87MG-TM). Moreover, in vitro inhibition of the CXCR4 signaling significantly decreased the U87MG-SVZ cell migration in response to the SVZ-CM. Very interestingly, treating U87MG-xenografted mice with daily doses of AMD3100, a specific CXCR4 antagonist, prevented the specific invasion of the SVZ. Another in vivo experiment, using CXCR4-invalidated GBM cells, displayed similar results.

Do adult mouse subventricular zones stimulate glioblastoma stem cells specific invasion through CXCL12/CXCR4 signaling?

The effects of exercise training on nocturnal blood pressure (BP) dipping status remain unclear. African Americans have the highest prevalence of nondippers compared with other racial/ethnic populations. In this 6-month study we tested the hypothesis that long-term aerobic exercise training would increase the levels of nocturnal BP dipping in African American nondippers. We recruited African Americans who were nondiabetic, nonsmoking, and free from cardiovascular and renal disease. For this analysis, only African Americans with a nondipping profile, defined as those with the absence of a nocturnal decline in systolic or diastolic BP (<10% of daytime values), which was determined by ambulatory BP monitoring, were chosen. A pre-post design was used, with baseline and final evaluation including office blood pressure measurement, 24-h ambulatory blood pressure monitoring, fasted blood sampling, and graded exercise testing. Participants engaged in 6 months of supervised aerobic exercise training (AEXT). Following the AEXT intervention, there were significant increases in systolic BP dipping (baseline: 5.8±3.9% vs. final: 9.4±6.1%, P=0.0055) and pulse pressure dipping (baseline: -3.1±6.6% vs. final: 5.0±12.8%, P=0.0109). Of the 18 participants with a nondipping profile at baseline, eight were nonclassified as nondippers after the AEXT intervention. There were no significant changes in office systolic BP/diastolic BP values following the AEXT intervention.

Does chronic aerobic exercise improve blood pressure dipping status in African American nondippers?

Transcatheter aortic valve implantation (TAVI) without predilatation has fewer procedural steps and thereby potentially fewer complications. This has been demonstrated for the antegrade transapical access; however, whether TAVI can be safely performed without predilatation using the retrograde transfemoral route is unknown. We postulated that TAVI is feasible with a balloon-expandable device without predilatation using the retrograde transfemoral route. Twenty-six consecutive patients with stenosis of the native aortic valve (AV) undergoing transfemoral TAVI with the Edwards SAPIEN XT prosthesis without predilatation were enrolled in this retrospective study and compared with 30 patients treated previously with predilatation. The procedure was successfully performed in all 26 patients, irrespective of the AV area and the extent of AV calcification. At baseline mean AV area, mean AV gradient, and median left ventricular ejection fraction were 0.7 ± 0.2 cm(2) , 36.0 ± 17.3 mm Hg, and 55.0% (interquartile range [IQR], 35.0-60.0], respectively; prior to discharge these values were 1.7 ± 0.3 (P < 0.001), 9.8 ± 6.1 mm Hg (P < 0.001), and 57.5% (IQR, 38.7-60.0) (P = not significant). Postdilatation was required in 3 patients due to aortic regurgitation > 2°; this was reduced by the procedure to < 2° in all cases. Radiation dose and amount of contrast dye were significantly reduced in comparison with the predilatation group. No periprocedural neurological adverse events occurred. Mortality at 30 days was 0%.

Is transfemoral aortic valve implantation of Edwards SAPIEN XT without predilatation feasible?

Human papillomaviruses (HPV) seem to be related to distant metastasis (DM) in advanced oral cavity squamous cell carcinoma (OSCC) patients. This study aimed to investigate whether high-risk HPV viral load may predict DM among OSCC patients and stratify patients for risk-adapted treatment. Viral loads of E7 oncogenes for HPV 16/18 were measured by quantitative PCR tests in paraffin-embedded lesional specimens from 312 OSCC of which the HPV genotypes had been determined previously. Multivariable Cox regression analysis was used to identify the independent prognostic factors for 5-year DM and C statistics were further computed. By multivariable analysis, high HPV 16 E7 viral load (≥15.0 copies/genome); high HPV 18 E7 viral load (≥15.0 copies/genome); pathological N2 status (pN2); tumor depth ≥11 mm; extracapsular spread (ECS); and level IV/V metastases were independent risk factors for DM. We further identified three prognostic groups. In the high-risk group (level IV/V metastases or high HPV 16/18 E7 viral load plus pN2, tumor depth ≥11 mm, or ECS), the 5-year distant metastasis rate was 74%. In the intermediate-risk group (high HPV 16/18 E7 viral load, pN2, tumor depth ≥11 mm, or ECS), the 5-year DM rate was 17%. Finally, the 5-year DM rate was 1% in the low-risk group (no risk factors). The value of the C statistics was 0.78.

Do human papillomavirus 16/18 E7 viral loads predict distant metastasis in oral cavity squamous cell carcinoma?

The objective of this study was to use a well-established monkey model of atherosclerosis to determine how life stage and preexisting atherosclerosis influence the effectiveness of high-isoflavone soy diet in inhibiting progression of atherosclerosis. For 34 months, premenopausal monkeys were fed an atherogenic diet, with protein derived primarily from either animal sources (casein-lactalbumin [CL], n = 37) or high-isoflavone soy beans (Soy, n = 34). Animals were ovariectomized and randomized to groups fed the same diet (CL-CL, n = 20; Soy-Soy, n = 17) or an alternate diet (CL-Soy, n = 17; Soy-CL, n = 17) for an additional 34 months. At ovariectomy, the left common iliac artery was removed to determine the amount of premenopausal atherosclerosis. At necropsy, the right common iliac artery and coronary arteries were collected, and atherosclerosis extent was quantified. CL-CL condition was considered "control." Modeling Asian women who remain in Asia, monkeys fed soy protein both premenopausally and postmenopausally had a markedly reduced extent of coronary artery atherosclerosis relative to CL controls (P = 0.008). The subset of animals that modeled Asian women who migrate to a Western country (consuming soy premenopausally and CL postmenopausally) had increased progression of postmenopausal iliac artery atherosclerosis (P = 0.003) and was not protected against the development of coronary artery atherosclerosis relative to controls. Relevant to the administration of soy diets to postmenopausal Western women, monkeys fed CL premenopausally and switched to soy postmenopausally derived atheroprotective benefits only if they began the postmenopausal treatment period with relatively small (below the median) plaques. Relative to controls, this group (with small plaques at ovariectomy) had reduced progression of iliac atherosclerosis (P = 0.038) and smaller coronary artery plaques (P = 0.0001) that were less complicated (P = 0.05) relative to controls.

Are beneficial effects of soy supplementation on postmenopausal atherosclerosis dependent on pretreatment stage of plaque progression?

This study aims to evaluate the potential effects of renal function variations on vascular structure before the development of hypertension. This pilot study included 141 postmenopausal women without evidence of renal dysfunction or hypertension. Markers of renal function and levels of glomerular filtration rate (GFR)--using standard calculations (GFR based on levels of creatinine [GFR(epi)]) and newer creatinine and/or cystatin calculations (GFR based on levels of creatinine and cystatin [GFR(cr cystatin)] and GFR based on levels of cystatin [GFR(cystatin)])--were associated with hemodynamic parameters and markers of vascular structure (intima-media thickness [IMT] and presence of atheromatous plaques in carotid and femoral arteries). Levels of GFR(epi), GFR(cr cystatin), and GFR(cystatin) exhibited a significant negative correlation with femoral artery IMT, whereas levels of GFR(epi) correlated significantly with mean carotid bulb (CB) IMT. Multivariate analysis showed that CB-IMT was predicted by GFR(epi) levels and age (β-coefficient = -0.212, P = 0.020), whereas femoral artery IMT was predicted by GFR(epi) levels (β-coefficient = -0.293, P = 0.001). GFR(epi) levels lower than the 25th percentile were associated with higher CB-IMT (P = 0.009), femoral artery IMT (P = 0.001), and combined IMT (P = 0.035) compared with higher GFR(epi) levels. Moreover, GFR(epi) levels greater than the 25th percentile were associated with lower odds for the presence of atherosclerotic plaques at the CB and carotid arteries combined (CB: odds ratio, 0.146; P = 0.006; combined: odds ratio, 0.249; P = 0.043) compared with lower GFR(epi) levels.

Are variations in glomerular filtration rate associated with subclinical atherosclerosis in healthy postmenopausal women?

Experimentally measured pullout forces for stent grafts (SGs) are used in clinical discussions and as reference values in bench studies and computer simulations. Previous values of these forces are available from studies in which the SG was pulled out in the straight caudal direction. However, clinical and numerical studies have suggested that displacement forces acting on SGs are directed more anteriorly. The objective of this study was to measure pullout forces as a function of angulation and to test the hypothesis that pullout forces decrease with increasing angulation. Six different SGs (Bolton Treovance, Cook Zenith Flex, Cook Zenith LP, Medtronic Endurant, Medtronic Talent, and Vascutek Anaconda) were deployed in fresh bovine aortas, then pulled out by an electronic motor at 1 mm/s, while tension force was measured continuously with a digital load cell. The SG off-axis angulation was changed from 0 to 90 degrees in increments of 10 degrees. The test system was submerged in a custom-built temperature-controlled saline bath at 37°C. At least three tests were performed for each device at each angle (with the exception of the Cook Zenith Flex, which experienced plastic deformation of its barbs after a single test per device). Each aortic specimen was used only once and then discarded. Hand-sutured graft anastomoses were also tested at 0 degrees to provide a reference value. A total of 374 pullout tests were performed for the SGs and anastomoses. Sixty-four tests were excluded because of failure of the aorta or apparatus before device pullout. The remaining 310 tests showed pullout forces that demonstrated a decrease in the average pullout force for all six devices from 0 to 90 degrees (Bolton Treovance from 39.3 N to 23.9 N; Cook Zenith Flex from 59.8 N to 48.9 N; Cook Zenith LP from 50.3 N to 41.8 N; Medtronic Endurant from 29.9 N to 25.8 N; Medtronic Talent from 6.0 N to 5.5 N; and Vascutek Anaconda from 37.0 N to 30.3 N). For reference, the mean pullout force for the hand-sutured anastomoses was 63 N.

Does increasing angulation decrease measured aortic stent graft pullout forces?

Salivary gland adenoid cystic carcinoma (ACC) is one of the most common malignant tumours in the oral and maxillofacial region, and has high aggressive potential. Tumour and stroma interactions are critical in determining the biological characteristics of malignancy. The aim of this study was to investigate the presence of myofibroblasts and their roles in the invasive characteristics of ACC. Immunohistochemistry was used to detect the expression of vimentin (VIM), α-smooth muscle actin (α-SMA), matrix metalloproteinase 2 (MMP2) and CD34 in ACCs and normal salivary gland controls. A significant difference in α-SMA expression was found between normal controls and ACCs, suggesting the presence of myofibroblasts in ACCs. Immunohistochemical staining also demonstrated higher MMP2 expression in the stroma of ACCs than in the controls (P < 0.001). Primary culture of myofibroblasts from one ACC showed great invasive activity, with high expression of MMP2 and C-X-C motif chemokine 12 (CXCL12) by reverse transcription polymerase chain reaction (RT-PCR) analysis.

Do myofibroblasts from salivary gland adenoid cystic carcinomas promote cancer invasion by expressing MMP2 and CXCL12?

Obesity is associated with metabolic derangement and non-alcoholic fatty liver disease (NAFLD). Macrophages are involved in liver inflammation and fibrosis, and soluble (s)CD163 is a macrophage activation marker. To associate sCD163 with parameters of paediatric obesity and NAFLD, as well as changes in these parameters during lifestyle intervention. We studied 117 obese children during a 10-week lifestyle intervention; 71 completed the 12-month follow-up. We recorded clinical and biochemical data, and performed liver ultrasonography. Baseline sCD163 was higher in children with elevated alanine transaminase (ALT) (2.3 ± 0.7 vs. 2.0 ± 0.6 mg L(-1), P = 0.03), steatosis (2.3 ± 0.7 vs. 2.0 ± 0.6 mg L(-1), P = 0.01) and high paediatric NAFLD fibrosis index (2.3 ± 0.7 vs. 1.9 ± 0.6 mg L(-1) , P = 0.03). Baseline sCD163 was independently associated with ALT, cholesterol and high-sensitivity C-reactive protein (hs-CRP). The change in sCD163 during lifestyle intervention was associated with changes in ALT, homeostatic model assessment of insulin resistance (HOMA-IR), hs-CRP and cholesterol, and inversely associated with the change in high-density lipoprotein cholesterol.

Is the macrophage activation marker sCD163 associated with changes in NAFLD and metabolic profile during lifestyle intervention in obese children?

Women with antiphospholipid syndrome (APS) are at increased risk of recurrent pregnancy loss (RPL) and preeclampsia. Antiphospholipid antibodies (aPL) directly alter trophoblast function. Treatment with low molecular weight heparin (LMWH) reduces the risk of RPL but not preeclampsia. Moreover, LMWH stimulates trophoblast sFlt-1 release, an anti-angiogenic factor associated with preeclampsia. Since vitamin D deficiency is associated with APS and preeclampsia, this study sought to determine the effect of vitamin D on trophoblast function in the setting of aPL and LMWH. A human first trimester trophoblast cell line (HTR8) and primary trophoblast cultures were treated with or without aPL in the presence and absence of vitamin D, LMWH or both. Trophoblast secretion of inflammatory cytokines and angiogenic factors were measured by ELISA. Vitamin D alone or in combination with LMWH attenuated the aPL-induced trophoblast inflammatory response in the HTR8 cells and primary cultures. While vitamin D did not have any impact on aPL-mediated modulation of angiogenic factors in the primary trophoblast, it significantly inhibited LMWH-induced sFlt-1 release.

Does vitamin D reverse aPL-induced inflammation and LMWH-induced sFlt-1 release by human trophoblast?

Wnt signaling is a master regulator of joint homeostasis, but its role in osteoarthritis (OA) remains unclear. This study was undertaken to characterize the activation of Wnt/β-catenin in knee joints of mice with OA and to assess how inhibiting this pathway in bone could affect cartilage. OA was induced by partial meniscectomy in Topgal mice and in transgenic mice overexpressing Dkk-1 under the control of the 2.3-kb Col1a1 promoter (Col1a1-Dkk-1-Tg mice). Wnt/β-catenin activation was assessed by X-Gal staining at baseline and at weeks 4, 6, and 9. Cartilage and bone damage was analyzed in Col1a1-Dkk-1-Tg mice with OA at week 6. Primary chondrocytes and cartilage explants were used to assess the effect of Dkk-1 on cartilage catabolism. In meniscectomized Topgal mice, Wnt was mainly activated in osteocytes from the subchondral bone at week 6 after OA induction, as well as in osteophytes and synovium at week 4. Chondrocytes from damaged zones expressed X-Gal from week 4. Dkk-1 expression was high in chondrocytes in control mouse knees (mean ± SEM 84.2 ± 3.1%) but decreased greatly in knees of meniscectomized mice from week 4 (mean ± SEM 14.4 ± 3.8%). The OA score was lower in meniscectomized Col1a1-Dkk-1-Tg mice at week 6 compared with wild-type mice (5.1 ± 0.6 versus 8.4 ± 0.6; P = 0.002). Subchondral bone fraction and osteophyte volume were decreased. However, cartilage explants from Col1a1-Dkk-1-Tg mice showed proteoglycan loss and increased NITEGE expression. Expression of vascular endothelial growth factor (VEGF) was reduced in osteoblasts from Col1a1-Dkk-1-Tg mice, thereby decreasing expression of messenger RNA for matrix metalloproteinases in chondrocytes.

Does dkk-1-mediated inhibition of Wnt signaling in bone ameliorate osteoarthritis in mice?

Fluid balance for the surgical patient has been proven very important for the postoperative outcome and development of complications. The aim of this study was to evaluate, for the first time in modern times, the accordance between nurse-based fluid charting (cumulated fluid balance) and body weight change for general surgical patients. This was a descriptive study with prospectively collected data from two clinical randomized multicenter trials. A total of 113 patients from American Society of Anesthesiology group I-III undergoing elective colorectal surgery were included. Cumulated fluid balance and body weight change were charted preoperatively and daily at the same time during a postoperative period of 6 days. Differences were calculated by subtracting cumulated fluid balance from body weight change (1 g = 1 mL), and agreement was assessed by making Bland-Altman plots as well as Pearson correlations. From day 1 to 4, the mean difference between cumulated fluid balance and body weight change was below 0.4 kg/L. On day 5 and 6, the discrepancies increased with mean differences of, respectively, 1.2 kg/L (p < 0.002*) and 2 kg/L (p < 0.0001*). Bland-Altman plots showed increasingly poor agreement for all postoperative days with wide limits of agreement, ranging from more than 6 kg/L to almost 10 kg/L. Pearson correlations were moderate to strong at all times ranging from 0.437 (day 1) to 0.758 (day 4).

Is clinical Assessment of Fluid Balance Incomplete for Colorectal Surgical Patients?

Back pain is among the most prevalent pain disorders causing chronic disability among adults, and insomnia is a common co-morbidity. However, whether insomnia precedes back pain or vice versa remains unclear. The current study tested the temporal association between insomnia and back pain. A longitudinal design was used to investigate whether changes in insomnia over time predict the onset of back pain and vice versa. The study was conducted on a cohort of active healthy working adults (N = 2,131, 34% women) at three time points (T1, T2, and T3) over a period of 3.7 years (range = 2.2-5.12) years. Logistic regression analysis was used to test whether increased insomnia symptoms from T1 to T2 predicted the onset of new back pain. Ordinary least squares regression was used to test whether the existence of back pain at T2 predicted an increase in insomnia from T2 to T3. The results indicated that after controlling for socioeconomic variables, self-reported health, lifestyle behaviors, and anthropometrics, a T1-T2 increase in insomnia symptoms was associated with a 1.40-fold increased risk of back pain at T3 (OR = 1.40; 95% CI = 1.10-1.71). No support was found for reverse causation; i.e., that back pain predicts subsequent increase in insomnia.

Do increased insomnia symptoms predict the onset of back pain among employed adults?

To test the use of diffusion-weighted magnetic resonance imaging (DW-MRI) to differentiate between different degrees of severity of acute pancreatitis (AP). Thirty-six patients who underwent DW-MRI and magnetic resonance cholangiopancreatography were divided into patients with mild AP (mAP, n = 15), patients with necrotizing AP (nAP, n = 8), and patients with a normal pancreas (nP, n = 15; controls). The pancreas was divided into head, body, and tail, and each segment was classified according to image features: pattern 1, normal; pattern 2, mild inflammation; and pattern 3, necrosis. Apparent diffusion coefficients (ADCs) were measured in each segment and correlated with clinical diagnoses. A total of 108 segments was assessed (three segments per patient). Segments classified as pattern 1 in the nP and mAP groups showed similar ADC values (P = 0.29). ADC values calculated for the pancreatic segments grouped according to the different image patterns (1-3) were significantly different (P < 0.001). Comparisons revealed significant differences in signal intensity between all three patterns (P < 0.05).

Does diffusion-weighted magnetic resonance imaging indicate the severity of acute pancreatitis?

This study characterizes ovariectomized (OVX)-induced osteoporotic fracture healing with focus on estrogen receptors (ERs). Callus formation plays a critical role in fracture healing, and ERs are well-known mechanosensors in osteogenic pathways. It was hypothesized that callus formation was related to and partially determined by the difference in expression patterns of ERs in both normal and OVX-induced osteoporotic fractures. Closed femoral fracture in SHAM and ovariectomized rats were used in this study. Weekly callus width (CW) and area (CA), endpoint mechanical properties, gene expressions of Col-1, BMP-2, ER-α, ER-β and ER-α:ER-β ratios (ER-ratios), and correlations were assessed at 2, 4 and 8 weeks post-fracture. CW and CA results confirmed that OVX-induced osteoporotic fracture was delayed at 2-4 weeks with impaired endpoint mechanical properties. Gene expressions of ER-α and ER-β were higher in the SHAM group at week 2 (p < 0.05) and later lowered at week 8; whereas the OVX group showed an opposing trend. Moderate correlation existed between ER-α and BMP-2 (0.545, p = 0.003), and ER-ratio and BMP-2 (0.601, p = 0.001), and BMP-2 to CW and CA (r = 0.709, p = 0.000 and r = 0.588, p = 0.001, respectively). ER-α and ER-β proteins expressions were confirmed by immunohistochemistry at the fracture callus in reparative progenitor cells, osteoblasts- and osteoclasts-like cells.

Is callus formation related to the expression ratios of estrogen receptors-alpha and -beta in ovariectomy-induced osteoporotic fracture healing?

The purpose of this study was to examine whether oral administration of an angiotensin II type 1 receptor blocker (ARB) inhibited in-stent neointimal hyperplasia in carotid arteries of hypercholesterolemic rabbits. Eleven male New Zealand white rabbits were subjected to endothelial injuries of the right common carotid arteries using a balloon catheter and then received chow containing 1% cholesterol for 6 weeks. A balloon-expandable stainless steel stent was subsequently inserted at the injured sites of the arteries. After stenting, five rabbits were randomly treated with an oral ARB, candesartan cilexetil (5 mg/kg per day orally), while the remaining six rabbits acted as untreated controls. Four weeks after the implantation, the rabbits were killed, followed by collection of the arteries including the stents. After careful removal of the stents, tissue sections were prepared and analyzed by morphometric and immunohistochemical methods. The mean thickness of the neointima was 53.6 ± 17.0 μm in the ARB-treated group, which was significantly reduced compared to 95.9 ± 16.7 μm in the control group (P = 0.0012). Immunohistochemistry showed a decrease in accumulation of macrophages and tenascin-C expression in the arterial wall in the ARB-treated animals.

Do angiotensin II type 1 receptor blockers suppress neointimal hyperplasia after stent implantation in carotid arteries of hypercholesterolemic rabbits?

Prostate cancer is a common malignancy in men, and inevitably some patients experience biochemical recurrence after radical prostatectomy. To date, there are no reliable predictors for prostate cancer recurrence, and novel predictors are urgently needed. PCDH10 (protocadherin-10) is a novel tumor suppressor gene, which is down-regulated by promoter methylation in prostate cancer. The aim of this study was to evaluate the feasibility of using PCDH10 methylation to predict the biochemical recurrence (BCR) of prostate cancer after radical prostatectomy. Fresh tissue samples were obtained from 151 patients with primary prostate cancer, and from 34 patients with benign prostatic hyperplasia (BPH) as control. The methylation status of PCDH10 in prostate cancer tissues and controls were examined using methylation-specific PCR (MSP), and then associated with clinicopathological features and BCR-free survival of patients with prostate cancer. We found that PCDH10 methylation was detected in 79 (52.3%) patients with prostate cancer, but no methylation was found in controls (P<0.0001). Moreover, PCDH10 methylation was significantly associated with higher preoperative prostate-specific antigen (PSA) level (P <0.0001), higher Gleason Score (P<0.0001), advanced clinical stage (P=0.0002), lymph node metastasis (P=0.0389), angiolymphatic invasion (P=0.0303), and biochemical recurrence (P=0.0068). Moreover, PCDH10 methylation was associated with poor BCR-free survival (P<0.0001), and may be used as an independent predictor of BCR-free survival (P=0.0046).

Does aberrant methylation of PCDH10 predict worse biochemical recurrence-free survival in patients with prostate cancer after radical prostatectomy?

Our previous reports demonstrated that genetic deletion of μ-opioid receptor has no influence on the anaesthetic and antinociceptive effects of nitrous oxide (N2O) in mice, and that an antagonist selective for κ-opioid receptor (KOP), but not that selective for δ-opioid receptor, suppresses the antinociceptive effect of N2O. However, it is not known whether genetic deletion of KOP affects the N2O actions. We measured the minimum alveolar concentration (MAC) of volatile anaesthetics in the absence and presence of N2O. The antinociceptive action of N2O was tested by an acetic acid-writhing test and a hot-plate test. The number of c-Fos-immunopositive cells in sections from the lumbar spinal cord was counted to test whether the descending inhibitory system participates in the pharmacological action of N2O. The hypnotic action of N2O was assessed by measuring the N2O-induced decrease in the EC50 for loss of the righting reflex (EC50-LORR) of sevoflurane. Sevoflurane MAC was not significantly reduced by N2O and its antinociceptive action was almost completely abolished in KOP-knockout (KO) mice. The N2O-induced increase in c-Fos-immunopositive cells in laminae III-IV of the lumbar spinal cord was significant in wild-type (WT), but not in KOP-KO mice. In contrast, sevoflurane EC50-LORR was similarly reduced by N2O in WT and KOP-KO mice.

Does κ-Opioid receptor mediate the antinociceptive effect of nitrous oxide in mice?

Ovarian cancer (OvCa) is the most lethal gynecologic malignancy in the United States because of chemoresistant recurrent disease. Our objective was to investigate the efficacy of inhibiting the Notch pathway with a γ-secretase inhibitor (GSI) in an OvCa patient-derived xenograft model as a single agent therapy and in combination with standard chemotherapy. Immunocompromised mice bearing xenografts derived from clinically platinum-sensitive human ovarian serous carcinomas were treated with vehicle, GSI (MRK-003) alone, paclitaxel and carboplatin (P/C) alone, or the combination of GSI and P/C. Mice bearing platinum-resistant xenografts were given GSI with or without paclitaxel. Gene transcript levels of the Notch pathway target Hes1 were analyzed using RT-PCR. Notch1 and Notch3 protein levels were evaluated. The Wilcoxon rank-sum test was used to assess significance between the different treatment groups. Expression of Notch1 and 3 was variable. GSI alone decreased tumor growth in two of three platinum-sensitive ovarian tumors (p < 0.05), as well as in one of three platinum-sensitive tumors (p = 0.04). The combination of GSI and paclitaxel was significantly more effective than GSI alone and paclitaxel alone in all platinum-resistant ovarian tumors (all p < 0.05). The addition of GSI did not alter the effect of P/C in platinum-sensitive tumors. Interestingly, although the response of each tumor to chronic GSI exposure did not correlate with its endogenous level of Notch expression, GSI did negatively affect Notch signaling in an acute setting.

Does inhibition of notch signaling in combination with Paclitaxel reduce platinum-resistant ovarian tumor growth?

Stem/progenitor cells are in the focus of research as a future therapeutic option to stimulate regeneration in diseased renal parenchyma. However, current data indicate that successful seeding of implanted stem/progenitor cells is prevented by harmful interstitial fluid and altered extracellular matrix. To find out possible parameters for cell adaptation, the present investigation was performed. Renal stem/progenitor cells were mounted in an artificial interstitium for perfusion culture. Exposure to chemically defined but CO2-independent culture media was tested during 13 days. Cell biological features were then analyzed by histochemistry, while structural details were investigated by transmission electron microscopy after conventional and improved fixation of specimens. Culture of renal stem/progenitor cells as well in Leibovitz's L-15 Medium as CO2 Independent Medium shows in fluorescence microscopy spatial development of numerous tubules. Specimens of both media fixed by conventional glutaraldehyde exhibit in electron microscopy a homogeneous cell population in developed tubules. In contrast, fixation by glutaraldehyde including tannic acid illuminates that dispersed dark marked cells of unknown function are present. The screening further demonstrates that the dark cell type does not comply with cells found in embryonic, maturing or matured renal parenchyma.

Does tannic acid label indicate abnormal cell development coinciding with regeneration of renal tubules?

Endoplasmic reticulum (ER) stress is induced in many forms of chronic liver disease and may promote the development of hepatocellular carcinoma. The activator protein 1 (AP-1) complex is a transcription factor that promotes hepatic carcinogenesis in response to cellular stress. The aim of this study was to determine the role of ER stress in the regulation of the hepatic AP-1 complex. Human hepatocellular carcinoma (HepG2) cells and C57BL/6J mice were subjected to pharmacologic ER stress and the expression of AP-1-associated genes and proteins was assessed. To determine the role of MAPK signaling in ER stress-induced AP-1 activation, ER stress was induced in JNK- and ERK-inhibited HepG2 cells. Induction of ER stress promoted the activation of both Jun- and Fos-related genes and proteins of the AP-1 complex in HepG2 cells and murine liver. Inhibition of ERK phosphorylation in HepG2 cells completely prevented ER stress-induced activation of the fos-related components of AP-1 whereas activation of Jun-related components was only partially attenuated. Conversely, inhibition of JNK phosphorylation in HepG2 cells reduced ER stress-induced activation of Jun-related components but did not prevent activation of fos-related components.

Does endoplasmic reticulum stress activate the hepatic activator protein 1 complex via mitogen activated protein kinase-dependent signaling pathways?

Nuclear reprogramming inculcates pluripotent capacity by which de novo tissue differentiation is enabled. Yet, introduction of ectopic reprogramming factors may desynchronize natural developmental schedules. This study aims to evaluate the effect of imposed transgene load on the cardiogenic competency of induced pluripotent stem (iPS) cells. Targeted inclusion and exclusion of reprogramming transgenes (c-MYC, KLF4, OCT4, and SOX2) was achieved using a drug-inducible and removable cassette according to the piggyBac transposon/transposase system. Pulsed transgene overexpression, before iPS cell differentiation, hindered cardiogenic outcomes. Delayed in counterparts with maintained integrated transgenes, transgene removal enabled proficient differentiation of iPS cells into functional cardiac tissue. Transgene-free iPS cells generated reproducible beating activity with robust expression of cardiac α-actinin, connexin 43, myosin light chain 2a, α/β-myosin heavy chain, and troponin I. Although operational excitation-contraction coupling was demonstrable in the presence or absence of transgenes, factor-free derivatives exhibited an expedited maturing phenotype with canonical responsiveness to adrenergic stimulation.

Is iPS cell-derived cardiogenicity hindered by sustained integration of reprogramming transgenes?

Heme oxygenase catalyzes the conversion of heme to iron, carbon monoxide and biliverdin employing oxygen and reducing equivalents. This enzyme is essential for heme-iron utilization and contributes to virulence in Leptospira interrogans. A phylogenetic analysis was performed using heme oxygenases sequences from different organisms including saprophytic and pathogenic Leptospira species. L. interrogans heme oxygenase (LepHO) was cloned, overexpressed and purified. The structural and enzymatic properties of LepHO were analyzed by UV-vis spectrophotometry and (1)H NMR. Heme-degrading activity, ferrous iron release and biliverdin production were studied with different redox partners. A plastidic type, high efficiently ferredoxin-NADP(+) reductase (LepFNR) provides the electrons for heme turnover by heme oxygenase in L. interrogans. This catalytic reaction does not require a ferredoxin. Moreover, LepFNR drives the heme degradation to completeness producing free iron and α-biliverdin as the final products. The phylogenetic divergence between heme oxygenases from saprophytic and pathogenic species supports the functional role of this enzyme in L. interrogans pathogenesis.

Does heme-iron utilization by Leptospira interrogans require a heme oxygenase and a plastidic-type ferredoxin-NADP ( + ) reductase?

Asteatotic eczema (AE) is characterized by itchy, dry, rough, and scaling skin. The treatments for AE are mainly emollients, usually containing urea, lactic acid, or a lactate salt. N-palmitoylethanolamine (PEA) and N-acetylethanolamine (AEA) are both endogenous lipids used as novel therapeutic tools in the treatment of many skin diseases. The purpose of this study was to compare a PEA/AEA emollient with a traditional emollient in the treatment of AE. A monocentric, randomized, double-blind, comparative trial was conducted in 60 AE patients to evaluate and compare the efficacy of the two emollients. The level of skin dryness among the subjects ranged from mild to moderate. The subjects' skin barrier function and the current perception threshold were tested for 28 days by clinical scoring and bioengineering technology. The results showed that, although some aspects were improved in both groups, the group using the emollient containing PEA/AEA presented a better skin surface change in capacitance. However, the most impressive finding was the ability of the PEA/AEA emollient to increase the 5 Hz current perception threshold to a normal level after 7 days, with a significant difference between values at baseline and after 14 days. A current perception threshold of 5 Hz was positively and significantly correlated with skin surface hydration and negatively correlated with transepidermal water loss in the PEA/AEA emollient group.

Are n-palmitoylethanolamine and N-acetylethanolamine effective in asteatotic eczema : results of a randomized , double-blind , controlled study in 60 patients?

Experimental autoimmune encephalomyelitis (EAE) is an animal model of autoimmune inflammatory demyelination that is mediated by Th1 and Th17 cells. The transcription factor interferon regulatory factor 3 (IRF3) is activated by pathogen recognition receptors and induces interferon-β production. To determine the role of IRF3 in autoimmune inflammation, we immunised wild-type (WT) and irf3(-/-) mice to induce EAE. Splenocytes from WT and irf3(-/-) mice were also activated in vitro in Th17-polarising conditions. Clinical signs of disease were significantly lower in mice lacking IRF3, with reduced Th1 and Th17 cells in the central nervous system. Peripheral T-cell responses were also diminished, including impaired proliferation and Th17 development in irf3(-/-) mice. Myelin-reactive CD4+ cells lacking IRF3 completely failed to transfer EAE in Th17-polarised models as did WT cells transferred into irf3(-/-) recipients. Furthermore, IRF3 deficiency in non-CD4+ cells conferred impairment of Th17 development in antigen-activated cultures.

Is interferon regulatory factor ( IRF ) 3 critical for the development of experimental autoimmune encephalomyelitis?

Soft tissue sarcomas (STS) are malignant tumors of mesenchymal origin. A substantial portion of these tumors exhibits complex karyotypes and lack characterized chromosomal aberrations. Owing to such properties, both histopathologic and molecular classification of these tumors has been a significant challenge. This study examines the protein expression of a large number of human STS, including subtype heterogeneity, using two-dimensional gel proteomics. In addition, detailed proteome profiles of a subset of pleomorphic STS specimens using an in-depth mass-spectrometry approach identified subgroups within the leiomyosarcomas with distinct protein expression patterns. Pathways analysis indicates that key biologic nodes like apoptosis, cytoskeleton remodeling, and telomere regulation are differentially regulated among these subgroups. Finally, investigating the similarities between protein expression of leiomyosarcomas and undifferentiated pleomorphic sarcomas (UPS) revealed similar protein expression profiles for these tumors, in comparison with pleomorphic leiomyosarcomas.

Does discovery-based protein expression profiling identify distinct subgroups and pathways in leiomyosarcomas?

miRNAs have been implicated in the regulation of key metabolic, inflammatory, and malignant pathways; hence, they might be considered both predictors and players of cancer development. Using a case-control study design nested in the ORDET prospective cohort study, we addressed the possibility that specific mRNAs can serve as early predictors of breast cancer incidence in postmenopausal women. We compared leukocyte miRNA profiles of 133 incident postmenopausal breast cancer cases and profiles of 133 women who remained healthy over a follow-up period of 20 years. The analysis identified 20 differentially expressed miRNAs, 15 of which were downregulated. Of the 20 miRNAs, miR145-5p and miR145-3p, each derived from another arm of the respective pre-miRNA, were consistently and significantly downregulated in all the databases that we surveyed. For example, analysis of more than 1,500 patients (the UK Metabric cohort) indicated that high abundance of miR145-3p and miR145-5p was associated with longer, and for miR145-3p also statistically significant, survival. The experimental data attributed different roles to the identified miRNAs: Although the 5p isoform was associated with invasion and metastasis, the other isoform seems related to cell proliferation.

Is downregulation of microRNAs 145-3p and 145-5p a long-term predictor of postmenopausal breast cancer risk : The ORDET prospective study?

KIR genes coding for natural killer cell immunoglobulin-like receptors, KIR, influence the effector and regulatory function of NK cells as well as some subpopulations of T lymphocytes (e.g. CD4+CD28-KIR+) depending on presence of ligands (particularly HLA-C molecules). KIR-KIR ligand interaction may lead to the development of autoimmune disorders, including rheumatoid arthritis (RA). However, their role in the response of RA patients to methotrexate therapy is not known. KIR genes and KIR-ligand (HLA-C C1/C2 allomorphs) genotyping was performed using the PCR-SSP method in 312 RA patients (179 classified as good responders and 133 as poor responders using DAS28 criteria). Thus, we evaluated the association of KIR genes and HLA-C allomorphs with the response to methotrexate (MTX) treatment. We observed that patients possessing the full-length KIR2DS4 (KIR2DS4f) gene had a lower chance of responding in comparison to KIR2DS4f-negative cases. This phenomenon was observed both in erosive disease (ED) and rheumatoid factor (RF) positive and in ED- and RF-negative patients. Interestingly, the observed effect of the KIR2DS4f gene was strongest in individuals possessing medium values (20-33 mm/h) of the erythrocyte sedimentation rate (ESR). Patients with high ESR values had low probability and, in contrast, patients with low ESR had a high probability of MTX response, and the presence of KIR2DS4f did not affect their outcome. Additionally, we show that the KIR2DS4f effect did not depend on the presence of either C1 or C2 allomorphs.

Does presence of the full-length KIR2DS4 gene reduce the chance of rheumatoid arthritis patients to respond to methotrexate treatment?

Previous studies demonstrated that a history of childhood trauma is linked to mental disorders in adulthood, particularly to depression. Adverse childhood experiences are also considered to contribute to the risk of hypochondriasis, but the results of previous studies have not been conclusive with respect to the strength and specificity of this association. Therefore, we compared the association of adverse childhood experiences with both hypochondriasis and depression. Fifty-eight patients with hypochondriasis, 52 patients with depression, and 52 healthy control participants completed the Childhood Trauma Questionnaire (CTQ) which assesses 5 varieties of abuse and neglect. A clinical interview (SCID-I) was used to establish DSM-IV diagnoses. Associations between childhood maltreatment, hypochondriasis and depression were estimated by means of analyses of variance and multiple linear regression analyses. In comparison to hypochondriacal and healthy participants, patients with a current depressive disorder reported more emotional abuse as well as more emotional and physical neglect during childhood. Patients with hypochondriasis reported more emotional neglect than healthy individuals. However, when predicting the CTQ trauma types by diagnostic category adjusting for sex and comorbid DSM-IV diagnoses, emotional abuse, emotional neglect, physical abuse, physical neglect, as well as the CTQ total score were significantly associated with depression, but none of the CTQ scores was significantly related to hypochondriasis.

Is childhood maltreatment associated with depression but not with hypochondriasis in later life?

Religious involvement may help individuals with chronic medical illness cope better with physical disability and other life changes. We examine the relationships between religiosity, depressive symptoms, and positive emotions in persons with major depression and chronic illness. 129 persons who were at least somewhat religious/spiritual were recruited into a clinical trial to evaluate the effectiveness of religious vs. secular cognitive behavioral therapy. Reported here are the relationships at baseline between religious involvement and depressive symptoms, purpose in life, optimism, generosity, and gratefulness using standard measures. Although religiosity was unrelated to depressive symptoms (F=0.96, p=0.43) and did not buffer the disability-depression relationship (B=-1.56, SE 2.90, p=0.59), strong relationships were found between religious indicators and greater purpose, optimism, generosity, and gratefulness (F=7.08, p<0.0001).

Is religious involvement associated with greater purpose , optimism , generosity and gratitude in persons with major depression and chronic medical illness?

Complex regional pain syndrome (CRPS) is a painful condition with approximately 50,000 annual new cases in the United States. It is a major cause of work-related disability, chronic pain after limb fractures, and persistent pain after extremity surgery. Additionally, CRPS patients often experience cognitive changes, anxiety, and depression. The supraspinal mechanisms linked to these CRPS-related comorbidities remain poorly understood. The authors used a previously characterized mouse model of tibia fracture/cast immobilization showing the principal stigmata of CRPS (n = 8 to 20 per group) observed in humans. The central hypothesis was that fracture/cast mice manifest changes in measures of thigmotaxis (indicative of anxiety) and working memory reflected in neuroplastic changes in amygdala, perirhinal cortex, and hippocampus. The authors demonstrate that nociceptive sensitization in these mice is accompanied by altered thigmotactic behaviors in the zero maze but not open field assay, and working memory dysfunction in novel object recognition and social memory but not in novel location recognition. Furthermore, the authors found evidence of structural changes and synaptic plasticity including changes in dendritic architecture and decreased levels of synaptophysin and brain-derived neurotrophic factor in specific brain regions.

Do brain neuroplastic changes accompany anxiety and memory deficits in a model of complex regional pain syndrome?

To determine the effect of pre-existing maternal obesity and gestational diabetes mellitus (GDM) on the circulating levels of insulin growth factor-binding protein (IGFBPs) in cord and maternal plasma. IGFBP-1-7 levels were measured on maternal and cord plasma from women with normal glucose tolerance (NGT) (30 non-obese and 36 obese) and GDM (44 non-obese and 26 obese) at the time of term elective cesarean section. Maternal plasma IGFBP-1, IGFBP-6 and IGFBP-rP1 concentrations were significantly lower in NGT obese compared with NGT non-obese women and in non-obese GDM women compared with non-obese NGT women. In cord plasma, IGFBP-1-3 and IGFBP-rP1 concentrations were significantly lower in NGT obese compared with NGT non-obese women and in non-obese GDM women compared with non-obese NGT women. Significant positive correlations were observed between maternal and cord plasma IGFBP-1 and IGFBP-rP1 levels and maternal insulin resistance. In cord plasma, significant positive correlations were observed between IGFBP-1-3 and IGFBP-rP1 levels and fetal insulin resistance. Fetal birthweight was inversely correlated with maternal plasma IGFBP-1 levels and cord plasma IGFBP-1 and IGFBP-2 levels. When corrected for maternal body mass index, the only significant relationship that still existed was between cord plasma IGFBP-1 concentrations and fetal birthweight.

Are insulin-like growth factor-binding protein 1 and 7 concentrations lower in obese pregnant women , women with gestational diabetes and their fetuses?

To investigate the potential role of prostasin, as an invasion suppressor, in the process of trophoblast invasion in preeclampsia. This case-control study included 19 early-onset severe preeclampsia (⩽ 34 weeks), 20 late-onset severe preeclampsia (>34 weeks) and 20 normal term pregnant women. Immunohistochemistry was conducted to identify the cellular localization of prostasin, as well as the matrix metalloproteinase 2 (MMP2) and MMP9 in the placenta tissues. Enzyme-linked immunosorbent assay was performed to analyze the expression of these three proteins in placental homogenates. The effect of prostasin on the invasive and migratory ability of trophoblast cells was detected by transwell assays. We also examined the regulation of the prostasin antibody in the MMP2 and MMP9 secretion by HTR-8/SVneo cells via blocking the prostasin activity. This study demonstrated that the prostasin, MMP2 and MMP9 were all expressed in the placental syncytiotrophoblasts. Increased expression of prostasin was detected in cases with early-onset severe preeclampsia compared with the late-onset and control groups (P < 0.05), whereas the expression patterns of MMP2 and MMP9 in placental homogenates were opposite to that of prostasin (P < 0.05). Recombinant prostasin inhibited the invasion and migration of trophoblast cells, whereas prostasin antibody enhanced the MMP2 and MMP9 secretion in a dose- and time-dependent manner.

Does increased expression of prostasin contribute to early-onset severe preeclampsia through inhibiting trophoblast invasion?

There have seen several studies evaluating the efficacy of anti-tumor necrosis factor α (anti-TNFα) compared with conventional therapy (i.e. immunomodulators, mesalamine, or placebo) at preventing postoperative Crohn's disease (CD) recurrence. The results of these studies have been variable and the magnitude by which anti-TNFα therapy alters the natural history of CD in the postoperative setting has not yet been fully defined. A comprehensive search of PubMed/MEDLINE, Scopus, CINAHL, and Cochrane databases was performed (May 2014). All studies on adult patients with CD that compared anti-TNFα therapy versus conventional therapy or placebo to prevent CD recurrence were included. Meta-analysis was performed using the Mantel-Haenszel (fixed effects) model with odds ratio (OR) to assess for clinical remission. In the pooled analysis, there was a higher frequency of achieving clinical remission beyond 1 year from time of surgery among patients receiving anti-TNFα therapy compared with conventional therapy [OR 6.41; 95% confidence interval (CI) 2.88-14.27]. There was also a significantly higher rate of achieving both endoscopic (OR 26.44; 95% CI 10.48-66.68) and histologic remission (OR 9.80; 95% CI 2.54-37.81) in the anti-TNFα therapy group compared with the conventional therapy group.

Is antitumor necrosis factor α more effective than conventional medical therapy for the prevention of postoperative recurrence of Crohn 's disease : a meta-analysis?

Critical illness-related corticosteroid insufficiency has been reported in acute variceal bleeding (AVB). In cirrhosis, free serum cortisol (FC) is considered optimal to assess adrenal function. Salivary cortisol (SC) is considered a surrogate for FC. We evaluated FC and its prognostic role in AVB. Total serum cortisol, SC, cortisol-binding globulin, and FC (Coolens' formula) were evaluated in AVB (n=38) and in stable cirrhosis (CC) (n=31). A Cox proportional hazards model was evaluated for 6-week survival. In AVB, the median FC and SC levels were higher with worse liver dysfunction [Child-Pugh (CP) A/B/C: 1.59/2.62/3.26 μg/dl, P=0.019; CPA/B/C: 0.48/0.897/1.81 μg/ml, P<0.001, respectively]. In AVB compared with CC, median total serum cortisol: 24.3 versus 11.6 μg/dl (P<0.001), SC: 0.86 versus 0.407 μg/ml (P<0.001); FC 2.4 versus 0.57 μg/dl (P<0.001). In AVB, 5-day rebleeding was 10.5%, and 6-week and total mortality were 21.1 and 23.7%, respectively. Independent associations with 6-week mortality in AVB were FC at least 3.2 μg/dl (P<0.001), hepatocellular carcinoma (P<0.001), CPC (P<0.001), and early rebleeding (P<0.001). Among patients with normal cortisol-binding globulin (n=14) and albumin (n=31), the factors were hepatocellular carcinoma (P=0.003), CP (P=0.003), and FC (P=0.036). SC was also found to be an independent predictor of 6-week mortality (P<0.001). Area under the curve of FC for predicting 6-week mortality was 0.79.

Is higher free serum cortisol associated with worse survival in acute variceal bleeding because of cirrhosis : a prospective study?

Growth retardation is a frequent complication of paediatric inflammatory bowel disease (IBD). Only a few studies report the final height of these patients, with controversial results. We compared adult height of patients with paediatric IBD with that of patients with adult-onset disease. Height data of 675 women 19-44 years of age and 454 men 23-44 years of age obtained at inclusion in the Swiss IBD cohort study registry were grouped according to the age at diagnosis: (a) prepubertal (men≤13, women≤11 years), (b) pubertal (men 13-22, women 11-18 years) and (c) adult (men>22, women>18 years of age), and compared with each other and with healthy controls. Male patients with prepubertal onset of Crohn's disease (CD) had significantly lower final height (mean 172±6 cm, range 161-182) compared with men with pubertal (179±6 cm, 161-192) or adult (178±7 cm, 162-200) age at onset and the general population (178±7 cm, 142-204). Height z-scores standardized against heights of the normal population were significantly lower in all patients with a prepubertal diagnosis of CD (-0.8±0.9) compared with the other patient groups (-0.1±0.8, P<0.001). Prepubertal onset of CD emerged as a risk factor for reduced final height in patients with prepubertal CD. No difference for final height was found between patients with ulcerative or unclassified IBD diagnosed at prepubertal, pubertal or adult age.

Is early-onset Crohn 's disease a risk factor for smaller final height?

Uveal melanoma (UM) is the most common primary intraocular tumor in adults and the presence of infiltrating leucocytes is associated with a poor prognosis. Little is known how infiltrating leucocytes influence the tumor cells. The purpose of this study was to investigate the effect of activated T cells on the expression of chemotactic cytokines in UM cells. Furthermore, we examined the ability of stimulated UM cells to attract monocytes. We used an in vitro coculture system in which UM cell lines and T cells were cultured together, but separated by a membrane. Uveal melanoma gene expression was quantified using a microarray. Protein expression in the supernatant was quantified with ELISA or cytometric bead array. For the monocyte migration assay, a transwell plate was used. Gene-expression analysis of UM cell lines showed that coculture with activated T cells resulted in an upregulation of chemokines such as CXCL8, CXCL9, CXCL10, CXCL11, CCL2, CCL5, VEGF, intracellular adhesion molecule 1 (ICAM1), and granulocyte-macrophage colony-stimulating factor (GM-CSF). The upregulation of these molecules was confirmed at the protein level. This increase of chemokines coincided with an increased chemotactic capacity of the supernatant toward monocytes.

Does inflammation-induced chemokine expression in uveal melanoma cell lines stimulate monocyte chemotaxis?

Hirschsprung's disease is characterized by a developmental arrest of neural crest cell migration, causing distal aganglionosis. Transplanted cells derived from the neural crest may regenerate enteric ganglia in this condition. We investigated the potential of skin-derived precursor cells (SKPs) to engraft and to differentiate into enteric ganglia in aganglionic rat intestine in vivo. Adult Lewis rat jejunal segments were separated from intestinal continuity and treated with benzalkonium chloride to induce aganglionosis. Ganglia were identified via immunohistochemical stains for S100 and β-III tubulin (TUJ1). SKPs were procured from neonatal Lewis rats expressing enhanced green fluorescent protein (GFP) and cultured in neuroglial-selective media. SKP cell line expansion was quantified, and immunophenotypes were assessed by immunocytochemistry. Aganglionic segments underwent SKP transplantation 21-79days after benzalkonium chloride treatment. The presence of GFP+cells, mature neurons, and mature glia was evaluated at posttransplant days 1, 6, and 9. Benzalkonium chloride-induced aganglionosis persisted for at least 85days. Prior to differentiation, SKPs expressed S100, denoting neural crest lineage, and nestin, a marker of neuronal precursors. Differentiated SKPs in vitro expressed GFAP, a marker of glial differentiation, as well as TUJ1 and several enteric neurotransmitters. After transplantation, GFP+structures resembling ganglia were identified between longitudinal and circular smooth muscle layers.

Do transplanted skin-derived precursor stem cells generate enteric ganglion-like structures in vivo?

Headache is a common complaint for emergency visits. Common drugs used in relief of headache are opioids and their agonists and antagonists, ergot alkaloids, and nonsteroidal anti-inflammatory drugs (NSAIDs). Lack of appropriate medications or serious side effects of available drugs, motivated us to perform the study for evaluating the efficacy of intranasal lidocaine on different types of headache. A double-blind, randomized clinical trial (RCT) was performed among 90 adult patients with acute headache in Shahid Rahnemoon Emergency Center of Yazd city of Iran (45 patients in lidocaine group and 45 patients in placebo group). Patients with history of epilepsy, allergy to lidocaine, signs of skull base fracture, Glasgow Coma Scale (GCS) < 15, patients younger than 14 years and patients who had received any medication in previous 2 h were excluded. After checking vital signs and taking the demographic data, one puff of 10% lidocaine or normal saline (placebo) was sprayed into each nostril. Patients' headache severity measured by visual analog scale (VAS) before drug administration and at 1, 5, 15, and 30 min after intervention. Data were analyzed by Statistical Package for Social Sciences (SPSS) version 17 and statistical tests including t-test, repeated measures analysis of variance (ANOVA), Fisher's exact test, and Mann-Whitney test were performed. Descriptive variables were expressed by mean ± standard deviation (SD) and quantitative variables reported by frequency and percentages. P-values less than 0.05 were considered significant. 57.8% of patients were female. The mean age of patients was 35.32 years. According to sex and age, there was no significant difference between groups (P-values were 0.83 and 0.21; respectively). The mean base pain score was 6.97 in lidocaine group and 6.42 in placebo group which was not significantly different (P-value = 0.198). After intervention, the mean scores were significantly lower in lidocaine group than placebo group in all mentioned times (P-value < 0.001). The primary and secondary headaches had no significant difference in mean pain relief score in lidocaine group (P = 0.602).

Do evaluation of efficacy of intra-nasal lidocaine for headache relief in patients refer to emergency department?

To evaluate whether core length impacts biopsy accuracy and Gleason score underestimation compared to radical prostatectomy (RP) specimens. From 2010 to 2011, 8,928 cores were trans-rectal obtained from 744 consecutive patients (178 RP, 24%), 557 by an experienced performer (>250/year) and 187 (25%) by in-training urology residents. Prospectively analyzed variables were core length, age, prostate volume, free and total prostate-specific antigen (PSA), PSA density and free/total PSA ratio. Mean core length for Gleason upgrading on RP (42.7%, n = 76) was 11.61 (±2.5, median 11.40) compared to 13.52 (±3.2, median 13.70), p < 0.001 for perfect biopsy-RP Gleason agreement (57.3%, n = 102). In multivariate analysis, for each unit of core length increment in millimeter, the Gleason upgrading risk decreased 89.9%, p = 0.049 [odds ratio (OR) 0.10, 95% confidence interval (CI) 0.01-0.99]. Biopsy positivity between experienced (35.5%) and in-training performer (30.1%) was not significantly different (p = 0.20), with comparable mean patient age (65.1 vs. 64.1), prostate volume (52.3 vs. 50.7) and median PSA (5.2 vs. 5.1), respectively. Denoting wider variability in terms of core length, in-training performers obtained significantly larger cores for positive biopsies (11.33 ± 3.42 vs. 10.83 ± 3.68), p = 0.043, compared to experienced performer (11.39 ± 3.36 vs. 11.37 ± 3.64), p = 0.30. In multivariate analysis, PSA density (OR 1.14, 95% CI 1.02-1.28) and age (OR 1.04, 95% CI 1.01-1.07) were significantly associated with biopsy positivity, p = 0.021 and p = 0.011, respectively.

Is gleason underestimation predicted by prostate biopsy core length?

To determine whether PTEN status in prostate biopsy represents a predictor of intermediate and long-term oncological outcomes after radical prostatectomy, and whether PTEN status predicts response to androgen deprivation therapy. In a retrospective analysis of 77 men treated by radical prostatectomy who underwent diagnostic biopsy between 1992-2006, biopsy samples were stained for PTEN expression by the PREZEON assay with >10% staining reported as positive. Cox proportional hazards and log-rank models were used to assess the correlation between PTEN loss and clinical outcomes. During a median follow-up period after radical prostatectomy of 8.8 years, 39 men (51%) developed biochemical recurrence, four (5%) had castration-resistant prostate cancer, two (3%) had metastasis and two (3%) died from prostate cancer. PTEN loss was not significantly associated with biochemical recurrence (hazard ratio 2.1, 95% confidence interval 0.9-5.1, P = 0.10), but significantly predicted increased risk of castration-resistant prostate cancer, metastasis and prostate cancer-specific mortality (all log-rank, P < 0.0001), and time from androgen deprivation therapy to castration-resistant prostate cancer (log-rank, P = 0.003). No patient without PTEN loss developed metastases or died from prostate cancer.

Does pTEN loss in biopsy tissue predict poor clinical outcomes in prostate cancer?

Loading otoprotective drug into cochlear implant might change its mechanical properties, thus compromising atraumatic insertion. This study evaluated the effect of incorporation of dexamethasone (DXM) in the silicone of cochlear implant arrays on insertion forces. Local administration of DXM with embedded array can potentially reduce inflammation and fibrosis after cochlear implantation procedure to improve hearing preservation and reduce long-term impedances. Four models of arrays have been tested: 0.5-mm distal diameter array (n = 5) used as a control, drug-free 0.4-mm distal diameter array (n = 5), 0.4-mm distal diameter array with 1% eluded DXM silicone (n = 5), and 0.4-mm distal diameter array with 10% eluded DXM silicone (n = 5). Via a motorized insertion bench, each array has been inserted into an artificial scala tympani model. The forces were recorded by a 6-axis force sensor. Each array was tested seven times for a total number of 140 insertions. During the first 10-mm insertion, no difference between the four models was observed. From 10- to 24-mm insertion, the 0.5-mm distal diameter array presented higher insertion forces than the drug-free 0.4-mm distal diameter arrays, with or without DXM. Friction forces for drug-free 0.4-mm distal diameter array and 0.4-mm distal diameter DXM eluded arrays were similar on all insertion lengths.

Do effect of embedded dexamethasone in cochlear implant array on insertion forces in an artificial model of scala tympani?

Both diet quality (DQ) and physical activity (PA) have been shown to play a role in the prevention of functional capacity (FC) decline. Because older adults (OA) with T2D are at a higher risk of FC decline compared to their non-diabetic counterparts, our aim was to determine if DQ alone, or combined with PA is associated with FC decline in OA with T2D over a 3-year follow-up in a secondary analysis of the NuAge cohort. In 159 OA with T2D (mean age=75 years), FC change was calculated as the difference in FC scores at T1 and T4 measured by the SMAF (Système de Mesure de l'Autonomie Fonctionnelle). Baseline DQ was calculated from three non-consecutive 24-h dietary recalls collected at T1 using the validated Canadian Healthy Eating Index (C-HEI). PA change was calculated from Physical Activity Scale for the Elderly (PASE) as T4-T1. Associations were evaluated between FC decline and four combinations of variables: C-HEI score < or ≥70 with PASE change < or > median and analyzed by GLM while controlling for covariates. Neither DQ alone nor DQ combined with PA change were associated with FC decline over follow-up.

Is decline in functional capacity unaffected by diet quality alone or in combination with physical activity among generally healthy older adults with T2D from the NuAge cohort?

Thrombocytopenia is a common complication in malaria patients. The relationship between abnormal platelet profile and clinical status in malaria patients is unclear. In low and unstable endemic regions where vivax malaria predominates, the hematologic profiles of malaria patients and their clinical utility are poorly understood. The aim of this study was to characterize the thrombograms of malaria patients from Colombia, where Plasmodium vivax infection is common, and to explore the relationship between thrombograms and clinical status. Eight hundred sixty-two malaria patients were enrolled, including 533 (61.8%) patients infected with Plasmodium falciparum, 311 (36.1%) patients infected with Plasmodium vivax and 18 (2.1%) patients with mixed infections. The most frequently observed changes were low platelet count (PC) and high platelet distribution width (PDW), which were observed in 65% of patients; thrombocytopenia with <50,000 platelets/µL was identified in 11% of patients. Patients with complications had lower PC and plateletcrit (PT) and higher PDW values. A higher risk of thrombocytopenia was identified in patients with severe anemia, neurologic complications, pulmonary complications, liver dysfunction, renal impairment and severe hypoglycemia. The presence of thrombocytopenia (<150,000 platelets/µL) was associated with a higher probability of liver dysfunction.

Is platelet profile associated with clinical complications in patients with vivax and falciparum malaria in Colombia?

The aim of this study was to determine whether the diagnostic yield of thyroid fine-needle aspirations (FNAs) changes over the course of residency training. We identified 5418 ultrasound-guided thyroid nodule FNAs performed in our radiology department from 2004 through 2012. For each FNA, we recorded if the FNA was performed by a resident and if so the name of the resident and supervising attending radiologist. For each resident, we determined the level of training based on their graduation year from our residency program and the date of the FNA as well as prior surgical training and if they completed subsequent interventional radiology fellowship. Pathology reports were reviewed, and FNAs were classified as diagnostic or nondiagnostic (ND). Generalized mixed models were used to assess ND rate with postgraduate years, including residents with and without prior surgical training or if they subsequently completed an interventional radiology fellowship. Of the 5418 thyroid FNAs, 3164 (58.4%) were performed by a radiology resident under the direct supervision of an attending physician. There was a significant decrease in ND rate as postgraduate years increased (P < .05). A significant decrease in ND rate was found as postgraduate years increased for residents without prior surgical training (P = .0007) or subsequent training in interventional radiology (P = .0014); however, no significant decrease was found for residents with surgical training (P = .37) or completing an interventional radiology fellowship (P = .08). In addition, no significant difference was found for ND rate between postgraduate year 4 (PGY4) and PGY5 (P > .05).

Does resident experience increase diagnostic rate of thyroid fine-needle aspiration biopsies?

After myocardial infarction (MI), baroreflex function is impaired and heart rate (HR) variability is reduced. An impaired baroreflex has been observed also in coronary patients with no previous MI, leading to hypothesize alterations of HR variability also in these patients. The aim of the present work was, therefore, to study whether and to what extent cardiovascular variability is altered in coronary patients with no previous MI. Thirty-two individuals were studied: eleven patients with coronary artery disease but no previous MI [coronary artery disease (CAD)], eleven patients with a reduced left ventricular ejection fraction [congestive heart failure (CHF)] and ten age-matched controls (CNT). Overall HR variability was significantly and similarly reduced in CAD (630 ± 272 ms) and CHF patients (594 ± 395 ms) with respect to CNT (1405 ± 837 ms), this being the case also for the low and high frequency spectral components. Low-frequency oscillations of blood pressure (BP) were also significantly and similarly less pronounced in CAD (0.7 ± 0.7 mmHg) and CHF patients (0.7 ± 0.7 mmHg) compared with CNT (1.8 ± 1.4 mmHg). Moreover, both CAD and CHF patients showed a significantly reduced baroreflex function and an increased pulse-wave velocity with respect to CNT.

Is cardiovascular variability similarly altered in coronary patients with normal left ventricular function and in heart failure patients?

Advanced glycation end products (AGE) are involved in the progression of diabetic complications. Although our previous reports show that AGE increased dental pulp calcification, AGE accumulation is also associated with inflammation. This study examined AGE effect on the expression of inflammation factors using rat dental pulp tissues and cell cultures. Receptor for AGE (RAGE), S100A8, S100A9, and interleukin (IL)-1β were selected as inflammation parameters. Rat dental pulp cells were cultured and treated with AGE, and the effects were determined by real-time PCR. An anti-RAGE antibody or MAPK pathway inhibitors (PD98059, SB203580, and SP60012) were used to investigate AGE signaling pathway. The mRNA levels of RAGE, S100A8, S100A9, and IL-1β were higher in diabetic pulp tissues. AGE increased mRNA expressions of S100A8, S100A9, and IL-1β in cultured dental pulp cells. In the presence of anti-RAGE antibody, AGE did not increase in S100A8 or S100A9 expressions. The AGE-induced increases in S100A8 and S100A9 were inhibited by PD98059 and SB203580, respectively.

Do advanced glycation end products increase expression of S100A8 and A9 via RAGE-MAPK in rat dental pulp cells?

To assess whether zoledronic acid (ZOL) adds to the effect of combined androgen blockade (CAB) in patients with hormone-naive bone metastatic prostate cancer. Patients were treated with either a combination of CAB (luteinizing hormone-releasing hormone agonist and bicalutamide) and ZOL (CAB-Z group) or CAB-alone (historical control patients, CAB-C group). ZOL was injected intravenously at 4 mg every 4 weeks. One hundred and five and 100 patients among 205 enrolled patients were assigned to the CAB-Z group and CAB-C group, respectively. The time to prostate-specific antigen (PSA) failure in patients in the CAB-Z group was compared to that in the CAB-C group. The primary end-point of the study was the time-to-PSA failure. PSA and serum N-telopeptide of type I collagen (NTx) levels were examined before treatment and every 3 months after treatment. PSA failure occurred in 42 (40.0%) patients in the CAB-Z group and 48 (48.0%) patients in the CAB-C group. The biochemical recurrence-free rate was significantly lower in patients in the CAB-C group (p=0.004, by log-rank test). The categorical biopsy Gleason score pre-treatment serum NTx and treatment with ZOL were shown to be independent predictors of PSA failure-free survival time (p=0.040, p=0.005 and p=0.026, respectively).

Does zoledronic acid improve clinical outcomes in patients with bone metastatic hormone-naïve prostate cancer in a multicenter clinical trial?

Evaluate the effect of a anterior cruciate ligament injury prevention program coaching workshop on elite-level youth soccer coaches' behavioral determinants to implement a injury prevention program and describe coaches' subsequent injury prevention program implementation compliance. Descriptive study. We evaluated a soccer club's coaches' behavioral determinants regarding injury prevention programming implementation before and after a coaching workshop using pre- and post-workshop surveys. We then described the club's coaches' subsequent adoption of and implementation compliance with the injury prevention programming during the following season. The injury prevention workshop increased coaches' attitudes toward conducting a program at the beginning of practice (p<0.05), substituting the program for a warm-up prior to practice (p<0.05), and improving player cutting and landing technique by implementing the program (p<0.05). The injury prevention program workshop increased coaches' perceived behavioral control; feeling more comfortable in their ability to teach their team a program (p<0.05), and more confident leading a program if given instructions (p<0.05). The injury prevention program workshop increased coaches' intent to implement a program the next season (p<0.05), to implement a program for 15min (p<0.05), and 20min (p<0.05) prior to the start of a training session. Only 53% of the club's teams implemented the injury prevention program, with implementers demonstrating high variability in program fidelity.

Does high levels of coach intent to integrate a ACL injury prevention program into training translate to effective implementation?

Behavioral measures of cochlear implant (CI) device stimulation levels can be difficult to obtain in individuals with limited or no hearing experience. Loudness measures are particularly challenging. It would therefore be useful to have a battery of objective and behavioral measures to determine CI stimulation levels in listeners with childhood deafness. In the present study, the authors characterized loudness growth in 20 adolescents: 8 with normal hearing and 12 CI participants with pre/perilingual bilateral sensorineural hearing loss. They asked (1) do adolescent CI users with childhood deafness experience similar increases in loudness as their peers with normal hearing? and (2) can loudness be predicted by objective measures of auditory activity? The authors hypothesized that loudness perception would be significantly different between CI and normal-hearing groups and that it would correlate with objective measures. CI users were recruited from the Cochlear Implant Program at The Hospital for Sick Children and all had used unilateral Nucleus CIs for at least 2 years. The dynamic range for each participant was defined as the difference between the behavioral threshold and the electrically evoked stapedius reflex (ESR) threshold. Loudness growth was assessed within this range behaviorally on a continuous visual scale and objectively with physiological measures. Auditory brainstem responses (ABRs) and ESRs were recorded in both groups and electrically evoked compound action potentials (ECAPs) of the auditory nerve were recorded in addition in CI listeners. The regression line slopes of ECAP and ABR amplitude growth functions were then calculated and compared with behavioral loudness growth slopes in the upper portion (40-100%) and lower portion (0-40%) of the dynamic range. Electrical pulse stimuli (in CI users) and acoustic clicks (in normal-hearing participants) were presented within each participant's dynamic range. The mean dynamic range in CI listeners was more variable than in normal-hearing individuals. Despite this difference, loudness at the ESR threshold was not significantly different in CI adolescents from their normal-hearing peers, and CI users exhibited normal-like loudness growth. There was a significantly positive correlation between ECAP amplitude growth and loudness growth in CI users in the upper portion of the dynamic range, while ABR wave V amplitude growth was not related to loudness growth in either group.

Do unilateral cochlear implant use promotes normal-like loudness perception in adolescents with childhood deafness?

Hearing loss is a commonly experienced disability in a variety of populations including veterans and the elderly and can often cause significant impairment in the ability to understand spoken language. In this study, we tested the hypothesis that neural and behavioral responses to speech will be differentially impaired in an animal model after two forms of hearing loss. Sixteen female Sprague-Dawley rats were exposed to one of two types of broadband noise which was either moderate or intense. In nine of these rats, auditory cortex recordings were taken 4 weeks after noise exposure (NE). The other seven were pretrained on a speech sound discrimination task prior to NE and were then tested on the same task after hearing loss. Following intense NE, rats had few neural responses to speech stimuli. These rats were able to detect speech sounds but were no longer able to discriminate between speech sounds. Following moderate NE, rats had reorganized cortical maps and altered neural responses to speech stimuli but were still able to accurately discriminate between similar speech sounds during behavioral testing.

Does behavioral and neural discrimination of speech sound after moderate or intense noise exposure in rats?

1,8-Cineole, the main monoterpene in many essential oils, has been used as an ingredient in flavourings and medicine. 1,8-Cineole has been shown to possess pharmacological properties, including anti-oxidative, anti-inflammatory and anti-nociceptive actions. However, to date, no studies have examined the potential of 1,8-cineole to protect against cerebral ischaemic injury. In this study, we investigated the neuroprotective effects of 1,8-cineole against cortical neuronal/glial cell injury caused by oxygen-glucose deprivation/reoxygenation (OGD/R) in an in-vitro model of ischaemia. 1,8-Cineole significantly attenuated OGD/R-induced cortical cell injury, as well as reduced n-methyl-d-aspartate (NMDA)-induced cell injury. However, it did not inhibit NMDA-induced cytosolic calcium overload. Nevertheless, 1,8-cineole significantly reduced the OGD/R- and NMDA-induced overproduction of reactive oxygen species (ROS). These results indicate that 1,8-cineole exerts neuroprotection through its anti-oxidative rather than its anti-excitotoxic, properties. The decrease in OGD/R-induced intracellular superoxide in 1,8-cineole-treated cortical cells was associated with the upregulation of superoxide dismutase activity. Moreover, 1,8-cineole showed direct ROS scavenging activity in an assay of oxygen radical absorbance capacity.

Does 1,8-Cineole ameliorate oxygen-glucose deprivation/reoxygenation-induced ischaemic injury by reducing oxidative stress in rat cortical neuron/glia?

Dynamic pelvic magnetic resonance imaging (DP-MRI) offers a comprehensive evaluation of pelvic organ structure in addition to functional information regarding evacuation. Opportunity to apply this technology can be limited due to regional lack of availability. Ideally, clues from standard anorectal testing could predict abnormalities on DP-MRI, leading to its efficient use. The aim of this study is to determine whether high-resolution anorectal manometry (HR-ARM) correlates with findings on DP-MRI. This is a retrospective study of HR-ARM performed on patients with constipation who also underwent DP-MRI. Studies were reviewed for significant findings including posterior pelvic organ prolapse, rectocele > 3 cm, rectal intussusception, and anorectal angle. Statistical analysis was performed using Pearson's correlation coefficient, Student's t-test, and Fisher's exact test. Twenty-three patients undergoing HR-ARM (age range 25-78) also underwent DP-MRI. All were female; 76% were Caucasian. Twenty had significant structural findings: small pelvic prolapse (n = 2), moderate pelvic prolapse (n = 10), large pelvic prolapse (n = 9), rectocele (n = 8), or rectal intussusception (n = 3). Only intrarectal pressure on HR-ARM weakly correlated with size of rectocele (r = 0.46; P = 0.03) and degree of pelvic organ prolapse (r = 0.48; P = 0.02). The remainder of the HR-ARM parameters did not significantly correlate with DP-MRI findings. Patients with dyssynergy were not more likely to have rectoceles > 3 cm (44.4% versus 35.7%; P = 0.5) or large prolapses (44.4% versus 50%, P = 1.0), compared with those without dyssynergy, on HR-ARM.

Are high-resolution anorectal manometry and dynamic pelvic magnetic resonance imaging complementary technologies?

Recognising colorectal cancer (CRC) patients with Lynch syndrome (LS) can increase life expectancy of these patients and their close relatives. To improve identification of this under-diagnosed disease, experts suggested raising the age limit for CRC tumour genetic testing from 50 to 70 years. The present study evaluates the efficacy and cost-effectiveness of this strategy. Probabilistic efficacy and cost-effectiveness analyses were carried out comparing tumour genetic testing of CRC diagnosed at age 70 or below (experimental strategy) versus CRC diagnosed at age 50 or below (current practice). The proportions of LS patients identified and cost-effectiveness including cascade screening of relatives, were calculated by decision analytic models based on real-life data. Using the experimental strategy, four times more LS patients can be identified among CRC patients when compared with current practice. Both the costs to detect one LS patient (€9437/carrier versus €4837/carrier), and the number needed to test for detecting one LS patient (42 versus 19) doubled. When family cascade screening was included, the experimental strategy was found to be highly cost-effective according to Dutch standards, resulting in an overall ratio of €2703 per extra life-year gained in additionally tested patients.

Is fourfold increased detection of Lynch syndrome by raising age limit for tumour genetic testing from 50 to 70 years cost-effective?

Early diagnosis is important in preventing mortality from malaria. The hypothesis that guardians' fear of covert human immunodeficiency virus (HIV) testing delays presentation of children with suspected malaria was tested. The study design is a cross-sectional survey. The study population consisted of guardians of children with suspected malaria who presented to health centres in Oromia Region, Ethiopia. Data were collected on attitudes to HIV testing and the duration of children's symptoms using interview administered questionnaires. Some 830 individuals provided data representing a response rate of 99% of eligible participants. Of these, 423 (51%) guardians perceived that HIV testing was routinely done on blood donated for malaria diagnosis, and 353 (43%) were aware of community members who delayed seeking medical advice because of these concerns. Children whose guardians suspected that blood was covertly tested for HIV had longer median delay to presentation for evaluation at health centres compared to those children whose guardians did not hold this belief (three days compared to two days, p < 0.001). Children whose guardians were concerned about covert HIV testing were at a higher odds of a prolonged delay before being seen at a health centre (odds ratio 1.73, 95% confidence intervals: 1.10 to 270 for a delay of ≥ 3 days compared to those seen in ≤ 2 days).

Are concerns about covert HIV testing associated with delayed presentation of suspected malaria in Ethiopian children : a cross-sectional study?

Fractional CO2 laser has recently emerged as a promising therapeutic modality to improve the texture and appearance of burn scars. An issue in many burn scars is persistent erythema, which traditionally has been treated with vascular lasers. Interestingly, fractional CO2 lasers have been shown to improve the appearance of burn scars, including erythema, but no mechanism has been proposed for this change. Our objective is to evaluate the histopathologic changes in vasculature in burn scars treated with fractionated CO2 laser, and to attempt to describe the mechanism behind reduced erythema following treatment. Uncontrolled, prospective study of ten patients with mature burn scars, from a clinical and histological perspective. Biopsy specimens were obtained before and 2 months after 3 treatment sessions. Anti-CD31 immunostaining was performed to highlight vascular patterns in biopsy specimens. In histological analysis, an increase in vascular density, particularly of small caliber vessels, was seen following treatment, with an 82.6% average increase in vasculature (P = 0.028). This increase in vascularity correlated with a decrease in clinical erythema and vascularity scores, measured using the Vancouver Scar Scale.

Do vascular patterns in mature hypertrophic burn scars treated with fractional CO2 laser?

Annual seasonal and pandemic influenza vaccines need to be produced in a very tight time frame. Haemagglutinin (HA) is the major immunogenic component of influenza vaccines, and there is a lot of interest in improving candidate vaccine viruses. It has been shown elsewhere that mutations introduced in the non-coding region of influenza genome segments can upregulate protein expression. Our objective was to assess a virus based on the laboratory strain A/PR/8/34 (PR8) containing a modified 3' non-coding region of RNA segment 4 (haemagglutinin). NIBRG-93 was generated using reverse genetics. HA protein expression and growth properties were assessed. The virus phenotype suggested that it could be a candidate for use as a live attenuated vaccine, so in vivo studies were performed to assess its suitability. NIBRG-93 virus has enhanced haemagglutinin production and is significantly attenuated. Electron microscopy (EM) shows that the modified virus produces a large proportion of 'virus-like particles' that consist of budded cell membrane covered in HA but lacking M1 protein. The virus was shown to be attenuated in mice and offered complete protection against lethal challenge.

Does a promoter mutation in the haemagglutinin segment of influenza A virus generate an effective candidate live attenuated vaccine?

Obesity adversely inhibits antibody response to vaccination. Three doses of HPV4 may or may not provide adequate long term protection against HPV 16/18 in obese females. The aim of this study was to determine whether adherence to HPV4 vaccination in a safety net population was reduced with increasing body mass index (BMI). We designed a historical prospective study evaluating the number and dates of HPV4 dosing that occurred from July 1, 2006 through October 1, 2009 by the demographic characteristics of the 10-26 year old recipient females. The defined dosing intervals were adapted from the literature and obesity categories were defined by the WHO. 1240 females with BMI measurements received at least one dose of HPV4; 38% were obese (class I, II and III) and 25% were overweight. Females with normal BMI received on-time triplet dosing significantly more often than did the obese class II and III females (30% vs. 18%, p<0.001). Obese class II/III females have a significant 45% less chance of completing the on-time triplet HPV4 series than normal women (OR = 0.55, 95% CI: 0.37, 0.83). Pregnancy history has a significant influence on BMI and HPV4 dosing compliance in this safety net population where 71% had been gravid. Hispanic females were less likely to complete HPV4 dosing regardless of BMI (aOR = 0.39, 95% CI: 0.16, 0.95).

Does in a safety net population HPV4 vaccine adherence worsen as BMI increases?

The membrane protein CD46, a ubiquitous cell surface pathogen receptor, can bind Streptococcus to trigger cell autophagy, which is a critical step in the control of infection. In this study, we found a new splice variant designated CD46 transcript variant (CD46-TV). The splice variant is characterized by the retention of a 48 bp sequence from intron 8 of the bovine CD46 gene, which encodes a putative protein enlarged by 16 amino acids. CD46-TV mRNA was found to be over expressed in mastitis-infected mammary gland tissues relative to healthy tissues. A single nucleotide polymorphism (c. 1033 + 2184 C > T) in the exonic splicing enhancer (ESE) motif region was shown to result in the CD46-TV aberrant splice variant through constructing alternative alleles using the pSPL3 exon capturing vector and transfecting these into 293 T cells. Allelic frequency in 56,682 individuals belonging to 112 Bos taurus, Bos indicus, Bos javanicus, Bos grunniens and Bos mutus, etc. suggests that the C allele (80.09%) is the ancestral allele. Association analysis found that the mean genomic estimated breeding values (gEBV) for milk somatic cell score and the occurrence of clinical mastitis, as well as the milk somatic cell score of Chinese Holsteins with the CT genotype was lower than those of individuals with either the CC or TT genotypes. The mean gEBV for udder health synthesis for the TT genotype was greater than those for the CC or CT genotypes.

Does a SNP in intron 8 of CD46 cause a novel transcript associated with mastitis in Holsteins?

Residual disease (RD) at definitive resection of incidental gallbladder cancer (IGBCA) influences outcome, but its clinical relevance with respect to anatomic site is incompletely characterized. Consecutive patients with IGBCA undergoing re-exploration from 1998 to 2009 were identified; those submitted to a complete resection were analyzed. Demographics and tumor- and treatment-related variables were correlated with RD and survival. Cancer-specific survival was stratified by site of RD (local [gallbladder bed]; regional [bile duct, lymph nodes]; distant [discontiguous liver, port site, peritoneal]). Of the 135 patients submitted to re-exploration, RD was found in 82 (61%) overall and in 63 (54%) of 116 patients submitted to resection; the most common site was regional (n = 27, 43%). The T stage of the gallbladder specimen was the only independent predictor of RD (T1b = 35.7%, T2 = 48.3%, T3 = 70%, p = 0.015). The presence of RD at any site dramatically reduced median disease-free survival (DFS) (11.2 vs 93.4 months, p < 0.0001) and disease-specific survival (DSS) (25.2 months vs not reached, p < 0.0001) compared with no RD, respectively. Disease-specific survival did not differ according to RD location, with all anatomic sites being equally poor (p = 0.87). Residual disease at any site predicted DFS (hazard ratio [HR] 3.3, 95% CI 1.9 to 5.7, p = 0.0003) and DSS (HR 2.4, 95% CI 1.2 to 4.6, p = 0.01), independent of all other tumor-related variables.

Does residual disease predict outcomes after definitive resection for incidental gallbladder cancer?

Weight-loss is a near societal obsession and many diet programs use significant calorie restriction including fasting/short term starvation to generate rapid effects. Fasting is also a well-recognized cause of immunosuppression especially within the innate immune system. In this study, we sought to determine if the IL-1 arm of the neuroimmune system was down-regulated by a 24 h fast and how fasting might generate this effect. Mice were allowed ad libitum access to food or had food withheld for 24 h. Expression of the endogenous IL-1 antagonists, IL-1 receptor type 2 (IL-1R2), and IL-1 receptor antagonist (IL-1RA) was determined as were sickness behaviors before and after IL-1β administration. Fasting markedly increased gene expression of IL-1R2 (83-fold in adipose tissue, 9.5-fold in liver) and IL-1RA (68-fold in liver). Fasted mice were protected from IL-1β-induced weight-loss, hypoglycemia, loss of locomotor, and social anxiety. These protections were coupled to a large positive interaction of fasting and IL-1β on IL-1R2 gene expression in adipose tissue and liver (2.6- and 1.6-fold, respectively). Fasting not only increased IL-1RA and IL-1R2 protein 2.5- and 3.2-fold, respectively, in liver but also increased IL-1R2 1.8-fold in adipose tissue. Fasting, in turn, triggered a 2.4-fold increase in plasma free-fatty acids (FFAs) and a 2.1-fold increase in plasma corticosterone. Inhibition, of glucocorticoid action with mifepristone did not impact fasting-dependent IL-1R2 or IL-1RA gene expression. Administration of the FFA, palmitate, to mice increased liver IL-1R2 and IL-1RA gene expression by 14- and 11-fold, respectively.

Does fasting induce IL-1 Resistance and Free-Fatty Acid-Mediated Up-Regulation of IL-1R2 and IL-1RA?

Aurora kinase A (AurkA) is over-expressed in melanoma and its inhibition has been observed to limit tumor growth, suggesting a potential role in melanoma treatment. A human melanoma cell line with the B-RAF (V600E) mutation (A375mel) was exposed to B-RAF inhibitor (GSK2118436), MEK inhibitor (GSK1120212) and AurkA inhibitor (MLN8054) as single agents or in various combinations (BRAF plus AurkA inhibitor, MEK plus AurkA inhibitor or triple combination BRAF plus MEK plus AurkA inhibitor). Cell proliferation was assessed using xCELLigence technology. Total protein extracts were examined for p53 and c-Myc protein expression by Western blot analysis. Drug anti-tumor effects were further assessed using a 3D-human melanoma skin reconstruction model, in which tissues were incubated with serum-free medium containing control, B-RAF plus MEK inhibitor, MEK plus AurkA inhibitor or the triple combination. AurkA inhibitor plus B-RAF inhibitor, AurkA inhibitor plus MEK inhibitor or triple combination had a markedly greater anti-proliferative effect on A375 (BRAFV600E) melanoma cells than single agents. In the 3D human skin model, the triple combination had a greater anti-tumor effect at the epidermal/dermal junction than control or either double combination. However, S-100 and Ki-67 positively stained spindle-shaped cells were detected in the dermal stratum, suggesting the presence of alive and proliferating melanoma cells.

Do aurkA inhibitors enhance the effects of B-RAF and MEK inhibitors in melanoma treatment?

Maternal diabetes is a risk factor for pregnancy complications, including stillbirth and macrosomia. Evolving data suggest that diabetes during pregnancy also has long-term consequences for offspring, putting them at risk for obesity and the metabolic syndrome in childhood. Because nonalcoholic fatty liver disease is known to occur in adults and children with insulin resistance, we hypothesized that altered lipid metabolism in fetuses of diabetic mothers may manifest with hepatic steatosis. We undertook a retrospective autopsy study to compare the presence and degree of hepatic steatosis between stillborns delivered to women with pregestational or gestational diabetes mellitus (gestational age 20-40 weeks; n = 33) and age-matched nondiabetic control stillbirth cases (n = 48), the latter enriched for maternal obesity, macrosomia, and similar cause of demise. Histopathologic hepatic steatosis was significantly more prevalent and severe in the diabetic subjects (26/33, 78.8%) than in the controls (8/48, 16.6%) (P < 0.001). Within the diabetic cohort, the severity of steatosis was related directly to gestational age, birth weight, and liver weight, with no correlation of presence or severity of steatosis in the control group to maternal or fetal factors, including maternal body mass index or fetal macrosomia. Although macrosomic stillborns were more common in diabetic women with %hemoglobin A1c >6 and body mass index >30 kg/m, fetal steatosis was independent of glycemic control, maternal obesity, type of diabetes, ethnicity, or fetal sex in our cohort.

Is hepatic steatosis prevalent in stillborns delivered to women with diabetes mellitus?

To examine the effects of lunches with different dietary energy densities on food preferences between genders. Randomized crossover study. Participants were administered the following packed test meals once weekly on a specified day during six sessions: control (150 g of rice with a sautéed beef entrée containing 40 g of raw beef and 240 g of vegetables), high-meat/low-rice, low-vegetable, medium-fat/low-vegetable, high-fat and high-fat/low-vegetable meals. Subjective levels of sensory properties were assessed over time using visual analogue scales. University of Tokushima Graduate School, Tokushima, Japan. Sixty-five men and sixty-five women matched by age and BMI. Men showed significantly stronger desires for salty and fatty foods after meals (P<0.05). Women showed a significantly stronger desire for sweetness from 2 h after the low-vegetable meal, and increasing fat content under high-vegetable conditions caused a significant stimulated sweetness desire in women more than in men (P<0.05). Moreover, after a high-meat/low-rice meal with 100 g of rice, sweetness desire was stronger in women (P=0.024), whereas no significant differences in sweetness desire were shown between genders after another low-energy-density control meal with 150 g of rice.

Is high-fat diet-related stimulation of sweetness desire greater in women than in men despite high vegetable intake?

Although allergic sensitization can be generated against various allergens, it is unknown how such a diversity of antigens is able to promote TH2-mediated inflammation leading to atopy. Our previous studies demonstrated that allergen-specific IgG immune complexes (ICs) and house dust mite (HDM) extract both induced dendritic cells (DCs) to drive TH2-mediated inflammation, but the mechanism by which these diverse stimuli produce similar responses is unknown. We sought to identify the DC signaling pathways used by TH2 stimuli to promote TH2-mediated inflammation. C57BL/6, FcγRIII(-/-), FcRγ(-/-), and ST2(-/-) mice were sensitized and challenged with HDM, and inflammation was assessed based on results of flow cytometry and histology and cytokine production. Bone marrow-derived DCs from these strains were used in signaling and adoptive transfer experiments. Our findings indicate that 2 distinct TH2 stimuli, ICs and HDM, use the FcRγ-associated receptors FcγRIII and Dectin-2, respectively, to promote TH2-mediated lung inflammation. In this study we demonstrate that both ICs and HDM induce expression of IL-33, a critical mediator in asthma pathogenesis and the differentiation of TH2 cells, in DCs. Upregulation of IL-33 in DCs is dependent on FcRγ, Toll-like receptor 4, and phosphoinositide 3-kinase. Exogenous IL-33 is sufficient to restore the development of TH2 responses in FcRγ-deficient mice. Finally, adoptive transfer of allergen-pulsed FcRγ(+/-) bone-marrow derived DCs restores the development of TH2-type inflammation in FcRγ-deficient mice, demonstrating the necessity of this signaling pathway in DCs for allergen-induced inflammation.

Does signaling through FcRγ-associated receptors on dendritic cells drive IL-33-dependent TH2-type responses?

Alzheimer's disease (AD) is characterized by cerebral deposition of β-amyloid peptide (Aβ). Aβ is produced by sequential cleavage of the Amyloid Precursor Protein (APP) by β- and γ-secretases. Many studies have demonstrated that the internalization of APP from the cell surface can regulate Aβ production, although the exact organelle in which Aβ is produced remains contentious. A number of recent studies suggest that intracellular trafficking also plays a role in regulating Aβ production, but these pathways are relatively under-studied. The goal of this study was to elucidate the intracellular trafficking of APP, and to examine the site of intracellular APP processing. We have tagged APP on its C-terminal cytoplasmic tail with photoactivatable Green Fluorescent Protein (paGFP). By photoactivating APP-paGFP in the Golgi, using the Golgi marker Galactosyltranferase fused to Cyan Fluorescent Protein (GalT-CFP) as a target, we are able to follow a population of nascent APP molecules from the Golgi to downstream compartments identified with compartment markers tagged with red fluorescent protein (mRFP or mCherry); including rab5 (early endosomes) rab9 (late endosomes) and LAMP1 (lysosomes). Because γ-cleavage of APP releases the cytoplasmic tail of APP including the photoactivated GFP, resulting in loss of fluorescence, we are able to visualize the cleavage of APP in these compartments. Using APP-paGFP, we show that APP is rapidly trafficked from the Golgi apparatus to the lysosome; where it is rapidly cleared. Chloroquine and the highly selective γ-secretase inhibitor, L685, 458, cause the accumulation of APP in lysosomes implying that APP is being cleaved by secretases in the lysosome. The Swedish mutation dramatically increases the rate of lysosomal APP processing, which is also inhibited by chloroquine and L685, 458. By knocking down adaptor protein 3 (AP-3; a heterotetrameric protein complex required for trafficking many proteins to the lysosome) using siRNA, we are able to reduce this lysosomal transport. Blocking lysosomal transport of APP reduces Aβ production by more than a third.

Is the Amyloid Precursor Protein rapidly transported from the Golgi apparatus to the lysosome and where it is processed into beta-amyloid?

The study aimed to test the hypothesis that therapeutic treatment with a mammalian target of rapamycin complex 1 inhibitor reduces renal cell proliferation and attenuates glomerular and tubulointerstitial injury in the early phase of nephrotoxic serum nephritis (NSN) in rats. Male Wistar-Kyoto rats received a single tail-vein injection of sheep anti-rat glomerular basement membrane serum (day 0) and were treated with vehicle or sirolimus (0.25 mg/kg/day by subcutaneous injection) from day 1 until day 14. Treatment with sirolimus attenuated kidney enlargement by 41% (P<0.05), improved endogenous creatinine clearance by 50% (P<0.05), and reduced glomerular and tubulointerstitial cell proliferation by 53% and 70%, respectively, (P<0.05 compared to vehicle) in rats with NSN. In glomeruli, sirolimus reduced segmental fibrinoid necrosis by 69%, autologous rat immunoglobulin G deposition, glomerular capillary tuft enlargement, and periglomerular myofibroblast (α-smooth muscle actin-positive cells) accumulation (all P<0.05) but did not significantly affect glomerular crescent formation (P=0.15), macrophage accumulation (P=0.25), or the progression of proteinuria. In contrast, sirolimus preserved tubulointerstitial structure and attenuated all markers of injury (interstitial ED-1- and α-smooth muscle actin-positive cells and tubular vimentin expression; all P<0.05). By immunohistochemistry and Western blot analysis, sirolimus reduced the glomerular and tubulointerstitial expression of phosphorylated (Ser 235/236) S6-ribosomal protein (P<0.05).

Does induction monotherapy with sirolimus have selected beneficial effects on glomerular and tubulointersititial injury in nephrotoxic serum nephritis?

Serrated lesions are an important contributor to colorectal cancer (CRC), notably in the proximal colon. Findings in the distal colorectum are markers of advanced proximal adenomatous neoplasia. However, it is not known whether they affect the odds of advanced proximal serrated lesions. We performed a retrospective cross-sectional study of data from 1910 patients (59.3 ± 8.0 years, 53.8% female) who underwent an average-risk screening colonoscopy from August 2005 through April 2012 at Indiana University Hospital and an associated ambulatory surgery center. Colonoscopies were performed by an endoscopist with high rates of detection of adenomas and serrated polyps. Tissue samples of all serrated polyps (hyperplastic, sessile serrated adenoma/polyp [SSA/P], or traditional serrated adenoma) proximal to the sigmoid colon and serrated polyps >5 mm in the rectum or sigmoid colon were reviewed by a gastrointestinal pathologist and reclassified on the basis of World Health Organization criteria. Advanced serrated lesion (ASL) was defined as SSA/P with cytologic dysplasia, SSA/P ≥10 mm, or traditional serrated adenoma. Advanced conventional adenomatous neoplasia (ACN) was defined as tubular adenoma ≥10 mm, villous histology, high-grade dysplasia, or cancer. The prevalence of proximal ASL and ACN was calculated on the basis of distal colorectal findings. Multivariable logistic regression analysis was performed to determine the age-adjusted and sex-adjusted odds of advanced proximal adenomatous and serrated lesions. Secondary analyses were performed to examine the effect of variable ASL definitions. Fifty-two patients (2.7%) had proximal ASL, and 99 (5.2%) had proximal ACN. Of the 52 patients with proximal ASL, 27 (52%) had no distal polyps. Of the 99 patients with proximal ACN, 40 (40%) had no distal polyps. Age and type of distal adenomas were significantly associated with proximal ACN. There were no significant associations between distal polyp type and proximal ASL. In secondary analyses, distal SSA/Ps (P = .008) but not distal hyperplastic polyps or conventional adenomas were associated with any proximal SSA/P.

Are findings in the distal colorectum associated with proximal advanced serrated lesions?

Bradykinin is a neuropeptide released after tissue damage which plays an important role in inflammatory pain. The up-regulation of the bradykinin B1 receptor in response to inflammation makes it an attractive target for drug development. Aim was to investigate if the selective B1 receptor antagonist BI113823 reduces inflammation-induced mechanical hyperalgesia and if the effect is mediated via peripheral and/or spinal B1 receptor antagonism. Electrophysiological recordings of peripheral afferents and spinal neurons were combined with behavioural experiments to better understand the underlying mechanisms of B1 receptor antagonism. Experiments were performed 24 h after injection of complete Freund's adjuvant (CFA) or saline into the paw of Wistar rats. A gene expression analysis for the B1 receptor was performed in different tissues. BI113823 was administered orally or intrathecally to assess effects on CFA-induced hyperalgesia. Peripheral afferents of the saphenous nerve as well as spinal wide dynamic range (WDR) and nociceptive-specific (NS) neurons were recorded, and mechanosensitivity was measured before and after BI113823 administration. BI113823 reduced CFA-induced mechanical hyperalgesia when administered orally or intrathecally. An increased B1 receptor gene expression was found in peripheral and spinal neural tissue. BI113823 significantly reduced mechanosensitivity of peripheral afferents and spinal NS neurons, but had no effect on WDR neurons.

Does the bradykinin B1 receptor antagonist BI113823 reverse inflammatory hyperalgesia by desensitization of peripheral and spinal neurons?

Recent work has identified deficits in dual-task gait balance control for up to 2 months after adolescent concussion; however, how resumption of preinjury physical activities affects recovery is unknown. The objective of this study is to examine how return to activity (RTA) affects recovery from concussion on measures of symptom severity, cognition, and balance control during single-task and dual-task walking. Nineteen adolescents with concussion who returned to preinjury activity within 2 months after injury and 19 uninjured, matched controls completed symptom inventories, computerized cognitive testing, and single-task and dual-task gait analyses. Concussion participants were assessed at five time points: within 72 h, 1 wk, 2 wk, 1 month, and 2 months postinjury. Control participants were assessed at the same time points as their matched concussion counterparts. RTA day was documented as the postinjury day in which physical activity participation was allowed. The effect of returning to physical activity was assessed by examining the percent change on each dependent variable across time before and directly after the RTA. Data were analyzed by two-way mixed effects ANOVAs. After the RTA day, concussion participants significantly increased their total center-of-mass medial/lateral displacement (P = 0.009, ηp = .175) and peak velocity (P = 0.048, ηp = 0.104) during dual-task walking when compared with pre-RTA data, whereas no changes for the concussion group or between groups were detected on measures of single-task walking, forward movement, or cognition.

Does return to activity after concussion affect dual-task gait balance control recovery?

Clinically, early life stress and anxiety disorders are associated with increased vulnerability for alcohol use disorders. In male rats, early life stress, imparted by adolescent social isolation, results in long-lasting increases in a number of behavioral risk factors for alcoholism, including greater anxiety-like behaviors and ethanol (EtOH) intake. Several recent studies have begun to use this model to gain insight into the relationships among anxiety measures, stress, EtOH intake, and neurobiological correlates driving these behaviors. As prior research has noted significant sex differences in the impact of adolescent stress on anxiety measures and EtOH drinking, the current study was conducted to determine if this same model produces an "addiction vulnerable" phenotype in female rodents. Female Long Evans rats were socially isolated (SI; 1/cage) or group housed (GH; 4/cage) for 6 weeks during adolescence. After this housing manipulation, behavioral assessment was conducted using the elevated plus maze, response to novelty in an open field environment, and the light/dark box. After behavioral testing, home cage EtOH drinking was assessed across an 8-week period. No group differences were detected in any of the behavioral measures of unconditioned anxiety-like behavior. Greater EtOH intake and preference were observed in SI females but these differences did not persist.

Does adolescent social isolation lead to persistent increases in anxiety- like behavior or ethanol intake in female long-evans rats?

Previous studies have suggested that DNA methylation contributes to coronary artery disease (CAD) risk variability. DNA hypermethylation at the ATP-binding cassette transporter A1 (ABCA1) gene, an important modulator of high-density lipoprotein cholesterol and reverse cholesterol transport, has been previously associated with plasma lipid levels, aging and CAD, but the association with CAD has yet to be replicated. ABCA1 DNA methylation levels were measured in leucocytes of 88 men using bis-pyrosequencing. We first showed that DNA methylation at the ABCA1 gene promoter locus is associated with aging and CAD occurrence in men (P < 0.05). The latter association is stronger among older men with CAD (≥61 years old; n = 19), who showed at least 4.7% higher ABCA1 DNA methylation levels as compared to younger men with CAD (<61 years old; n = 19) or men without CAD (n = 50; P < 0.001). Higher ABCA1 DNA methylation levels in older men were also associated with higher total cholesterol (r = 0.34, P = 0.03), low-density lipoprotein cholesterol (r = 0.32, P = 0.04) and triglyceride levels (r = 0.26, P = 0.09). Furthermore, we showed that acetylsalicylic acid therapy is associated with 3.6% lower ABCA1 DNA methylation levels (P = 0.006), independent of aging and CAD status of patients.

Are acetylsalicylic acid , aging and coronary artery disease associated with ABCA1 DNA methylation in men?

In advanced cancer, including glioblastoma, the TGFβ pathway acts as an oncogenic factor. Some tumors exhibit aberrantly high TGFβ activity, and the mechanisms underlying this phenomenon are not well understood. We have observed that TGFβ can induce TGFβ2, generating an autocrine loop leading to aberrantly high levels of TGFβ2. We identified cAMP-responsive element-binding protein 1 (CREB1) as the critical mediator of the induction of TGFβ2 by TGFβ. CREB1 binds to the TGFB2 gene promoter in cooperation with SMAD3 and is required for TGFβ to activate transcription. Moreover, the PI3K-AKT and RSK pathways regulate the TGFβ2 autocrine loop through CREB1. The levels of CREB1 and active phosphorylated CREB1 correlate with TGFβ2 in glioblastoma. In addition, using patient-derived in vivo models of glioblastoma, we found that CREB1 levels determine the expression of TGFβ2. Our results show that CREB1 can be considered a biomarker to stratify patients for anti-TGFβ treatments and a therapeutic target in glioblastoma.

Does active CREB1 promote a malignant TGFβ2 autocrine loop in glioblastoma?

Are submaximal and maximal exercise tests reliable, valid and acceptable in people with chronic pain, fibromyalgia and fatigue disorders? Systematic review of studies of the psychometric properties of exercise tests. People older than 18 years with chronic pain, fibromyalgia and chronic fatigue disorders. Studies of the measurement properties of tests of physical capacity in people with chronic pain, fibromyalgia or chronic fatigue disorders were included. Studies were required to report: reliability coefficients (intraclass correlation coefficient, alpha reliability coefficient, limits of agreements and Bland-Altman plots); validity coefficients (intraclass correlation coefficient, Spearman's correlation, Kendal T coefficient, Pearson's correlation); or dropout rates. Fourteen studies were eligible: none had low risk of bias, 10 had unclear risk of bias and four had high risk of bias. The included studies evaluated: Åstrand test; modified Åstrand test; Lean body mass-based Åstrand test; submaximal bicycle ergometer test following another protocol other than Åstrand test; 2-km walk test; 5-minute, 6-minute and 10-minute walk tests; shuttle walk test; and modified symptom-limited Bruce treadmill test. None of the studies assessed maximal exercise tests. Where they had been tested, reliability and validity were generally high. Dropout rates were generally acceptable. The 2-km walk test was not recommended in fibromyalgia.

Are several submaximal exercise tests reliable , valid and acceptable in people with chronic pain , fibromyalgia or chronic fatigue : a systematic review?

Anorectal manometry provides objective information about anorectal function, but its results depend on the examiner's skill, the type of equipment, and subject characteristics like age or gender. This single institution, prospective study was performed to investigate the effect of gender and age on the results of anorectal manometry. All included subjects completed a questionnaire to assess their bowel function. The survey included 13 validated questions (eight on constipation and five on incontinence) and was used to exclude subjects with pathological constipation or incontinence. Subjects with normal bowel function underwent anorectal manometry to measure anal sphincter length (ASL), maximum resting pressure (MRP), and maximum squeeze pressure (MSP), and the results were compared by gender and age. The mean age of the 154 participants (94 male and 60 female) was 59.1 years. ASL was greater in men (4.23 vs. 3.85 cm, p < 0.001). MRP was not significantly different according to gender (p = 0.93), but MSP was higher in men (190.18 vs. 116.49 mmHg, p < 0.001). ASL did not correlate with age (p = 0.707). MRP was inversely related to age in both men (R (2) = 0.152, p < 0.001) and women (R (2) = 0.282, p < 0.001), and MSP only in women (R (2) = 0.210, p < 0.001).

Are anorectal manometric parameters influenced by gender and age in subjects with normal bowel function?

In breast cancer, distinct expression profiles of microRNAs (miRNAs) have been associated with molecular subgroups and clinicopathological characteristics, implicating a diagnostic and prognostic role of miRNAs. However, the biological functions of deregulated miRNAs in tumor progression are not yet completely defined. In this study, we investigated the function of miR-18a in regulating breast cancer metastasis through the hypoxia-inducible factor 1α (HIF1A)-dependent hypoxic response. An orthotopic metastatic breast cancer xenograft model (MDA-MB-231 cells) was used to identify miRNAs associated with spontaneous lung metastasis. The function of miR-18a in regulating HIF1A expression, as well as cellular responses to hypoxia and metastasis, were then studied in vitro and in vivo by assessing ectopic miR-18a expression or miR-18a inhibition. miRNA-mRNA interactions (AGO2 immunoprecipitation and 3' untranslated region Luciferase reporter assays), gene expression (quantitative PCR and microarray), cell migration and invasion, and cell growth were assessed under normoxic or hypoxic conditions, complemented by orthotopic xenograft of tumor cells to the mammary fat pad to investigate the effect of modulating miR-18a expression on primary tumor growth and lung metastasis. Last, clinically relevant correlations between miR-18a, HIF1A, hypoxia-responsive gene expression and distant metastasis-free survival (DMFS) were assessed using published expression array breast tumors data sets. miRNAs encoded by the MIR17HG gene were downregulated in lung metastases compared to primary tumors. Ectopic expression of miR-18a, a MIR17HG family member, in a metastatic variant of MDA-MB-231 cells reduced primary tumor growth and lung metastasis, whereas miR-18a inhibition in the parental cells promoted tumor growth and lung metastasis. We identified HIF1A as a direct target of miR-18a. Modulating miR-18a expression significantly affected hypoxic gene expression, cell invasiveness and sensitivity to anoikis and hypoxia in vitro in a HIF1A-dependent manner. Analysis of previously published data revealed that higher expression of HIF1A and a panel of hypoxic genes is associated with shorter DMFS interval in patients with basal-like breast tumors, and that, within this subtype, miR-18a expression is inversely correlated with hypoxic gene expression. Together, these data support a role of miR-18a in repressing distant metastasis through a HIF1A-dependent pathway.

Does microRNA-18a inhibit hypoxia-inducible factor 1α activity and lung metastasis in basal breast cancers?

Embryo transfer to a developed endometrium is an important prognostic factor in frozen-thawed embryo transfer cycle outcome. Vaginal estrogen, such as Vagifem vaginal tablets and Premarin vaginal cream, is a regimen used for the patients with refractive endometria. Our objective was to compare the effects of Vagifem and Premarin on the endometrial thickness of the patients with refractive endometria. In this randomized clinical trial, 30 patients with refractive endometria in frozen-thawed embryo transfer cycles received Vagifem vaginal tablets and 30 women received Premarin vaginal cream. Endometrial thickness was measured on the 14th day of drug administration. Comparing the endometrial thicknesses of the two groups showed that the endometria of the Vagifem group was significantly thicker than that of the Premarin group (5.93±0.38 vs. 6.74±0.32; p<0.001).

Is vagifem superior to vaginal Premarin in induction of endometrial thickness in the frozen-thawed cycle patients with refractory endometria : A randomized clinical trial?

SUMO-specific protease 1 (SENP1) removes SUMO from proteins and plays important roles in the regulation of multiple cellular signalling pathways. However, little is known about the role of SENP1 in coronary heart disease. In this study, we tested the hypothesis that SENP1 protects against myocardial ischaemia/reperfusion (I/R) injury and investigated the underlying molecular mechanisms involved. First, we found that SENP1 levels increased after I/R in human and mouse myocardium in vivo and in rat cardiomyocytes in vitro. We then performed coronary artery ligation to induce I/R injury in wild-type (WT) and heterozygous SENP1-knockdown (SENP1(+/-)) mice. Compared with WT mice, SENP1(+/-) mice had normal cardiac function at baseline but lower systolic function after I/R. Post-I/R myocardial infarction sizes were larger in SENP1(+/-) mice. Furthermore, we demonstrated that SENP1 regulates the expression of hypoxia-inducible factor 1 α (HIF1α), a critical protective factor during I/R, in vivo and in vitro. Overexpression of HIF1α reversed the deteriorating effect of SENP1 knockdown on cellular death.

Does sENP1 protect against myocardial ischaemia/reperfusion injury via a HIF1α-dependent pathway?

From our previous clinical trials, intracoronary infusion of granulocyte-colony stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cells ((mob)PBMCs) proved to be effective in improving myocardial contractility and reducing infarct volume in acute myocardial infarction. We tested the effect of priming (mob)PBMCs with erythropoietin (EPO) to augment its therapeutic efficacy. (mob)PBMCs were obtained from healthy volunteers after a 3-day subcutaneous injection of G-CSF (10 μg/kg). About 40% of (mob)PBMCs were EPO receptor (EPOR) (+) and responded to 6 h EPO-priming (10 IU/mL) by increasing the expression of vasculogenic factors (i.e. IL8, IL10, bFGF, PDGF, MMP9) and adhesion molecules (i.e. integrin αV, β1, β2, β8) through the JAK2 and Akt pathway. These responses were also observed in PBMCs from elderly patients with coronary disease. The conditioned media from EPO-primed (mob)PBMCs contained various cytokines such as IL8, IL10, TNFα, and PDGF, which enhanced the migration and tube formation capability of endothelial cells. EPO-primed (mob)PBMCs also showed increased adhesion on endothelial cells or fibronectin. Augmented vasculogenic potential of EPO-primed (mob)PBMCs was confirmed in a Matrigel plug assay, ischaemic hindlimb, and myocardial infarction models of athymic nude mice. There were two action mechanisms: (i) cellular effects confirmed by direct incorporation of human (mob)PBSCs into mouse vasculature and (ii) indirect humoral effects confirmed by the therapeutic effect of the supernatant of EPO-primed (mob)PBMCs.

Does erythropoietin priming improve the vasculogenic potential of G-CSF mobilized human peripheral blood mononuclear cells?

We investigated whether glucose fluctuations aggravate cardiac fibrosis and increase the occurrence of atrial fibrillation (AF) in rats with diabetes mellitus (DM). Streptozotocin-induced diabetic rats were randomly divided into three groups: uncontrolled DM (U-STZ) group, controlled DM (C-STZ) group, and DM with glucose fluctuations (STZ-GF) group. Glucose fluctuations were induced by fasting for 24 h and additional regular insulin injections (0.5 IU/kg) administered three times per week for three consecutive weeks. C-STZ rats were administered long acting insulin (20 IU/kg) twice a day to control blood glucose levels. Cardiac fibrosis evaluated by Masson trichrome staining and the expressions of collagen type 1, collagen type 3, and α-smooth muscle actin were increased in U-STZ rats compared with C-STZ rats, which were more pronounced in STZ-GF rats. The inducibility of AF was significantly larger in U-STZ rats than C-STZ rats and was greatest in STZ-GF rats. To explore the mechanism of cardiac fibrosis, we investigated the levels of reactive oxygen species (ROS) and apoptosis. The expression of malondialdehyde, an indicator of ROS levels, was significantly upregulated in STZ-GF rats compared with U-STZ rats, along with increased thioredoxin-interacting protein (Txnip) expression in STZ-GF rats. Furthermore, caspase-3 expression and the number of TUNEL-positive cells were significantly increased in STZ-GF rats compared with U-STZ and C-STZ rats.

Do glucose fluctuations increase the incidence of atrial fibrillation in diabetic rats?

Physical activity and sedentary behavior measurement tools need to be validated in free-living settings. Direct observation (DO) may be an appropriate criterion for these studies. However, it is not known if trained observers can correctly judge the absolute intensity of free-living activities. To compare DO estimates of total MET-hours and time in activity intensity categories to a criterion measure from indirect calorimetry (IC). Fifteen participants were directly observed on three separate days for two hours each day. During this time participants wore an Oxycon Mobile indirect calorimeter and performed any activity of their choice within the reception area of the wireless metabolic equipment. Participants were provided with a desk for sedentary activities (writing, reading, computer use) and had access to exercise equipment (treadmill, bike). DO accurately and precisely estimated MET-hours [% bias (95% CI) = -12.7% (-16.4, -7.3), ICC = 0.98], time in low intensity activity [% bias (95% CI) = 2.1% (1.1, 3.2), ICC = 1.00] and time in moderate to vigorous intensity activity [% bias (95% CI) -4.9% (-7.4, -2.5), ICC = 1.00].

Is direct observation a valid criterion for estimating physical activity and sedentary behavior?

Increased expression of nitric oxide synthase (NOS) and an increase in plasma nitrite plus nitrate (NOx) have been reported in patients with pulmonary fibrosis, suggesting that nitric oxide (NO) plays an important role in its development. However, the roles of the entire NO and NOS system in the pathogenesis of pulmonary fibrosis still remain to be fully elucidated. The aim of the present study is to clarify the roles of NO and the NOS system in pulmonary fibrosis by using the mice lacking all three NOS isoforms. Wild-type, single NOS knockout and triple NOS knockout (n/i/eNOS-/-) mice were administered bleomycin (BLM) intraperitoneally at a dose of 8.0 mg/kg/day for 10 consecutive days. Two weeks after the end of the procedure, the fibrotic and inflammatory changes of the lung were evaluated. In addition, we evaluated the effects of long-term treatment with isosorbide dinitrate, a NO donor, on the n/i/eNOS-/- mice with BLM-induced pulmonary fibrosis. The histopathological findings, collagen content and the total cell number in bronchoalveolar lavage fluid were the most severe/highest in the n/i/eNOS-/- mice. Long-term treatment with the supplemental NO donor in n/i/eNOS-/- mice significantly prevented the progression of the histopathological findings and the increase of the collagen content in the lungs.

Does nitric oxide exert protective effects against bleomycin-induced pulmonary fibrosis in mice?

Inhaled corticosteroids are anti-inflammatory medications that can down-regulate the immunologic response in patients with COPD; however, their role at onset of COPD exacerbation is still not understood. The aim of this study was to assess the early inflammatory response and clinical presentation of patients with COPD exacerbation mediated by inhaled corticosteroids. Prospective data were collected on 123 hospitalized subjects with COPD exacerbation over a 30-month period at 2 Spanish university hospitals. Based on domiciliary use, comparative analyses were performed between subjects who did not use inhaled corticosteroids (n = 58) and subjects who did (n = 65). Measurements of serum biomarkers were recorded on admission to the hospital (day 1) and on day 3; clinical, physiological, microbiological, and severity data and mortality/readmission rates were also recorded. At days 1 and 3, both groups showed a similar inflammatory response; fluticasone produced lower levels of interleukin-8 compared with budesonide (P < .01). All clinical features considered were similar in the 2 groups; multivariate analysis predicting clinical complications on hospitalization showed air-flow obstruction severity as the only predictive factor (odds ratio 3.13, 95% CI 1.13-8.63, P = .02).

Do inhaled corticosteroids influence the early inflammatory response and clinical presentation of hospitalized subjects with COPD exacerbation?