Cytoreductive surgery and intraperitoneal hyperthermic chemotherapy in the treatment of peritoneal carcinomatosis.
Cytoreductive surgery (CS) and intraperitoneal hyperthermic chemotherapy (IPHC) in the treatment of peritoneal carcinomatosis (PC) in 15 patients are described. Fifteen patients with PC who were treated with CS and IPHC were retrospectively identified between January 2002 and December 2006. All patients underwent cytoreduction immediately followed by IPHC with mitomycin or cisplatin. The time between undergoing CS and IPHC and the date of the last follow-up appointment or the date of death was used to calculate survival data for each patient. Nine patients had complete cytoreduction, and all but one patient had evidence of invasive disease at the time of surgery. Eleven patients required concomitant bowel resection at the time of debulking. Thirteen patients required blood transfusions during the perioperative period. Nine patients were discharged home, and four were discharged to a rehabilitation facility. Two patients died during the perioperative hospital admission, both of whom had a preoperative Eastern Cooperative Oncology Group (ECOG) performance status score of 2. The median survival time was 8.4 months, similar to the findings of previously published studies. Further studies are needed to see if tumor type, ECOG performance status score, degree of cytoreduction, and the chemotherapy agent used in IPHC can be correlated to quality of life and survival in patients with heterogeneous primary sources of intraabdominal malignancies. Combination treatment with CS followed by IPHC in 15 patients with heterogeneous primary sources of intraabdominal malignancies resulted in a median survival time of 8.4 months.


Immunohistologic demonstration of abnormal colonic crypt cell kinetics in ulcerative colitis.
A monoclonal antibody, Ki-67, that reacts with cells in the proliferative phases (G1, G2, S, and M) of the cell cycle was used in an immunohistochemical labeling reaction to examine the colonic crypt epithelium in active ulcerative colitis, inactive ulcerative colitis, and normal mucosa. The proportions of labeled cells in the lower two thirds (proliferative zone) and in the upper quarter of the crypt were determined. The proportions of Ki-67-positive crypt epithelial cells in both the proliferative zone and the upper crypt were higher in biopsy specimens from patients with active ulcerative colitis than from patients with normal mucosa or with inactive ulcerative colitis. In inactive ulcerative colitis the proportion of Ki-67-positive epithelial cells in the proliferative zone of the crypt was higher than in normal mucosa. These results are similar to those obtained in studies using tritiated thymidine to determine the proportion of cells in the DNA-synthesizing thymidine to determine the proportion of cells in the DNA-synthesizing phase of the cell cycle and suggest that immuno-histochemical staining with Ki-67 may be a practical method for measuring the proliferative activity of epithelial cells in patients with ulcerative colitis and other disorders of the gastrointestinal tract.


Carbon footprint of Canadian dairy products: calculations and issues.
The Canadian dairy sector is a major industry with about 1 million cows. This industry emits about 20% of the total greenhouse gas (GHG) emissions from the main livestock sectors (beef, dairy, swine, and poultry). In 2006, the Canadian dairy herd produced about 7.7 Mt of raw milk, resulting in about 4.4 Mt of dairy products (notably 64% fluid milk and 12% cheese). An integrated cradle-to-gate model (field to processing plant) has been developed to estimate the carbon footprint (CF) of 11 Canadian dairy products. The on-farm part of the model is the Unified Livestock Industry and Crop Emissions Estimation System (ULICEES). It considers all GHG emissions associated with livestock production but, for this study, it was run for the dairy sector specifically. Off-farm GHG emissions were estimated using the Canadian Food Carbon Footprint calculator, (cafoo)(2)-milk. It considers GHG emissions from the farm gate to the exit gate of the processing plants. The CF of the raw milk has been found lower in western provinces [0.93 kg of CO2 equivalents (CO2e)/L of milk] than in eastern provinces (1.12 kg of CO2e/L of milk) because of differences in climate conditions and dairy herd management. Most of the CF estimates of dairy products ranged between 1 and 3 kg of CO2e/kg of product. Three products were, however, significantly higher: cheese (5.3 kg of CO2e/kg), butter (7.3 kg of CO2e/kg), and milk powder (10.1 kg of CO2e/kg). The CF results depend on the milk volume needed, the co-product allocation process (based on milk solids content), and the amount of energy used to manufacture each product. The GHG emissions per kilogram of protein ranged from 13 to 40 kg of CO2e. Two products had higher values: cream and sour cream, at 83 and 78 kg of CO2e/kg, respectively. Finally, the highest CF value was for butter, at about 730 kg of CO2e/kg. This extremely high value is due to the fact that the intensity indicator per kilogram of product is high and that butter is almost exclusively fat. Protein content is often used to compare the CF of products; however, this study demonstrates that the use of a common food component is not suitable as a comparison unit in some cases. Functionality has to be considered too, but it might be insufficient for food product labeling because different reporting units (adapted to a specific food product) will be used, and the resulting confusion could lead consumers to lose confidence in such labeling. Therefore, simple units might not be ideal and a more comprehensive approach will likely have to be developed.


Randomized trial of iReadMore word reading training and brain stimulation in central alexia.
Central alexia is an acquired reading disorder co-occurring with a generalized language deficit (aphasia). We tested the impact of a novel training app, 'iReadMore', and anodal transcranial direct current stimulation of the left inferior frontal gyrus, on word reading ability in central alexia. The trial was registered at www.clinicaltrials.gov (NCT02062619). Twenty-one chronic stroke patients with central alexia participated. A baseline-controlled, repeated-measures, crossover design was used. Participants completed two 4-week blocks of iReadMore training, one with anodal stimulation and one with sham stimulation (order counterbalanced between participants). Each block comprised 34 h of iReadMore training and 11 stimulation sessions. Outcome measures were assessed before, between and after the two blocks. The primary outcome measures were reading ability for trained and untrained words. Secondary outcome measures included semantic word matching, sentence reading, text reading and a self-report measure. iReadMore training resulted in an 8.7% improvement in reading accuracy for trained words (95% confidence interval 6.0 to 11.4; Cohen's d = 1.38) but did not generalize to untrained words. Reaction times also improved. Reading accuracy gains were still significant (but reduced) 3 months after training cessation. Anodal transcranial direct current stimulation (compared to sham), delivered concurrently with iReadMore, resulted in a 2.6% (95% confidence interval -0.1 to 5.3; d = 0.41) facilitation for reading accuracy, both for trained and untrained words. iReadMore also improved performance on the semantic word-matching test. There was a non-significant trend towards improved self-reported reading ability. However, no significant changes were seen at the sentence or text reading level. In summary, iReadMore training in post-stroke central alexia improved reading ability for trained words, with good maintenance of the therapy effect. Anodal stimulation resulted in a small facilitation (d = 0.41) of learning and also generalized to untrained items.10.1093/brain/awy138_video1awy138media15796149281001.


Cell surface-binding motifs of L2 that facilitate papillomavirus infection.
Human papillomavirus type 16 (HPV16) is the primary etiologic agent of cervical carcinoma, whereas bovine papillomavirus type 1 (BPV1) causes benign fibropapillomas. However, the capsid proteins, L1 and L2, of these divergent papillomaviruses exhibit functional conservation. A peptide comprising residues 1 to 88 of BPV1 L2 binds to a variety of cell lines, but not to the monocyte-derived cell line D32, and blocks BPV1 infection of mouse C127 cells. Residues 13 to 31 of HPV16 L2 and BPV1 L2 residues 1 to 88 compete for binding to the cell surface, and their binding, unlike that of HPV16 L1/L2 virus-like particles, is unaffected by heparinase or trypsin pretreatment of HeLa cells. A fusion of HPV16 L2 peptide 13-31 and GFP binds (K(d), approximately 1 nM) to approximately 45,000 receptors per HeLa cell. Furthermore, mutation of L2 residues 18 and 19 or 21 and 22 significantly reduces both the ability of the HPV16 L2 13-31-GFP fusion protein to bind to SiHa cells and the infectivity of HPV16 pseudovirions. Antibody to BPV1 L2 peptides comprising residues 115 to 135 binds to intact BPV1 virions, but fails to neutralize at a 1:10 dilution. However, deletion of residues 91 to 129 from L2 abolishes the infectivity of BPV1, but not their binding to the cell surface. In summary, L2 residues 91 to 129 contain epitopes displayed on the virion surface and are required for infection, but not virion binding to the cell surface. Upon the binding of papillomavirus to the cell surface, residues 13 to 31 of L2 interact with a widely expressed, trypsin- and heparinase-resistant cell surface molecule and facilitate infection.


Mouse lung and spleen natural killer cells have phenotypic and functional differences, in part influenced by macrophages.
NK cells are lymphocytes of the innate immune system which are a first line of defense against infections and tumor cells, in bone marrow and peripheral organs like lung and spleen. The lung is an organ in contact with respiratory pathogens and the site of inflammatory disorders triggered by the respiratory environment. In contrast, spleen is a lymphatic organ connected to the blood system which regulates the systemic immune response. Here we compare NK cell maturation and expansion as well as expression of NK cell receptors in spleen and lung compartments. We show that spleen and lung NK cells differ in phenotypic and functional characteristics due to a difference of maturity and cellular microenvironment. Indeed we observe that spleen and lung macrophages have the capacity to influence the cytotoxicity of NK cells by cell-to-cell contact. This suggests that the differences of NK cell subsets are in part due to a modulation by the organ environment.


Family carer perspectives of acute hospital care following a diagnosis of motor neuron disease: a qualitative secondary analysis.
The multifaceted nature of the problems faced by someone with motor neuron disease requires a knowledgeable multidisciplinary team approach. Where available, generally, such services are only provided on an outpatient basis, meaning that hospitalised patients are frequently admitted to non-specialist wards where understanding of their needs is limited. Little is known regarding the inpatient care received by patients. Our objective was to address this by exploring the experience of hospitalisation following a diagnosis of motor neuron disease from the perspective of family carers of those diagnosed with the illness. This was a qualitative secondary analysis of pre-existing data from two previously published, separately conducted, qualitative studies. The study involved interview data from 18 bereaved carers and 3 current carers of family members diagnosed with motor neuron disease in Northwest England. The findings reveal dissatisfaction with the inpatient care received, which impacted negatively not only on patient and carer enthusiasm for future hospital admissions but also on carer bereavement. Patients with motor neuron disease have specialist needs that are not always met during hospital admission, particularly to non-specialist units. The inpatient care provided for these patients must be improved as must the knowledge and understanding of the illness among healthcare professionals who treat them.


In vivo tomographic imaging of deep-seated cancer using fluorescence lifetime contrast.
Preclinical cancer research would benefit from noninvasive imaging methods that allow tracking and visualization of early-stage metastasis in vivo. Although fluorescent proteins revolutionized intravital microscopy, two major challenges that still remain are tissue autofluorescence and hemoglobin absorption, which act to limit intravital optical techniques to large or subcutaneous tumors. Here, we use time-domain (TD) technology for the effective separation of tissue autofluorescence from extrinsic fluorophores, based on their distinct fluorescence lifetimes. In addition, we use cancer cells labeled with near infrared fluorescent proteins (iRFP) to allow deep-tissue imaging. Our results demonstrate that TD imaging allows the detection of metastasis in deep-seated organs of living mice with a more than 20-fold increase in sensitivity compared with conventional continuous wave techniques. Furthermore, the distinct fluorescence lifetimes of iRFPs enable lifetime multiplexing of three different tumors, each expressing unique iRFP labels in the same animal. Fluorescence tomographic reconstructions reveal three-dimensional distributions of iRFP720-expressing cancer cells in lungs and brain of live mice, allowing ready longitudinal monitoring of cancer cell fate with greater sensitivity than otherwise currently possible.


Should single or distributed parameters be used to explain the steepness of tumour control probability curves?
Linear quadratic (LQ) modelling allows easy comparison of different fractionation schedules in radiotherapy. However, estimating the radiation effect of a single fractionated treatment introduces many questions with respect to the parameters to be used in the modelling process. Several studies have used tumour control probability (TCP) curves in order to derive the values for the LQ parameters that may be used further for the analysis and ranking of treatment plans. Unfortunately, little attention has been paid to the biological relevance of these derived parameters, either for the initial number of cells or their intrinsic radiosensitivity, or both. This paper investigates the relationship between single values for the TCP parameters and the resulting dose-response curve. The results of this modelling study show how clinical observations for the position and steepness of the TCP curve can be explained only by the choice of extreme values for the parameters, if they are single values. These extreme values are in contradiction with experimental observations. This contradiction suggests that single values for the parameters are not likely to explain reasonably the clinical observations and that some distributions of input parameters should be taken into consideration.


Effects of caffeine supplementation on physical performance and mood dimensions in elite and trained-recreational athletes.
Caffeine supplementation (CAFF) has an established ergogenic effect on physical performance and the psychological response to exercise. However, few studies have compared the response to CAFF intake among athletes of different competition level. This study compares the acute effects of CAFF on anaerobic performance, mood and perceived effort in elite and moderately-trained recreational athletes. Participants for this randomized, controlled, crossover study were 8 elite athletes (in the senior boxing national team) and 10 trained-recreational athletes. Under two experimental conditions, CAFF supplementation (6 mg/kg) or placebo (PLAC), the athletes completed a Wingate test. Subjective exertion during the test was recorded as the rating of perceived exertion (RPE) both at the general level (RPEgeneral) and at the levels muscular (RPEmuscular) and cardiorespiratory (RPEcardio). Before the Wingate test, participants completed the questionnaires Profiles of Moods States (POMS) and Subjective Vitality Scale (SVS). In response to CAFF intake, improvements were noted in Wpeak (11.22 ± 0.65 vs 10.70 ± 0.84; p = 0.003; [Formula: see text] =0.44), Wavg (8.75 ± 0.55 vs 8.41 0.46; p = 0.001; [Formula: see text] =0.53) and time taken to reach Wpeak (7.56 ± 1.58 vs 9.11 ± 1.53; p < 0.001; [Formula: see text] =0.57) both in the elite and trained-recreational athletes. However, only the elite athletes showed significant increases in tension (+ 325%), vigor (+ 31%) and SVS (+ 28%) scores after the intake of CAFF compared to levels recorded under the condition PLAC (p < 0.05). Similarly, levels of vigor after consuming CAFF were significantly higher in the elite than the trained-recreational athletes (+ 5.8%). CAFF supplementation improved anaerobic performance in both the elite and recreational athletes. However, the ergogenic effect of CAFF on several mood dimensions and subjective vitality was greater in the elite athletes.


Prostaglandin D2 Attenuates Bleomycin-Induced Lung Inflammation and Pulmonary Fibrosis.
Pulmonary fibrosis is a progressive and fatal lung disease with limited therapeutic options. Although it is well known that lipid mediator prostaglandins are involved in the development of pulmonary fibrosis, the role of prostaglandin D2 (PGD2) remains unknown. Here, we investigated whether genetic disruption of hematopoietic PGD synthase (H-PGDS) affects the bleomycin-induced lung inflammation and pulmonary fibrosis in mouse. Compared with H-PGDS naïve (WT) mice, H-PGDS-deficient mice (H-PGDS-/-) represented increased collagen deposition in lungs 14 days after the bleomycin injection. The enhanced fibrotic response was accompanied by an increased mRNA expression of inflammatory mediators, including tumor necrosis factor-α, monocyte chemoattractant protein-1, and cyclooxygenase-2 on day 3. H-PGDS deficiency also increased vascular permeability on day 3 and infiltration of neutrophils and macrophages in lungs on day 3 and 7. Immunostaining showed that the neutrophils and macrophages expressed H-PGDS, and its mRNA expression was increased on day 3and 7 in WT lungs. These observations suggest that H-PGDS-derived PGD2 plays a protective role in bleomycin-induced lung inflammation and pulmonary fibrosis.


Potential influence of in utero and early neonatal exposures on the later development of endometriosis.
To investigate the possible correlation between maternal characteristics, in utero and early neonatal life exposures, and the development of endometriosis in adult life. Case-control study. University hospital. A group of 161 patients with endometriosis and a control group of 230 women undergoing laparoscopy for benign adnexal diseases and free of endometriosis. All women included in the study were requested to answer a series of questions about their mothers' gestational data and on their own perinatal and early postnatal lives. Odds ratio, adjusted odds ratios, and 95% confidence intervals for the associations between maternal characteristics during the patient's pregnancy, in utero exposure to obstetrical and perinatal complications, and the type of feeding received during the neonatal period with the development of endometriosis in adult life. Mothers of women with endometriosis were significantly more likely to be affected by endometriosis or uterine fibroids, with a higher incidence of smoking during pregnancy. Women with endometriosis were more frequently born prematurely, with a significantly lower birth weight, and their mothers experienced preeclampsia during their pregnancies more often than control subjects. They were also more frequently formula fed than breast fed in early life. However, only prematurity and formula feeding were retained in the multivariate analysis model. Among intrauterine and early neonatal exposures, prematurity and formula feeding were risk factors for the development of endometriosis in adult life. Further studies should evaluate the underlying biologic mechanisms.


Alternative access options for transcatheter aortic valve replacement in patients with no conventional access and chest pathology.
Aortic stenosis is the most common valvular pathology in the elderly. Transcatheter aortic valve replacement has emerged as a safe and feasible alternative for high-risk patients. However, a significant number of patients are still not transcatheter aortic valve replacement candidates because of poor peripheral access and chest pathology. We report the use of alternative access options for such patients. Seven patients who had poor peripheral access and chest pathology had transcatheter aortic valve replacement using alternative access techniques. Five patients had the valve delivered by direct cannulation of the aorta via a mini-sternotomy, and 1 patient had the valve delivered via a mini-right thoracotomy. In 1 patient, the right subclavian artery was cannulated. Intraprocedural and 30-day outcome data were analyzed. The mean age of patients was 85.00 ± 9.59 years, with a Society of Thoracic Surgeons score of 16.81% ± 6.87% and logistic European System for Cardiac Operative Risk Evaluation of 21.59% ± 8.46%. Procedural success was 100%. Procedural and 30-day mortality were zero. There were no access-related complications or neurologic events. Two patients had worsening renal function that did not require dialysis. All patients were discharged with a median hospital stay of 7 days. In our experience of 138 transapical or alternative access patients, 7 died (5%) and for 257 transfemoral patients, 1 died (0.4%). Despite the high surgical risk of the study population, these techniques had excellent outcome with no mortality and acceptable morbidity. With the use of currently available technologies, these approaches are promising and offer alternative options in patients with no access and prohibitive chest pathology or pulmonary function.


Topical application of Heparanase-1 facilitates bone remodeling during the healing of bone defects in a mouse model.
Although previous studies have suggested a stimulatory role of heparanase in physiological bone turnover, the potential therapeutic role of heparanase in bone healing has not been elucidated. The purpose of this study was to assess the effect of topical application of heparanase-1 on bone healing. Two different dosages of recombinant mouse heparanase-1 and vehicle control were prepared and delivered via an osmotic pump to provide continuous topical infusion of the therapeutic reagent in a mouse bone defect model at the distal femoral metaphysis. The bone healing progress was evaluated by micro-computed tomography and histological examination at 7, 14, and 21 days after the bone defect was created. The peak of trabecular bone generation was achieved earlier than anticipated with the use of heparanase as measured by medullary bone volume fraction and trabecular number observed in micro-computed tomography, while the remodeling of trabecular bone to cortical bone was also achieved earlier than anticipated with the use of heparanase as measured by connectivity density. Histopathological observation revealed a higher frequency of the presence of cartilaginous tissue in the heparanase-treated groups. Both bone mineral density and cortical bone volume fraction showed the best healing outcome with low-dose heparanase, implying a biphasic effect of its mode of action. These results indicated that with the appropriate dose of topical heparanase-1, the progress of bone healing could be accelerated in vivo.


Multi-Organ toxicity demonstration in a functional human in vitro system composed of four organs.
We report on a functional human model to evaluate multi-organ toxicity in a 4-organ system under continuous flow conditions in a serum-free defined medium utilizing a pumpless platform for 14 days. Computer simulations of the platform established flow rates and resultant shear stress within accepted ranges. Viability of the system was demonstrated for 14 days as well as functional activity of cardiac, muscle, neuronal and liver modules. The pharmacological relevance of the integrated modules were evaluated for their response at 7 days to 5 drugs with known side effects after a 48 hour drug treatment regime. The results of all drug treatments were in general agreement with published toxicity results from human and animal data. The presented phenotypic culture model exhibits a multi-organ toxicity response, representing the next generation of in vitro systems, and constitutes a step towards an in vitro "human-on-a-chip" assay for systemic toxicity screening.


Assessment of the prognostic impact of the Epstein-Barr virus-encoded latent membrane protein-1 expression in Hodgkin's disease.
We have examined expression of the Epstein-Barr virus (EBV) latent membrane protein-1 (LMP1) in the malignant Hodgkin and Reed-Sternberg (HRS) cells of Hodgkin's disease (HD) and its impact on response to treatment and on survival. Paraffin tissue from 100 adult immunocompetent patients with HD were analysed using immunohistochemistry to identify LMP1 expression. According to the Rye classification, 8% of patients had lymphocyte predominance (LP) subtype, 48% had nodular sclerosis (NS) disease, 37% were of the mixed cellularity (MC) subtype and 7% were of the lymphocyte depletion (LD) subtype. During the five year follow-up period 27 patients died and 74 patients achieved a complete remission. Patients with LD subtype were older (P = 0.03), less frequently achieved complete remission (P = 0.01), had shorter disease-free survival (P = 0.01) and overall survival (P = 0.002) compared with the other subtypes of HD. LMP1 expression was found in the tumour cells of 26% of cases of HD. LMP1 expression was less common in NS disease than in the other subtypes (P = 0.05), whereas an association between MC subtype and LMP1 expression was not found (P = 0.22). Using the log-rank test there were no differences in overall survival or disease-free survival based on EBV status either when all patients were analysed or when LD and LP subtypes were excluded. However, the presence of EBV was associated with significantly longer disease-free survival in the subgroup of patients </= 30 years old (P = 0.02) and in those patients </= 34 years old (P = 0.05). In contrast, there was a trend for shorter disease-free survival for EBV-positive patients in the subgroup > 35 years old, but this difference was not statistically significant (P = 0.11). A similar trend was observed in patients > 50 years old. Analysis of the impact of LMP1 expression in patients who had different stage and B symptoms status showed that expression of EBV was associated with longer disease-free survival (P = 0.019) in early stage (1 + 2) patients without B symptoms. Significant differences in the other subgroups based on EBV status was not found. Factors adversely affecting the likelihood to achieve a complete remission were: absence of LMP1 expression (OR 6.4, 95% Cl 1.07-38.5, P = 0.04), age (OR 1.68, 95%Cl 1.15-2.5, P = 0.007) and subtype of HD (OR 3.32, 95%Cl 1.11-9.94, P = 0.03). Age and subtype of HD had an independent impact on overall survival (P = 0.01). We conclude that expression of LMP1 in HRS cells has a favourable impact on prognosis for HD patients, but that this effect may be restricted to young adult patients and those with early stage disease.


Characterization of RNA in exosomes secreted by human breast cancer cell lines using next-generation sequencing.
Exosomes are nanosized (30-100 nm) membrane vesicles secreted by most cell types. Exosomes have been found to contain various RNA species including miRNA, mRNA and long non-protein coding RNAs. A number of cancer cells produce elevated levels of exosomes. Because exosomes have been isolated from most body fluids they may provide a source for non-invasive cancer diagnostics. Transcriptome profiling that uses deep-sequencing technologies (RNA-Seq) offers enormous amount of data that can be used for biomarkers discovery, however, in case of exosomes this approach was applied only for the analysis of small RNAs. In this study, we utilized RNA-Seq technology to analyze RNAs present in microvesicles secreted by human breast cancer cell lines. Exosomes were isolated from the media conditioned by two human breast cancer cell lines, MDA-MB-231 and MDA-MB-436. Exosomal RNA was profiled using the Ion Torrent semiconductor chip-based technology. Exosomes were found to contain various classes of RNA with the major class represented by fragmented ribosomal RNA (rRNA), in particular 28S and 18S rRNA subunits. Analysis of exosomal RNA content revealed that it reflects RNA content of the donor cells. Although exosomes produced by the two cancer cell lines shared most of the RNA species, there was a number of non-coding transcripts unique to MDA-MB-231 and MDA-MB-436 cells. This suggests that RNA analysis might distinguish exosomes produced by low metastatic breast cancer cell line (MDA-MB-436) from that produced by highly metastatic breast cancer cell line (MDA-MB-231). The analysis of gene ontologies (GOs) associated with the most abundant transcripts present in exosomes revealed significant enrichment in genes encoding proteins involved in translation and rRNA and ncRNA processing. These GO terms indicate most expressed genes for both, cellular and exosomal RNA. For the first time, using RNA-seq, we examined the transcriptomes of exosomes secreted by human breast cancer cells. We found that most abundant exosomal RNA species are the fragments of 28S and 18S rRNA subunits. This limits the number of reads from other RNAs. To increase the number of detectable transcripts and improve the accuracy of their expression level the protocols allowing depletion of fragmented rRNA should be utilized in the future RNA-seq analyses on exosomes. Present data revealed that exosomal transcripts are representative of their cells of origin and thus could form basis for detection of tumor specific markers.


The long noncoding RNA Tug1 connects metabolic changes with kidney disease in podocytes.
An increasing amount of evidence suggests that metabolic alterations play a key role in chronic kidney disease (CKD) pathogenesis. In this issue of the JCI, Long et al. report that the long noncoding RNA (lncRNA) taurine-upregulated 1 (Tug1) contributes to CKD development. The authors show that Tug1 regulates mitochondrial function in podocytes by epigenetic targeting of expression of the transcription factor PPARγ coactivator 1α (PGC-1α, encoded by Ppargc1a). Transgenic overexpression of Tug1 specifically in podocytes ameliorated diabetes-induced CKD in mice. Together, these results highlight an important connection between lncRNA-mediated metabolic alterations in podocytes and kidney disease development.


Clinical features and oncological outcomes of intestinal cancers associated with ulcerative colitis and Crohn's disease.
Patients with longstanding inflammatory bowel disease are at high risk of developing intestinal cancers. In this study, we aimed to elucidate the differences between intestinal cancers associated with ulcerative colitis and Crohn's disease. Intestinal cancers in ulcerative colitis and Crohn's disease patients treated between 1983 and 2020 at 43 Japanese institutions were retrospectively analyzed.. A total of 1505 intestinal cancers in 1189 ulcerative colitis and 316 Crohn's disease patients were studied. Almost all of ulcerative colitis-associated cancers (99%) were in the colon and rectum, whereas half of Crohn's disease-associated cancers (44%) were in the anus, with 11% in the small intestine. Ulcerative colitis-associated cancers were diagnosed more frequently by surveillance (67% vs. 25%, P < 0.0001) and at earlier stages (stages 0-1, 71% vs. 27%, P < 0.0001) compared with Crohn's disease-associated cancers. Colorectal cancers associated with Crohn's disease showed a significantly worse 5-year overall survival rate than those associated with ulcerative colitis (stage 2, 76% vs. 89%, P = 0.01, stage 3, 18% vs. 68%, P = 0.0009, and stage 4, 0% vs. 13%, P = 0.04). Surveillance correlated with earlier diagnoses for ulcerative colitis- and Crohn's disease-associated intestinal cancers, whereas shorter intervals between endoscopic examinations correlated with an earlier cancer diagnosis in ulcerative colitis patients but not in Crohn's disease patients. The clinical and oncological features of ulcerative colitis- and Crohn's disease-associated cancers were very different. Crohn's disease-associated cancers were diagnosed at more advanced stages and were detected less frequently by surveillance. Additionally, they showed a significantly poorer prognosis.


Quantifying the Impact of Excess Moisture From Transpiration From Crops on an Extreme Heat Wave Event in the Midwestern U.S.: A Top-Down Constraint From Moderate Resolution Imaging Spectroradiometer Water Vapor Retrieval.
The primary focus of this study is to understand the contribution from excess moisture from crop transpiration to the severity of a heat wave episode that hit the Midwestern U.S. from 16 to 20 July 2011. To elucidate this, we first provide an optimal estimate of the transpiration water vapor flux using satellite total column water vapor retrievals whose accuracy and precision are characterized using independent observations. The posterior transpiration flux is estimated using a local ensemble transform Kalman filter that employs a mesoscale weather model as the forward model. The new estimation suggests that the prior values of transpiration flux from crops are biased high by 15%. We further use the constrained flux to examine the sensitivity of meteorology to the contributions from crops. Over the agricultural areas during daytime, elevated moisture (up to 40%) from crops not only increases humidity (thus the heat index) but also provides a positive radiative forcing by increasing downward longwave radiation (13 ± 4 W m-2) that results in even higher surface air temperature (+0.4 °C). Consequently, we find that the elevated moisture generally provides positive feedback to aggravate the heat wave, with daytime enhancements of heat index by as large as 3.3 ± 0.8 °C. Due to a strong diurnal cycle in the transpiration, the feedback tends to be stronger in the afternoon (up to 5 °C) and weaker at night. Results offer a potential basis for designing mitigation strategies for the effect of transpiration from agriculture in the future, in addition to improving the estimation of canopy transpiration.


The prevalence of cutaneous manifestations in IDDM patients and their association with diabetes risk factors and microvascular complications.
The aim of our study was to evaluate the frequency of skin manifestations, including the diabetic hand syndrome, in young IDDM patients. In addition, we studied the relation of the cutaneous manifestations to diabetes duration, glycemic control, and microvascular complications. The frequency of skin manifestations, including the diabetic hand syndrome, were examined in 238 IDDM patients (disease duration > 5 years) and 122 healthy control subjects in a cross-sectional study. In addition, we studied the relation of the cutaneous manifestations with diabetes duration, glycemic control, BMI, microvascular complications, and stratum corneum hydration using a stepwise logistic regression. Diabetic skin manifestations were detected in 168 of 238 (71%) IDDM patients and in 18 of 122 (14%) of the control subjects. Ichthyosiform skin changes of the shins, scleroderma-like skin changes, tinea pedis, and dry scaly palms were detected in 48 vs. 7%, 39 vs. 0%, 32 vs. 7%, and 21 vs. 0.8% of the patients and control subjects, respectively. In the diabetic patients, a significant association was found between ichthyosis of the shins and scleroderma-like skin changes of the hand (P < 0.001) and between scleroderma-like skin changes and the skin dryness of the palms (P < 0.0001). When diabetic risk factors were considered, diabetes duration was significantly associated with scleroderma-like skin changes and ichthyosis of the shins (P < 0.0001). The latter was also found to be related to diabetic retinopathy (P < 0.0001). Keratosis pilaris was present in 21% of the patients versus 9% in control subjects and was found to be exclusively associated with high BMI. Acquired ichthyosis is a common finding and the most prevalent skin manifestation in young IDDM patients. The development of several skin manifestations in insulin-dependent patients seems to be related to duration of diabetes and to development of diabetic microvascular complications.


The incidence of first Hickman catheter-related infection and predictors of catheter removal in cancer patients.
To describe the incidence and types of first Hickman catheter-related infection (HCRI) in cancer patients and to identify indicators for catheter removal. Retrospective cohort study. A regional, tertiary, referral cancer center and its supportive care university teaching hospital. A retrospective review was conducted of 316 consecutive adult oncology patients who underwent Hickman catheter placement from 1986 to 1990 at a regional oncology center. HCRI was determined on the basis of clinical information incriminating the Hickman catheter as the source of infection. Patient characteristics and data about HCRIs (exit site cellulitis, tunnel infection with concomitant exit site cellulitis, bloodstream infection, and exit site cellulitis with bloodstream infection) were abstracted from patient medical records. Subsequently, univariate and multivariate analyses for the risk of HCRI and catheter removal were completed. The incidence of first HCRI was 5.98 infections per 1,000 catheter days. Overall, 156 (49%) of 316 patients developed their first HCRI prior to catheter removal. The median time to HCRI was 90 days. Male gender (P = .0004) and hematologic malignancy (P = .0001) emerged as significant risk factors for HCRI in the univariate analysis. A cox model verified that male gender (P = .02) and hematologic malignancy (P = .004) were associated with an enhanced risk of HCRI. There were 35 exit site infections (23%), three infections of the tunnel and the exit site (2%), 80 bloodstream infections (51%), and another 38 bloodstream infections with concomitant exist site infections (24%). The incidence of bloodstream infection was 3.05 per 1,000 catheter days. Gram-positive pathogens outnumbered gram-negatives and fungi, with Staphylococcus epidermidis being most common. Fifty (32%) of 156 HCRIs resulted in catheter removal. Predictors of Hickman catheter removal in the univariate analysis were bloodstream infection (P = .046) and pathogen type (P = .006). Multiple regression analysis suggested that having a gram-negative (P = .014) or fungal (P = .057) pathogen was the most important factor for catheter removal. These data suggest that first HCRIs occur more commonly in male patients with hematologic malignancies than in patients with solid tumors. The removal of Hickman catheters in oncology patients probably is predicated on the causative pathogen, but further investigations are necessary to delineate this issue.


Multicenter study of Clostridium difficile infection rates from 2000 to 2006.
To compare incidence rates of Clostridium difficile infection (CDI) during a 6-year period among 5 geographically diverse academic medical centers across the United States by use of recommended standardized surveillance definitions of CDI that incorporate recent information on healthcare facility (HCF) exposure. Data on C. difficile toxin assay results and dates of hospital admission and discharge were collected from electronic databases. Chart review was performed for patients with a positive C. difficile toxin assay result who were identified within 48 hours after hospital admission to determine whether they had any HCF exposure during the 90 days prior to their hospital admission. CDI cases, defined as any inpatient with a stool toxin assay positive for C. difficile, were categorized into 5 surveillance definitions based on recent HCF exposure. Annual CDI rates were calculated and evaluated by use of the chi(2) test for trend and the chi(2) summary test. During the study period, there were significant increases in the overall incidence rates of HCF-onset, HCF-associated CDI (from 7.0 to 8.5 cases per 10,000 patient-days; P < .001); community-onset, HCF-associated CDI attributed to a study hospital (from 1.1 to 1.3 cases per 10,000 patient-days; P = .003); and community-onset, HCF-associated CDI not attributed to a study hospital (from 0.8 to 1.5 cases per 1,000 admissions overall; P < .001). For each surveillance definition of CDI, there were significant differences in the total incidence rate between HCFs. The increasing incidence rates of CDI over time and across healthcare institutions and the correlation of CDI incidence in different surveillance categories suggest that CDI may be a regional problem and not isolated to a single HCF within a community.


Genome instability due to ribonucleotide incorporation into DNA.
Maintaining the chemical identity of DNA depends on ribonucleotide exclusion by DNA polymerases. However, ribonucleotide exclusion during DNA synthesis in vitro is imperfect. To determine whether ribonucleotides are incorporated during DNA replication in vivo, we substituted leucine or glycine for an active-site methionine in yeast DNA polymerase ϵ (Pol ϵ). Ribonucleotide incorporation in vitro was three-fold lower for M644L and 11-fold higher for M644G Pol ϵ compared to wild-type Pol ϵ. This hierarchy was recapitulated in vivo in yeast strains lacking RNase H2. Moreover, the pol2-M644G rnh201Δ strain progressed more slowly through S phase, had elevated dNTP pools and generated 2-5-base-pair deletions in repetitive sequences at a high rate and in a gene orientation-dependent manner. The data indicate that ribonucleotides are incorporated during replication in vivo, that they are removed by RNase H2-dependent repair and that defective repair results in replicative stress and genome instability via DNA strand misalignment.


Ubiquitination of protein kinase C-alpha and degradation by the proteasome.
Bryostatins and phorbol esters acutely activate and subsequently down-regulate protein kinase C (PKC) by inducing its proteolysis via an unknown pathway. Here we show that treatment of renal epithelial cells with bryostatin 1 (Bryo) produced novel PKC-alpha species, which were larger than the native protein (80 kDa). The >80 kDa PKC-alpha species contained Ubi as indicated by immunostaining and accumulated in the presence of lactacystin, a selective inhibitor of proteolysis by the proteasome. In vitro experiments with 125I-ubiquitin and membranes from Bryo-treated cells showed that PKC-alpha became ubiquitinated by a reaction that depended on ATP and a cytosolic fraction. Lactacystin or a peptidyl aldehyde, Bz-Gly-Leu-Ala-leucinal, which inhibits certain proteinase activities of the proteasome, inhibited Bryo-evoked disappearance of PKC-alpha protein from the cells. Lacta preserved Bryo-induced 32P-labeled PKC-alpha indicating that the proteasome inhibitor spared activated enzyme from down-regulation in vivo. These findings show that Bryo induces the degradation of PKC-alpha by the ubiquitin-proteasome complex.


Mechanics and Energetics of Electromembranes.
The recent discovery of electroactive polymers has shown great promises in the field of soft robotics and was logically followed by experimental, numerical, and theoretical developments. Most of these studies were concerned with systems entirely covered by electrodes. However, there is a growing interest for partially active polymers, in which the electrode covers only one part of the membrane. Indeed, such actuation can trigger buckling instabilities and so represents a route toward the control of three-dimensional shapes. Here, we study theoretically the behavior of such partially active electroactive polymer. We address two problems: (1) the electrostatic elastica including geometric nonlinearities and partially electroactive strip using a variational approach. We propose a new interpretation of the equations of deformation, by drawing analogies with biological growth, in which the effect of the electric voltage is seen as a change in the reference stress-free state. (2) We explain the nature of the distribution of electrostatic forces on this simple system, which is not trivial. In particular, we find that edge effects are playing a major role in this problem.


Identification of the covalent flavin attachment site in sarcosine oxidase.
Sarcosine oxidase from Corynebacterium sp. P-1 is a heterotetrameric enzyme (alphabetagammadelta) that contains two noncovalently bound coenzymes (FAD, NAD+) and covalently bound FMN [8alpha-(N3-histidyl)FMN] which is attached to the beta subunit. Chlumsky et al. [(1995) J. Biol. Chem. 270, 18252-18259] tentatively identified His175 as the covalent FMN attachment site in the beta subunit, based on an alignment of the sequence of C. sp. P-1 beta subunit with a highly homologous flavin-containing peptide from another corynebacterial sarcosine oxidase (C. sp. U-96). To test this hypothesis, His175 in the C. sp. P-1 beta subunit was mutated to an alanine. Unexpectedly, the mutant enzyme was found to contain 1 mol of covalently bound flavin and to exhibit catalytic activity similar to wild-type enzyme. Covalent flavin-containing peptides were isolated from wild-type and mutant enzymes and analyzed by electrospray mass spectrometry. The mass observed for the mutant peptide (1152.4 Da) matched that predicted for an FMN-containing hexapeptide, corresponding to residues 173-178 (1152.1 Da). In the mutant, this region (HDAVAW) contains a single histidine (His173) which must be the covalent flavin attachment site. The mass observed for the wild-type peptide (1218.6 Da) matched that predicted for an FMN-containing hexapeptide, also corresponding to residues 173-178 in the beta subunit (1218.2 Da). This region in the wild-type enzyme includes two histidine residues (HDHVAW). Attempts to sequence the wild-type or mutant peptides by automated Edman degradation were unsuccessful. Instead, the peptide sequences were investigated by collisional-activated dissociation (CAD) and tandem mass spectrometry. The CAD mass spectral data with the mutant peptide confirmed the sequence deduced based on the mass of the intact peptide. The CAD mass spectral results with the wild-type peptide showed that FMN was covalently attached to the N-terminal histidine in the hexapeptide, which corresponds to His173 in the beta subunit.


Calculation of the Optical Effects of a 27.5-m Spherical Mirror.
People standing under a large spherical mirror see the world inverted, hanging above them as a real image. The shape of this image world depends upon where on the floor the observer stands. In this paper formulas for calculating image positions as a function of observer position are derived and depicted in diagrams of typical image worlds. The images formed by light reflecting several times in the mirror are also calculated. There are both an erect real image world and doubled rings of inverted images surrounding the single-reflection image world.


MR imaging of cerebral ischemia: findings in the first 24 hours.
MR changes of cerebral ischemia have been shown to occur as early as 1-2 hr after vessel occlusion in experimental models of stroke. However, the MR findings in the early stages of ischemic stroke in the clinical population have not been well established. We studied 41 lesions in 39 patients in whom MR was performed within the first 24 hr after onset of ischemic symptoms. Twenty-five lesions were studied with gadopentetate dimeglumine. Vascular flow-related abnormalities, including absence of normal flow void and presence of arterial enhancement, were the earliest MR findings, detected within minutes of onset. Morphologic changes (brain swelling) on T1-weighted images without signal changes on T2-weighted images could be detected within the first few hours. Signal changes were not usually found before 8 hr on T2-weighted images or before 16 hr on T1-weighted images. In contrast to the absence of parenchymal enhancement typically found in cortical infarctions in the first 24 hr, a few lesions (including transient occlusions, partial occlusions, and isolated watershed infarctions) exhibited early, exaggerated parenchymal enhancement. We conclude that signal changes may not be reliable in detecting ischemic stroke within the first 8 hr after onset. Vascular abnormalities, when present, are the most reliable and earliest findings. Other MR findings of early ischemic stroke, including morphologic changes and early, exaggerated parenchymal enhancement, may also precede signal changes. Paramagnetic contrast administration often provides valuable information in the detection and evaluation of acute ischemia.


Uvulopalatopharyngoplasty and barbed reposition pharyngoplasty with and without hyoid suspension for obstructive sleep apnea hypopnea syndrome: A comparison of long-term functional results.
Obstructive sleep apnea hypopnea syndrome (OSAHS) is a common condition; when conservative approaches are not effective, surgical techniques aimed at reducing the airway obstruction effect are used. This retrospective study aimed at comparing the functional outcomes in patients with OSAHS undergoing uvulopalatopharyngoplasty (UPPP) according to Fairbanks and barbed reposition pharyngoplasty (BRP) according to Mantovani, with or without hyoid suspension (HS). One-hundred twenty-two consecutive OSAHS patients who underwent surgical treatment were included in the study. Patients were divided into 4 groups; all patients underwent preoperative and postoperative polysomnography (PSG) with apnea/hypopnea index (AHI) and oxygen desaturation index (ODI) evaluation, and Epworth Sleepiness Scale (ESS) evaluation. The results were analyzed according to the different surgical procedures in relation to the preoperative PSG and anthropometric data. A significant reduction was observed at 18-month follow-up for patients in BRP group for body mass index (p = 0.004), ESS (p < 0.0001), ODI (p < 0.0001), and AHI (p < 0.0001). Risk factors for poor postoperative AHI reduction were evaluated; preoperative AHI was the strongest independent protective factor, while preoperative ODI was the strongest risk factor. The association of HS with UPPP or BRP showed significant results in terms of higher postoperative AHI reduction only when associated to UPPP (p < 0.0001). This study showed that the BRP technique was more effective compared to UPPP for patients with OSAHS. The association of HS showed greater benefits in UPPP compared to BRP. Randomized prospective trials with longer follow-up are necessary to confirm our results and formulate a more accurate indication of the optimal therapeutic strategy.


HIV and AIDS: where is the epidemic going?
Routine surveillance of HIV (human immunodeficiency virus) infection and AIDS has been established over the past decade in many countries around the world. HIV estimates derived from empirical data are essential to the assessment of the HIV situation in different parts of the world and trends are used in tracking the development of regional epidemics, thereby keeping intervention activities focused on realities. As of the end of 1995, and following an extensive country-by-country review of HIV/AIDS data, a cumulative total of 6 million AIDS cases were estimated to have occurred in adults and children worldwide and currently 20.1 million adults are estimated to be alive and infected with HIV or have AIDS. Of the total prevalent HIV infections, the majority remain concentrated in eastern, central and southern Africa, but the epidemic is evolving with spread of infection from urban to rural areas, as well as to West and South Africa, India and South-east Asia, and to a lesser extent--with proportional shifts to heterosexual infections--in North America, western Europe and Latin America. While the longer-term dimensions of the HIV epidemic at global level cannot be forecast with confidence, WHO currently projects a cumulative total of close to 40 million HIV infections in men, women and children by the year 2000. By that time, the male:female ratio of new infections will be close to 1:1. Recent trends indicate that HIV prevalence levels may be stabilizing or even decreasing among pregnant women in southern Zaire and parts of Uganda, among military recruits aged 21 in Thailand, and in some populations of northern Europe and the USA. While these changes may take place as part of the intrinsic dynamic of the epidemic, there is some evidence that declines in HIV prevalence are related to declines in HIV incidence which are, at least partly, due to prevention efforts. The challenge of surveillance and evaluation methods is now to identify the ingredients of success which may reveal a glimmer of hope.


Relationship of balance and mobility to fall incidence in people with chronic stroke.
People with stroke are at risk for falls. The purpose of this study was to estimate the strength of the relationship of balance and mobility to falls. The participants were 99 community-dwelling people with chronic stroke. An interview was used to record fall history, and physical performance assessments were used to measure balance (Berg Balance Scale [BBS]) and mobility (gait speed). No differences were found between subjects who fell once and subjects who did not fall or between subjects who fell more than once and subjects who did not fall. Neither balance nor mobility was able to explain falls in people with chronic stroke. Clinicians should be cautious when using the BBS or gait speed to determine fall risk in this population. Falls occurred frequently during walking; it may be necessary to focus on reactive balance and environmental interaction when assessing individuals for risk of falls and devising fall prevention programs for individuals with chronic stroke. The authors' observations suggest that the prescription of 4-wheel walkers for individuals with a low BBS score (</=45) may be a mobility aid that could reduce the risk of falls.


Sleep problems and early developmental delay: implications for early intervention programs.
Sleep disorders negatively impact behavior, cognition, and growth--the same areas targeted by early intervention. Conversely, developmental delays and disabilities may themselves precipitate sleep disorders. Young children with developmental delays experience sleep disorders at a higher rate than do typically developing children; the most common types are difficulties initiating or maintaining sleep and sleep disordered breathing. To date, attention has been focused on sleep problems in children with specific conditions (e.g., autism, genetic syndromes, prematurity, and seizure disorder). The authors review evidence of sleep problems' broader impact across the range of children screened for early intervention. Eligibility evaluations for early intervention address the five developmental domains: adaptive, motor, cognitive, communication, and socioemotional. Disordered sleep may be symptomatic of socioemotional and adaptive problems. Assessing sleep problems within the evaluation may help establish eligibility for early intervention services and would maximize developmental potential by ensuring timely identification, referral, and treatment.


Multiple cargo binding sites on the COPII subunit Sec24p ensure capture of diverse membrane proteins into transport vesicles.
We have characterized the mechanisms of cargo selection into ER-derived vesicles by the COPII subunit Sec24p. We identified a site on Sec24p that recognizes the v-SNARE Bet1p and show that packaging of a number of cargo molecules is disrupted when mutations are introduced at this site. Surprisingly, cargo proteins affected by these mutations did not share a single common sorting signal, nor were proteins sharing a putative class of signal affected to the same degree. We show that the same site is conserved as a cargo-interaction domain on the Sec24p homolog Lst1p, which only packages a subset of the cargoes recognized by Sec24p. Finally, we identified an additional mutation that defines another cargo binding domain on Sec24p, which specifically interacts with the SNARE Sec22p. Together, our data support a model whereby Sec24p proteins contain multiple independent cargo binding domains that allow for recognition of a diverse set of sorting signals.


Endothelin in hypertensive resistance arteries. Intraluminal and extraluminal dysfunction.
The effects of intraluminal and extraluminal endothelin-1 and its interactions with endothelium-derived relaxing factor were studied in perfused mesenteric resistance arteries of Wistar-Kyoto rats and spontaneously hypertensive rats. Changes in intraluminal diameter were recorded. In adult Wistar-Kyoto rats, but not spontaneously hypertensive rats, low concentrations of intraluminal endothelin-1 (10(-10) to 10(-9) M) caused relaxations of quiescent arteries blocked by indomethacin. After endothelial removal, intraluminal endothelin-1 evoked concentration-dependent contractions in both strains. Extraluminal endothelin-1 caused greater contractions of arteries with endothelium than intraluminal endothelin-1, and the sensitivity was lower in adult hypertensive rats; endothelial removal enhanced the contractions to extraluminal endothelin-1 to a greater extent in hypertensive than in normotensive rats. In arteries without endothelium, intraluminal and extraluminal endothelin-1 caused comparable contractions, but the sensitivity was reduced in adult but not young hypertensive as compared with normotensive rats. Both young spontaneously hypertensive and normotensive rats exhibited a high sensitivity to the peptide. In arteries precontracted with endothelin-1, endothelium-dependent relaxation to intraluminal acetylcholine was reduced in hypertensive as compared with normotensive rats, whereas relaxations to extraluminal acetylcholine were increased in hypertensive rats. Thus, endothelin-1 interacts with both vascular smooth muscle and the endothelium. The sensitivity of vascular smooth muscle to endothelin-1 is reduced in adult hypertensive rats. Intraluminal activation of the endothelium by endothelin-1 or acetylcholine is reduced in spontaneously hypertensive rats, whereas extraluminal activation causes more pronounced responses in hypertensive than in normotensive rats, suggesting a prominent dysfunction of the intraluminal surface of the endothelium in hypertension.


Magnetic resonance imaging of electrolysis.
This study explores the hypothesis that Magnetic Resonance Imaging (MRI) can image the process of electrolysis by detecting pH fronts. The study has relevance to real time control of cell ablation with electrolysis. To investigate the hypothesis we compare the following MR imaging sequences: T1 weighted, T2 weighted and Proton Density (PD), with optical images acquired using pH-sensitive dyes embedded in a physiological saline agar solution phantom treated with electrolysis and discrete measurements with a pH microprobe. We further demonstrate the biological relevance of our work using a bacterial E. Coli model, grown on the phantom. The results demonstrate the ability of MRI to image electrolysis produced pH changes in a physiological saline phantom and show that these changes correlate with cell death in the E. Coli model grown on the phantom. The results are promising and invite further experimental research.


Early Austronesians Cultivated Rice and Millet Together: Tracing Taiwan's First Neolithic Crops.
This study presents the first directly dated physical evidence of crop remains from the Early Neolithic archaeological layers in Taiwan. Systematic sampling and analysis of macro-plant remains suggested that Neolithic farmers at the Zhiwuyuan (Botanical Garden) site in Taipei, northern Taiwan, had cultivated rice and foxtail millet together at least 4,500 years ago. A more comprehensive review of all related radiocarbon dates suggests that agriculture emerged in Taiwan around 4,800-4,600 cal. BP, instead of the previous claim of 5,000 cal. BP. According to the rice grain metrics from three study sites of Zhiwuyuan, Dalongdong, and Anhe, the rice cultivated in northern and western-central Taiwan was mainly a short-grained type of the japonica subspecies, similar to the discoveries from the southeast coast of mainland China and the middle Yangtze valley. These new findings support the hypothesis that the southeast coast of mainland China was the origin of proto-Austronesian people who brought their crops and other cultural traditions across the Taiwan Strait 4,800 years ago and eventually farther into Island Southeast Asia.


Impact of bacterial colonization on exhaled inflammatory markers in wheezing preschool children.
Wheeze is a common symptom in preschool children. The role of bacteria, regulatory T (T(reg)) cells and their association with airway inflammation in preschool wheeze is largely unknown. We evaluated inflammatory markers in exhaled breath condensate (EBC), bacterial colonization and circulating T(reg) cells in preschool children with and without recurrent wheeze. We recruited 252 children (aged two to four years) with (N = 202) and without (N = 50) recurrent wheeze. EBC was collected using an efficient closed glass condenser. Inflammatory markers in EBC (Interleukin(IL)-2, IL-4, IL-8, IL-10, IL-13) were assessed using multiplex immunoassay. Nasal and throat swabs were analysed for presence of Streptococcus pneumoniae, Haemophilus (para)influenzae and Staphylococcus aureus. Proportions of T(reg) cells (CD4(+)CD25(high)CD127(-)) were quantified by flow cytometry. Recurrent wheezing children had elevated EBC levels of IL-2, IL-4, IL-10 and IL-13 compared to non-wheezers (odds ratio (95% confidence interval): 1.67 (1.23-2.27): 1.58 (1.15-2.18): 1.47 (1.14-1.90): 1.55 (1.16-2.06), p <0.05, respectively). Bacteria were frequently present in children with and without wheeze, with no difference in prevalence (16-52% versus 16-50%, respectively). Moreover, the proportion of T(reg) cells did not differ between both groups. Wheezing children with bacterial colonization did not significantly differ in exhaled levels of inflammatory markers or proportion of T(reg) cells compared to wheezing children without colonization. The analysis of EBC might serve as a helpful non-invasive tool to early assess airway inflammation in wheezing children. The various elevated exhaled inflammatory markers indicate increased airway inflammation in wheezing preschool children. In the presence of wheeze, we found no evidence for bacterial induced airway inflammation.


Treatment with a toll-like receptor inhibitory GpG oligonucleotide delays and attenuates lupus nephritis in NZB/W mice.
Activation of the innate immune system by DNA containing hypomethylated CpG motifs has been implicated in the pathogenesis of systemic lupus erythematosus (SLE). Here, we examined the consequences of immunostimulatory CpG-oligodeoxynucleotide (ODN) and inhibitory GpG-ODN treatment in the NZB x NZW F1 (NZB/W) murine model of SLE. Beginning at 5 months of age, we administered CpG-ODN or GpG-ODN at regular intervals to female NZB/W animals. We also determined the effects of ODN administration on NZB/W mouse lymphocyte function, and the specificity of ODN binding to Toll-like receptors (TLRs) other than TLR-9. While CpG-ODN treatment did not appear to have a major impact on disease severity, GpG-ODN treatment significantly delayed the onset of proteinuria in NZB/W mice. Interestingly, short-term GpG-ODN treatment promoted Th2-type T and B cell responses, and inhibited B lymphocyte proliferation in vitro. On the other hand, extended GpG-ODN treatment did not result in sustained Th2 responses or significantly reduced renal disease. Moreover, the binding of CpG-ODN and GpG-ODN was not restricted to TLR-9 as both ODNs also interacted with TLR-3, TLR-7, and TLR-8. Taken together, the data indicate that the protective mechanism of GpG-ODN treatment in the NZB/W model of lupus nephritis involves modulating T cell cytokine profiles and B lymphocyte activation through the inhibition of several TLRs, including TLR-7 and TLR-9.


Illegal drug use among female university students in Slovakia.
This study is focused on the issue of illegal drug use among female university students preparing to become teachers. The main aim was to determine the frequency of drug abuse in a group of young women (n=215, mean age 20.44 years). Using survey methods, we determined that 33.48% of female university students in Slovakia use illegal drugs and 66.51% of students have never used illegal drugs. Differences between these groups were determined using statistical analysis, mostly in 4 areas of survey questions. We determined that education of parents has a statistically significant influence on use of illegal drugs by their children (χ2=10.14; P<0.05). Communication between parents and children and parental attention to children have a significant role in determining risky behavior (illegal drug use, χ2=8.698, P<0.05). Parents of students not using illegal drugs were interested in how their children spend their free time (68.53%). We confirmed the relationship between consumption of alcohol and illegal drug use (χ2=16.645; P<0.001) and smoking (χ2=6.226; P<0.05). The first contact with drugs occurs most frequently at high school age. The most consumed "soft" drug in our group of female university students is marijuana. Our findings are relevant for comparison and generalization regarding causes of the steady increase in number of young people using illegal drugs.


The impact of genetic background on neurodegeneration and behavior in seizured mice.
We used pilocarpine-induced seizures in mice to determine the impact of genetic background on the vulnerability of hippocampal neurons and associated changes of behavioral performance. The susceptibility of hippocampal neurons to seizure-induced cell death paralleled the severity of the seizures and depended on genetic background. Hippocampal neurons in C57BL/6 mice were most resistant to cell death, whereas they were highly vulnerable in FVB/N mice. The degree of neuronal degeneration in F1 hybrid mice obtained by crossing the two strains was at an intermediate level between the parent strains. Two weeks after the severe seizures, performance in a water-maze place navigation task showed a bimodal distribution. Seventeen of 19 (90%) F1 mice were completely unable to learn while the other two learned reasonably well. Of 28 C57BL/6 mice with similarly severe seizures, six were as strongly impaired as their F1 counterparts (22%). The remaining 22 performed normally, indicating a much lower probability of C57BL/6 mice to be affected. Treated mice showed a deficit of open-field exploration which was strongly correlated with the impairment in the place navigation task and was again more severe in F1 mice. Our results show that the vulnerability of hippocampal neurons to pilocarpine-induced seizures, as well as the associated behavioral changes, depended on genetic background. Furthermore, they confirm and extend our earlier finding that a relatively modest reduction of hippocampal cell death can be associated with dramatic changes of behavioral performance and emphasize the importance of tightly-controlled genetic backgrounds in biological studies.


Percutaneous ablation of renal masses measuring 3.0 cm and smaller: comparative local control and complications after radiofrequency ablation and cryoablation.
The purpose of this article is to compare the efficacy and complication rates of percutaneous radiofrequency ablation (RFA) and cryoablation in the treatment of renal masses measuring 3.0 cm and smaller. A retrospective review was performed of 385 patients with 445 tumors measuring 3.0 cm or smaller treated with thermal ablation from 2000 through 2010. Two hundred fifty-six tumors in 222 patients were treated with RFA (mean [± SD] tumor size, 1.9 ± 0.5 cm), and 189 tumors in 163 patients were treated with cryoablation (mean tumor size, 2.3 ± 0.5 cm). Major complications and efficacy as measured by technical success and local tumor recurrence rates were recorded. There were five (1.1%) technical failures, including one (0.4%) among tumors treated with RFA and four (2.1%) among tumors treated with cryoablation (p = 0.17). Of the 218 tumors treated with RFA and with follow-up beyond 3 months, seven (3.2%) developed local tumor recurrence, at a mean of 2.8 years after treatment (range, 1.2-4.1 years). Of the 145 tumors treated with cryoablation and with follow-up beyond 3 months, four (2.8%) developed local tumor recurrence at a mean of 0.9 years after treatment (range, 0.3-1.6 years). For biopsy-proven renal cell carcinoma, estimated local recurrence-free survival rates at 1, 3, and 5 years after RFA were 100%, 98.1%, and 98.1%, respectively, compared with 97.3%, 90.6%, and 90.6%, respectively, after cryoablation (p = 0.09). Major complications occurred after 4.3% (10/232) of RFAs and 4.5% (8/176) of cryoablation procedures (p = 0.91). RFA and cryoablation are both effective in the treatment of renal masses measuring 3 cm or smaller. Major complications with either procedure are infrequent.


Sustained growth of the ex vivo ablation zones' critical short axis using gas-cooled radiofrequency applicators.
To evaluate the ablation zones created with a gas-cooled bipolar radiofrequency applicator performed on ex vivo bovine liver tissue. A total of 320 ablations with an internally gas-cooled bipolar radiofrequency applicator were performed on fresh ex vivo bovine liver tissue, varying the ablation time (5, 10, 15, and 20 min), power (20, 30, 40, and 50 W), and gas pressure of the CO(2) used for cooling (585, 600, 615, 630, 645 psi), leading to a total of 80 different parameter combinations. Size and shape of the white coagulation zone were assessed. The largest complete ablation zone was achieved after 20 min of implementing 50 W and 645 psi, resulting in a short axis of mean 46 ± 1 mm and a long axis of 56 ± 2 mm (mean ± standard deviation). Short-axis diameters increased between 5 and 20 min of ablation time at 585 psi (increase of the short axis was 45% at 30 W, 29% at 40 W, and 39% at 50 W). This increase was larger at 645 psi (113% at 30 W, 67% at 40 W, and 70% at 50 W). Macroscopic assessment and NADH (nicotinamide adenine dinucleotide) staining revealed incompletely ablated tissue along the needle track in 18 parameter combinations including low-power settings (20 and 30 W) and different cooling levels and ablation times. Gas-cooled radiofrequency applicators increase the short-axis diameter of coagulation in an ex vivo setting if appropriate parameters are selected.


Dose equivalence and bronchoprotective effects of salmeterol and salbutamol in asthma.
Salbutamol is the most widely prescribed short acting beta 2 agonist and salmeterol is the first long acting inhaled beta 2 agonist. The dose equivalence of salmeterol and salbutamol is disputed. Estimates of weight-for-weight dose ratio have ranged from 1:2 to 1:16. A study was undertaken to clarify the true dose ratio. The bronchoprotection afforded against repeated methacholine challenge by inhaled salmeterol 25 micrograms and 100 micrograms and salbutamol 100 micrograms and 400 micrograms was compared in a randomised, double blind, placebo controlled, crossover trial. Subjects were 16 stable asthmatics with a baseline forced expiratory volume in one second (FEV1) of > or = 65% predicted, screening concentration provoking a fall in FEV1 of 20% (PC20FEV1) of < or = 8mg/ml, and a shift in PC20FEV1 of more than two doubling concentration steps following inhalation of salbutamol 400 micrograms. On five separate occasions subjects underwent methacholine challenge before and 30 and 120 minutes after drug administration. PD20FEV1 was calculated for each challenge. FEV1 at 90 minutes after drug administration was also recorded. Bronchoprotection afforded by salmeterol was increased at 120 minutes compared with 30 minutes and protection by salbutamol was decreased. Protection by both doses of salmeterol was similar to salbutamol 100 micrograms at 30 minutes but significantly greater at 120 minutes. FEV1 at 90 minutes was significantly greater after salmeterol 100 micrograms than after placebo, but there were no other significant differences between treatments. Maximal observed protection was equivalent for salmeterol 100 micrograms and salbutamol 400 micrograms. The data are compatible with a weight-for-weight dose ratio for salmeterol:salbutamol of < or = 1:4.


Sex differences in social focus across the life cycle in humans.
Age and gender are two important factors that play crucial roles in the way organisms allocate their social effort. In this study, we analyse a large mobile phone dataset to explore the way life history influences human sociality and the way social networks are structured. Our results indicate that these aspects of human behaviour are strongly related to age and gender such that younger individuals have more contacts and, among them, males more than females. However, the rate of decrease in the number of contacts with age differs between males and females, such that there is a reversal in the number of contacts around the late 30s. We suggest that this pattern can be attributed to the difference in reproductive investments that are made by the two sexes. We analyse the inequality in social investment patterns and suggest that the age- and gender-related differences we find reflect the constraints imposed by reproduction in a context where time (a form of social capital) is limited.


Amelioration of radiation-induced hematopoietic and gastrointestinal damage by Ex-RAD(R) in mice.
The aim of the present study was to assess recovery from hematopoietic and gastrointestinal damage by Ex-RAD(®), also known as ON01210.Na (4-carboxystyryl-4-chlorobenzylsulfone, sodium salt), after total body radiation. In our previous study, we reported that Ex-RAD, a small-molecule radioprotectant, enhances survival of mice exposed to gamma radiation, and prevents radiation-induced apoptosis as measured by the inhibition of radiation-induced protein 53 (p53) expression in cultured cells. We have expanded this study to determine best effective dose, dose-reduction factor (DRF), hematological and gastrointestinal protection, and in vivo inhibition of p53 signaling. A total of 500 mg/kg of Ex-RAD administered at 24 h and 15 min before radiation resulted in a DRF of 1.16. Ex-RAD ameliorated radiation-induced hematopoietic damage as monitored by the accelerated recovery of peripheral blood cells, and protection of granulocyte macrophage colony-forming units (GM-CFU) in bone marrow. Western blot analysis on spleen indicated that Ex-RAD treatment inhibited p53 phosphorylation. Ex-RAD treatment reduces terminal deoxynucleotidyl transferase mediated dUTP nick end labeling assay (TUNEL)-positive cells in jejunum compared with vehicle-treated mice after radiation injury. Finally, Ex-RAD preserved intestinal crypt cells compared with the vehicle control at 13 and 14 Gy. The results demonstrated that Ex-RAD ameliorates radiation-induced peripheral blood cell depletion, promotes bone marrow recovery, reduces p53 signaling in spleen and protects intestine from radiation injury.


Community perspectives on parental influence on engagement in multiple concurrent sexual partnerships among youth in Tanzania: implications for HIV prevention programming.
Although concurrent sexual partnerships (CPs) have been hypothesized to be an important risk factor for HIV in sub-Saharan Africa, the social and cultural factors that encourage CPs are not well understood. This study explored the community's perspectives on the role that parents can play in influencing their children's decision to engage in CPs. We conducted 16 in-depth interviews, 32 focus group discussions, and 16 key informant interviews with 280 adult participants in Tanzania. Data were coded; findings and conclusions were developed based on themes that emerged from coding. Three parental influences on CPs emerged: parent-child communication about sex, both silent and explicit encouragement of CPs, and parental behavior modeling. Parents are typically either too busy or too "embarrassed" to talk with their children about sex and CPs. The information parents do give is often confusing, fear-based, inadequate, and/or only focused on daughters. Parents themselves also encourage CPs through complicity of silence when their daughters come home with extra cash or consumer goods. In some cases, parents overtly encourage their children, particularly daughters, to practice CPs due to the promise of money from wealthy partners. Finally, when parents engage in CPs, the children themselves learn to behave similarly. These results suggest that parents can influence their children's decision to engage in CPs. HIV prevention interventions should address this by promoting parent-child communication about sexuality; associated disease risks and gender-equitable relationships; promoting positive parental role modeling; and educating parents on the implications of encouragement of CPs in their children.


Physico-Chemical and Microbial Analysis of Selected Borehole Water in Mahikeng, South Africa.
Groundwater is generally considered a "safe source" of drinking water because it is abstracted with low microbial load with little need for treatment before drinking. However, groundwater resources are commonly vulnerable to pollution, which may degrade their quality. An assessment of microbial and physicochemical qualities of borehole water in the rural environs of Mahikeng town, South Africa, was carried out. The study aimed at determining levels of physicochemical (temperature, pH, turbidity and nitrate) and bacteriological (both faecal and total coliform bacteria) contaminants in drinking water using standard microbiology methods. Furthermore, identities of isolates were determined using the API 20E assay. Results were compared with World Health Organisation (WHO) and Department of Water Affairs (DWAF-SA) water quality drinking standards. All analyses for physicochemical parameters were within acceptable limits except for turbidity while microbial loads during spring were higher than the WHO and DWAF thresholds. The detection of Escherichia coli, Salmonella and Klebsiella species in borehole water that was intended for human consumption suggests that water from these sources may pose severe health risks to consumers and is unsuitable for direct human consumption without treatment. The study recommends mobilisation of onsite treatment interventions to protect the households from further possible consequences of using the water.


Combined Effect of Initial and Longitudinal Increases in γ-Glutamyltransferase on Incident Metabolic Syndrome: ARIRANG Study.
Although γ-glutamyltransferase (GGT) is well known to be associated with metabolic syndrome (MS), prospective data on baseline and longitudinal changes in GGT levels and incident cases of MS are limited. We aimed to examine prospective associations between changes in GGT levels over time, as well as at baseline, and incident MS in Korean adults. A total of 2579 Korean adults free of MS were followed up for 2.6 years. Data were collected from 2005-2008 (baseline) and from 2008-2011 (follow-up). Serum GGT levels were determined by enzymatic methods. During follow-up, 558 participants (21.6%) developed MS. A gradual increase in the incidence of MS was observed across GGT quartiles. After adjustment for confounding factors, the odds ratio and 95% confidence interval (CI) for new onset MS, comparing the highest to the lowest quartiles of baseline GGT, was 2.07 (95% CI: 1.52-2.80). The odds ratio for the highest GGT changes (>4 IU/L increase) in comparison to the lowest GGT changes (<-5 IU/L decrease) was 1.75 (95% CI: 1.32-2.33). Among participants with baseline GGT concentrations <the median, the odds ratio for incident MS, comparing participants with the highest GGT changes with the lowest GGT changes, was 1.52 (95% CI: 1.01-2.31). Among participants with baseline GGT concentration ≥the median, the corresponding odds ratio was 2.75 (95% CI: 1.84-4.10). High initial GGT concentration and increases in GGT concentration over time should be considered independent predictors of and to have a combined effect on incident MS.


Increased serum miR-193a-5p during non-alcoholic fatty liver disease progression: Diagnostic and mechanistic relevance.
Serum microRNA (miRNA) levels are known to change in non-alcoholic fatty liver disease (NAFLD) and may serve as useful biomarkers. This study aimed to profile miRNAs comprehensively at all NAFLD stages. We profiled 2,083 serum miRNAs in a discovery cohort (183 cases with NAFLD representing the complete NAFLD spectrum and 10 population controls). miRNA libraries generated by HTG EdgeSeq were sequenced by Illumina NextSeq. Selected serum miRNAs were profiled in 372 additional cases with NAFLD and 15 population controls by quantitative reverse transcriptase PCR. Levels of 275 miRNAs differed between cases and population controls. Fewer differences were seen within individual NAFLD stages, but miR-193a-5p consistently showed increased levels in all comparisons. Relative to NAFL/non-alcoholic steatohepatitis (NASH) with mild fibrosis (stage 0/1), 3 miRNAs (miR-193a-5p, miR-378d, and miR378d) were increased in cases with NASH and clinically significant fibrosis (stages 2-4), 7 (miR193a-5p, miR-378d, miR-378e, miR-320b, miR-320c, miR-320d, and miR-320e) increased in cases with NAFLD activity score (NAS) 5-8 compared with lower NAS, and 3 (miR-193a-5p, miR-378d, and miR-378e) increased but 1 (miR-19b-3p) decreased in steatosis, activity, and fibrosis (SAF) activity score 2-4 compared with lower SAF activity. The significant findings for miR-193a-5p were replicated in the additional cohort with NAFLD. Studies in Hep G2 cells showed that following palmitic acid treatment, miR-193a-5p expression decreased significantly. Gene targets for miR-193a-5p were investigated in liver RNAseq data for a case subgroup (n = 80); liver GPX8 levels correlated positively with serum miR-193a-5p. Serum miR-193a-5p levels correlate strongly with NAFLD activity grade and fibrosis stage. MiR-193a-5p may have a role in the hepatic response to oxidative stress and is a potential clinically tractable circulating biomarker for progressive NAFLD. MicroRNAs (miRNAs) are small pieces of nucleic acid that may turn expression of genes on or off. These molecules can be detected in the blood circulation, and their levels in blood may change in liver disease including non-alcoholic fatty liver disease (NAFLD). To see if we could detect specific miRNA associated with advanced stages of NAFLD, we carried out miRNA sequencing in a group of 183 patients with NAFLD of varying severity together with 10 population controls. We found that a number of miRNAs showed changes, mainly increases, in serum levels but that 1 particular miRNA miR-193a-5p consistently increased. We confirmed this increase in a second group of cases with NAFLD. Measuring this miRNA in a blood sample may be a useful way to determine whether a patient has advanced NAFLD without an invasive liver biopsy.


Prospective evaluation of a preoperative biomarker panel for prediction of upstaging at radical cystectomy.
To prospectively test whether a panel of biomarkers could identify patients with organ-confined disease likely to be upstaged at radical cystectomy (RC), as retrospective studies have found that cell-cycle- and proliferation-related biomarkers can help improve prognostic accuracy after RC. We prospectively performed p53, p21, p27, Ki67, and cyclin E1 immunohistochemical staining on transurethral resection of the bladder (TURB) specimens from 87 patients treated with RC for organ-confined urothelial carcinoma of the bladder (UCB). The number of altered biomarkers was categorised as 'favourable' (≤2 altered markers) or 'unfavourable' (>2). Expression of p53, p21, p27, cyclin E1, and Ki67 were altered in 61 (70%), 19 (22%), 26 (30%), four (5%), and 70 (80%) patients, respectively. The median number of positive markers was two. In all, 47 (54%) patients were upstaged when T-stage was considered alone and 49 (56%) when T- and/or N-stage were considered both as upstaging. In multivariable analyses that adjusted for the effects of age, clinical stage, concomitant carcinoma in situ, and time from TURB to RC, an 'unfavourable' biomarker score was independently associated with T-stage upstaging (hazard ratio [HR] 3.3, P = 0.024) but not T- and/or N-stage upstaging (HR 2.76, P = 0.06). Addition of p27, number of positive markers, and biomarker score each increased the discrimination of a base model for prediction of T-stage upstaging (5%, 6%, and 5%, respectively) and T- and/or N-stage upstaging (4%, 6%, and 3%, respectively). Cell-cycle- and proliferation-related markers in the TURB specimen improve the prediction of upstaging at RC. Such a marker panel may help identify patients with non-muscle-invasive UCB who are clinically under-staged needing RC and patients with muscle-invasive UCB who are likely to be non-organ-confined thereby potentially benefiting from neoadjuvant chemotherapy.


A comparison of individual and social vulnerabilities, health, and quality of life among Canadian women with mental diagnoses and young children.
this study examined whether differences exist among women with mental health issues who had either young, adult, or no children in relation to their individual and social vulnerabilities, health, and quality of life. the design of this study was a secondary quantitative analysis of data extracted from a larger Canadian 5-year study focused on mental health and housing. This study's sample included 234 female psychiatric consumer/survivors: 108 (46%) women reported having no children, 68 (29%) had at least one child younger than 18 years of age, and 58 (25%) had children 18 years of age or older. The women completed structured interviews between 2004 and 2006. seventy-nine percent of mothers were separated from their young children. In comparison with women with older children and those without children, women with young children were more often homeless, had fewer strengths/resources, greater physical but lower cognitive/intellectual functioning, and a low perception of quality of life regarding their financial situation. In addition, women with young children reported the greatest problem with substance use and poorest quality of life regarding daily activities, health, and overall quality of life. These results, however, were mediated by the confounding effects of housing. No differences were identified between groups regarding utilization of health and social services. these findings support the need for early integrated health and social interventions that assist women achieve their well-being.


A comparison of bilateral versus unilateral target and distractor presentation in the remote distractor paradigm.
The remote distractor effect (RDE) is a robust finding of an increase in saccade onset latencies (20-40 ms) when a distractor is presented simultaneously with a target, compared to when a target is presented on its own (Walker, Deubel, Schneider, & Findlay, 1997). Distractors presented at fixation produce the largest RDE and the effect decreases as distractors are moved into the periphery. Data from two experiments that contrast with these standard findings are reported. Under bilateral target presentation, larger RDE magnitudes occurred for peripheral than for central distractors, whereas under unilateral presentation, the pattern reversed. The findings are discussed with reference to discrimination processes, attentional factors and current models of oculomotor control. It is suggested that in bilateral target presentation the competition between the distractor and the target results in the programming of a saccade to the distractor, as well as a saccade to the target. Time taken to cancel the saccade to the distractor produces the increased saccade latency for peripheral distractors in that condition.


Phase I study of PF-03446962, a fully human monoclonal antibody against activin receptor-like kinase-1, in patients with hepatocellular carcinoma.
This expansion cohort of a multicenter, dose-escalation, phase I study (NCT00557856) evaluated safety, tolerability, antitumor activity, pharmacokinetics, and pharmacodynamic effects of the anti-activin receptor-like kinase-1 (ALK-1) monoclonal antibody PF-03446962 in advanced hepatocellular carcinoma (HCC). Patients with HCC and disease progression after prior antiangiogenic therapy or intolerance to treatment received PF-03446962 7 mg/kg intravenously biweekly, as recommended in the dose-escalation part of the study. Twenty-four patients received PF-03446962. The most frequent treatment-related adverse events (AEs) were thrombocytopenia (33.3%), asthenia (29.2), and chills (16.7%). Two patients experienced treatment-related telangiectasia, suggesting an in vivo knockout of ALK-1 function through ALK-1 pathway inhibition. Overall, treatment-related grade 3-4 AEs were reported in eight patients (33.3%). Treatment-related grade 3-4 thrombocytopenia was noted in four patients. No complete or partial responses were reported. Twelve (50%) patients achieved stable disease, which lasted ≥12 weeks in seven (29.2%) patients. The median time to progression was 3 months. Biomarker analyses showed higher mean tumor expression of c-tumor mesenchymal-epithelial transition factor and higher mean serum levels of bone morphogenetic protein-9 in patients with disease control (DC) for ≥12 weeks versus patients with disease progression. Conversely, lower mean serum transforming growth factor-β and vascular endothelial growth factor receptor-3 levels were detected in patients with DC versus patients with progression. The observed safety, tolerability, pharmacokinetic profile, and clinical activity support further evaluation of PF-03446962 in patients with HCC and other solid malignancies, as single agent or in combination with other antiangiogenic, chemotherapeutic, or immunotherapeutic agents. NCT00557856.


Circulating insulin-like growth factor-I, total and free testosterone concentrations and prostate cancer risk in 200 000 men in UK Biobank.
Insulin-like growth factor-I (IGF-I) and testosterone have been implicated in prostate cancer aetiology. Using data from a large prospective full-cohort with standardised assays and repeat blood measurements, and genetic data from an international consortium, we investigated the associations of circulating IGF-I, sex hormone-binding globulin (SHBG), and total and calculated free testosterone concentrations with prostate cancer incidence and mortality. For prospective analyses, risk was estimated using multivariable-adjusted Cox regression in 199 698 male UK Biobank participants. Hazard ratios (HRs) were corrected for regression dilution bias using repeat hormone measurements from a subsample. Two-sample Mendelian randomisation (MR) analysis of IGF-I and risk used genetic instruments identified from UK Biobank men and genetic outcome data from the PRACTICAL consortium (79 148 cases and 61 106 controls). We used cis- and all (cis and trans) SNP MR approaches. A total of 5402 men were diagnosed with and 295 died from prostate cancer (mean follow-up 6.9 years). Higher circulating IGF-I was associated with elevated prostate cancer diagnosis (HR per 5 nmol/L increment = 1.09, 95% CI 1.05-1.12) and mortality (HR per 5 nmol/L increment = 1.15, 1.02-1.29). MR analyses also supported the role of IGF-I in prostate cancer diagnosis (cis-MR odds ratio per 5 nmol/L increment = 1.34, 1.07-1.68). In observational analyses, higher free testosterone was associated with a higher risk of prostate cancer (HR per 50 pmol/L increment = 1.10, 1.05-1.15). Higher SHBG was associated with a lower risk (HR per 10 nmol/L increment = 0.95, 0.94-0.97), neither was associated with prostate cancer mortality. Total testosterone was not associated with prostate cancer. These findings implicate IGF-I and free testosterone in prostate cancer development and/or progression.


A mouse mammary tumor virus-like long terminal repeat superantigen in human breast cancer.
We previously reported a 660-bp mouse mammary tumor virus (MMTV)-like env gene sequence in approximately 38% of human breast cancer DNA, but not in normal breasts or other tumors. This MMTV-like env gene sequence was expressed in 66% of the env gene-positive human breast cancers. An entire proviral structure was identified in human breast cancer DNA with high homology to MMTV and low homology to known human endogenous retrovirus. MMTV-like long terminal repeat (LTR) sequences were also detected in 41.5% of human breast cancers. They contain hormone-responsive elements, TEF-1 family elements, and the open reading frame for the superantigen (SAg). We have now amplified and sequenced MMTV-like sag sequences from 10 human breast cancers, and we found that they are highly homologous to those of MMTV. However, deletions and insertions at the COOH-terminal of sag were observed. The immune function of the human MMTV-like LTR SAg was also investigated. The sag gene was cloned and expressed in a human B-cell line (Ramos). T-cell proliferation and cytokine releasing assays were performed after cocultivation of T cells with irradiated Ramos SAg-expressing cells. The results indicate that expression of the human SAg stimulates T-cell activation in vitro, as the mouse SAg does. Because the T-cell responses in vitro are considered similar to those in vivo, these results suggest that the human LTR SAg might also play a role in human breast carcinogenesis.


Orthostatic leg blood volume changes assessed by near-infrared spectroscopy.
Standing up shifts blood to dependent parts of the body, and blood vessels in the leg become filled. The orthostatic blood volume accumulation in the small vessels is relatively unknown, although these may contribute significantly. We hypothesized that in healthy humans exposed to the upright posture, volume accumulation in small blood vessels contributes significantly to the total fluid volume accumulated in the legs. Considering that near-infrared spectroscopy (NIRS) tracks postural blood volume changes within the small blood vessels of the lower leg, we evaluated the NIRS-determined changes in oxygenated (Δ[O(2)Hb]), deoxygenated (Δ[HHb]) and total haemoglobin tissue concentration (Δ[tHb]) and in total leg volume by strain-gauge plethysmography during 70 deg head-up tilt (HUT; n = 7). In a second experiment, spatial and temporal reproducibility were evaluated with three NIRS probes applied on two separate days (n = 8). In response to HUT, an initially fast increase in [O(2)Hb] was followed by a gradual decline, while [HHb] increased continuously. The increase in [tHb] during HUT was closely related to the increase in total leg volume (r(2) = 0.95 ± 0.03). After tilt back, [O(2)Hb] declined below and [HHb] remained above baseline, whereas all NIRS signals gradually returned to baseline. Spatial heterogeneity was observed, and for two probes [tHb] was highly correlated between days (r(2) = 0.92 ± 0.09 and 0.91 ± 0.12), but less for the third probe (r(2) = 0.44 ± 0.36). The results suggest a non-linear accumulation of blood volume in the small vessels of the leg, with an initial fast phase followed by a more gradual increase at least partly contributing to the relocation of fluid during orthostatic stress.


Kinase pathway inhibition restores PSD95 induction in neurons lacking fragile X mental retardation protein.
Fragile X syndrome (FXS) is the leading monogenic cause of autism and intellectual disability. FXS is caused by loss of expression of fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates translation of numerous mRNA targets, some of which are present at synapses. While protein synthesis deficits have long been postulated as an etiology of FXS, how FMRP loss affects distributions of newly synthesized proteins is unknown. Here we investigated the role of FMRP in regulating expression of new copies of the synaptic protein PSD95 in an in vitro model of synaptic plasticity. We find that local BDNF application promotes persistent accumulation of new PSD95 at stimulated synapses and dendrites of cultured neurons, and that this accumulation is absent in FMRP-deficient mouse neurons. New PSD95 accumulation at sites of BDNF stimulation does not require known mechanisms regulating FMRP-mRNA interactions but instead requires the PI3K-mTORC1-S6K1 pathway. Surprisingly, in FMRP-deficient neurons, BDNF induction of new PSD95 accumulation can be restored by mTORC1-S6K1 blockade, suggesting that constitutively high mTORC1-S6K1 activity occludes PSD95 regulation by BDNF and that alternative pathways exist to mediate induction when mTORC1-S6K1 is inhibited. This study provides direct evidence for deficits in local protein synthesis and accumulation of newly synthesized protein in response to local stimulation in FXS, and supports mTORC1-S6K1 pathway inhibition as a potential therapeutic approach for FXS.


The Process of Developing an Internet-Based Support System for Audiologists and First-Time Hearing Aid Clients.
In audiologic practice, complementary information sources and access to the clinician between appointments improve information retention and facilitate adjustment behaviors. An Internet-based support system is a novel way to support information sharing and clinician access. This research forum article describes the process of developing an Internet-based support system for audiologists and their first-time hearing aid clients. The iterative development process, including revisions by 4 research audiologists and 4 clinical audiologists, is described. The final system is exemplified. An Internet-based support system was successfully developed for audiologic practice.