The developing female genital tract: from genetics to epigenetics.
The mammalian female reproductive tract develops from the Mullerian ducts which differentiate, in a cranial to caudal direction, into oviducts, uterine horns, cervix and the anterior vagina. The developmental processes taking place during this organogenesis are notably under the control of steroid hormones, such as members of the Wnt and Hox families, which regulate key developmental genes. At later stages, steroid hormones also participate in the development of the female genital tract. Chemical compounds homologous to steroids can thus act as agonists or antagonists in fetuses exposed to them. These so-called endocrine disruptors are nowadays found in increasing amounts in the environment and may therefore have a particular impact on such developing organs. Epidemiological studies have revealed that endocrine disruptors have had drastic effects on female health and fertility during the last decades. Furthermore, these adverse effects might be transmitted to subsequent generations through epigenetic modifications. Given the potential hazard of inherited epigenetic marks altering reproduction and/or human health, such molecular mechanisms must be urgently investigated. This review aims to summarize the cellular and molecular mechanisms involved in female genital tract development, to highlight key genes involved in this process and to present epigenetic mechanisms triggered by endocrine disruptors and their consequences in regard to female reproductive tract development.


Differential roles for MBD2 and MBD3 at methylated CpG islands, active promoters and binding to exon sequences.
The heterogeneous collection of nucleosome remodelling and deacetylation (NuRD) complexes can be grouped into the MBD2- or MBD3-containing complexes MBD2-NuRD and MBD3-NuRD. MBD2 is known to bind to methylated CpG sequences in vitro in contrast to MBD3. Although functional differences have been described, a direct comparison of MBD2 and MBD3 in respect to genome-wide binding and function has been lacking. Here, we show that MBD2-NuRD, in contrast to MBD3-NuRD, converts open chromatin with euchromatic histone modifications into tightly compacted chromatin with repressive histone marks. Genome-wide, a strong enrichment for MBD2 at methylated CpG sequences is found, whereas CpGs bound by MBD3 are devoid of methylation. MBD2-bound genes are generally lower expressed as compared with MBD3-bound genes. When depleting cells for MBD2, the MBD2-bound genes increase their activity, whereas MBD2 plus MBD3-bound genes reduce their activity. Most strikingly, MBD3 is enriched at active promoters, whereas MBD2 is bound at methylated promoters and enriched at exon sequences of active genes.


Search for a supersymmetric partner to the top quark in final states with jets and missing transverse momentum at sqrt[s] = 7 TeV with the ATLAS detector.
A search for direct pair production of supersymmetric top squarks (t(1)) is presented, assuming the t(1) decays into a top quark and the lightest supersymmetric particle, χ(1)(0), and that both top quarks decay to purely hadronic final states. A total of 16 (4) events are observed compared to a predicted standard model background of 13.5(-3.6)(+3.7)(4.4(-1.3)(+1.7)) events in two signal regions based on ∫Ldt = 4.7 fb(-1) of pp collision data taken at sqrt[s] = 7 TeV with the ATLAS detector at the LHC. An exclusion region in the t(1) versus χ(1)(0) mass plane is evaluated: 370<m(t)(1)}<465 GeV is excluded for m(χ)(1)(0) ~ 0 GeV while m(t)(1) = 445 GeV is excluded for m(χ)(1)(0) ≤ 50 GeV.


Mechanism of N6-threonylcarbamoyladenonsine (t(6)A) biosynthesis: isolation and characterization of the intermediate threonylcarbamoyl-AMP.
Genetic and biochemical studies have recently implicated four proteins required in bacteria for the biosynthesis of the universal tRNA modified base N6-threonylcarbamoyl adenosine (t(6)A). In this work, t(6)A biosynthesis in Bacillus subtilis has been reconstituted in vitro and found to indeed require the four proteins YwlC (TsaC), YdiB (TsaE), YdiC (TsaB) and YdiE (TsaD). YwlC was found to catalyze the conversion of L-threonine, bicarbonate/CO(2) and ATP to give the intermediate L-threonylcarbamoyl-AMP (TC-AMP) and pyrophosphate as products. TC-AMP was isolated by HPLC and characterized by mass spectrometry and (1)H NMR. NMR analysis showed that TC-AMP decomposes to give AMP and a nearly equimolar mixture of L-threonine and 5-methyl-2-oxazolidinone-4-carboxylate as final products. Under physiological conditions (pH 7.5, 37 °C, 2 mM MgCl(2)), the half-life of TC-AMP was measured to be 3.5 min. Both YwlC (in the presence of pyrophosphatase) and its Escherichia coli homologue YrdC catalyze the formation of TC-AMP while producing only a small molar fraction of AMP. This suggests that CO(2) and not an activated form of bicarbonate is the true substrate for these enzymes. In the presence of pyrophosphate, both enzymes catalyze clean conversion of TC-AMP back to ATP. Purified TC-AMP is efficiently processed to t(6)A by the YdiBCE proteins in the presence of tRNA substrates. This reaction is ATP independent in vitro, despite the known ATPase activity of YdiB. The estimated rate of conversion of TC-AMP by YdiBCE to t(6)A is somewhat lower than the initial rate from L-threonine, bicarbonate and ATP, which together with the stability data, is consistent with previous studies that suggest channeling of this intermediate.


Memory Distortion and Its Avoidance: An Event-Related Potentials Study on False Recognition and Correct Rejection.
Memory researchers have long been captivated by the nature of memory distortions and have made efforts to identify the neural correlates of true and false memories. However, the underlying mechanisms of avoiding false memories by correctly rejecting related lures remains underexplored. In this study, we employed a variant of the Deese/Roediger-McDermott paradigm to explore neural signatures of committing and avoiding false memories. ERP were obtained for True recognition, False recognition, Correct rejection of new items, and, more importantly, Correct rejection of related lures. With these ERP data, early-frontal, left-parietal, and late right-frontal old/new effects (associated with familiarity, recollection, and monitoring processes, respectively) were analysed. Results indicated that there were similar patterns for True and False recognition in all three old/new effects analysed in our study. Also, False recognition and Correct rejection of related lures activities seemed to share common underlying familiarity-based processes. The ERP similarities between False recognition and Correct rejection of related lures disappeared when recollection processes were examined because only False recognition presented a parietal old/new effect. This finding supported the view that actual false recollections underlie false memories, providing evidence consistent with previous behavioural research and with most ERP and neuroimaging studies. Later, with the onset of monitoring processes, False recognition and Correct rejection of related lures waveforms presented, again, clearly dissociated patterns. Specifically, False recognition and True recognition showed more positive going patterns than Correct rejection of related lures signal and Correct rejection of new items signature. Since False recognition and Correct rejection of related lures triggered familiarity-recognition processes, our results suggest that deciding which items are studied is based more on recollection processes, which are later supported by monitoring processes. Results are discussed in terms of Activation-Monitoring Framework and Fuzzy Trace-Theory, the most prominent explanatory theories of false memory raised with the Deese/Roediger-McDermott paradigm.


Striatal prediction errors support dynamic control of declarative memory decisions.
Adaptive memory requires context-dependent control over how information is retrieved, evaluated and used to guide action, yet the signals that drive adjustments to memory decisions remain unknown. Here we show that prediction errors (PEs) coded by the striatum support control over memory decisions. Human participants completed a recognition memory test that incorporated biased feedback to influence participants' recognition criterion. Using model-based fMRI, we find that PEs-the deviation between the outcome and expected value of a memory decision-correlate with striatal activity and predict individuals' final criterion. Importantly, the striatal PEs are scaled relative to memory strength rather than the expected trial outcome. Follow-up experiments show that the learned recognition criterion transfers to free recall, and targeting biased feedback to experimentally manipulate the magnitude of PEs influences criterion consistent with PEs scaled relative to memory strength. This provides convergent evidence that declarative memory decisions can be regulated via striatally mediated reinforcement learning signals.


Frequentist and Bayesian approaches to prevalence estimation using examples from Johne's disease.
Although frequentist approaches to prevalence estimation are simple to apply, there are circumstances where it is difficult to satisfy assumptions of asymptotic normality and nonsensical point estimates (greater than 1 or less than 0) may result. This is particularly true when sample sizes are small, test prevalences are low and imperfect sensitivity and specificity of diagnostic tests need to be incorporated into calculations of true prevalence. Bayesian approaches offer several advantages including direct computation of range-respecting interval estimates (e.g. intervals between 0 and 1 for prevalence) without the requirement of transformations or large-sample approximations, direct probabilistic interpretation, and the flexibility to model in a straightforward manner the probability of zero prevalence. In this review, we present frequentist and Bayesian methods for animal- and herd-level true prevalence estimation based on individual and pooled samples. We provide statistical methods for detecting differences between population prevalence and frequentist methods for sample size and power calculations. All examples are motivated using Mycobacterium avium subspecies paratuberculosis infection and we provide WinBUGS code for all examples of Bayesian estimation.


Saccade velocity in idiopathic and autosomal dominant cerebellar ataxia.
Slow saccades are often found in degenerative ataxia. Experimental studies have shown that horizontal saccades are generated in the paramedian pontine reticular formation and that lesions in this area produce slow saccades. Based on these findings, saccade slowing should be a frequent feature of olivopontocerebellar atrophy, a type of cerebellar degeneration with prominent involvement of the pons. To test this hypothesis, saccade velocity was measured in 31 patients with autosomal dominant cerebellar ataxia (ADCA) and 17 patients with idiopathic cerebellar ataxia (IDCA). Saccade velocity was reduced in most patients with ADCA whereas it was normal in IDCA although olivopontocerebellar atrophy occurred in both groups. Saccade velocities correlated with pontine size in ADCA but not in IDCA. The data disprove the hypothesis that saccadic slowing is a clinical hallmark of olivopontocerebellar atrophy. Instead, only patients with ADCA and morphological features of olivopontocerebellar atrophy have slow saccades.


NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration.
Neurodegeneration can be triggered by genetic or environmental factors. Although the precise cause is often unknown, many neurodegenerative diseases share common features such as protein aggregation and age dependence. Recent studies in Drosophila have uncovered protective effects of NAD synthase nicotinamide mononucleotide adenylyltransferase (NMNAT) against activity-induced neurodegeneration and injury-induced axonal degeneration. Here we show that NMNAT overexpression can also protect against spinocerebellar ataxia 1 (SCA1)-induced neurodegeneration, suggesting a general neuroprotective function of NMNAT. It protects against neurodegeneration partly through a proteasome-mediated pathway in a manner similar to heat-shock protein 70 (Hsp70). NMNAT displays chaperone function both in biochemical assays and cultured cells, and it shares significant structural similarity with known chaperones. Furthermore, it is upregulated in the brain upon overexpression of poly-glutamine expanded protein and recruited with the chaperone Hsp70 into protein aggregates. Our results implicate NMNAT as a stress-response protein that acts as a chaperone for neuronal maintenance and protection. Our studies provide an entry point for understanding how normal neurons maintain activity, and offer clues for the common mechanisms underlying different neurodegenerative conditions.


Impact of Body Weight Loss From Maximum Weight on Fragility Bone Fractures in Japanese Patients With Type 2 Diabetes: The Fukuoka Diabetes Registry.
There is growing evidence that weight loss is associated with increased fracture risk in the general population. As patients with diabetes often lose weight intentionally or unintentionally, we aimed to investigate prospectively the relationship between weight loss from maximum body weight and fracture risk. A total of 4,706 Japanese participants with type 2 diabetes (mean age 66 years), including 2,755 men and 1,951 postmenopausal women, were followed for a median of 5.3 years and were divided according to weight loss from maximum weight: <10%, 10% to <20%, 20% to <30%, and ≥30%. The primary outcomes were fragility fractures defined as fractures at sites of hip and spine. During the follow-up period, fragility fractures occurred in 198 participants. The age- and sex-adjusted incidence rates per 1,000 person-years in all participants were 6.4 (<10% weight loss from maximum body weight), 7.8 (10% to <20%), 11.7 (20% to <30%), and 19.2 (≥30%) (P for trend <0.001). Multivariate-adjusted hazard ratios for fragility fractures compared with reference (<10% weight loss) were 1.48 (95% CI 0.79-2.77) in the 10% to <20% group, 2.23 (1.08-4.64) in 20% to <30%, and 5.20 (2.15-12.57) in ≥30% in men, and 1.19 (0.78-1.82) in 10% to <20%, 1.62 (0.96-2.73) in 20% to <30%, and 1.97 (0.84-4.62) in ≥30% in postmenopausal women. The current study demonstrates that ≥20% body weight loss from maximum weight is a significant risk factor for fragility fractures in patients with type 2 diabetes, especially in men.


Retrosigmoid intradural suprameatal approach to Meckel's cave and the middle fossa: surgical technique and outcome.
The goal of this study was to determine whether some petroclival tumors can be safely and efficiently treated using a modified retrosigmoid petrosal approach that is called the retrosigmoid intradural suprameatal approach (RISA). The RISA was introduced in 1983, and since that time 12 patients harboring petroclival meningiomas have been treated using this technique. The RISA includes a retrosigmoid craniotomy and drilling of the suprameatus petrous bone, which is located above and anterior to the internal auditory meatus, thus providing access to Meckel's cave and the middle fossa. Radical tumor resection (Simpson Grade I or II) was achieved in nine (75%) of the 12 patients. Two patients underwent subtotal resection (Simpson Grade III). and one patient underwent complete resection of tumor at the posterior fossa with subtotal resection at the middle fossa. There were no deaths or severe complications in this series; all patients did well postoperatively, being independent at the time of their last follow-up examinations (mean 5.6 years). Neurological deficits included facial paresis in one patient and worsening of hearing in two patients. The approach described here is a useful modification of the retrosigmoid approach, which allows resection of large petroclival tumors without the need for supratentorial craniotomies. Although technically meticulous, this approach is not time-consuming; it is safe and can produce good results. This is the first report on the use of this approach for petroclival meningiomas.


Does Leaving the Biopsy Needle in Povidone-Iodine Solution Reduce Infective Complications after Biopsy?
Aim. The aim of this study is to evaluate whether leaving the biopsy needle used during prostate needle biopsy in 10% povidone-iodine (betadine) solution affects the infectious complications forming after biopsy. Material and Method. This study retrospectively evaluated the data of 176 patients with prostate biopsy performed between December 2012 and April 2014. Patients in Group 1 (n = 89) were given ofloxacin as a prophylactic antibiotic before biopsy. Patients in Group 2 (n = 87) had the biopsy needle left in povidone-iodine solution for 1 minute before each use, in addition to antibiotic prophylaxis. The two groups were compared in terms of infective complications developing after biopsy. Results were analyzed using the Mann-Whitney U test and Fisher's exact test. Results. The distribution of infective complications after biopsy according to group was as follows. Group 1, not using betadine, had 15.7% fever, 13.5% hospital stay, 12.4% urinary retention, 10.1% prostatitis, and 5.6% sepsis. The distribution of the same complications in Group 2 using betadine was identified as 5.7% fever, 4.6% hospital stay, 3.4% urinary retention, 2.3% prostatitis, and 0% sepsis. The use of betadine was found to significantly reduce the infectious complications after biopsy compared to the control group (p < 0.05). Conclusion. At the end of this study leaving the prostate needle in povidone-iodine solution before each use during prostate biopsy was found to reduce the infective complications and hospital stay after biopsy.


Interventions for smoking cessation in hospitalised patients.
Smoking contributes to reasons for hospitalisation, and the period of hospitalisation may be a good time to provide help with quitting. To determine the effectiveness of interventions for smoking cessation that are initiated for hospitalised patients. We searched the Cochrane Tobacco Addiction Group register which includes papers identified from CENTRAL, MEDLINE, EMBASE and PsycINFO in December 2011 for studies of interventions for smoking cessation in hospitalised patients, using terms including (hospital and patient*) or hospitali* or inpatient* or admission* or admitted. Randomized and quasi-randomized trials of behavioural, pharmacological or multicomponent interventions to help patients stop smoking, conducted with hospitalised patients who were current smokers or recent quitters (defined as having quit more than one month before hospital admission). The intervention had to start in the hospital but could continue after hospital discharge. We excluded studies of patients admitted to facilities that primarily treat psychiatric disorders or substance abuse, studies that did not report abstinence rates and studies with follow-up of less than six months. Both acute care hospitals and rehabilitation hospitals were included in this update, with separate analyses done for each type of hospital. Two authors extracted data independently for each paper, with disagreements resolved by consensus. Fifty trials met the inclusion criteria. Intensive counselling interventions that began during the hospital stay and continued with supportive contacts for at least one month after discharge increased smoking cessation rates after discharge (risk ratio (RR) 1.37, 95% confidence interval (CI) 1.27 to 1.48; 25 trials). A specific benefit for post-discharge contact compared with usual care was found in a subset of trials in which all participants received a counselling intervention in the hospital and were randomly assigned to post-discharge contact or usual care. No statistically significant benefit was found for less intensive counselling interventions. Adding nicotine replacement therapy (NRT) to an intensive counselling intervention increased smoking cessation rates compared with intensive counselling alone (RR 1.54, 95% CI 1.34 to 1.79, six trials). Adding varenicline to intensive counselling had a non-significant effect in two trials (RR 1.28, 95% CI 0.95 to 1.74). Adding bupropion did not produce a statistically significant increase in cessation over intensive counselling alone (RR 1.04, 95% CI 0.75 to 1.45, three trials). A similar pattern of results was observed in a subgroup of smokers admitted to hospital because of cardiovascular disease (CVD). In this subgroup, intensive intervention with follow-up support increased the rate of smoking cessation (RR 1.42, 95% CI 1.29 to 1.56), but less intensive interventions did not. One trial of intensive intervention including counselling and pharmacotherapy for smokers admitted with CVD assessed clinical and health care utilization endpoints, and found significant reductions in all-cause mortality and hospital readmission rates over a two-year follow-up period. These trials were all conducted in acute care hospitals. A comparable increase in smoking cessation rates was observed in a separate pooled analysis of intensive counselling interventions in rehabilitation hospitals (RR 1.71, 95% CI 1.37 to 2.14, three trials). High intensity behavioural interventions that begin during a hospital stay and include at least one month of supportive contact after discharge promote smoking cessation among hospitalised patients. The effect of these interventions was independent of the patient's admitting diagnosis and was found in rehabilitation settings as well as acute care hospitals. There was no evidence of effect for interventions of lower intensity or shorter duration. This update found that adding NRT to intensive counselling significantly increases cessation rates over counselling alone. There is insufficient direct evidence to conclude that adding bupropion or varenicline to intensive counselling increases cessation rates over what is achieved by counselling alone.


Sequential capsule endoscopy of the small bowel for follow-up of patients with known Crohn's disease.
The aim of this study was to perform sequential small bowel (SB) capsule endoscopy (CE) studies in patients with known active Crohn's disease (CD) during different treatments, to characterize the changes in the SB mucosa over time, and to correlate the CE findings with clinical and laboratory parameters of inflammation. Consecutive patients with known moderately active CD were prospectively recruited. After proven patency with Agile capsule, CE studies were performed at baseline and after 4, 12 and 24 weeks. CE parameters and a Lewis score were calculated. Clinical and laboratory parameters were correlated. A control group of 178 non-CD patients was used for comparisons. Thirty-one CD patients were recruited and 19 met the inclusion criteria. A total of 43 CE studies were performed over the time. There was no capsule retention despite a high rate of previous SB surgery. The mean baseline CDAI, IBDQ and Lewis scores were 306±56, 135±26.6 and 1730±1780, respectively. There was no correlation at the baseline between clinical and laboratory parameters (CDAI, CRP, IBDQ) and mucosal disease (Lewis scores). CDAI and IBDQ changes over a period of 4 and 12 weeks did not correlate with the Lewis score. The cecum arrival rate of the CD patients was significantly lower (p=0.0047) and the SB transit time was significantly longer (p=0.005) compared to those of the controls. Sequential CE studies are feasible and safe in CD patients. In patients with complete CE studies, they provide reliable information on mucosal changes in CD and should be considered as an independent and objective follow-up tool in known CD patients.


Perception of Visual Variables on Tiled Wall-Sized Displays for Information Visualization Applications.
We present the results of two user studies on the perception of visual variables on tiled high-resolution wall-sized displays. We contribute an understanding of, and indicators predicting how, large variations in viewing distances and viewing angles affect the accurate perception of angles, areas, and lengths. Our work, thus, helps visualization researchers with design considerations on how to create effective visualizations for these spaces. The first study showed that perception accuracy was impacted most when viewers were close to the wall but differently for each variable (Angle, Area, Length). Our second study examined the effect of perception when participants could move freely compared to when they had a static viewpoint. We found that a far but static viewpoint was as accurate but less time consuming than one that included free motion. Based on our findings, we recommend encouraging viewers to stand further back from the display when conducting perception estimation tasks. If tasks need to be conducted close to the wall display, important information should be placed directly in front of the viewer or above, and viewers should be provided with an estimation of the distortion effects predicted by our work-or encouraged to physically navigate the wall in specific ways to reduce judgement error.


Rapid and simple PCR assay for quantitation of human immunodeficiency virus type 1 RNA in plasma: application to acute retroviral infection.
A method for quantitating human immunodeficiency virus type 1 plasma viremia may be useful in monitoring disease progression and the responsiveness of patients to a therapeutic regimen or vaccine. A quantitative assay for viral RNA in plasma or sera that differs in several aspects from those reported previously was developed. First, whereas conventional reverse transcriptase-PCR assays involve a two-step process and use two enzymes, the method described uses a single enzyme, rTth DNA polymerase, for both reverse transcription and PCR. The reactions are carried out in a single tube and with a single buffer solution with uninterrupted thermal cycling. Second, uracil-N-glycosylase and dUTP are incorporated into the reaction mixtures to ensure that any carryover of DNA from previous amplifications will not compromise quantitation. Third, a quantitation standard is incorporated into each reaction mixture so that differences in amplification efficiency caused by sample interferents, variability in reaction conditions, or thermal cycling can be normalized. To ensure comparable amplification efficiency, the quantitation standard has the same primer-binding regions as the human immunodeficiency virus type 1 target and generates an amplified product of the same size and base composition. The probe-binding region was replaced with a sequence that can be detected separately. Fourth, a colorimetric detection format was modified to provide at least a four-log-unit dynamic range. The quantitative assay requires only a single amplification of the sample and can be completed in less than 8 h. The procedure was used on archival samples to demonstrate the viremic spike in acute infection and the suppressed levels of circulating virus following seroconversion.


Broken Windows, Broken Zzs: Poor Housing and Neighborhood Conditions Are Associated with Objective Measures of Sleep Health.
African Americans and socioeconomically disadvantaged individuals have higher rates of a variety of sleep disturbances, including short sleep duration, poor sleep quality, and fragmented sleep. Such sleep disturbances may contribute to pervasive and widening racial and socioeconomic (SES) disparities in health. A growing body of literature demonstrates that over and above individual-level SES, indicators of neighborhood disadvantage are associated with poor sleep. However, there has been scant investigation of the association between sleep and the most proximal environments, the home and residential block. This is the first study to examine the association between objective and self-reported measures of housing and block conditions and sleep. The sample included 634 adults (mean age = 58.7 years; 95% African American) from two low-income urban neighborhoods. Study participants reported whether they experienced problems with any of seven different housing problems (e.g., broken windows) and rated the overall condition of their home. Trained data collectors rated residential block quality. Seven days of wrist actigraphy were used to measure average sleep duration, efficiency, and wakefulness after sleep onset (WASO), and a sleep diary assessed sleep quality. Multivariate regression analyses were conducted for each sleep outcome with housing or block conditions as predictors in separate models. Participants reporting "fair" or "poor" housing conditions had an adjusted average sleep duration that was 15.4 min shorter than that of participants reporting "good" or "excellent" conditions. Those reporting any home distress had 15.9 min shorter sleep and .19 units lower mean sleep quality as compared with participants who did not report home distress. Poor objectively measured block quality was associated with 14.0 min shorter sleep duration, 1.95% lower sleep efficiency, and 10.7 additional minutes of WASO. Adverse housing and proximal neighborhood conditions are independently associated with poor sleep health. Findings highlight the importance of considering strategies that target upstream determinants of sleep health disparities.


Pseudomonas aeruginosa PAO1 resistance to Zinc pyrithione: phenotypic changes suggest the involvement of efflux pumps.
The aim of this study is to investigate the involvement of an efflux pump in the development of Pseudomonas aeruginosa resistance to zinc pyrithione (ZnPT). In the presence of efflux inhibitor carbonyl cyanide m-chlorophenyl-hydrazone (CCCP), the minimum inhibitory concentration of ZnPT for P. aeruginosa resistant cells is reduced significantly (p < 0.05). In addition, the concentration of ZnPT excluded by the resistant bacteria was reduced significantly (p < 0.01). However, the above reductions did not reach the levels measured for P. aeruginosa PAO1 sensitive strain. Furthermore, such changes in P. aeruginosa resistant cells were correlated with the overexpression of outer membrane proteins, reduced sensitivity toward imipenem (p < 0.01) and increased sensitivity toward sulphatriad and chloramphenicol (p < 0.05). In a continuation to a previous study, we conclude that P. aeruginosa resistance to ZnPT is multifactorial and involves induced efflux systems.


Accuracy of Canadian food labels for sodium content of food.
The accuracy of the Nutrition Facts table (NFt) has a significant impact on Canadian efforts to reduce dietary sodium and monitor sodium content in foods. This study assessed the accuracy of sodium (and calories, trans fat, saturated fat, sugar) reported on the NFt for selected foods and beverages in Canada. The Canadian Food Inspection Agency (CFIA) sampled over 1000 foods and beverages from supermarkets, bakeries, and restaurants across Canada between January 2006 and December 2010. The samples were analyzed in CFIA laboratories. Results were requested for products with ≥1 of the following nutrients tested: sodium, calories, saturated fat, trans fat, and sugar. Differences between the label and laboratory values were calculated for each product. Overall, 16.7% (n = 169) of products were "unsatisfactory" with laboratory values exceeding ±20% of the NFt value. Sodium had the highest number of unsatisfactory products (n = 49, 18.4%) and trans fat had the lowest number of unsatisfactory products (n = 16, 4.3%). The proportion of unsatisfactory products for saturated fat, calories, and sugar was 15.8%, 14.2%, and 12.9%, respectively. All of the unsatisfactory products had excess nutrient content relative to the NFt. Sodium and calories were consistently underreported (p < 0.05), while NFt values for the other nutrients were not statistically different than laboratory values. Increased monitoring of NFt sodium values is recommended in order to increase consumer confidence in this nutrition tool, to encourage industry to accurately report nutrient content and to continue using the NFt to guide research, education, and policy development.


Phyllotaxis involves auxin drainage through leaf primordia.
The spatial arrangement of leaves and flowers around the stem, known as phyllotaxis, is controlled by an auxin-dependent reiterative mechanism that leads to regular spacing of the organs and thereby to remarkably precise phyllotactic patterns. The mechanism is based on the active cellular transport of the phytohormone auxin by cellular influx and efflux carriers, such as AUX1 and PIN1. Their important role in phyllotaxis is evident from mutant phenotypes, but their exact roles in space and time are difficult to address due to the strong pleiotropic phenotypes of most mutants in phyllotaxis. Models of phyllotaxis invoke the accumulation of auxin at leaf initials and removal of auxin through their developing vascular strand, the midvein. We have developed a precise microsurgical tool to ablate the midvein at high spatial and temporal resolution in order to test its function in leaf formation and phyllotaxis. Using amplified femtosecond laser pulses, we ablated the internal tissues in young leaf primordia of tomato (Solanum lycopersicum) without damaging the overlying L1 and L2 layers. Our results show that ablation of the future midvein leads to a transient accumulation of auxin in the primordia and to an increase in their width. Phyllotaxis was transiently affected after midvein ablations, but readjusted after two plastochrons. These results indicate that the developing midvein is involved in the basipetal transport of auxin through young primordia, which contributes to phyllotactic spacing and stability.


Identification of distinct depressive symptom trajectories in women following surgery for breast cancer.
Depressive symptoms, common in breast cancer patients, may increase, decrease, or remain stable over the course of treatment. Most longitudinal studies have reported mean symptom scores that tend to obscure interindividual heterogeneity in the symptom experience. The identification of different trajectories of depressive symptoms may help identify patients who require an intervention. This study aimed to identify distinct subgroups of breast cancer patients with different trajectories of depressive symptoms in the first six months after surgery. Among 398 patients with breast cancer, growth mixture modeling was used to identify latent classes of patients with distinct depressive symptom profiles. These profiles were identified based on Center for Epidemiological Studies-Depression (CES-D) scale scores completed just prior to surgery, and 1, 2, 3, 4, 5, and 6 months after surgery. Four latent classes of breast cancer patients with distinct depressive symptom trajectories were identified: Low Decelerating (38.9%), Intermediate (45.2%), Late Accelerating (11.3%), and Parabolic (4.5%) classes. Patients in the Intermediate class were younger, on average, than those in the Low Decelerating class. The Intermediate, Late Accelerating, and Parabolic classes had higher mean baseline anxiety scores compared to the Low Decelerating class. Breast cancer patients experience different trajectories of depressive symptoms after surgery. Of note, over 60% of these women were classified into one of three distinct subgroups with clinically significant levels of depressive symptoms. Identification of phenotypic and genotypic predictors of these depressive symptom trajectories after cancer treatment warrants additional investigation.


Deciphering human ribonucleoprotein regulatory networks.
RNA-binding proteins (RBPs) control and coordinate each stage in the life cycle of RNAs. Although in vivo binding sites of RBPs can now be determined genome-wide, most studies typically focused on individual RBPs. Here, we examined a large compendium of 114 high-quality transcriptome-wide in vivo RBP-RNA cross-linking interaction datasets generated by the same protocol in the same cell line and representing 64 distinct RBPs. Comparative analysis of categories of target RNA binding preference, sequence preference, and transcript region specificity was performed, and identified potential posttranscriptional regulatory modules, i.e. specific combinations of RBPs that bind to specific sets of RNAs and targeted regions. These regulatory modules represented functionally related proteins and exhibited distinct differences in RNA metabolism, expression variance, as well as subcellular localization. This integrative investigation of experimental RBP-RNA interaction evidence and RBP regulatory function in a human cell line will be a valuable resource for understanding the complexity of post-transcriptional regulation.


Fibrosis-related biomarkers and large and small vessel disease: the Cardiovascular Health Study.
Fibrosis has been implicated in a number of pathological, organ-based conditions of the liver, kidney, heart, and lungs. The objective of this study was to determine whether biomarkers of fibrosis are associated with vascular disease in the large and/or small vessels. We evaluated the associations of two circulating biomarkers of fibrosis, transforming growth factor-β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP), with incident peripheral artery disease (PAD) and subclinical macrovascular (carotid intima-media thickness, flow-mediated vasodilation, ankle-brachial index, retinal vein diameter), and microvascular (retinal artery diameter and retinopathy) disease among older adults in the Cardiovascular Health Study. We measured TGF-β and PIIINP from samples collected in 1996 and ascertained clinical PAD through 2011. Measurements of large and small vessels were collected between 1996 and 1998. After adjustment for sociodemographic, clinical, and biochemical risk factors, TGF-β was associated with incident PAD (hazard ratio [HR] = 1.36 per doubling of TGF-β, 95% confidence interval [CI] = 1.04, 1.78) and retinal venular diameter (1.63 μm per doubling of TGF-β, CI = 0.23, 3.02). PIIINP was not associated with incident PAD, but was associated with carotid intima-media thickness (0.102 mm per doubling of PIIINP, CI = 0.029, 0.174) and impaired brachial artery reactivity (-0.20% change per doubling of PIIINP, CI = -0.39, -0.02). Neither TGF-β nor PIIINP were associated with retinal arteriolar diameter or retinopathy. Serum concentrations of fibrosis-related biomarkers were associated with several measures of large vessel disease, including incident PAD, but not with small vessel disease. Fibrosis may contribute to large vessel atherosclerosis in older adults.


Coronary artery bypass grafting for left main disease and the risk of stroke: Incidence, aetiology and prevention.
This review explores the association between left main disease and the increased risk of perioperative stroke following coronary artery bypass grafting, specifically addressing the potential underlying mechanisms and its potential prevention. In particular, this correlation appears stronger for patients with left main disease when compared to patients with isolated triple vessel disease. Even though evidence on this topic is limited and of modest quality, there appears to be a significant association between ascending aorta atherosclerosis and coronary artery disease. Furthermore, there seems to be a relationship between the severity and extent of carotid artery stenosis and coronary artery disease. Carotid artery disease is itself associated with atherosclerosis of the ascending aorta, a well-recognised risk factor for postoperative atheroembolic stroke. The association between left main disease, ascending aorta atherosclerosis and carotid artery stenosis may reflect an increased systemic atherosclerotic burden and hence explain, at least partially, the higher risk of perioperative cerebrovascular events. Potential pre-, intra- and post-operative strategies for stroke prevention are discussed.


Arrival by ambulance explains variation in mortality by time of admission: retrospective study of admissions to hospital following emergency department attendance in England.
Studies finding higher mortality rates for patients admitted to hospital at weekends rely on routine administrative data to adjust for risk of death, but these data may not adequately capture severity of illness. We examined how rates of patient arrival at accident and emergency (A&E) departments by ambulance-a marker of illness severity-were associated with in-hospital mortality by day and time of attendance. Retrospective observational study of 3 027 946 admissions to 140 non-specialist hospital trusts in England between April 2013 and February 2014. Patient admissions were linked with A&E records containing mode of arrival and date and time of attendance. We classified arrival times by day of the week and daytime (07:00 to 18:59) versus night (19:00 to 06:59 the following day). We examined the association with in-hospital mortality within 30 days using multivariate logistic regression. Over the week, 20.9% of daytime arrivals were in the highest risk quintile compared with 18.5% for night arrivals. Daytime arrivals on Sundays contained the highest proportion of patients in the highest risk quintile at 21.6%. Proportions of admitted patients brought in by ambulance were substantially higher at night and higher on Saturday (61.1%) and Sunday (60.1%) daytimes compared with other daytimes in the week (57.0%). Without adjusting for arrival by ambulance, risk-adjusted mortality for patients arriving at night was higher than for daytime attendances on Wednesday (0.16 percentage points). Compared with Wednesday daytime, risk-adjusted mortality was also higher on Thursday night (0.15 percentage points) and increased throughout the weekend from Saturday daytime (0.16 percentage points) to Sunday night (0.26 percentage points). After adjusting for arrival by ambulance, the raised mortality only reached statistical significance for patients arriving at A&E on Sunday daytime (0.17 percentage points). Using conventional risk-adjustment methods, there appears to be a higher risk of mortality following emergency admission to hospital at nights and at weekends. After accounting for mode of arrival at hospital, this pattern changes substantially, with no increased risk of mortality following admission at night or for any period of the weekend apart from Sunday daytime. This suggests that risk-adjustment based on inpatient administrative data does not adequately account for illness severity and that elevated mortality at weekends and at night reflects a higher proportion of more severely ill patients arriving by ambulance at these times.


Invariant pattern recognition by use of a spatial code division multiplexing approach.
Invariant pattern recognition can be achieved by use of harmonic decomposition, for example circular harmonics are used for rotation invariant recognition. A common problem with such methods is that often only a single term of the harmonic decomposition is used, and it does not contain a sufficient amount of the reference energy. Thus discrimination capability is limited, especially in the presence of noise or other disturbances. By using several terms of the harmonic decomposition together this problem can be solved; this can be achieved by the use of code division filter multiplexing. Several harmonic terms are encoded onto a single filter, and the signal is simultaneously correlated with all of them, hence producing enhanced discrimination capabilities. Here two methods are suggested for such encoding. The first involves multiplexing the filters in the Fourier plane, while the second involves multiplexing in the image plane.


Efficacy of cisplatin, 5-fluorouracil, and paclitaxel regimen for carcinoma of the esophagus.
Eighteen patients with esophageal carcinoma (16 adenocarcinoma, two squamous cell carcinoma) were treated with two cycles of induction chemotherapy consisting of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) 175 mg/m2 (3-hour infusion), cisplatin 20 mg/m2/d x 4 days, and 5-fluorouracil 1 g/m2/d (continuous infusion x 4 days) separated by a 28-day interval before surgical resection. After resection, patients received two more cycles of the same regimen. A thorough staging evaluation was performed before patients were enrolled in the study. The salient chemotherapy toxicities included grade 3 nausea (two patients), grade 3 vomiting (two patients), grades 3 and 4 diarrhea (one patient each), and grades 3 and 4 neutropenia (two and 10 patients, respectively). No deaths occurred due to toxicity. Surgical resection was attempted in all 18 patients (100%) after two cycles of induction chemotherapy. Esophageal resection was successfully completed in 17 patients. Liver metastases were noted at laparotomy in the one patient who subsequently did not undergo esophageal resection. Surgical complications were minor, and no postoperative deaths occurred. Fifteen patients received two additional cycles of the paclitaxel/5-fluorouracil/cisplatin regimen postoperatively, two received only one cycle, and one refused further therapy. Of 15 patients alive, 14 show no evidence of disease. The 1-year actuarial survival rate of this group of patients is 82%. In conclusion, the paclitaxel/5-fluorouracil/cisplatin combination is well tolerated and is an active regimen in esophageal carcinoma.


Lactobacillus rhamnosus lowers zebrafish lipid content by changing gut microbiota and host transcription of genes involved in lipid metabolism.
The microbiome plays an important role in lipid metabolism but how the introduction of probiotic communities affects host lipid metabolism is poorly understood. Using a multidisciplinary approach we addressed this knowledge gap using the zebrafish model by coupling high-throughput sequencing with biochemical, molecular and morphological analysis to evaluate the changes in the intestine. Analysis of bacterial 16S libraries revealed that Lactobacillus rhamnosus was able to modulate the gut microbiome of zebrafish larvae, elevating the abundance of Firmicutes sequences and reducing the abundance of Actinobacteria. The gut microbiome changes modulated host lipid processing by inducing transcriptional down-regulation of genes involved in cholesterol and triglycerides metabolism (fit2, agpat4, dgat2, mgll, hnf4α, scap, and cck) concomitantly decreasing total body cholesterol and triglyceride content and increasing fatty acid levels. L. rhamnosus treatment also increased microvilli and enterocyte lengths and decreased lipid droplet size in the intestinal epithelium. These changes resulted in elevated zebrafish larval growth. This integrated system investigation demonstrates probiotic modulation of the gut microbiome, highlights a novel gene network involved in lipid metabolism, provides an insight into how the microbiome regulates molecules involved in lipid metabolism, and reveals a new potential role for L. rhamnosus in the treatment of lipid disorders.


Green's-function method for the analysis of propagation in holey fibers.
A Green's-function method is employed to provide a rigorous analysis to the propagation and coupling phenomena in holey fibers. The analysis is carried out for an arbitrary grid of circular air holes of the fiber guide, while the electromagnetic field is taken to be a vector quantity. Application of the Green's-function concept leads to a coupled system of equations incorporating as unknowns the field expansion coefficients to cylindrical wave functions within the air holes. The propagation constants of the guided waves are computed accurately by determining the singular points of the corresponding system's matrix. Field distribution and dispersion properties of guided modes as well as coupling phenomena between parallel-running holey fibers are investigated, and numerical results are presented.


Evolution of statewide EMS drug formularies and regulations.
To characterize and follow the variability present in statewide emergency medical services (EMS) medication formularies across the United States over a ten-year period. Investigators contacted the lead EMS agencies in all 50 states during three years (1992, 1997, and 2002). Using a standardized form, the investigators collected information about each state's prehospital medication policies, including whether a statewide EMS medication formulary existed, the authority of local medical directors to modify it, and what medications it contained. The investigators then sorted states into categories based on the regulatory intent of their EMS medication policies and compared medication listings across years. Responses were obtained from all 50 states (n = 50, 100%) during each of the survey periods. There appeared to be a trend toward stricter state control and toward less variation between statewide formularies. State regulations in seven states stopped allowing local medical directors to retain full control of their systems' formularies, and eight states implemented mandatory statewide formularies. There was a trend toward more consistency between states, with more "most commonly" listed medications (6.9% in 1992 versus 22.1% in 2002) and fewer "least commonly" listed medications (58.3% in 1992 versus 42.3% in 2002). Controversial medications such as neuromuscular blockers and thrombolytics appeared in a small but increasing number of statewide formularies. Considerable variation was found among statewide EMS medication formularies, both in how they were established and in their contents. Although several states continued to rely solely on local medical direction, there seemed to be a trend toward more uniformity and stricter state control over prehospital medication formularies during the study period.


Shared decision making in chronic medication use: Scenarios depicting exemplary care.
Patient-centred care includes patients and their values in the healthcare decision-making process. Shared decision-making is essential for patient satisfaction, medication adherence, and positive clinical outcomes. It also empowers patients to play an active role in managing their health condition by improving their sense of agency, allowing them to personalise their care. Long-term prescriptions are an unexplored area where shared decision-making could be impactful. This paper provides 5 common clinical prescription scenarios pertaining to route of administration, medication timing, side effects, and length of prescription. Minor tailoring of treatment plans could significantly improve clinical outcomes. These serve as exemplars as to how to personalise prescriptions through shared decision making in accordance with patient values.


The carboxy-terminal region of human lipoprotein lipase is necessary for its exit from the endoplasmic reticulum.
Certain missense substitutions on the human lipase (hLPL) gene produce mutated proteins that are retained in different compartments along the secretory pathway. The purpose of the present study was to elucidate whether the C-terminal domain of the hLPL molecule could be important for secretion. We constructed by site-directed mutagenesis three carboxy-terminal mutated (F388-->Stop, K428-->Stop and K441-->Stop) hLPL cDNAs that were expressed in COS1 cells. Immunoblotting of cell extracts showed that all three constructs led to similar levels of protein. Both wild type (WT) hLPL and the truncated K441-->Stop hLPL were secreted to the extracellular medium, and presented a similar intracellular distribution pattern as shown by immunofluorescence. Neither F388-->Stop nor K428-->Stop hLPL protein was detected in cell medium. Immunofluorescence experiments showed that both truncated hLPL were retained within an intracellular compartment, which became larger. Double immunofluorescence analysis using antibodies against LPL and antiprotein disulfide isomerase as a marker showed that the truncated K428-->Stop hLPL was retained within the rough endoplasmic reticulum. This truncated protein was not found in other compartments in the secretory pathway, such as Golgi complex and lysosomes, indicating that it did not exit the endoplasmic reticulum. Further analysis of the C-terminal region of the LPL molecular model showed both that F388-->Stop and K428-->Stop hLPL truncated proteins are highly hydrophobic. As retention of secretory proteins in the rough endoplasmic reticulum is a quality control mechanism of the secretory pathway, we conclude that the C-terminal domain of hLPL is critical for correct intracellular processing of the newly synthesized protein.


Multi-well imaging of development and behavior in Caenorhabditis elegans.
The nematode Caenorhabditis elegans is widely used as a model for understanding the neuronal and genetic bases of behavior. Recent studies have required longitudinal assessment of individual animal's behavior over extended periods. Here we present a technique for automated monitoring of multiple worms for several days. Our method uses an array of plano-concave glass wells containing standard agar media. The concave well geometry allows worms to be imaged even at the edge of the agar surface and prevents them from burrowing under the agar. We transfer one worm or embryo into each well, and perform imaging of the array of wells using a single camera. Machine vision software is used to quantify size, activity, and/or fluorescence of each worm over time. We demonstrate the utility of our method in two applications: (1) quantifying behavioral quiescence and developmental rate in wild-type and mutant animals, and (2) characterizing differences in mating behavior between two C. elegans strains. Current techniques for tracking behavior in identified worms are generally restricted to imaging either single animals or have not been shown to work with arbitrary developmental stages; many are also technically complex. Our system works with up to 24 animals of any stages and is technically simple. Our multi-well imaging method is a powerful tool for quantification of long-term behavioral phenotypes in C. elegans.


Characterization and sequence of a cDNA clone of gamma-glutamyltranspeptidase.
We have isolated several cDNA's complementary to gamma-glutamyltranspeptidase (GGT) mRNA by screening a rat kidney library constructed in lambda gtll with antibodies specifically reactive to the enzyme protein. The clone selected an mRNA that was translated into a 62 Kd peptide, corresponding to the GGT precursor. The longest clone isolated was 1842 bp long with an open reading frame coding for 565 amino acids. The length of the mRNA coding for GGT was estimated to be 2.2 kb long. The amino acid sequence derived from the nucleotide sequence matched the short sequences determined by us as well as by other authors.


Strengthening district-based health reporting through the district health management information software system: the Ugandan experience.
Untimely, incomplete and inaccurate data are common challenges in planning, monitoring and evaluation of health sector performance, and health service delivery in many sub-Saharan African settings. We document Uganda's experience in strengthening routine health data reporting through the roll-out of the District Health Management Information Software System version 2 (DHIS2). DHIS2 was adopted at the national level in January 2011. The system was initially piloted in 4 districts, before it was rolled out to all the 112 districts by July 2012. As part of the roll-out process, 35 training workshops targeting 972 users were conducted throughout the country. Those trained included Records Assistants (168, 17.3%), District Health Officers (112, 11.5%), Health Management Information System Focal Persons (HMIS-FPs) (112, 11.5%), District Biostatisticians (107, 11%) and other health workers (473, 48.7%). To assess improvements in health reporting, we compared data on completeness and timeliness of outpatient and inpatient reporting for the period before (2011/12) and after (2012/13) the introduction of DHIS2. We reviewed data on the reporting of selected health service coverage indicators as a proxy for improved health reporting, and documented implementation challenges and lessons learned during the DHIS2 roll-out process. Completeness of outpatient reporting increased from 36.3% in 2011/12 to 85.3% in 2012/13 while timeliness of outpatient reporting increased from 22.4% to 77.6%. Similarly, completeness of inpatient reporting increased from 20.6% to 57.9% while timeliness of inpatient reporting increased from 22.5% to 75.6%. There was increased reporting on selected health coverage indicators (e.g. the reporting of one-year old children who were immunized with three doses of pentavelent vaccine increased from 57% in 2011/12 to 87% in 2012/13). Implementation challenges included limited access to computers and internet (34%), inadequate technical support (23%) and limited worker force (18%). Implementation of DHIS2 resulted in improved timeliness and completeness in reporting of routine outpatient, inpatient and health service usage data from the district to the national level. Continued onsite support supervision and mentorship and additional system/infrastructure enhancements, including internet connectivity, are needed to further enhance the performance of DHIS2.


Oncology patients' and professional nurses' perceptions of important nurse caring behaviors.
Caring is the essence of nursing. Caring to be meaningful needs to be based on mutual agreement between nurses and patients as to what constitutes nurse caring behaviors. As a result, healthcare professional can enhance patients' satisfaction of care by providing appropriate caring behavior. However, previous research that combined multiple types of patients, nurses and institutions demonstrated disagreement in prioritizing important behaviors. This paper reports a study that aimed at determining the caring behaviors which oncology patients and oncology nurses perceive to be the most important. This study is a comparative descriptive design that was conducted in an Iranian oncology centre. Convenience sampling was used to recruit 200 patients and 40 nurses to take part in the study. Data were collected over a period of 4 months in 2009 using the Caring Assessment Questionnaire, developed by Larson. Caring behaviors (n = 57) were ranked on a 5-point Likert-type scale and ordered in six subscales: "Being accessible", "Explains and facilitates", "Comforts", "Anticipates", "Trusting relationship", "Monitors and follows through". The data were analyzed using SPSS software version 13.0. The overall mean was calculated for each subscale to determine the rank distribution of the subscales. The nonparametric Mann-Whitney U test analysis of variables was used to compare patients' and nurses' scores on subscales. The results demonstrate that both groups considered the same order of importance of caring, the high ranking of "Monitors and Follows through and "Being Accessible" and the low ranking of "Comforts" and "Trusting Relationships". Also, Patients only ranked "Being accessible" (p = 0.04) and "Explains and facilitates" (p = 0.03) higher than nurses. The oncology patients and nurses perceived highly physical aspects of caring and the results provide for nurses to be aware of the need, during their interactions with patients, to validate the effect their intended caring has upon patients. By so doing and with further refinement of the concept of caring for nursing in studies such as this, the practical aim of making patients feel cared for can be achieved.


Thrombotic thrombocytopenic purpura associated with ticlopidine in the setting of coronary artery stents and stroke prevention.
One of the most unusual causes of thrombotic thrombocytopenic purpura (TTP), a life-threatening disease, is ticlopidine hydrochloride, an antiplatelet agent used to prevent strokes in high-risk populations or following coronary artery stent placement. Recently, Hoffman-LaRoche Pharmaceuticals, following reports of 20 deaths from ticlopidine-associated TTP, updated the information about the hematologic adverse effects of the drug. To review our recent findings on ticlopidine-associated hematologic toxic effects, which served as the impetus for the revised warnings, and to discuss the implications of these findings. Data were obtained from the Food and Drug Administration's MedWatch program, published phase 3 clinical trials and case reports, hematologists, and plasmapheresis centers. No cases of TTP have been reported in phase 3 ticlopidine trials. In contrast, postmarketing surveillance has identified serious adverse drug reactions to ticlopidine, resulting in 259 deaths, with TTP accounting for 40 of these deaths. Detailed information was available on 98 cases of ticlopidine-associated TTP. Compared with 42 patients in the coronary artery stent setting, 56 patients with ticlopidine-associated TTP in the stroke prevention setting were more likely to be women (62.5% vs 28.6%; P = .01). Before the onset of TTP in patients receiving stroke prevention therapy and patients with stent placement, ticlopidine had been used for less than 2 weeks in 5.4% and 2.4%, between 2 and 3 weeks in 17.9% and 21.4%, between 3 and 4 weeks in 30.4% and 38.1%, and between 4 and 12 weeks in 46.4% and 38.1%, respectively. Death occurred in almost 60% of all patients not receiving plasmapheresis compared with 21.9% of patients receiving plasmapheresis for stroke prevention and 14.3% of patients receiving plasmapheresis in the stent setting. Use of ticlopidine requires frequent physician visits and laboratory tests for at least 3 months in the stroke prevention setting, while, with short-term use in the coronary artery stent setting, adverse events are less likely to occur. These factors, as well as competition from clopidogrel bisulfate, a new antiplatelet agent, potentially limit the feasibility of ticlopidine as a stroke prevention agent, while having less impact on its use following coronary artery stent placement.


The effect of co-location on human communication networks.
The ability to rewire ties in communication networks is vital for large-scale human cooperation and the spread of new ideas. We show that lack of researcher co-location during the COVID-19 lockdown caused the loss of more than 4,800 weak ties-ties between distant parts of the social system that enable the flow of novel information-over 18 months in the email network of a large North American university. Furthermore, we find that the reintroduction of partial co-location through a hybrid work mode led to a partial regeneration of weak ties. We quantify the effect of co-location in forming ties through a model based on physical proximity, which is able to reproduce all empirical observations. Results indicate that employees who are not co-located are less likely to form ties, weakening the spread of information in the workplace. Such findings could contribute to a better understanding of the spatiotemporal dynamics of human communication networks and help organizations that are moving towards the implementation of hybrid work policies to evaluate the minimum amount of in-person interaction necessary for a productive work environment.


Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells.
Mutations in the adenomatous polyposis coli (APC) tumour-suppressor gene occur in most human colon cancers. Loss of functional APC protein results in the accumulation of beta-catenin. Mutant forms of beta-catenin have been discovered in colon cancers that retain wild-type APC genes, and also in melanomas, medulloblastomas, prostate cancer and gastric and hepatocellular carcinomas. The accumulation of beta-catenin activates genes that are responsive to transcription factors of the TCF/LEF family, with which beta-catenin interacts. Here we show that beta-catenin activates transcription from the cyclin D1 promoter, and that sequences within the promoter that are related to consensus TCF/LEF-binding sites are necessary for activation. The oncoprotein p21ras further activates transcription of the cyclin D1 gene, through sites within the promoter that bind the transcriptional regulators Ets or CREB. Cells expressing mutant beta-catenin produce high levels of cyclin D1 messenger RNA and protein constitutively. Furthermore, expression of a dominant-negative form of TCF in colon-cancer cells strongly inhibits expression of cyclin D1 without affecting expression of cyclin D2, cyclin E, or cyclin-dependent kinases 2, 4 or 6. This dominant-negative TCF causes cells to arrest in the G1 phase of the cell cycle; this phenotype can be rescued by expression of cyclin D1 under the cytomegalovirus promoter. Abnormal levels of beta-catenin may therefore contribute to neoplastic transformation by causing accumulation of cyclin D1.


Fate and Transport of Molybdenum Disulfide Nanomaterials in Sand Columns.
Research and development of two-dimensional transition metal dichalcogenides (TMDC) (e.g., molybdenum disulfide [MoS2]) in electronic, optical, and catalytic applications has been growing rapidly. However, there is little known regarding the behavior of these particles once released into aquatic environments. Therefore, an in-depth study regarding the fate and transport of two popular types of MoS2 nanomaterials, lithiated (MoS2-Li) and Pluronic PF-87 dispersed (MoS2-PL), was conducted in saturated porous media (quartz sand) to identify which form would be least mobile in aquatic environments. The electrokinetic properties and hydrodynamic diameters of MoS2 as a function of ionic strength and pH were determined using a zeta potential analyzer and dynamic light scattering techniques. Results suggest that the stability is significantly decreased beginning at 10 and 31.6 mM KCl, for MoS2-PL and MoS2-Li, respectively. Transport study results from breakthrough curves, column dissections, and release experiments suggest that MoS2-PL exhibits a greater affinity to be irreversibly bound to quartz surfaces as compared with the MoS2-Li at a similar ionic strength. Derjaguin-Landau-Verwey-Overbeek theory was used to help explain the unique interactions between the MoS2-PL and MoS2-Li surfaces between particles and with the quartz collectors. Overall, the results suggest that the fate and transport of MoS2 is dependent on the type of MoS2 that enters the environment, where MoS2-PL will be least mobile and more likely be deposited in porous media from pluronic-quartz interactions, whereas MoS2-Li will travel greater distances and have a greater tendency to be remobilized in sand columns.


Gas and liquid transport in steady-state aqueous foam.
Experiments are performed on the transport of gas and liquid in a column of aqueous foam maintained in steady state by a constant gas flux at the bottom. We measure vertical profiles of the bubble velocities, the bubble radii, and the liquid fraction, for four different gas fluxes. In steady state the bubbles move upwards with constant speed equal to the measured gas flux, which accounts for all transport of gas. The bubbles also coarsen by gas diffusion at a rate that depends on liquid fraction. Away from the bottom, the Plateau border radii are constant. Therefore capillary effects are negligible and the steady-state liquid-fraction profile is set chiefly by the balance of viscous forces and gravity. The flow within the Plateau borders may be modeled with a no-slip boundary condition for our system. These findings provide a simple description of steady-state foams via the coarsening and drainage equations, which can be combined and solved analytically for bubble radius and liquid-fraction profiles.


Considerations for Temporomandibular Joint Procurement in Vascularized Composite Allotransplantation.
Methods for harvest of the temporomandibular joint (TMJ) for transplantation may involve several anatomic levels. The authors aim to assess the feasibility and identify challenges with 2 such methods, resuspending the donor condyles from the recipient glenoid fossae and en bloc harvest of the joint and surrounding temporal bone with plate-fixation to the recipient skull base. Two mock face transplantations were carried out using 4 fresh cadavers. Computed tomography imaging was obtained before and after the procedures to assess the technical success of each method. Both techniques were technically successful, allowing for full passive jaw range of motion following graft transfer and appropriate condyle positioning as assessed by computed tomography. En bloc TMJ harvest allowed for transfer of the entire joint without violating its capsule or altering its biomechanics. The authors found this technique better able to avoid issues with size mismatch between the donor mandible and recipient skull base width. When no such mismatch exists, graft harvest at the level of the mandibular condyle is technically easier and less time consuming. Although both methods of TMJ harvest are technically feasible with acceptable immediate postoperative jaw position and range of motion, the en bloc technique allows for more natural jaw function with less risk of postoperative joint immobility by preserving the joint capsule and its ligamentous support.


Causes of death in men with localized prostate cancer: a nationwide, population-based study.
To detail the distribution of causes of death from localized prostate cancer (PCa). The database PCBase Sweden links the Swedish National Prostate Cancer Register with other nationwide population-based healthcare registers. We selected all 57 187 men diagnosed with localized PCa between 1997 and 2009 and their 114 374 PCa-free control subjects, matched according to age and county of residence. Mortality was calculated using competing risk regression analyses, taking into account PCa risk category, age and Charlson comorbidity index (CCI). In men with low-risk PCa, all-cause mortality was lower compared with that in corresponding PCa-free men: 10-year all-cause mortality was 18% for men diagnosed at age 70 years, with a CCI score of 0, and 21% among corresponding control subjects. Of these cases, 31% died from cardiovascular disease (CVD) compared with 37% of the corresponding control subjects. For men with low-risk PCa, 10-year PCa-mortality was 0.4, 1 and 3% when diagnosed at age 50, 60 and 70 years, respectively. PCa was the third most common cause of death (18%), after CVD (31%) and other cancers (30%). By contrast, PCa was the most common cause of death in men with intermediate- and high-risk localized PCa. Men with low-risk PCa had lower all-cause mortality than PCa-free men because of lower CVD mortality, driven by early detection selection; however, for men with intermediate- or high-risk disease, the rate of PCa death was substantial, irrespective of CCI score, and this was even more pronounced for those diagnosed at age 50 or 60 years.


The regulation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumor promotion by estradiol in female A/J mice.
Epidemiological studies indicate that women are at a higher risk developing lung cancer than men are. It is suggested that estrogen is one of the most important factors in lung cancer development in females. Additionally, cigarette smoke, and environmental pollutants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), may play salient roles in female lung carcinogenesis. However, the mechanisms responsible for the interaction of these factors in the promotion of lung cancer are still poorly understood. The present study was designed to explore two ideas: first, the synergistic lung tumorigenic effects of 4-(methylnitrosamino)-1-(3-pyridyl)-butanol (NNK) combined with TCDD, 17β-estradiol (E2) or both through a long-term treatment experiment, and second, to identify early changes in the inflammatory and signaling pathways through short-term treatment experiments. The results indicate that A/J mice given E2 had strong effects in potentiating NNK-induced activation of MAPK signaling, NFκB, and COX-2 expression. In the long-term exposure model, E2 had a strong tumor promoting effect, whereas TCDD antagonized this effect in A/J mice. We conclude that treatment with NNK combined with either E2 or TCDD induces lung carcinogenesis and the promotion effects could be correlated with lung inflammation. E2 was shown to potentiate NNK-induced inflammation, cell proliferation, thereby leading to lung tumorigenesis.


Calibration of the 1064 nm lidar channel using water phase and cirrus clouds.
Calibration is essential to derive aerosol backscatter coefficients from elastic scattering lidar. Unlike the visible UV wavelengths where calibration is based on a molecular reference, calibration of the 1064 nm lidar channel requires other approaches, which depend on various assumptions. In this paper, we analyze two independent calibration methods which use (i) low-altitude water phase clouds and (ii) high cirrus clouds. In particular, we show that to achieve optimal performance, aerosol attenuation below the cloud base and cloud multiple scattering must be accounted for. When all important processes are considered, we find that these two independent methods can provide a consistent calibration constant with relative differences less than 15%. We apply these calibration techniques to demonstrate the stability of our lidar on a monthly scale, along with a natural reduction of the lidar efficiency on an annual scale. Furthermore, our calibration procedure allows us to derive consistent aerosol backscatter coefficients and angstrom coefficient profiles (532-1064 nm) along with column extinction-to-backscatter ratios which are in good agreement with sky radiometer inversions.


FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders.
Autism spectrum disorder (ASD) is a disorder of brain development. Most cases lack a clear etiology or genetic basis, and the difficulty of re-enacting human brain development has precluded understanding of ASD pathophysiology. Here we use three-dimensional neural cultures (organoids) derived from induced pluripotent stem cells (iPSCs) to investigate neurodevelopmental alterations in individuals with severe idiopathic ASD. While no known underlying genomic mutation could be identified, transcriptome and gene network analyses revealed upregulation of genes involved in cell proliferation, neuronal differentiation, and synaptic assembly. ASD-derived organoids exhibit an accelerated cell cycle and overproduction of GABAergic inhibitory neurons. Using RNA interference, we show that overexpression of the transcription factor FOXG1 is responsible for the overproduction of GABAergic neurons. Altered expression of gene network modules and FOXG1 are positively correlated with symptom severity. Our data suggest that a shift toward GABAergic neuron fate caused by FOXG1 is a developmental precursor of ASD.


Foxp3 expressing CD4+CD25(high) regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells.
Dominant tolerance is mediated by regulatory T cells (T(reg)) that control harmful autoimmune T cells in the periphery. In this study, we investigate the implication of T(reg) in modulating infiltrating T lymphocytes in human metastatic melanoma. We found that CD4(+)CD25(high) T cells are overrepresented in metastatic lymph nodes (LNs) with a 2-fold increased frequency compared with both tumor-free LNs and autologous PBMCs. These cells express the Foxp3 transcription factor, display an activated phenotype, and display a polyclonal TCR Vbeta chain repertoire. They inhibit in vitro the proliferation and cytokine production of infiltrating CD4(+)CD25(-) and CD8(+) T cells (IL-2, IFN-gamma) through a cell-contact-dependent mechanism, thus behaving as T(reg). In some cases, the presence of T(reg) type 1/Th3-like lymphocytes could also be demonstrated. Thus, T(reg) are a major component of the immunosuppressive microenvironment of metastatic melanoma LNs. This could explain the poor clinical response of cancer patients under immunotherapeutic protocols, and provides a new basis for future immunotherapeutic strategies counteracting in vivo T(reg) to reinforce local antitumor immune responses.


[Archives of "comprehensive approach on asbestos-related diseases" supported by the "special coordination funds for promoting science and technology (H18-1-3-3-1)"-- overview of group research project, care and specimen registration, cellular characteristics of mesothelioma and immunological effects of asbestos].
The research project entitled "Comprehensive approach on asbestos-related diseases" supported by the "Special Coordination Funds for Promoting Science and Technology (H18-1-3-3-1)" began in 2006 and was completed at the end of the Japanese fiscal year of 2010. This project included four parts; (1) malignant mesothelioma (MM) cases and specimen registration, (2) development of procedures for the early diagnosis of MM, (3) commencement of clinical investigations including multimodal approaches, and (4) basic research comprising three components; (i) cellular and molecular characterization of mesothelioma cells, (ii) immunological effects of asbestos, and (iii) elucidation of asbestos-induced carcinogenesis using animal models. In this special issue of the Japanese Journal of Hygiene, we briefly introduce the achievements of our project. The second and third parts and the third component of the fourth part are described in other manuscripts written by Professors Fukuoka, Hasegawa, and Toyokuni. In this manuscript, we introduce a brief summary of the first part "MM cases and specimen registration", the first component of the fourth part "Cellular and molecular characterization of mesothelioma cells" and the second component of the fourth part "Immunological effects of asbestos". In addition, a previous special issue presented by the Study Group of Fibrous and Particulate Substances (SGFPS) (chaired by Professor Otsuki, Kawasaki Medical School, Japan) for the Japanese Society of Hygiene and published in Environmental Health and Preventive Medicine Volume 13, 2008, included reviews of the aforementioned first component of the fourth part of the project. Taken together, our project led medical investigations regarding asbestos and MM progress and contributed towards the care and examination of patients with asbestos-related diseases during these five years. Further investigations are required to facilitate the development of preventive measures and the cure of asbestos-related diseases, particularly in Japan, where asbestos-related diseases are predicted to increase in the next 10 to 20 years.


Mental health in UK Biobank: development, implementation and results from an online questionnaire completed by 157 366 participants.
UK Biobank is a well-characterised cohort of over 500 000 participants that offers unique opportunities to investigate multiple diseases and risk factors. An online mental health questionnaire completed by UK Biobank participants was expected to expand the potential for research into mental disorders. An expert working group designed the questionnaire, using established measures where possible, and consulting with a patient group regarding acceptability. Case definitions were defined using operational criteria for lifetime depression, mania, anxiety disorder, psychotic-like experiences and self-harm, as well as current post-traumatic stress and alcohol use disorders. 157 366 completed online questionnaires were available by August 2017. Comparison of self-reported diagnosed mental disorder with a contemporary study shows a similar prevalence, despite respondents being of higher average socioeconomic status than the general population across a range of indicators. Thirty-five per cent (55 750) of participants had at least one defined syndrome, of which lifetime depression was the most common at 24% (37 434). There was extensive comorbidity among the syndromes. Mental disorders were associated with high neuroticism score, adverse life events and long-term illness; addiction and bipolar affective disorder in particular were associated with measures of deprivation. The questionnaire represents a very large mental health survey in itself, and the results presented here show high face validity, although caution is needed owing to selection bias. Built into UK Biobank, these data intersect with other health data to offer unparalleled potential for crosscutting biomedical research involving mental health. G.B. received grants from the National Institute for Health Research during the study; and support from Illumina Ltd. and the European Commission outside the submitted work. B.C. received grants from the Scottish Executive Chief Scientist Office and from The Dr Mortimer and Theresa Sackler Foundation during the study. C.S. received grants from the Medical Research Council and Wellcome Trust during the study, and is the Chief Scientist for UK Biobank. M.H. received grants from the Innovative Medicines Initiative via the RADAR-CNS programme and personal fees as an expert witness outside the submitted work.


The Contribution of Individual Differences in Memory Span and Language Ability to Spatial Release From Masking in Young Children.
Purpose Working memory capacity and language ability modulate speech reception; however, the respective roles of peripheral and cognitive processing are unclear. The contribution of individual differences in these abilities to utilization of spatial cues when separating speech from informational and energetic masking backgrounds in children has not yet been determined. Therefore, this study explored whether speech reception in children is modulated by environmental factors, such as the type of background noise and spatial configuration of target and noise sources, and individual differences in the cognitive and linguistic abilities of listeners. Method Speech reception thresholds were assessed in 39 children aged 5-7 years in simulated school listening environments. Speech reception thresholds of target sentences spoken by an adult male consisting of number and color combinations were measured using an adaptive procedure, with speech-shaped white noise and single-talker backgrounds that were either collocated (target and back-ground at 0°) or spatially separated (target at 0°, background noise at 90° to the right). Spatial release from masking was assessed alongside memory span and expressive language. Results and Conclusion Significant main effect results showed that speech reception thresholds were highest for informational maskers and collocated conditions. Significant interactions indicated that individual differences in memory span and language ability were related to spatial release from masking advantages. Specifically, individual differences in memory span and language were related to the utilization of spatial cues in separated conditions. Language differences were related to auditory stream segregation abilities in collocated conditions that lack helpful spatial cues, pointing to the utilization of language processes to make up for losses in spatial information.


Polycomb condensates can promote epigenetic marks but are not required for sustained chromatin compaction.
Organization of the genome into transcriptionally active euchromatin and silenced heterochromatin is essential for eukaryotic cell function. Phase-separation has been implicated in heterochromatin formation, but it is unclear how phase-separated condensates can contribute to stable repression, particularly for heritable epigenetic changes. Polycomb complex PRC1 is key for heterochromatin formation, but the multitude of Polycomb proteins has hindered our understanding of their collective contribution to chromatin repression. Here, we show that PRC1 forms multicomponent condensates through hetero-oligomerization. They preferentially seed at H3K27me3 marks, and subsequently write H2AK119Ub marks. We show that inducing Polycomb phase-separation can cause chromatin compaction, but polycomb condensates are dispensable for maintenance of the compacted state. Our data and simulations are consistent with a model in which the time integral of Polycomb phase-separation is progressively recorded in repressive histone marks, which subsequently drive compaction. These findings link the equilibrium thermodynamics of phase-separation with the fundamentally non-equilibrium concept of epigenetic memory.


Pathfinding in a large vertebrate axon tract: isotypic interactions guide retinotectal axons at multiple choice points.
Navigating axons respond to environmental guidance signals, but can also follow axons that have gone before--pioneer axons. Pioneers have been studied extensively in simple systems, but the role of axon-axon interactions remains largely unexplored in large vertebrate axon tracts, where cohorts of identical axons could potentially use isotypic interactions to guide each other through multiple choice points. Furthermore, the relative importance of axon-axon interactions compared with axon-autonomous receptor function has not been assessed. Here, we test the role of axon-axon interactions in retinotectal development, by devising a technique to selectively remove or replace early-born retinal ganglion cells (RGCs). We find that early RGCs are both necessary and sufficient for later axons to exit the eye. Furthermore, introducing misrouted axons by transplantation reveals that guidance from eye to tectum relies heavily on interactions between axons, including both pioneer-follower and community effects. We conclude that axon-axon interactions and ligand-receptor signaling have co-equal roles, cooperating to ensure the fidelity of axon guidance in developing vertebrate tracts.


Cytological and biochemical requirements for the establishment of a polar cell.
Our research is aimed at understanding the biochemical and cytological basis of cell polarity in zygotes of the brown alga, Fucus distichus L. Powell. One manifestation of this polar cell is the localization of a sulphated fucan polysaccharide (F2) in only one region of the zygote cell surface, the rhizoid cell wall. The focus of this paper is centered around the mechanism responsible for the directional transport of Golgi vesicles containing F2 and the biochemical properties of F2 that might specify its localized fate. Recent findings indicate that the various sulphated polysaccharides in the brown algae are complexes resulting from linkages of two basic polymers: an alpha-(1----2)-linked fucan that contains high levels of ester sulphate (F3), and a uronic acid-rich polymer (F1). The fucan complex F2, which is localized in the rhizoid wall, is composed of a fucan sulphate core (F3) to which uronic acid polymers (similar to F1) are attached. Our results, using a purified endoguluronate lyase, indicate that guluronate bridges link these subunits of F2. The carbon backbone of F2 is not synthesized de novo after fertilization. However, F2 is sulphated, and possibly assembled, beginning 10 h after fertilization, after which it is locally inserted into the rhizoid wall, and held in the wall structure only by calcium ionic bonds. Although sulphation is required for localization of F2, it is not known if the uronic acid side-chains are also assembled at the time of sulphation, and/or required for localization. The fact that F3 (F2 without the side-chains) is secreted uniformly into the zygote wall suggests that the uronic acid chains of F2 may play a critical role in its localization. A sulphated F2 alone is not sufficient for its localization since in the presence of cytochalasin, vesicles containing F2 are not transported to the rhizoid. Recent studies point to a central role for a cytoskeletal element, possibly microfilaments, in the directional transport of these vesicles. We have used the techniques of isoelectric focusing and electrophoretic mobility to study surface charge of these Golgi vesicles to determine if charge might be one factor that specifies their localization. Vesicles that contain the sulphated fucan F3 are secreted randomly and have the same surface charge as those containing F2 that are directionally transported. However, there is no stable endogenous electrical current at the time when F3 vesicles are randomly secreted, whereas a current is detectable when F2 vesicles are localized.(ABSTRACT TRUNCATED AT 400 WORDS)


A physical catalyst for the electrolysis of nitrogen to ammonia.
Ammonia synthesis consumes 3 to 5% of the world's natural gas, making it a significant contributor to greenhouse gas emissions. Strategies for synthesizing ammonia that are not dependent on the energy-intensive and methane-based Haber-Bosch process are critically important for reducing global energy consumption and minimizing climate change. Motivated by a need to investigate novel nitrogen fixation mechanisms, we herein describe a highly textured physical catalyst, composed of N-doped carbon nanospikes, that electrochemically reduces dissolved N2 gas to ammonia in an aqueous electrolyte under ambient conditions. The Faradaic efficiency (FE) achieves 11.56 ± 0.85% at -1.19 V versus the reversible hydrogen electrode, and the maximum production rate is 97.18 ± 7.13 μg hour-1 cm-2. The catalyst contains no noble or rare metals but rather has a surface composed of sharp spikes, which concentrates the electric field at the tips, thereby promoting the electroreduction of dissolved N2 molecules near the electrode. The choice of electrolyte is also critically important because the reaction rate is dependent on the counterion type, suggesting a role in enhancing the electric field at the sharp spikes and increasing N2 concentration within the Stern layer. The energy efficiency of the reaction is estimated to be 5.25% at the current FE of 11.56%.


Serum metabonomic analysis of apoE(-/-) mice reveals progression axes for atherosclerosis based on NMR spectroscopy.
Atherosclerosis is a multifactorial and progressive disease commonly correlated with a high fat diet. The aim of this study was to identify potential biomarkers for the early diagnosis and monitoring of the progression of atherogenesis in apoE(-/-) mice using (1)H NMR-based metabonomics. The apoE(-/-) mice were split into four groups according to the duration of high fat feeding (0 w, 2 w, 4 w and 8 w), and each group possessed different pathological characteristics. Serum (1)H NMR-based metabonomics selectively captured the metabotypes that correlated with the degree of atherosclerosis, showing a time-dependent progression from the physiological to pathophysiological status. It was noted that changes in HDL, choline, taurine, glycine and glucose may be regarded as specific biomarkers of the early stage of atherosclerosis. With the progression of atherosclerosis, disorders in the metabolism of amino acids such as valine, alanine and methionine appeared when large atherosclerotic plaques existed. Multiple biochemical disorders involving lipid metabolism, energy and fatty acid metabolism were observed in the progression of atherosclerosis in apoE(-/-) mice. This study demonstrated that (1)H NMR-based metabonomics can provide biochemical information about the progression of atherogenesis and offer a non-invasive means to discover potential biomarkers for the onset and development of atherosclerosis.


Unspecific chronic low back pain - a simple functional classification tested in a case series of patients with spinal deformities.
Up to now, chronic low back pain without radicular symptoms is not classified and attributed in international literature as being "unspecific". For specific bracing of this patient group we use simple physical tests to predict the brace type the patient is most likely to benefit from. Based on these physical tests we have developed a simple functional classification of "unspecific" low back pain in patients with spinal deformities. Between January 2006 and July 2007 we have tested 130 patients (116 females and 14 males) with spinal deformities (average age 45 years, ranging from 14 years to 69) and chronic unspecific low back pain (pain for > 24 months) along with the indication for brace treatment for chronic unspecific low back pain. Some of the patients had symptoms of spinal claudication (n = 16). The "sagittal realignment test" (SRT) was applied, a lumbar hyperextension test, and the "sagittal delordosation test" (SDT). Additionally 3 female patients with spondylolisthesis were tested, including one female with symptoms of spinal claudication and 2 of these patients were 14 years of age and the other 43yrs old at the time of testing. 117 Patients reported significant pain release in the SRT and 13 in the SDT (> or = 2 steps in the Roland & Morris VRS). 3 Patients had no significant pain release in both of the tests (< 2 steps in the Roland & Morris VRS).Pain intensity was high (3,29) before performing the physical tests (VRS-scale 0-5) and low (1,37) while performing the physical test for the whole sample of patients. The differences where highly significant in the Wilcoxon test (z = -3,79; p < 0,0001).In the 16 patients who did not respond to the SRT in the manual investigation we found hypermobility at L5/S1 or a spondylolisthesis at level L5/S1. In the other patients who responded well to the SRT loss of lumbar lordosis was the main issue, a finding which, according to scientific literature, correlates well with low back pain. The 3 patients who did not respond to either test had a fair pain reduction in a generally delordosing brace with an isolated small foam pad inserted at the level of L 2/3, leading to a lordosation at this region. With the exception of 3 patients (2.3%) a clear distribution to one of the two classes has been possible. 117 patients were supplied successfully with a sagittal realignment test-brace (physio-logic brace) and 13 with a sagittal delordosing brace (spondylogic brace). There were patients with scoliosies and hyperkyphosiesbrace). Therefore a clear distribution of the patients from this sample to either chronic postural or chronic instability back pain was possible. In 2.3% a combined chronic low back pain from the findings obtained seems reasonable. Chronic unspecific low back pain is possible to clearly be classified physically. This functional classification is necessary to decide on which specific conservative approach (physical therapy, braces) should be used.Other factors than spinal deformities contribute to chronic low back pain.


Intracellular Delivery of Nanoparticles Mediated by Lactoferricin Cell-Penetrating Peptides in an Endocytic Pathway.
Cell-penetrating peptides (CPPs) containing a preponderance of basic amino acids are able to deliver biologically active macromolecules and nanomaterials into live cells. Quantum dots (QDs) are nanoparticles with unique fluorescence properties that have found wide application in biomedical imaging. In this study, we demonstrate transduction of an L6 CPP (RRWQWR) derived from bovine lactoferricin (LFcin) into human lung cancer cells. L6 noncovalently interacts with QDs to form stable complexes. L6/QD complexes enter cells most efficiently when prepared at a nitrogen/phosphate ratio of 60. Mechanistic studies indicate that L6/QD complexes enter cells by endocytosis. Treatment with 1,2-benzisothiazol-3(2H)-one (BIT), an industrial preservative that enhances uptake of certain CPPs, does not affect L6 CPP-mediated protein transduction efficiency. L6 and L6/QD complexes are not cytotoxic. These results indicate that L6 LFcin might be an efficient and safe nanoshuttle for nanoparticles or nanomedicines in biomedical applications.


Limited engagement with transparent and open science standards in the policies of pain journals: a cross-sectional evaluation.
Scientific progress requires transparency and openness. The ability to critique, replicate and implement scientific findings depends on the transparency of the study design and methods, and the open availability of study materials, data and code. Journals are key stakeholders in supporting transparency and openness. This study aimed to evaluate 10 highest ranked pain journals' authorship policies with respect to their support for transparent and open research practices. Two independent authors evaluated the journal policies (as at 27 May 2019) using three tools: the self-developed Transparency and Openness Evaluation Tool, the Centre for Open Science (COS) Transparency Factor and the International Committee of Medical Journal Editors (ICMJE) requirements for disclosure of conflicts of interest. We found that the journal policies had an overall low level of engagement with research transparency and openness standards. The median COS Transparency Factor score was 3.5 (IQR 2.8) of 29 possible points, and only 7 of 10 journals' stated requirements for disclosure of conflicts of interest aligned fully with the ICMJE recommendations. Improved transparency and openness of pain research has the potential to benefit all that are involved in generating and using research findings. Journal policies that endorse and facilitate transparent and open research practices will ultimately improve the evidence base that informs the care provided for people with pain.