Feasibility of a femoral nerve motor branch for transfer to the pudendal nerve for restoring continence: a cadaveric study.
Nerve transfers are an effective means of restoring control to paralyzed somatic muscle groups and, recently, even denervated detrusor muscle. The authors performed a cadaveric pilot project to examine the feasibility of restoring control to the urethral and anal sphincters using a femoral motor nerve branch to reinnervate the pudendal nerve through a perineal approach. Eleven cadavers were dissected bilaterally to expose the pudendal and femoral nerve branches. Pertinent landmarks and distances that could be used to locate these nerves were assessed and measured, as were nerve cross-sectional areas. A long motor branch of the femoral nerve was followed into the distal vastus medialis muscle for a distance of 17.4 ± 0.8 cm, split off from the main femoral nerve trunk, and transferred medially and superiorly to the pudendal nerve in the Alcock canal, a distance of 13.7 ± 0.71 cm. This was performed via a perineal approach. The cross-sectional area of the pudendal nerve was 5.64 ± 0.49 mm(2), and the femoral nerve motor branch at the suggested transection site was 4.40 ± 0.41 mm(2). The use of a femoral nerve motor branch to the vastus medialis muscle for heterotopic nerve transfer to the pudendal nerve is surgically feasible, based on anatomical location and cross-sectional areas.


Tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis is inhibited by Bcl-2 but restored by the small molecule Bcl-2 inhibitor, HA 14-1, in human colon cancer cells.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent that induces apoptosis in multiple tumor cell types while sparing most normal cells. We determined the effect of ectopic Bcl-2 expression on TRAIL-induced apoptosis and whether the small molecule Bcl-2 inhibitor, HA14-1, could increase TRAIL sensitivity. SW480 human colon cancer cells were stably transfected with the PC3-Bcl-2 plasmid or vector alone. Cells were incubated with recombinant human TRAIL +/- HA14-1 or caspase-9 inhibitor (Z-LEHD-FMK). Apoptosis was analyzed by Annexin V-fluorescein isothiocyanate labeling and DNA fragmentation factor 45 (DFF45) cleavage. Clonigenic survival was also studied. Caspase activation was determined by immunoblotting or colorimetric assay. The cytosolic expression of Bid, Bax, and XIAP and release of cytochrome c and Smac/DIABLO were determined by immunoblotting. Bcl-2 overexpression partially protected SW480 cells from a dose-dependent induction of apoptosis by TRAIL, as did a caspase-9 inhibitor, and increased their clonogenic survival. Bcl-2 overexpression attenuated TRAIL-induced cleavage of caspase-8, indicating its activation upstream and downstream of mitochondria, as well as cleavage of Bid and caspase-3. Bcl-2 inhibited TRAIL-induced Bax translocation, cytosolic release of cytochrome c and Smac/DIABLO, and the downstream cleavage of XIAP and DFF45. Coadministration of HA14-1 and TRAIL increased apoptosis in SW480/Bcl-2 cells by restoring Bax redistribution and cytochrome c release. Bcl-2 confers apoptosis resistance to TRAIL by inhibiting a mitochondrial amplification step and by inactivating downstream XIAP in SW480 cells. HA14-1 reversed Bcl-2-mediated TRAIL resistance, suggesting a novel strategy for increasing TRAIL sensitivity in Bcl-2-overexpressing colon cancers.


Dysplastic nevi of the scalp and forehead in children.
To determine if there is a significant difference in the relative frequency and degree of atypia of sporadic dysplastic nevi from the scalp, face, and neck area in children as compared with nevi from the rest of the body, we reviewed 99 consecutive biopsy specimens of melanocytic nevi from the scalp, face, and neck areas in children less than 18 years of age and compared them with 95 consecutive cases of nevi from other areas of the body in children of the same age. Large numbers of the nevi biopsied from the scalp (13 of 31; 41.93%) and forehead (2 of 10; 20%) were dysplastic. The number of dysplastic nevi from the neck (1 of 58; 1.72%) was not assessed as very different from the incidence found in other regions of the body, where 7 dysplastic nevi (7.36%) from a total of 95 nevi were found. Of the 13 dysplastic nevi from the scalp, 9 showed minimal atypia and 4 showed moderate atypia. No nevi with severe atypia were found. Many pigmented nevi from the scalp and forehead in children in this study were dysplastic. This finding points out the importance of examining the scalp of children for the presence of dysplastic nevi. The majority of nevi from the neck were common nevi.


Cholangiocarcinoma among offset colour proof-printing workers exposed to 1,2-dichloropropane and/or dichloromethane.
The present study was conducted to investigate the relationship between occupational chemical exposure and incidence of cholangiocarcinoma among workers in the offset colour proof-printing section of a small printing company in Osaka, Japan. We identified 51 men who had worked in the proof-printing room, and 11 men who had worked in the front room for at least 1 year between 1991 and 2006. We interviewed them about the chemicals they used, and estimated their levels of exposure to chemicals. We also investigated the medical records of 11 cholangiocarcinoma patients, and calculated the standardised mortality ratio (SMR) from 1991 to 2011. Workers used 1,2-dichloropropane (1,2-DCP) from approximately 1985 to 2006, and dichloromethane (DCM) from approximately 1985 to 1997/1998. Exposure concentrations were estimated to be 100-670 ppm for 1,2-DCP and 80-540 ppm for DCM among the proof-printing workers. All 11 patients were pathologically diagnosed with cholangiocarcinoma. Ages at diagnosis were 25-45 years, and ages at death were 27-46 years among the six deceased individuals. The primary cancer site was the intrahepatic bile duct for five patients, and the extrahepatic bile ducts for six. All patients were exposed to 1,2-DCP for 7-17 years and diagnosed with cholangiocarcinoma 7-20 years after their first exposure. Ten patients were also exposed to DCM for 1-13 years. The SMR for cholangiocarcinoma was 2900 (expected deaths: 0.00204, 95% CI 1100 to 6400) for all workers combined. These findings suggest that 1,2-DCP and/or DCM may cause cholangiocarcinoma in humans.


Angina pectoris with pharyngeal pain alone: a case report.
Patients with pharyngeal pain are frequently encountered in the department of otorhinolaryngology. The pharyngeal pain is usually caused by an inflammation or a malignant disease. In some cases, anginal pain radiates to the pharynx. However, patients with angina pectoris who suffer from pharyngeal pain without chest pain are believed to be very rare. The patient was a 70-year-old man whose chief complaint was only pharyngeal pain on exertion. The pharyngeal pain was similar to acute pharyngitis with burning pain. Upon cardiac catheterization, no abnormality was found in the right coronary artery or in the circumflex artery, but 99% stenosis was found in the middle portion of the left anterior descending artery. There was no collateral circulation to the left anterior descending artery. Thus, percutaneous coronary intervention was performed, and the pharyngeal pain vanished.


Adaptation and cross-cultural validation of the Spanish version of the Thyroid-Related Quality-of-Life Patient-Reported Outcome questionnaire.
The ThyPRO questionnaire is the most widely used tool for measuring quality of life in patients with benign thyroid diseases. The purpose of this study was to adapt and validate a Spanish translation of the ThyPRO and its abbreviated version (ThyPRO-39). Adaptation to the Spanish language was performed using the forward-backward translation method, followed by a pretesting study on five representative patients. The final questionnaire (ThyPROes) was administered to 155 patients with thyroid disorders recruited in a tertiary Spanish hospital. Psychometric properties were evaluated by multitrait scaling and estimation of internal consistency reliability (Cronbach's alpha coefficient). Data from a previous sample of 902 Danish patients were used to analyze differential item functioning (DIF) between the Spanish and the original Danish versions of the questionnaire using ordinal logistic regression. Three of 85 items in ThyPROes and four of the 39 items in ThyPRO-39es lacked convergent validity, while lack of discriminant validity was found for in nine and 14 items of each version respectively. Cronbach's alpha was >0.7 for 12 of 13 scales in the ThyPRO and 10 of 12 scales in the ThyPRO-39es. Eight items in the ThyPROes were flagged with DIF (one with non-uniform DIF), as were two items in the ThyPRO-39es. DIF magnitude was small (explained variance in the item score <3%) in most cases, with a minor impact on scale scores. The Spanish versions of the ThyPRO and ThyPRO-39 show acceptable psychometric properties and good cross-lingual validity, and are suitable for use in clinical studies.


Use of hypertonic (3%) saline/acetate infusion in the treatment of cerebral edema: Effect on intracranial pressure and lateral displacement of the brain.
To determine the effect of continuous hypertonic (3%) saline/acetate infusion on intracranial pressure (ICP) and lateral displacement of the brain in patients with cerebral edema. Retrospective chart review. Neurocritical care unit of a university hospital. Twenty-seven consecutive patients with cerebral edema (30 episodes), including patients with head trauma (n = 8), postoperative edema (n = 5), nontraumatic intracranial hemorrhage (n = 8), and cerebral infarction (n = 6). Intravenous infusion of 3% saline/acetate to increase serum sodium concentrations to 145 to 155 mmol/L. A reduction in mean ICP within the first 12 hrs correlating with an increase in the serum sodium concentration was observed in patients with head trauma (r2 = .91, p = .03), and postoperative edema (r2 = .82, p = .06), but not in patients with nontraumatic intracranial hemorrhage or cerebral infarction. In patients with head trauma, the beneficial effect of hypertonic saline on ICP was short-lasting, and after 72 hrs of infusion, four patients required intravenous pentobarbital due to poor ICP control. Among the 21 patients who had a repeat computed tomographic scan within 72 hrs of initiating hypertonic saline, lateral displacement of the brain was reduced in patients with head trauma (2.8 +/- 1.4 to 1.1 +/- 0.9 [SEM]) and in patients with postoperative edema (3.1 +/- 1.6 to 1.1 +/- 0.7). This effect was not observed in patients with nontraumatic intracranial bleeding or cerebral infarction. The treatment was terminated in three patients due to the development of pulmonary edema, and was terminated in another three patients due to development of diabetes insipidus. Hypertonic saline administration as a 3% infusion appears to be a promising therapy for cerebral edema in patients with head trauma or postoperative edema. Further studies are required to determine the optimal duration of benefit and the specific patient population that is most likely to benefit from this treatment.


A new approach to standardize multicenter studies: mobile lab technology for the German Environmental Specimen Bank.
Technical progress has simplified tasks in lab diagnosis and improved quality of test results. Errors occurring during the pre-analytical phase have more negative impact on the quality of test results than errors encountered during the total analytical process. Different infrastructures of sampling sites can highly influence the quality of samples and therewith of analytical results. Annually the German Environmental Specimen Bank (ESB) collects, characterizes, and stores blood, plasma, and urine samples of 120-150 volunteers each on four different sampling sites in Germany. Overarching goal is to investigate the exposure to environmental pollutants of non-occupational exposed young adults combining human biomonitoring with questionnaire data. We investigated the requirements of the study and the possibility to realize a highly standardized sampling procedure on a mobile platform in order to increase the required quality of the pre-analytical phase. The results lead to the development of a mobile epidemiologic laboratory (epiLab) in the project "Labor der Zukunft" (future's lab technology). This laboratory includes a 14.7 m(2) reception area to record medical history and exposure-relevant behavior, a 21.1 m(2) examination room to record dental fillings and for blood withdrawal, a 15.5 m(2) biological safety level 2 laboratory to process and analyze samples on site including a 2.8 m(2) personnel lock and a 3.6 m2 cryofacility to immediately freeze samples. Frozen samples can be transferred to their final destination within the vehicle without breaking the cold chain. To our knowledge, we herewith describe for the first time the implementation of a biological safety laboratory (BSL) 2 lab and an epidemiologic unit on a single mobile platform. Since 2013 we have been collecting up to 15.000 individual human samples annually under highly standardized conditions using the mobile laboratory. Characterized and free of alterations they are kept ready for retrospective analyses in their final archive, the German ESB.


The mountainous Cretan dietary patterns and their relationship with cardiovascular risk factors: the Hellenic Isolated Cohorts MANOLIS study.
We carried out de novo recruitment of a population-based cohort (MANOLIS study) and describe the specific population, which displays interesting characteristics in terms of diet and health in old age, through deep phenotyping. Cross-sectional study where anthropometric, biochemical and clinical measurements were taken in addition to interview-based completion of an extensive questionnaire on health and lifestyle parameters. Dietary patterns were derived through principal component analysis based on a validated FFQ. Geographically isolated Mylopotamos villages on Mount Idi, Crete, Greece. Adults (n 1553). Mean age of the participants was 61·6 years and 55·8 % were women. Of the population, 82·7 % were overweight or obese with a significantly different prevalence between overweight men and women (43·4 v. 34·7 %, P=0·002). The majority (70·6 %) of participants were married, while a larger proportion of women were widowed than men (27·8 v. 3·5 %, P<0·001). Smoking was more prevalent in men (38·7 v. 8·2 %, P<0·001), as 88·8% of women had never smoked. Four dietary patterns emerged as characteristic of the population; these were termed 'local', 'high fat and sugar, 'Greek café/tavern' and 'olive oil, fruits and vegetables'. Individuals more adherent to the local dietary pattern presented higher blood glucose (β=4·026, P<0·001). Similarly, individuals with higher compliance with the Greek café/tavern pattern had higher waist-to-hip ratio (β=0·012, P<0·001), blood pressure (β=1·015, P=0·005) and cholesterol (β=5·398, P<0·001). Profiling of the MANOLIS elderly population identifies unique unhealthy dietary patterns that are associated with cardiometabolic indices.


Photoelectric Properties of Silicon Nanocrystals/P3HT Bulk-Heterojunction Ordered in Titanium Dioxide Nanotube Arrays.
A silicon nanocrystals (Si-ncs) conjugated-polymer-based bulk-heterojunction represents a promising approach for low-cost hybrid solar cells. In this contribution, the bulk-heterojunction is based on Si-ncs prepared by electrochemical etching and poly(3-hexylthiophene) (P3HT) polymer. Photoelectric properties in parallel and vertical device-like configuration were investigated. Electronic interaction between the polymer and surfactant-free Si-ncs is achieved. Temperature-dependent photoluminescence and transport properties were studied and the ratio between the photo- and dark-conductivity of 1.7 was achieved at ambient conditions. Furthermore the porous titanium dioxide (TiO(2)) nanotubes' template was used for vertical order of photosensitive Si-ncs/P3HT-based blend. The anodization of titanium foil in ethylene glycol-based electrolyte containing fluoride ions and subsequent thermal annealing were used to prepare anatase TiO(2) nanotube arrays. The arrays with nanotube inner diameter of 90 and 50 nm were used for vertical ordering of the Si-ncs/P3HT bulk-heterojunction.


Treatment of Tourette syndrome with cannabinoids.
Cannabinoids have been used for hundred of years for medical purposes. To day, the cannabinoid delta-9-tetrahydrocannabinol (THC) and the cannabis extract nabiximols are approved for the treatment of nausea, anorexia and spasticity, respectively. In Tourette syndrome (TS) several anecdotal reports provided evidence that marijuana might be effective not only in the suppression of tics, but also in the treatment of associated behavioural problems. At the present time there are only two controlled trials available investigating the effect of THC in the treatment of TS. Using both self and examiner rating scales, in both studies a significant tic reduction could be observed after treatment with THC compared to placebo, without causing significant adverse effects. Available data about the effect of THC on obsessive-compulsive symptoms are inconsistent. According to a recent Cochrane review on the efficacy of cannabinoids in TS, definite conclusions cannot be drawn, because longer trials including a larger number of patients are missing. Notwithstanding this appraisal, by many experts THC is recommended for the treatment of TS in adult patients, when first line treatments failed to improve the tics. In treatment resistant adult patients, therefore, treatment with THC should be taken into consideration.


Early Detection of Silent Myocardial Impairment in Drug-Naive Patients With New-Onset Systemic Lupus Erythematosus: A Three-Center Prospective Study.
Cardiac magnetic resonance imaging (MRI) has enabled the assessment of myocardial features, from tissue characteristics to functional changes, in patients with systemic lupus erythematosus (SLE). Echocardiography, however, detects cardiac decompensation. This study was undertaken to investigate the use of cardiac MRI to explore early warning signs of silent cardiac involvement and determine treatment timing in SLE. Clinical assessment and cardiac MRI studies were performed in 50 drug-naive patients with new-onset SLE, 60 patients with longstanding SLE, and 50 healthy subjects in a 3-center prospective study. Analysis of cardiac enzymes, the presence and size of regional myocardial fibrosis as indicated by late gadolinium enhancement, strain changes, and biventricular ejection fraction did not indicate cardiac impairment in the patients with new-onset SLE. Native myocardial T1 and extracellular volume (ECV), which are extracellular matrix indices, were elevated in the patients with new-onset SLE (mean ± SD 1,369 ± 79 msec versus 1,092 ± 57 msec in the control group for native T1; 32 ± 5% versus 24 ± 3% in the control group for ECV; P < 0.001 for both). The elevation was independent of SLE disease activity. This is the first study to indicate that drug-naive patients with new-onset SLE, even those with inactive disease, are likely to have silent cardiac impairment. Structural and functional changes in the myocardium are related to SLE disease stage; this finding indicates the value of early detection of myocardial involvement. Native myocardial T1 values and ECV, rather than currently used clinical rheumatic and cardiac indices, could serve as early detection markers of myocardial injury before the presence of visual fibrosis and functional decompensation.


Persistent drying in the tropics linked to natural forcing.
Approximately half of the world's population lives in the tropics, and future changes in the hydrological cycle will impact not just the freshwater supplies but also energy production in areas dependent upon hydroelectric power. It is vital that we understand the mechanisms/processes that affect tropical precipitation and the eventual surface hydrological response to better assess projected future regional precipitation trends and variability. Paleo-climate proxies are well suited for this purpose as they provide long time series that pre-date and complement the present, often short instrumental observations. Here we present paleo-precipitation data from a speleothem located in Mesoamerica that reveal large multi-decadal declines in regional precipitation, whose onset coincides with clusters of large volcanic eruptions during the nineteenth and twentieth centuries. This reconstruction provides new independent evidence of long-lasting volcanic effects on climate and elucidates key aspects of the causal chain of physical processes determining the tropical climate response to global radiative forcing.


The impact of visual dysfunctions in recent-onset psychosis and clinical high-risk state for psychosis.
Subtle subjective visual dysfunctions (VisDys) are reported by about 50% of patients with schizophrenia and are suggested to predict psychosis states. Deeper insight into VisDys, particularly in early psychosis states, could foster the understanding of basic disease mechanisms mediating susceptibility to psychosis, and thereby inform preventive interventions. We systematically investigated the relationship between VisDys and core clinical measures across three early phase psychiatric conditions. Second, we used a novel multivariate pattern analysis approach to predict VisDys by resting-state functional connectivity within relevant brain systems. VisDys assessed with the Schizophrenia Proneness Instrument (SPI-A), clinical measures, and resting-state fMRI data were examined in recent-onset psychosis (ROP, n = 147), clinical high-risk states of psychosis (CHR, n = 143), recent-onset depression (ROD, n = 151), and healthy controls (HC, n = 280). Our multivariate pattern analysis approach used pairwise functional connectivity within occipital (ON) and frontoparietal (FPN) networks implicated in visual information processing to predict VisDys. VisDys were reported more often in ROP (50.34%), and CHR (55.94%) than in ROD (16.56%), and HC (4.28%). Higher severity of VisDys was associated with less functional remission in both CHR and ROP, and, in CHR specifically, lower quality of life (Qol), higher depressiveness, and more severe impairment of visuospatial constructability. ON functional connectivity predicted presence of VisDys in ROP (balanced accuracy 60.17%, p = 0.0001) and CHR (67.38%, p = 0.029), while in the combined ROP + CHR sample VisDys were predicted by FPN (61.11%, p = 0.006). These large-sample study findings suggest that VisDys are clinically highly relevant not only in ROP but especially in CHR, being closely related to aspects of functional outcome, depressiveness, and Qol. Findings from multivariate pattern analysis support a model of functional integrity within ON and FPN driving the VisDys phenomenon and being implicated in core disease mechanisms of early psychosis states.


Multi-domain training enhances attentional control.
Multi-domain training potentially increases the likelihood of overlap in processing components with transfer tasks and everyday life, and hence is a promising training approach for older adults. To empirically test this, 84 healthy older adults aged 64 to 75 years were randomly assigned to one of three single-domain training conditions (inhibition, visuomotor function, spatial navigation) or to the simultaneous training of all three cognitive functions (multi-domain training condition). All participants trained on an iPad at home for 50 training sessions. Before and after the training, and at a 6-month follow-up measurement, cognitive functioning and training transfer were assessed with a neuropsychological test battery including tests targeting the trained functions (near transfer) and transfer to executive functions (far transfer: attentional control, working memory, speed). Participants in all four training groups showed a linear increase in training performance over the 50 training sessions. Using a latent difference score model, the multi-domain training group, compared with the single-domain training groups, showed more improvement on the far transfer attentional control composite. Individuals with initially lower baseline performance showed higher training-related improvements, indicating that training compensated for lower initial cognitive performance. At the 6-month follow-up, performance on the cognitive test battery remained stable. This is one of the first studies to investigate systematically multi-domain training including comparable single-domain training conditions. Our findings suggest that multi-domain training enhances attentional control involved in handling several different tasks at the same time, an aspect in everyday life that is particularly challenging for older people. (PsycINFO Database Record


Dynamics and complexity of the Schelling segregation model.
In this paper we consider the Schelling social segregation model for two different populations. In Schelling's model, segregation appears as a consequence of discrimination, measured by the local difference between two populations. For that, the model defines a tolerance criterion on the neighborhood of an individual, indicating wether the individual is able to move to a new place or not. Next, the model chooses which of the available unhappy individuals really moves. In our work, we study the patterns generated by the dynamical evolution of the Schelling model in terms of various parameters or the initial condition, such as the size of the neighborhood of an inhabitant, the tolerance, and the initial number of individuals. As a general rule we observe that segregation patterns minimize the interface of zones of different people. In this context we introduce an energy functional associated with the configuration which is a strictly decreasing function for the tolerant people case. Moreover, as far as we know, we are the first to notice that in the case of a non-strictly-decreasing energy functional, the system may segregate very efficiently.


Effects of microplusin, a copper-chelating antimicrobial peptide, against Cryptococcus neoformans.
Microplusin is an antimicrobial peptide isolated from the cattle tick Rhipicephalus (Boophilus) microplus. Its copper-chelating ability is putatively responsible for its bacteriostatic activity against Micrococcus luteus as microplusin inhibits respiration in this species, which is a copper-dependent process. Microplusin is also active against Cryptococcus neoformans (MIC(50) = 0.09 μM), the etiologic agent of cryptococcosis. Here, we show that microplusin is fungistatic to C. neoformans and this inhibitory effect is abrogated by copper supplementation. Notably, microplusin drastically altered the respiratory profile of C. neoformans. In addition, microplusin affects important virulence factors of this fungus. We observed that microplusin completely inhibited fungal melanization, and this effect correlates with the inhibition of the related enzyme laccase. Also, microplusin significantly inhibited the capsule size of C. neoformans. Our studies reveal, for the first time, a copper-chelating antimicrobial peptide that inhibits respiration and growth of C. neoformans and modifies two major virulence factors: melanization and formation of a polysaccharide capsule. These features suggest that microplusin, or other copper-chelation approaches, may be a promising therapeutic for cryptococcosis.


Metabolic Serum Profiles for Patients Receiving Allogeneic Stem Cell Transplantation: The Pretransplant Profile Differs for Patients with and without Posttransplant Capillary Leak Syndrome.
Allogeneic stem cell transplantation is commonly used in the treatment of younger patients with severe hematological diseases, and endothelial cells seem to be important for the development of several posttransplant complications. Capillary leak syndrome is a common early posttransplant complication where endothelial cell dysfunction probably contributes to the pathogenesis. In the present study we investigated whether the pretreatment serum metabolic profile reflects a risk of posttransplant capillary leak syndrome. We investigated the pretransplant serum levels of 766 metabolites for 80 consecutive allotransplant recipients. Patients with later capillary leak syndrome showed increased pretherapy levels of metabolites associated with endothelial dysfunction (homocitrulline, adenosine) altered renal regulation of fluid and/or electrolyte balance (betaine, methoxytyramine, and taurine) and altered vascular function (cytidine, adenosine, and methoxytyramine). Additional bioinformatical analyses showed that capillary leak syndrome was also associated with altered purine/pyrimidine metabolism (i.e., metabolites involved in vascular regulation and endothelial functions), aminoglycosylation (possibly important for endothelial cell functions), and eicosanoid metabolism (also involved in vascular regulation). Our observations are consistent with the hypothesis that the pretransplant metabolic status can be a marker for posttransplant abnormal fluid and/or electrolyte balance.


A ratiometric fluorescent probe for the detection of hydroxyl radicals in living cells.
A naphthalimide-naphthyridine derivative has been synthesized for the detection of hydroxyl radicals. It can distinguish hydroxyl radicals from other reactive oxygen species with high selectivity and short response time. Moreover, it has no cellular toxicity, and can be effectively used for intracellular detection of hydroxyl radicals.


Methane destruction efficiency of natural gas flares associated with shale formation wells.
Flaring to dispose of natural gas has increased in the United States and is typically assumed to be 98% efficient, accounting for both incomplete combustion and venting during unintentional flame termination. However, no in situ measurements of flare emissions have been reported. We used an aircraft platform to sample 10 flares in North Dakota and 1 flare in Pennsylvania, measuring CO2, CH4, and meteorological data. Destruction removal efficiency (DRE) was calculated by assuming a flare natural gas input composition of 60-100% CH4. In all cases flares were >99.80 efficient at the 25% quartile. Crosswinds up to 15 m/s were observed, but did not significantly adversely affect efficiency. During analysis unidentified peaks of CH4, most likely from unknown venting practices, appeared much larger in magnitude than emissions from flaring practices. Our analysis suggests 98% efficiency for nonsputtering flares is a conservative estimate for incomplete combustion and that the unidentified venting is a greater contributor to CH4 emissions.


Pulse shear stress for anaerobic membrane bioreactor fouling control.
Increase of shear stress at membrane surfaces is a generally applied strategy to minimize membrane fouling. It has been reported that a two-phase flow, better known as slug flow, is an effective way to increase shear stress. Hence, slug flow was introduced into an anaerobic membrane bioreactor for membrane fouling control. Anaerobic suspended sludge was cultured in an anaerobic membrane bioreactor (AMBR) operated with a side stream inside-out tubular membrane unit applying sustainable flux flow regimes. The averaged particle diameter decreased from 20 to 5 microm during operation of the AMBR. However, the COD removal efficiency did not show any significant deterioration, whereas the specific methanogenic activity (SMA) increased from 0.16 to 0.41 gCOD/g VSS/day. Nevertheless, the imposed gas slug appeared to be insufficient for adequate fouling control, resulting in rapidly increasing trans membrane pressures (TMP) operating at a flux exceeding 16 L/m2/h. Addition of powdered activated carbon (PAC) enhanced the effect of slug flow on membrane fouling. However, the combined effect was still considered as not being significant. The tubular membrane was subsequently equipped with inert inserts for creating a locally increased shear stress for enhanced fouling control. Results show an increase in the membrane flux from 16 L/m2/h to 34 L/m2/h after the inserts were mounted in the membrane tube.


Models for predicting sleep latency and sleep duration.
Planning effective sleep-wake schedules for civilian and military settings depends on the ability to predict the extent to which restorative sleep is likely for a specified sleep period. Here, we developed and validated two mathematical models, one for predicting sleep latency and a second for predicting sleep duration, as decision aids to predict efficacious sleep periods. We extended the Unified Model of Performance (UMP), a well-validated mathematical model of neurobehavioral performance, to predict sleep latency and sleep duration, which vary nonlinearly as a function of the homeostatic sleep pressure and the circadian rhythm. To this end, we used the UMP to predict the time course of neurobehavioral performance under different conditions. We developed and validated the models using experimental data from 317 unique subjects from 24 different studies, which included sleep conditions spanning the entire circadian cycle. The sleep-latency and sleep-duration models accounted for 42% and 84% of the variance in the data, respectively, and yielded acceptable average prediction errors for planning sleep schedules (4.0 min for sleep latency and 0.8 h for sleep duration). Importantly, we identified conditions under which small shifts in sleep onset timing result in disproportionately large differences in sleep duration-knowledge that may be applied to improve performance, safety, and sustainability in civilian and military operations. These models extend the capabilities of existing predictive fatigue-management tools, allowing users to anticipate the most opportune times to schedule sleep periods.


Differential assessment of angiogenic activity and of vascular survival ability (VSA) in breast cancer.
Recent reports provide evidence that some growth factors behave as inhibitors of the apoptosis of the endothelial cells, bringing forward the concept of vascular survival as a post-angiogenesis process. At least two different vasculature development processes occur within a tumor: the angiogenic (formation of new vessels) and the vascular survival pathway, which is devoted to the preservation of the newly-formed vessels in layers that lose contact with the adjacent normal tissue. We developed a method to assess these processes in tissue samples. We noted that differences among tumors may exist not only in the tumor angiogenic activity (TAA) but also in the vascular survival ability (VSA). One third of the highly angiogenic breast cancer cases examined had a poor ability to maintain high vessel density in inner tumor areas. Both parameters are independently related to prognosis, while VSA was directly related to tumor dimensions and node involvement. Patients with high TAA and VSA had a particularly poor prognosis. It is suggested that although cancer angiogenic activity is important for the local invasion and dissemination into vessels and lymphatics, the VSA may be important for the effective formation of viable tumor foci in lymph nodes or distant organs. Recognition and quantification of the vascular survival ability in human tumors may significantly improve the prognostic value of the assessment of tumor vasculature, and may help to stratify patients for clinical trials with novel anti-angiogenic or angiotoxic drugs. Elucidation of the pathways may provide additional targets for antiangiogenic therapy.


Epicardial Catheter Ablation Using High-Intensity Ultrasound: Validation in a Swine Model.
Epicardial radiofrequency catheter ablation of ventricular tachycardia remains challenging because of the presence of deep myocardial scar and adjacent cardiac structures, such as the coronary arteries, phrenic nerve, and epicardial fat that limit delivery of radiofrequency energy. High-intensity ultrasound (HIU) is an acoustic energy source able to deliver deep lesions through fat, while sparing superficial structures. We developed and tested an epicardial HIU ablation catheter in a closed chest, in vivo swine model. The HIU catheter is an internally cooled, 14-French, side-facing catheter, integrated with A-mode ultrasound guidance. Swine underwent percutaneous subxyphoid epicardial access and ablation with HIU (n=10 swine) at 15, 20, and 30 W. Compared with irrigated radiofrequency lesions in control swine (n = 5), HIU demonstrated increased lesion depth (HIU 11.6±3.2 mm versus radiofrequency 4.7±1.6 mm; mean±SD) and epicardial sparing (HIU 2.9±2.1 mm versus radiofrequency 0.1±0.2 mm) at all HIU powers, and increased lesion volume at HIU 20 and 30 W (P<0.0001 for all comparisons). HIU ablation over coronary arteries and surrounding epicardial fat resulted in deep lesions with normal angiographic flow. Histological disruption of coronary adventitia, but not media or intima, was noted in 44% of lesions. Compared with radiofrequency, HIU ablation in vivo demonstrates significantly deeper and larger lesions with greater epicardial sparing in a dose-dependent manner. Further development of this catheter may lead to a promising alternative to epicardial radiofrequency ablation.


Prognostic factors of methotrexate-associated lymphoproliferative disorders associated with rheumatoid arthritis and plausible application of biological agents.
To determine prognostic factors of methotrexate-associated lymphoproliferative disorder (MTX-LPD) and evaluate the efficacy and safety of biological therapy in rheumatoid arthritis (RA) complicated with MTX-LPD. Thirty RA patients who developed MTX-LPD were investigated in this study. We compared the clinical and laboratory parameters of patients who achieved regression of LPD by MTX withdrawal with those who required chemotherapy and evaluated the clinical course of RA after LPD development. Twenty-three patients (76.7%) achieved regression of LPD by MTX withdrawal. Chemotherapy-free patients had a tendency of shorter RA duration (13.1 vs. 22.0 years, p = 0.108) and higher doses of MTX at LPD diagnosis (8.0 vs. 5.3 mg/w, p = 0.067) than patients who required chemotherapy. A significantly higher positive rate of peripheral blood Epstein-Barr virus (EBV)-DNA was observed in the chemotherapy-free group (9/9 vs. 0/3, p = 0.0002). Of 15 patients that received biological agents after LPD development, 14 patients (93.3%) demonstrated an improved disease activity of RA and persistent remission of LPD, whereas only one patient experienced relapse of LPD during tocilizumab therapy. Peripheral blood EBV-DNA positivity is a potential prognostic marker of better outcome in MTX-LPD. Biological agents could be an option for the treatment of RA patients with MTX-LPD.


Modeling routes of chronic wasting disease transmission: environmental prion persistence promotes deer population decline and extinction.
Chronic wasting disease (CWD) is a fatal disease of deer, elk, and moose transmitted through direct, animal-to-animal contact, and indirectly, via environmental contamination. Considerable attention has been paid to modeling direct transmission, but despite the fact that CWD prions can remain infectious in the environment for years, relatively little information exists about the potential effects of indirect transmission on CWD dynamics. In the present study, we use simulation models to demonstrate how indirect transmission and the duration of environmental prion persistence may affect epidemics of CWD and populations of North American deer. Existing data from Colorado, Wyoming, and Wisconsin's CWD epidemics were used to define plausible short-term outcomes and associated parameter spaces. Resulting long-term outcomes range from relatively low disease prevalence and limited host-population decline to host-population collapse and extinction. Our models suggest that disease prevalence and the severity of population decline is driven by the duration that prions remain infectious in the environment. Despite relatively low epidemic growth rates, the basic reproductive number, R(0), may be much larger than expected under the direct-transmission paradigm because the infectious period can vastly exceed the host's life span. High prion persistence is expected to lead to an increasing environmental pool of prions during the early phases (i.e. approximately during the first 50 years) of the epidemic. As a consequence, over this period of time, disease dynamics will become more heavily influenced by indirect transmission, which may explain some of the observed regional differences in age and sex-specific disease patterns. This suggests management interventions, such as culling or vaccination, will become increasingly less effective as CWD epidemics progress.


Long-term safety of pegloticase in chronic gout refractory to conventional treatment.
To evaluate the long-term safety (up to 3 years) of treatment with pegloticase in patients with refractory chronic gout. This open-label extension (OLE) study was conducted at 46 sites in the USA, Canada and Mexico. Patients completing either of two replicate randomised placebo-controlled 6-month trials received pegloticase 8 mg every 2 weeks (biweekly) or every 4 weeks (monthly). Safety was evaluated as the primary outcome, with special interest in gout flares and infusion-related reactions (IRs). Secondary outcomes included urate-lowering and clinical efficacy. Patients (n=149) received a mean±SD of 28±18 pegloticase infusions and were followed for a mean of 25±11 months. Gout flares and IRs were the most frequently reported adverse events; these were least common in patients with a sustained urate-lowering response to treatment and those receiving biweekly treatment. In 10 of the 11 patients with a serious IR, the event occurred when uric acid exceeded 6 mg/dl. Plasma and serum uric acid levels remained <6 mg/dl in most randomised controlled trial (RCT)-defined pegloticase responders throughout the OLE study and were accompanied by sustained and progressive improvements in tophus resolution and flare incidence. The safety profile of long-term pegloticase treatment was consistent with that observed during 6 months of RCT treatment; no new safety signals were identified. Improvements in clinical status, in the form of flare and tophus reduction initiated during RCT pegloticase treatment in patients maintaining goal range urate-lowering responses were sustained or advanced during up to 2.5 years of additional treatment.


Influence of fuels, weather and the built environment on the exposure of property to wildfire.
Wildfires can pose a significant risk to people and property. Billions of dollars are spent investing in fire management actions in an attempt to reduce the risk of loss. One of the key areas where money is spent is through fuel treatment--either fuel reduction (prescribed fire) or fuel removal (fuel breaks). Individual treatments can influence fire size and the maximum distance travelled from the ignition and presumably risk, but few studies have examined the landscape level effectiveness of these treatments. Here we use a Bayesian Network model to examine the relative influence of the built and natural environment, weather, fuel and fuel treatments in determining the risk posed from wildfire to the wildland-urban interface. Fire size and distance travelled was influenced most strongly by weather, with exposure to fires most sensitive to changes in the built environment and fire parameters. Natural environment variables and fuel load all had minor influences on fire size, distance travelled and exposure of assets. These results suggest that management of fuels provided minimal reductions in risk to assets and adequate planning of the changes in the built environment to cope with the expansion of human populations is going to be vital for managing risk from fire under future climates.


"Spicing up" of the immune system by curcumin.
Curcumin (diferuloylmethane) is an orange-yellow component of turmeric (Curcuma longa), a spice often found in curry powder. Traditionally known for its an antiinflammatory effects, curcumin has been shown in the last two decades to be a potent immunomodulatory agent that can modulate the activation of T cells, B cells, macrophages, neutrophils, natural killer cells, and dendritic cells. Curcumin can also downregulate the expression of various proinflammatory cytokines including TNF, IL-1, IL-2, IL-6, IL-8, IL-12, and chemokines, most likely through inactivation of the transcription factor NF-kappaB. Interestingly, however, curcumin at low doses can also enhance antibody responses. This suggests that curcumin's reported beneficial effects in arthritis, allergy, asthma, atherosclerosis, heart disease, Alzheimer's disease, diabetes, and cancer might be due in part to its ability to modulate the immune system. Together, these findings warrant further consideration of curcumin as a therapy for immune disorders.


Mesenchymal stem cells in pathogenesis of myelodysplastic syndromes.
Myelodysplastic syndromes (MDS) are clonal malignant stem cell disorders characterized by inefficient hematopoiesis. The role of the marrow microenvironment in the pathogenesis of the disease has been controversial. Emerging evidence indicated that mesenchymal stem cells (MSC) derived from MDS patients were cytogenetically abnormal, and they showed a deficient hematopoietic-supportive capacity and increased production of cytokine such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), interferon γ (IFN-γ). From the point of some evidence, the abnormal microenvironment seems to participate in the progression of the disease by contributing to the selective expansion of the malignant clone. In this review, we will discuss the most recent progress related to identification of normal MSC and the importance of the stem cell niche in development and maintenance of MDS.


Abnormalities of vascular prostaglandins in Henoch-Schönlein purpura.
The ability of plasma to support prostacyclin like activity from human umbilical arterial rings was studied in 17 patients with Henoch-Schönlein purpura and 17 controls matched for age and sex. Plasma from 13 of the 17 patients showed a diminished or absent ability to support prostacyclin like activity in vitro. Six patients whose plasma had a low or absent ability to support prostacyclin like activity showed evidence of inhibitory activity. Plasma from three of these patients also failed to preserve the effect of a stable prostacyclin like analogue (ZK36-374). The plasma concentration of prostacyclin metabolite and the serum concentration of thromboxane A2 metabolite, thromboxane B2, were measured simultaneously. The concentration of plasma prostacyclin metabolite in 10 of the 14 patients was decreased, and a positive correlation was found between the plasma prostacyclin metabolite values and the ability of the plasma to support prostacyclin like activity. There was no significant difference in the serum thromboxane A2 metabolite concentrations between the patients and controls. These data suggest that abnormalities of vascular prostaglandin metabolism are involved in the pathophysiology of Henoch-Schönlein purpura.


Rural FASD diagnostic services model: Lakeland Centre for fetal alcohol spectrum disorder.
There are few FASD multi-disciplinary diagnostic teams in rural regions of Canada. Families often have difficulty accessing their services because of the lack of clinics available in Canada and the distance rural residents must travel to access one. Since its grass-roots beginning in 1995, the Lakeland Centre for FASD in north eastern Alberta has developed a community-based FASD diagnostic services model that utilizes the resources available in local communities and enhances the support to individuals and families living far away from urban centers. The article describes the history of the Lakeland Centre for FASD relative to the development of the model and diagnostic process used to diagnose children and adults. Rural adaptations to similar urban models are discussed. Critical elements to rural, in-kind services are also discussed along with ongoing challenges. Acknowledging the change in terminology over the years covered by this article, the term FASD (Fetal Alcohol Spectrum Disorder) is used throughout.


Hypoxia suppresses glutamate transport in astrocytes.
Glutamate uptake by astrocytes is fundamentally important in the regulation of CNS function. Disruption of uptake can lead to excitotoxicity and is implicated in various neurodegenerative processes as well as a consequence of hypoxic/ischemic events. Here, we investigate the effect of hypoxia on activity and expression of the key glutamate transporters excitatory amino acid transporter 1 (EAAT1) [GLAST (glutamate-aspartate transporter)] and EAAT2 [GLT-1 (glutamate transporter 1)]. Electrogenic, Na+-dependent glutamate uptake was monitored via whole-cell patch-clamp recordings from cortical astrocytes. Under hypoxic conditions (2.5 and 1% O2 exposure for 24 h), glutamate uptake was significantly reduced, and pharmacological separation of uptake transporter subtypes suggested that the EAAT2 subtype was preferentially reduced relative to the EAAT1. This suppression was confirmed at the level of EAAT protein expression (via Western blots) and mRNA levels (via real-time PCR). These effects of hypoxia to inhibit glutamate uptake current and EAAT protein levels were not replicated by desferrioxamine, cobalt, FG0041, or FG4496, agents known to mimic effects of hypoxia mediated via the transcriptional regulator, hypoxia-inducible factor (HIF). Furthermore, the effects of hypoxia were not prevented by topotecan, which prevents HIF accumulation. In stark contrast, inhibition of nuclear factor-kappaB (NF-kappaB) with SN50 fully prevented the effects of hypoxia on glutamate uptake and EAAT expression. Our results indicate that prolonged hypoxia can suppress glutamate uptake in astrocytes and that this effect requires activation of NF-kappaB but not of HIF. Suppression of glutamate uptake via this mechanism may be an important contributory factor in hypoxic/ischemic triggered glutamate excitotoxicity.


Guide to family practitioners for the diagnosis and treatment of depression in children and adolescents.
Childhood and adolescent depression is probably more common in the primary care setting than most physicians realize. Because depression can result in suicide, it must be differentially diagnosed from the more common complaints seen in pediatric and adolescent patients. The cause of depression is usually multifactorial and may include psychodynamic, cognitive, behavioral, life stress/socioenvironmental, biologic/biochemical, and genetic components. Depending on the patient's age, depression can present as mood disturbances, and eating and sleeping disturbances, as well as somatic complaints. With no laboratory tests currently available to diagnose depression, physicians must rely on the history and physical examination as the best diagnostic tool. To aid family practitioners, the authors present criteria for diagnosing depression from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition along with treatment that includes psychotherapy and pharmacotherapy for the best possible outcome.


Phytochemical Composition and Cytotoxic Effects on Liver Hepatocellular Carcinoma Cells of Different Berries Following a Simulated In Vitro Gastrointestinal Digestion.
Berry fruits are rich in nutrients and polyphenols, providing potential health benefits. Understanding the factors that affect their bioavailability is becoming of utmost importance for evaluating their biological significance and efficacy as functional food. In this study, the phytochemical composition and the total antioxidant capacity of different varieties of five berries (blackberry, blackcurrant, blueberry, raspberry, and strawberry) were evaluated after an in vitro gastrointestinal digestion process. The cultivar of each berry that showed the higher content of total phenols and flavonoids was selected to study its cytotoxic effect on human hepatoma cells. Digestion resulted in a high reduction (p ˂ 0.05) of total phenolic, flavonoid and anthocyanin contents and total antioxidant capacity, in the "IN" samples compared to the "OUT" extracts, which represent the "serum-available" and the "colon-available" fractions, respectively. Incubation of the digested fraction for 24 h didn't exert any effect on cellular viability, while a dose- and time-dependent cytotoxicity was observed after 48 h and 72 h of incubation for all the berries analyzed. Our results suggest that the approach proposed in this work may represent a rapid tool for evaluating and identifying new berries with increased phytochemical bioavailability, highlighting their antiproliferative agents after an in vitro digestion.


[Treatment of pain due to unwanted lactation with a homeopathic preparation given in the immediate post-partum period].
Dopaminergic agonists, such as Parlodel((R)), are now widely used to inhibit lactation. However, some countries, such as the United States, no longer use these drugs in this indication because of their sometimes serious adverse effects. In this context, the authors tested a homeopathic treatment designed for parturients unable or not wanting to breastfeed. The APIS MELLIFICA 9 CH and BRYONIA 9 CH combination was chosen for its anti-inflammatory and analgesic effects. 71 patients were included in this double-blind placebo-controlled study. All received basic treatment comprising naproxen and fluid restriction. A significant improvement of lactation pain (main criterion of the study) was observed in parturients treated with homeopathy (p<0.02 on D2 and p<0.01 on D4). A similar effect (p<0.05 on D4) was observed for breast tension and spontaneous milk flow. No significant difference was observed for the other criteria of the study. The homeopathic combination studied was therefore effective on the pain of lactation and should be integrated into the therapeutic armamentarium.


Fever of unknown origin caused by multiple myeloma: a report of 9 cases.
Most authorities regard multiple myeloma as a rare cause of fever and not a cause of fever of unknown origin (FUO). To describe a series of patients with FUO caused by multiple myeloma. We reviewed the clinical features of 9 patients seen at Mayo Clinic from January 1, 1975, to February 1, 2001, with FUO caused by multiple myeloma. Fever of unknown origin caused by multiple myeloma was found in 9 patients (6 men and 3 women). All patients satisfied accepted criteria for FUO. The mean +/- SD time from the onset of fevers to the initial physician evaluation was 4.8 +/- 2.0 weeks. The mean time from the initial physician evaluation to the diagnosis of multiple myeloma was 11.4 +/- 6.5 weeks. The mean age at diagnosis of multiple myeloma was 55.9 +/- 6.9 years. All 9 patients were anemic. Peripheral blood smears were available for 8 patients, and all had rouleaux formations. All 9 patients underwent exhaustive testing to determine the cause of fevers. Further testing was done in 6 patients subsequent to the diagnosis of multiple myeloma. Acetaminophen or nonsteroidal anti-inflammatory drugs or both relieved fevers in all patients who received them. All 8 patients who received chemotherapy experienced resolution of fevers. The median actuarial survival of the patient cohort was 38 months. Multiple myeloma can cause FUO. When appropriate, clinicians should include multiple myeloma in the differential diagnosis of FUO to reduce unnecessary testing, rapidly establish the diagnosis, and initiate effective treatments.


TNFA deletion alters apoptosis as well as caspase 3 and 4 expression during otitis media.
Tumor necrosis factor (TNFA) is the canonical member of the TNF superfamily, which plays a major role in both inflammation and apoptosis. To evaluate the role of TNFs in otitis media (OM), the most common disease of childhood, we evaluated middle ear (ME) expression of genes encoding the TNF and TNF receptor superfamilies during bacterial OM in the mouse, characterized OM in TNFA-deficient mice, and assessed apoptosis during OM in normal versus TNF-deficient MEs. TNFs and TNF receptors were broadly regulated during OM, with TNFA showing the highest level of up-regulation. TNF deficient mice exhibited mucosal hyperplasia even in the absence of infection and exuberant growth of the mucosa during OM, including the formation of mucosal polyps. Mucosal recovery during OM was also delayed, in parallel with a delay in mucosal apoptosis and reduced caspase gene expression. The TNF and TNF receptor superfamilies mediate both inflammation and apoptosis during OM. TNF appears to be critical for the maintenance of mucosal architecture in both the normal and infected ME, since excessive accumulation of mucosal tissue is seen in TNFA-/- MEs both before and after bacterial inoculation of the ME. TNFA is also required for appropriate regulation of caspase genes.


Assessing the effects of HIV/AIDS and TB disease control programmes on health systems in low- and middle-income countries of Southeast Asia: a semi-systematic review of the literature.
To systematically review the literature on if and how HIV/AIDS and TB programmes have impacted on general healthcare systems in Association of Southeast Asian Nations (ASEAN) countries. Medline, Embase, Global Health and CINHAL were searched for English language literature published between 1st January 2003 and 31st March 2011. Papers included had to focus on: HIV and/or TB control programmes; the low- and-middle-income ASEAN countries; and factors related to any health systems functions. The effects were examined along six system functions: Stewardship and Governance; Financing; Planning; Service Delivery; Monitoring and Evaluation; and Demand Generation. A comprehensive thematic analytical tool aligned with the above six health systems functions was developed to support data extraction and analysis. 88 papers met the inclusion criteria. Most programme effects highlighted were related with health service delivery. The other five health system functions were seldom scrutinized, and each covered by less than a quarter of papers. Overall 69% of effects highlighted were positive effects whereas 31% were negative. There was a paucity of robust evidence. Effects on health systems were rarely a focus of research protocols but more often a minor component in the Results/Discussion sections. Particular attention should be paid by Global Health Initiatives to the negative effects that emerged from this study, such as the development of parallel systems, specific incentives not available to the general health systems, and lack of integration of services with private healthcare providers.


Integrated empirical ethics: loss of normativity?
An important discussion in contemporary ethics concerns the relevance of empirical research for ethics. Specifically, two crucial questions pertain, respectively, to the possibility of inferring normative statements from descriptive statements, and to the danger of a loss of normativity if normative statements should be based on empirical research. Here we take part in the debate and defend integrated empirical ethical research: research in which normative guidelines are established on the basis of empirical research and in which the guidelines are empirically evaluated by focusing on observable consequences. We argue that in our concrete example normative statements are not derived from descriptive statements, but are developed within a process of reflection and dialogue that goes on within a specific praxis. Moreover, we show that the distinction in experience between the desirable and the undesirable precludes relativism. The normative guidelines so developed are both critical and normative: they help in choosing the right action and in evaluating that action. Finally, following Aristotle, we plead for a return to the view that morality and ethics are inherently related to one another, and for an acknowledgment of the fact that moral judgments have their origin in experience which is always related to historical and cultural circumstances.


The effect of long-term macrolide treatment on respiratory microbiota composition in non-cystic fibrosis bronchiectasis: an analysis from the randomised, double-blind, placebo-controlled BLESS trial.
Long-term macrolide treatment has proven benefit in inflammatory airways diseases, but whether it leads to changes in the composition of respiratory microbiota is unknown. We aimed to assess whether long-term, low-dose erythromycin treatment changes the composition of respiratory microbiota in people with non-cystic fibrosis bronchiectasis. Microbiota composition was determined by 16S rRNA gene sequencing of sputum samples from participants in the BLESS trial, a 12-month, double-blind, placebo-controlled trial of twice-daily erythromycin ethylsuccinate (400 mg) in adult patients with non-cystic fibrosis bronchiectasis and at least two infective exacerbations in the preceding year. The primary outcome was within-patient change in respiratory microbiota composition (assessed by Bray-Curtis index) between baseline and week 48, comparing erythromycin with placebo. The BLESS trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12608000460303. The BLESS trial took place between Oct 15, 2008, and Dec 14, 2011. Paired sputum samples were available from 86 randomly assigned patients, 42 in the placebo group and 44 in the erythromycin group. The change in microbiota composition between baseline and week 48 was significantly greater with erythromycin than with placebo (median Bray-Curtis score 0·52 [IQR 0·14-0·78] vs 0·68 [0·46-0·93]; median difference 0·16, 95% CI 0·01-0·33; p=0·03). In patients with baseline airway infection dominated by Pseudomonas aeruginosa, erythromycin did not change microbiota composition significantly. In those with infection dominated by organisms other than P. aeruginosa, erythromycin caused a significant change in microbiota composition (p=0·03 [by analysis of similarity]), representing a reduced relative abundance of Haemophilus influenzae (35·3% [5·5-91·6] vs 6·7% [0·8-74·8]; median difference 12·6%, 95% CI 0·4-28·3; p=0·04; interaction p=0·02) and an increased relative abundance of P aeruginosa (0·02% [0·00-0·33] vs 0·13% [0·01-39·58]; median difference 6·6%, 95% CI 0·1-37·1; p=0·002; interaction p=0·45). Compared with placebo, erythromycin reduced the rate of pulmonary exacerbations over the 48 weeks of the study in patients with P. aeruginosa-dominated infection (median 1 [IQR 0-3] vs 3 [2-5]; median difference -2, 95% CI -4 to -1; p=0·01), but not in those without P. aeruginosa-dominated infection (1 [0-2] vs 1 [0-3]; median difference 0, -1 to 0; p=0·41; interaction p=0·04). Long-term erythromycin treatment changes the composition of respiratory microbiota in patients with bronchiectasis. In patients without P. aeruginosa airway infection, erythromycin did not significantly reduce exacerbations and promoted displacement of H. influenzae by more macrolide-tolerant pathogens including P. aeruginosa. These findings argue for a cautious approach to chronic macrolide use in patients without P. aeruginosa airway infection. Mater Adult Respiratory Research Trust Fund.


Clonality assessment and clonal ordering of individual neoplastic crypts shows polyclonality of colorectal adenomas.
According to the somatic mutation theory, monoclonal colorectal lesions arise from sequential mutations in the progeny of a single stem cell. However, studies in a sex chromosome mixoploid mosaic (XO/XY) patient indicated that colorectal adenomas were polyclonal. We assessed adenoma clonality on an individual crypt basis and completed a genetic dependency analysis in carcinomas-in-adenomas to assess mutation order and timing. Polyp samples were analyzed from the XO/XY individual, patients with familial adenomatous polyposis and attenuated familial adenomatous polyposis, patients with small sporadic adenomas, and patients with sporadic carcinoma-in-adenomas. Clonality was analyzed using X/Y chromosome fluorescence in situ hybridization, analysis of 5q loss of heterozygosity in XO/XY tissue, and sequencing of adenomatous polyposis coli. Individual crypts and different phenotypic areas of carcinoma-in-adenoma lesions were analyzed for mutations in adenomatous polyposis coli, p53, and K-RAS; loss of heterozygosity at 5q, 17p, and 18q; and aneuploidy. Phylogenetic trees were constructed. All familial adenomatous polyposis-associated adenomas and some sporadic lesions had polyclonal genetic defects. Some independent clones appeared to be maintained in advanced adenomas. No clear obligate order of genetic events was established. Top-down growth of dysplastic tissue into neighboring crypts was a possible mechanism of clonal competition. Human colorectal microadenomas are polyclonal and may arise from a combination of host genetic features, mucosal exposures, and active crypt interactions. Analyses of tumor phylogenies show that most lesions undergo intermittent genetic homogenization, but heterotypic mutation patterns indicate that independent clonal evolution can occur throughout adenoma development. Based on observations of clonal ordering the requirement and timing of genetic events during neoplastic progression may be more variable than previously thought.


Development of illusory-contour perception in infants.
We investigated whether infants from 8-22 weeks of age were sensitive to the illusory contour created by aligned line terminators. Previous reports of illusory-contour detection in infants under 4 months old could be due to infants' preference for the presence of terminators rather than their configuration. We generated preferential-looking stimuli containing sinusoidal lines whose oscillating, abutting terminators give a strong illusory contour in adult perception. Our experiments demonstrated a preference in infants 8 weeks old and above for an oscillating illusory contour compared with a stimulus containing equal terminator density and movement. Control experiments excluded local line density, or attention to alignment in general, as the basis for this result. In the youngest age group (8-10 weeks) stimulus velocity appears to be critical in determining the visibility of illusory contours, which is consistent with other data on motion processing at this age. We conclude that, by 2 months of age, the infant's visual system contains the nonlinear mechanisms necessary to extract an illusory contour from aligned terminators.


Resilience Factors in Children with Juvenile Idiopathic Arthritis and Their Parents: The Role of Child and Parent Psychological Flexibility.
Chronic pain is central to juvenile idiopathic arthritis (JIA) and is predictive of impaired functioning. Whereas most work has focused on identifying psychosocial risk factors for maladaptive outcomes, we explored the idea that child and parental psychological flexibility (PF) represent resilience factors for adaptive functioning of the child. We also explored differences between general vs pain-specific PF in contributing to child outcomes. Children with JIA (age eight to 18 years) and (one of) their parents were recruited at the Department of Pediatric Rheumatology at the Ghent University Hospital in Belgium. They completed questionnaires assessing child and parent general and pain-specific PF and child psychosocial and emotional functioning and disability. The final sample consisted of 59 children and 48 parents. Multiple regression analyses revealed that child PF contributed to better psychosocial functioning and less negative affect. Child pain acceptance contributed to better psychosocial functioning, lower levels of disability, and lower negative affect, and also buffered the negative influence of pain intensity on disability. Bootstrap mediation analyses demonstrated that parental (general) PF indirectly contributed to child psychosocial functioning and affect via the child's (general) PF. Parent pain-specific PF was indirectly linked to child psychosocial functioning, disability, and negative affect via child pain acceptance. Our findings indicate that child and parental PF are resilience factors and that pain acceptance buffers the negative impact of pain intensity. Implications for psychosocial interventions that target (pain-specific) PF in children and parents are discussed.


Frequent basal cell cancer development is a clinical marker for inherited cancer susceptibility.
Innate DNA repair mechanisms play a critical role in protecting skin keratinocytes from UV mutagenesis and skin cancer development. We hypothesized that individuals who develop frequent skin cancers may harbor germline defects in DNA repair genes and have increased predisposition to internal malignancies. We enrolled 61 patients with unusually frequent basal cell carcinoma (BCC) development, seen at Stanford Hospital and Clinics from January 2005 until December 2015, for germline analysis of 29 DNA repair genes. In parallel, a case-control retrospective review was performed to interrogate the association of malignancies with frequent BCC development in a large US medical insurance claims database (Truven), which included 13,264 individuals with 6 or more BCCs from 2007 to 2011. 19.7% of the frequent BCC cohort harbored pathogenic mutations in DNA repair genes: APC, BARD1, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NBN, and PALB2. Individuals with 6 or more BCCs had an increased risk of other malignancies, with a 3.5-fold increase in the frequent BCC cohort and a 3.2-fold increase in the Truven database. Individuals who developed frequent BCCs have an increased prevalence of germline mutations in DNA repair genes and increased malignancy risk. Our data implicate frequent BCC development as an external marker of inherited cancer risk.


Extensive amplification of the E2F transcription factor binding sites by transposons during evolution of Brassica species.
Transposable elements (TEs) are major players in genome evolution. The effects of their movement vary from gene knockouts to more subtle effects such as changes in gene expression. It has recently been shown that TEs may contain transcription factor binding sites (TFBSs), and it has been proposed that they may rewire new genes into existing transcriptional networks. However, little is known about the dynamics of this process and its effect on transcription factor binding. Here we show that TEs have extensively amplified the number of sequences that match the E2F TFBS during Brassica speciation, and, as a result, as many as 85% of the sequences that fit the E2F TFBS consensus are within TEs in some Brassica species. We show that these sequences found within TEs bind E2Fa in vivo, which indicates a direct effect of these TEs on E2F-mediated gene regulation. Our results suggest that the TEs located close to genes may directly participate in gene promoters, whereas those located far from genes may have an indirect effect by diluting the effective amount of E2F protein able to bind to its cognate promoters. These results illustrate an extreme case of the effect of TEs in TFBS evolution, and suggest a singular way by which they affect host genes by modulating essential transcriptional networks.


Vitamin D and Calcium for the Prevention of Fracture: A Systematic Review and Meta-analysis.
Vitamin D and calcium supplements are recommended for the prevention of fracture, but previous randomized clinical trials (RCTs) have reported conflicting results, with uncertainty about optimal doses and regimens for supplementation and their overall effectiveness. To assess the risks of fracture associated with differences in concentrations of 25-hydroxyvitamin D (25[OH]D) in observational studies and the risks of fracture associated with supplementation with vitamin D alone or in combination with calcium in RCTs. PubMed, EMBASE, Cochrane Library, and other RCT databases were searched from database inception until December 31, 2018. Searches were performed between July 2018 and December 2018. Observational studies involving at least 200 fracture cases and RCTs enrolling at least 500 participants and reporting at least 10 incident fractures were included. Randomized clinical trials compared vitamin D or vitamin D and calcium with control. Two researchers independently extracted data according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and assessed possible bias. Rate ratios (RRs) were estimated using fixed-effects meta-analysis. Data extraction and synthesis took place between July 2018 and June 2019. Any fracture and hip fracture. In a meta-analysis of 11 observational studies (39 141 participants, 6278 fractures, 2367 hip fractures), each increase of 10.0 ng/mL (ie, 25 nmol/L) in 25 (OH)D concentration was associated with an adjusted RR for any fracture of 0.93 (95% CI, 0.89-0.96) and an adjusted RR for hip fracture of 0.80 (95% CI, 0.75-0.86). A meta-analysis of 11 RCTs (34 243 participants, 2843 fractures, 740 hip fractures) of vitamin D supplementation alone (daily or intermittent dose of 400-30 000 IU, yielding a median difference in 25[OH]D concentration of 8.4 ng/mL) did not find a reduced risk of any fracture (RR, 1.06; 95% CI, 0.98-1.14) or hip fracture (RR, 1.14; 95% CI, 0.98-1.32), but these trials were constrained by infrequent intermittent dosing, low daily doses of vitamin D, or an inadequate number of participants. In contrast, a meta-analysis of 6 RCTs (49 282 participants, 5449 fractures, 730 hip fractures) of combined supplementation with vitamin D (daily doses of 400-800 IU, yielding a median difference in 25[OH]D concentration of 9.2 ng/mL) and calcium (daily doses of 1000-1200 mg) found a 6% reduced risk of any fracture (RR, 0.94; 95% CI, 0.89-0.99) and a 16% reduced risk of hip fracture (RR, 0.84; 95% CI, 0.72-0.97). In this systematic review and meta-analysis, neither intermittent nor daily dosing with standard doses of vitamin D alone was associated with reduced risk of fracture, but daily supplementation with both vitamin D and calcium was a more promising strategy.


A Prospective Study of Leukocyte Telomere Length and Risk of Gestational Diabetes in a Multiracial Cohort.
Short telomere length (TL), an indicator of cellular aging and oxidative stress, has been implicated in glucose homeostasis. Additionally, studies have illustrated that the association of TL with health outcomes may vary by age. Yet, data on the association between TL and gestational diabetes mellitus (GDM) are sparse and the potential effect modification by age remains unknown. We prospectively investigated TL in early pregnancy in relation to the subsequent GDM risk in a case-control study of 93 women with GDM and 186 randomly selected controls matched on age, race/ethnicity, and gestational weeks at blood collection. TL was measured using blood samples collected at 10-14 gestational weeks and reported as the T/S ratio, a ratio of telomere repeat length T to copy number of a single copy gene S. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression adjusted for major risk factors. Overall, TL was not significantly associated with GDM risk. The TL-GDM association was significantly modified by age (Pinteraction = 0.02). Shorter TL in early pregnancy was associated with an increased GDM risk among women <30 years old (adjusted OR comparing the shortest vs. longest tertile: 3.1, 95% CI = 1.2, 8.1), but not associated with GDM risk among women ≥30 years. Our findings suggest that TL in early pregnancy may be implicated in GDM development, particularly among younger women.


CSM-SD: methodology for contrast set mining through subgroup discovery.
This paper addresses a data analysis task, known as contrast set mining, whose goal is to find differences between contrasting groups. As a methodological novelty, it is shown that this task can be effectively solved by transforming it to a more common and well-understood subgroup discovery task. The transformation is studied in two learning settings, a one-versus-all and a pairwise contrast set mining setting, uncovering the conditions for each of the two choices. Moreover, the paper shows that the explanatory potential of discovered contrast sets can be improved by offering additional contrast set descriptors, called the supporting factors. The proposed methodology has been applied to uncover distinguishing characteristics of two groups of brain stroke patients, both with rapidly developing loss of brain function due to ischemia:those with ischemia caused by thrombosis and by embolism, respectively.


Characterization of high-resolution diffractive X-ray optics by ptychographic coherent diffractive imaging.
We have employed ptychographic coherent diffractive imaging to completely characterize the focal spot wavefield and wavefront aberrations of a high-resolution diffractive X-ray lens. The ptychographic data from a strongly scattering object was acquired using the radiation cone emanating from a coherently illuminated Fresnel zone plate at a photon energy of 6.2 keV. Reconstructed images of the object were retrieved with a spatial resolution of 8 nm by combining the difference-map phase retrieval algorithm with a non-linear optimization refinement. By numerically propagating the reconstructed illumination function, we have obtained the X-ray wavefield profile of the 23 nm round focus of the Fresnel zone plate (outermost zone width, Δr = 20 nm) as well as the X-ray wavefront at the exit pupil of the lens. The measurements of the wavefront aberrations were repeatable to within a root mean square error of 0.006 waves, and we demonstrate that they can be related to manufacturing aspects of the diffractive optical element and to errors on the incident X-ray wavefront introduced by the upstream beamline optics.


Femoral Derotation Osteotomy Technique for Excessive Femoral Anteversion.
Excessive femoral anteversion may lead to increasing stress placed on the anterior acetabulum and soft tissues, which can predispose to intra-articular hip pathology. By addressing the excessive femoral anteversion in combination with intra-articular hip pathology, the results will be durable over time. This technique details how to perform a femoral derotation osteotomy for excessive femoral anteversion after addressing intra-articular pathology with hip arthroscopy in one surgical intervention. This allows the surgeon to address both the underlying pathoanatomy and the resultant intra-articular sequelae.


Effect of humor on interpersonal attraction and mate selection.
The authors examined whether different levels of sense of humor would influence respondents' ratings about a potentially desirable partner. The authors used vignettes to predict that the targets who possessed a good sense of humor would receive significantly higher ratings in measures of attractiveness and suitability as a long-term partner than would those who possessed an average or no sense of humor. In an experimental design--with gender and humor as independent variables and level of attractiveness and suitability as a long-term partner as dependent variables--the authors analyzed the data using a multivariate analysis of variance. Results show that the targets with a good sense of humor received significantly higher ratings of attractiveness and suitability than did those with an average or no sense of humor. Furthermore, male participants rated female targets as significantly more attractive than female participants rated male targets. The authors found no significant interaction between gender and humor.


A NH2 tau fragment targets neuronal mitochondria at AD synapses: possible implications for neurodegeneration.
Synapses are ultrastructural sites for memory storage in brain, and synaptic damage is the best pathologic correlate of cognitive decline in Alzheimer's disease (AD). Post-translational hyperphosphorylation, enzyme-mediated truncation, conformational modifications, and aggregation of tau protein into neurofibrillary tangles (NFTs) are hallmarks for a heterogeneous group of neurodegenerative disorders, so-called tauopathies. AD is a secondary tauopathy since it is pathologically distinguished by the presence of amyloid-beta (Abeta)-containing senile plaques and the presence of tau-positive NFTs in the neocortex and hippocampus. Here, we report that a 20-22 kDa NH2-truncated tau fragment is largely enriched in human mitochondria from cryopreserved synaptosomes of AD brains and that its amount in terminal fields correlates with the pathological synaptic changes and with the organelle functional impairment. This NH2-truncated tau form is also found in other human, not AD-tauopathies, while its presence in AD patients is linked to Abeta multimeric species and likely to pathology severity. Finally native, patient-derived, Abeta oligomers-enriched extracts likely impair the mitochondrial function by the in vitro production of 20-22 kDa NH2-tau fragments in mature human SY5Y and in rat hippocampal neurons. Thus our findings suggest that the mitochondrial NH2-derived tau peptide distribution may exacerbate the synapse degeneration occurring in tauopathies, including AD, and sustain the in vivo NH-2 tau cleavage inhibitors as an alternative drug discovery strategies for AD therapy.


Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction.
Recent evidence suggests that cardiac progenitor cells (CPCs) may improve cardiac function after injury. The underlying mechanisms are indirect, but their mediators remain unidentified. Exosomes and other secreted membrane vesicles, hereafter collectively referred to as extracellular vesicles (EVs), act as paracrine signalling mediators. Here, we report that EVs secreted by human CPCs are crucial cardioprotective agents. CPCs were derived from atrial appendage explants from patients who underwent heart valve surgery. CPC-conditioned medium (CM) inhibited apoptosis in mouse HL-1 cardiomyocytic cells, while enhancing tube formation in human umbilical vein endothelial cells. These effects were abrogated by depleting CM of EVs. They were reproduced by EVs secreted by CPCs, but not by those secreted by human dermal fibroblasts. Transmission electron microscopy and nanoparticle tracking analysis showed most EVs to be 30-90 nm in diameter, the size of exosomes, although smaller and larger vesicles were also present. MicroRNAs most highly enriched in EVs secreted by CPCs compared with fibroblasts included miR-210, miR-132, and miR-146a-3p. miR-210 down-regulated its known targets, ephrin A3 and PTP1b, inhibiting apoptosis in cardiomyocytic cells. miR-132 down-regulated its target, RasGAP-p120, enhancing tube formation in endothelial cells. Infarcted hearts injected with EVs from CPCs, but not from fibroblasts, exhibited less cardiomyocyte apoptosis, enhanced angiogenesis, and improved LV ejection fraction (0.8 ± 6.8 vs. -21.3 ± 4.5%; P < 0.05) compared with those injected with control medium. EVs are the active component of the paracrine secretion by human CPCs. As a cell-free approach, EVs could circumvent many of the limitations of cell transplantation.


RF absorption involving biological macromolecules.
The fundamental intramolecular frequency of a globular protein can be obtained from the measurements of acoustic velocities of bulk protein matter. This lowest frequency for common size molecules is shown to be above several hundred GHz. All modes below this frequency would then be intermolecular modes or bulk modes of the molecule and surrounding matter or tissue. The lowest frequency modes of an extended DNA double helix are also shown to be bulk modes because of interaction with water. Only DNA modes, whose frequency is well above 4 GHz, can be intrahelical modes, that is, confined to the helix rather than in the helix plus surroundings. Near 4 GHz, they are heavily damped and, therefore, not able to resonantly absorb. Modes that absorb radio frequency (RF) below this frequency are bulk modes of the supporting matter. Bulk modes rapidly thermalize all absorbed energy. The implication of these findings for the possibility of athermal RF effects is considered. The applicability of these findings for other biological molecules is discussed.


The potential synergistic effects between psychedelic administration and nature contact for the improvement of mental health.
Therapeutic psychedelic administration and contact with nature have been associated with the same psychological mechanisms: decreased rumination and negative affect, enhanced psychological connectedness and mindfulness-related capacities, and heightened states of awe and transcendent experiences, all processes linked to improvements in mental health amongst clinical and healthy populations. Nature-based settings can have inherently psychologically soothing properties which may complement all stages of psychedelic therapy (mainly preparation and integration) whilst potentiating increases in nature relatedness, with associated psychological benefits. Maximising enhancement of nature relatedness through therapeutic psychedelic administration may constitute an independent and complementary pathway towards improvements in mental health that can be elicited by psychedelics.


Revealing Hidden Gender Biases in Competence Impressions of Faces.
Competence impressions from faces affect important decisions, such as hiring and voting. Here, using data-driven computational models, we identified the components of the competence stereotype. Faces manipulated by a competence model varied in attractiveness (Experiment 1a). However, faces could be manipulated on perceived competence controlling for attractiveness (Experiment 1b); moreover, faces perceived as more competent but not attractive were also perceived as more confident and masculine, suggesting a bias to perceive male faces as more competent than female faces (Experiment 2). Correspondingly, faces manipulated to appear competent but not attractive were more likely to be classified as male (Experiment 3). When masculinity cues that induced competence impressions were applied to real-life images, these cues were more effective on male faces (Experiment 4). These findings suggest that the main components of competence impressions are attractiveness, confidence, and masculinity, and they reveal gender biases in how we form important impressions of other people.


Publication bias in the pulmonary/allergy literature: effect of pharmaceutical company sponsorship.
A publication bias exists towards positive results in studies funded by pharmaceutical companies. To determine whether drug studies in the pulmonary/allergy literature also demonstrate a publication bias towards more favorable results when a pharmaceutical company funds the study. We reviewed all original articles published in seven pulmonary and allergy journals between October 2002 and September 2003. Included in the review were studies of inhaled corticosteroids (oral or nasal), long- or short-acting bronchodilators, or leukotriene receptor antagonists. Articles with funding from a pharmaceutical company and/or one or more authors employed by a pharmaceutical company were considered pharmaceutical company-sponsored studies. The remaining studies were considered not sponsored by a pharmaceutical company. Results were compared to ascertain whether positive results were obtained more frequently in the company-sponsored studies. Of the 100 articles included in this review 63 were considered pharmaceutical company-sponsored research. Results favorable for the drugs studies were significantly more common in those funded by a pharmaceutical company (98% vs. 32%). In the pulmonary and allergy literature, as in other fields, there is a publication bias towards positive results in pharmaceutical company-sponsored research.


p-Chloroamphetamine (PCA), 3,4-methylenedioxy-methamphetamine (MDMA) and d-fenfluramine pretreatment attenuates d-fenfluramine-evoked release of 5-HT in vivo.
Previous work has suggested that repeated treatment with substituted amphetamines including PCA, MDMA and d-fenfluramine produces a persistent neurodegeneration which is relatively selective for the fine serotoninergic terminals arising from the dorsal raphe nucleus. The aim of the present study was to investigate whether the acute releasing effect of d-fenfluramine might also be sensitive to lesions produced by PCA, MDMA and d-fenfluramine itself. Basal and 5-HT release evoked by d-fenfluramine or 100 mM KCl was measured by microdialysis in frontal or parietal cortex of rats 2 weeks after they had been treated with a neurodegenerative regime of PCA, MDMA, d-fenfluramine, or vehicle. In frontal cortex of vehicle controls, d-fenfluramine (10 mg/kg IP) and KCl (100 mM via microdialysis probe) evoked an increase in 5-HT of 1740% and 779% of basal, respectively. PCA pretreatment reduced d-fenfluramine-evoked 5-HT release by 90.9% while potassium-evoked release was reduced by only 66.8%. Similar results were obtained in parietal cortex. MDMA (20 mg/kg x 8) and d-fenfluramine (1.25 mg/kg x 8) pretreatment reduced d-fenfluramine-evoked release of 5-HT in frontal cortex by 45.2% and 72.0%, respectively. Overall, the present data are consistent with the hypothesis that the acute release of 5-HT evoked by d-fenfluramine occurs via those terminals destroyed by pretreatment with PCA, MDMA and d-fenfluramine, while KCl evokes release from both PCA-sensitive and PCA-insensitive terminals. The significance of these results for the interpretation of neuroendocrine data from d-fenfluramine challenge tests is discussed.


Epigenetic control of the angiotensin-converting enzyme in endothelial cells during inflammation.
The angiotensin-converting enzyme (ACE) plays a central role in the renin-angiotensin system, which is involved in the regulation of blood pressure. Alterations in ACE expression or activity are associated with various pathological phenotypes, particularly cardiovascular diseases. In human endothelial cells, ACE was shown to be negatively regulated by tumor necrosis factor (TNF) α. To examine, whether or not, epigenetic factors were involved in ACE expression regulation, methylated DNA immunoprecipitation and RNA interference experiments directed against regulators of DNA methylation homeostasis i.e., DNA methyltransferases (DNMTs) and ten-eleven translocation methylcytosine dioxygenases (TETs), were performed. TNFα stimulation enhanced DNA methylation in two distinct regions within the ACE promoter via a mechanism linked to DNMT3a and DNMT3b, but not to DNMT1. At the same time, TET1 protein expression was downregulated. In addition, DNA methylation decreased the binding affinity of the transcription factor MYC associated factor X to the ACE promoter. In conclusion, DNA methylation determines the TNFα-dependent regulation of ACE gene transcription and thus protein expression in human endothelial cells.


LncRNA loc285194 is a p53-regulated tumor suppressor.
Protein-coding genes account for only a small part of the human genome, whereas the vast majority of transcripts make up the non-coding RNAs including long non-coding RNAs (lncRNAs). Accumulating evidence indicates that lncRNAs could play a critical role in regulation of cellular processes such as cell growth and apoptosis as well as cancer progression and metastasis. LncRNA loc285194 was previously shown to be within a tumor suppressor unit in osteosarcoma and to suppress tumor cell growth. However, it is unknown regarding the regulation of loc285194. Moreover, the underlying mechanism by which loc285194 functions as a potential tumor suppressor is elusive. In this study, we show that loc285194 is a p53 transcription target; ectopic expression of loc285194 inhibits tumor cell growth both in vitro and in vivo. Through deletion analysis, we identify an active region responsible for tumor cell growth inhibition within exon 4, which harbors two miR-211 binding sites. Importantly, this loc285194-mediated growth inhibition is in part due to specific suppression of miR-211. We further demonstrate a reciprocal repression between loc285194 and miR-211; in contrast to loc285194, miR-211 promotes cell growth. Finally, we detect downregulation of loc285194 in colon cancer specimens by quantitative PCR arrays and in situ hybridization of tissue microarrays. Together, these results suggest that loc285194 is a p53-regulated tumor suppressor, which acts in part through repression of miR-211.


The effect of EDTA in attachment gain and root coverage.
Root surface biomodification using low pH agents such as citric acid and tetracycline has been proposed to enhance root coverage following connective tissue grafting. The authors hypothesized that root conditioning with neutral pH edetic acid would improve vertical recession depth, root surface coverage, pocket depth, and clinical attachment levels. Twenty teeth in 10 patients with Miller class I and II recession were treated with connective tissue grafting. The experimental sites received 24% edetic acid in sterile distilled water applied to the root surface for 2 minutes before grafting. Controls were pretreated with only sterile distilled water. Measurements were evaluated before surgery and 6 months after surgery. Analysis of variance was used to determine differences between experimental and control groups. We found significant postoperative improvements in vertical recession depth, root surface coverage, and clinical attachment levels in test and control groups, compared to postoperative data. Pocket depth differences were not significant (P<.01).


Stereoscopic acuity and observation distance.
The amount of depth perceived from a fixed pattern of horizontal disparities varies with viewing distance. We investigated whether thresholds for discriminating stereoscopic corrugations at a range of spatial frequencies were also affected by viewing distance or whether they were determined solely by the angular disparity in the stimulus prior to scaling. Although thresholds were found to be determined primarily by disparity over a broad range of viewing distances, they were on average a factor of two higher at the shortest viewing distance (28.5 cm) than at larger viewing distances (57 to 450 cm). We found the same pattern of results when subjects' accommodation was arranged to be the same at all viewing distances. The change in thresholds at close distances is in the direction expected if subjects' performance is limited by a minimum perceived depth.


What will it take to meet UNAIDS targets for preexposure prophylaxis users?
Preexposure prophylaxis (PrEP) is a critical strategy to curb new HIV infections globally. National and global targets have been set for people starting PrEP. However, global PrEP initiations fell short of UNAIDS 2020 targets, and reflection is needed on how we set and meet targets for PrEP use. Recent literature documents challenges to meeting ambitious goals for PrEP coverage in multiple phases of PrEP: PrEP initiations are limited by gaps in the identification of those who might benefit from PrEP. Conversely, getting PrEP to those who need it most is threatened by inaccurate risk perception and HIV and PrEP stigma. Once people are on PrEP, a substantial number discontinue PrEP in the first year (the 'PrEP Cliff'), a finding that is robust across groups of PrEP users (e.g., women, men who have sex with men, transwomen) and across global prevention settings. Further, PrEP inequities - by which we refer to utilization of PrEP in a specific group that is not commensurate with their epidemic risk - threaten the overall population benefit of PrEP because those at highest risk of acquiring HIV are not adequately protected. To realize global goals for PrEP utilization and impact, we must address multiple points of PrEP delivery programs that address not just PrEP starts, but also retention in PrEP and measurement and accountability to PrEP equity. We call for new approaches to better identify PrEP candidates, suggest additional research to address the known and consistent reasons for PrEP discontinuations, and advocate for metrics to measure and be accountable to PrEP equity.


A qualitative study of the aspirations and challenges of low-income mothers in feeding their preschool-aged children.
The prevalence of obesity among preschool-aged children has increased, especially among those in low-income households. Two promising behavioral targets for preventing obesity include limiting children's portion sizes and their intake of foods high in solid fats and/or added sugars, but these approaches have not been studied in low-income preschoolers in the home setting. The purpose of this study was to understand the contextual factors that might influence how low-income mothers felt about addressing these behavioral targets and mothers' aspirations in feeding their children. We recruited 32 English-speaking women in Philadelphia, Pennsylvania who were eligible for the Supplemental Nutrition Assistance Program and who were the biologic mothers of children 36 to 66 months of age. Each mother participated in 1 of 7 focus groups and completed a brief socio-demographic questionnaire. Focus group questions centered on eating occasions, foods and drinks consumed in the home, and portion sizes. Each focus group lasted 90 minutes and was digitally recorded and transcribed verbatim. Three authors independently identified key themes and supporting quotations. Themes were condensed and modified through discussion among all authors. Thirty-one mothers identified themselves as black, 15 had a high school education or less, and 22 lived with another adult. Six themes emerged, with three about aspirations mothers held in feeding their children and three about challenges to achieving these aspirations. Mothers' aspirations were to: 1) prevent hyperactivity and tooth decay by limiting children's sugar intake, 2) use feeding to teach their children life lessons about limit setting and structure, and 3) be responsive to children during mealtimes to guide decisions about portions. Especially around setting limits with sweets and snacks, mothers faced the challenges of: 1) being nagged by children's food requests, 2) being undermined by other adults in the family, and 3) having bad memories from childhood that made it hard to deny children's food requests. Although the primary aspirations of low-income mothers in feeding their preschool-aged children were not focused on children's weight, these aspirations were compatible with obesity prevention strategies to limit children's portion sizes and their intake of solid fats and/or added sugars.