Clinical evidence for the activity of tetrahydroxypropyl ethylenediamine (THPE), a new anti-aging active cosmetic.
BACKGROUND/ OBJECTIVES: The cellular surface modification of superficial epidermal keratinocytes can induce immediate skin tensioning effects and may improve signs of skin aging. Tetrahydroxypropyl ethylenediamine (THPE) is an active that has been described to induce keratinocytes' morphological changes in vitro. We conducted an in vivo study to assess anti-aging clinical benefits of a THPE-containing product. An eight-week double-blind, randomized intra-individual placebo controlled clinical study was performed to evaluate the clinical benefits of a 2.5% THPE-containing cream. This study included 41 Caucasian women who received the THPE cream product on one side of the face and a placebo cream on the other side daily. Evaluations were performed at baseline, 45 minutes after first application, week 4 and week 8 and included clinical examination and digital photography. The study demonstrated the immediate lifting effect of a 2.5% THPE-containing cream. Forty-five minutes after a single application on the face, as the skin surface smoothed out, light reflection was modified: healthy glow and radiance of the skin were significantly improved (respectively 22.9% and 40% of improvement) and skin yellowishness was reduced (7.1%). Notably, the THPE-treated side was significantly lifted, both immediately after product application (8.1%) and after 8 weeks of application (14%), compared to the placebo-treated side. This clinical study demonstrated that the effect of a 2.5% THPE-containing cream on the keratinocytes cells leads to an immediate and long-term clinical improvement of the skin appearance (radiance and skin firmness, skin lifting) and can therefore be considered as a new anti-aging cosmetic active.


Coffee, tea, and caffeine consumption and prevention of late-life cognitive decline and dementia: a systematic review.
A prolonged preclinical phase of more than two decades before the onset of dementia suggested that initial brain changes of Alzheimer's disease (AD) and the symptoms of advanced AD may represent a unique continuum. Given the very limited therapeutic value of drugs currently used in the treatment of AD and dementia, preventing or postponing the onset of AD and delaying or slowing its progression are becoming mandatory. Among possible reversible risk factors of dementia and AD, vascular, metabolic, and lifestyle-related factors were associated with the development of dementia and late-life cognitive disorders, opening new avenues for the prevention of these diseases. Among diet-associated factors, coffee is regularly consumed by millions of people around the world and owing to its caffeine content, it is the best known psychoactive stimulant resulting in heightened alertness and arousal and improvement of cognitive performance. Besides its short-term effect, some case-control and cross-sectional and longitudinal population-based studies evaluated the long-term effects on brain function and provided some evidence that coffee, tea, and caffeine consumption or higher plasma caffeine levels may be protective against cognitive impairment/decline and dementia. In particular, several cross-sectional and longitudinal population-based studies suggested a protective effect of coffee, tea, and caffeine use against late-life cognitive impairment/decline, although the association was not found in all cognitive domains investigated and there was a lack of a distinct dose-response association, with a stronger effect among women than men. The findings on the association of coffee, tea, and caffeine consumption or plasma caffeine levels with incident mild cognitive impairment and its progression to dementia were too limited to draw any conclusion. Furthermore, for dementia and AD prevention, some studies with baseline examination in midlife pointed to a lack of association, although other case-control and longitudinal population-based studies with briefer follow-up periods supported favourable effects of coffee, tea, and caffeine consumption against AD. Larger studies with longer follow-up periods should be encouraged, addressing other potential bias and confounding sources, so hopefully opening new ways for diet-related prevention of dementia and AD.


Comorbidity Burden and Health Services Use in Community-Living Older Adults with Diabetes Mellitus: A Retrospective Cohort Study.
Diabetes frequently coexists with other conditions, resulting in poorer diabetes self-management and quality of life, higher risk for diabetes-related complications and higher health service use compared to those with diabetes only. Few Canadian studies have undertaken a comprehensive, population-level analysis of comorbidity and health service utilization by older adults with diabetes. This study examined comorbidity and its association with a broad range of health services in a cohort of community-dwelling older adults with diabetes in Ontario, Canada. We linked multiple administrative databases to create a cohort of 448,736 older adults with diabetes, described their comorbidities and obtained their 1-year use of health services (physician visits, emergency department visits, inpatient hospital admissions, home care use, nursing home admissions). We examined comorbidity patterns by age and gender and estimated the prevalence of 20 comorbid conditions and the most common condition clusters. The association between number of comorbidities and health service use was also examined. More than 90% of the cohort had at least 1 comorbid condition. The number of comorbidities increased with age for both genders, and hypertension was the most common, affecting 79.1% of the cohort. Other common conditions included other cardiovascular conditions, ischemic heart disease, arthritis and anxiety. Utilization of all health services increased with the number of comorbid conditions. Health service use was driven by the number of comorbid conditions, including diabetes and nondiabetes-related conditions, highlighting the importance of aligning diabetes care plans with patients' comorbidities.


Medium-term determinants of left ventricular mass index after stentless aortic valve replacement.
This study aimed to investigate the risk factors for elevated left ventricular mass index 3 to 5 years after stentless aortic valve replacement, and to elucidate the underlying physiologic mechanisms. Eighty-nine patients (age, 76 +/- 6 years, 51 males) having a stentless porcine valve for aortic stenosis (n = 76) or regurgitation (n = 13) were prospectively studied by Doppler echocardiography 3 to 5 years after operation. Left ventricular systolic function, mass index, blood pressure, cardiac rhythm, and New York Heart Association function class were all determined. Stentless valve effective orifice area, mean pressure drop, and the presence and degree of aortic regurgitation were quantified. The mean stentless aortic valve size was 24 +/- 2 mm. At follow-up time of 45 +/- 9 months, effective orifice area index was 1.2 +/- 0.35 cm2 x m(-2), and mean pressure drop was 5.7 +/- 3.8 mm Hg. Left ventricular mass index was 128 +/- 47 g x m(-2), and ejection fraction was 63% +/- 14%. Multivariant analysis showed a greater left ventricular mass index to be associated with nonsinus rhythm (versus sinus) (163 +/- 8 versus 131 +/- 7 g x m(-2)), greater pulse pressure (> 84 mm Hg) (161 +/- 7 versus 133 +/- 7 g x m(-2)), New York Heart Association class II or III (versus class I) (166 +/- 10 versus 128 +/- 5 g x m(-2)), and male sex (versus female) (160 +/- 7 versus 134 +/- 8 g x m(-2)), all p < 0.01. Mean pressure drop (> 8 mm Hg), effective orifice area index (< 1.0 cm2 x m(-2)), the presence of mild regurgitation of the stentless valve, or the type of previous valve disease were insignificant determinants of left ventricular mass index. Three to five years after the implantation, stentless aortic valve hemodynamics remain excellent. Left ventricular hypertrophy caused by previous native aortic valve disease had largely regressed. However, patient-related factors, particularly systemic blood pressure, cardiac rhythm, and function, are significant causes of late residual left ventricular hypertrophy. Thus, continued medical care and earlier surgical intervention may further improve the outlook for these patients.


Optimum air-demand ratio for maximum aeration efficiency in high-head gated circular conduits.
Oxygen is an important component of water quality and its ability to sustain life. Water aeration is the process of introducing air into a body of water to increase its oxygen saturation. Water aeration can be accomplished in a variety of ways, for instance, closed-conduit aeration. High-speed flow in a closed conduit involves air-water mixture flow. The air flow results from the subatmospheric pressure downstream of the gate. The air entrained by the high-speed flow is supplied by the air vent. The air entrained into the flow in the form of a large number of bubbles accelerates oxygen transfer and hence also increases aeration efficiency. In the present work, the optimum air-demand ratio for maximum aeration efficiency in high-head gated circular conduits was studied experimentally. Results showed that aeration efficiency increased with the air-demand ratio to a certain point and then aeration efficiency did not change with a further increase of the air-demand ratio. Thus, there was an optimum value for the air-demand ratio, depending on the Froude number, which provides maximum aeration efficiency. Furthermore, a design formula for aeration efficiency was presented relating aeration efficiency to the air-demand ratio and Froude number.


Depression, apolipoprotein E genotype, and the incidence of mild cognitive impairment: a prospective cohort study.
It remains unknown whether depression and apolipoprotein E genotype are risk factors for incident mild cognitive impairment (MCI). To determine whether elderly individuals with depression (measured by the short Geriatric Depression Scale) are at increased risk of developing incident MCI. Prospective cohort study. Primary care clinic. A cohort of 840 cognitively normal elderly subjects without depression at recruitment who were followed up prospectively for a median of 3.5 years (range, 0.4-12.8 years). Subjects who developed depression (score of >/=6 on the short Geriatric Depression Scale; depression cohort) were compared with all remaining subjects (referent cohort). Incidence of MCI (primary outcome) and incidence of MCI or dementia (composite secondary outcome). Individuals in the depression cohort were at significantly increased risk of subsequent incident MCI (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.2-4.1) after adjusting for age (time scale), sex, and education, and considering dementia as a competing outcome. The association was stronger in men but did not vary by severity of depression. We observed a synergistic interaction between apolipoprotein E genotype (epsilon3/epsilon4 or epsilon4/epsilon4) and depression (joint effect HR, 5.1; 95% CI, 1.9-13.6; test for additive interaction, P = .03). We found a similar association between depression and the subsequent composite outcome of incident MCI or dementia (HR, 2.6; 95% CI, 1.6-4.3). Cognitively normal elderly individuals who develop depression are at increased risk of subsequent MCI. We found a synergistic interaction between depression and apolipoprotein E genotype.


Duration-Response of Light-Intensity Physical Activity and Glucose Dynamics in Older Adults.
Older adults spend 30% of their day in light-intensity physical activity (LPA). This study was designed to determine if increasing the proportion of time spent in LPA would affect glucose control. Older adults (N = 9) completed four 3-hour treatment conditions consisting of a seated control and 3 randomized conditions: (1) 20% time spent in continuous LPA, 80% seated; (2) 40% time spent in continuous LPA, 60% seated; and (3) 60% time spent in continuous LPA, 40% seated. Energy expenditure was measured continuously, and glucose was measured prior to mixed-meal ingestion and hourly thereafter. Glucose area under the curve was compared between conditions using Friedman test. There was a significant difference in glucose area under the curve by time spent in LPA (P < .001); specifically, between the seated and 60% LPA (mean difference = 35.0 [24.6] mg/dL, P = .01), seated and 40% LPA (mean difference = 25.2 [11.8] mg/dL, P = .03), seated and 20% LPA (mean difference = 17.8 [22.5] mg/dL, P = .03), 20% LPA and 60% LPA (mean difference = 17.2 [22.5] mg/dL, P = .01), and 40% LPA and 60% LPA (mean difference = 9.8 [7.3] mg/dL, P = .01). These results provide experimental evidence to the importance LPA has on metabolic health. If older adults who already spend, on average, about 3 hours per day in LPA, further increase their LPA, they could see benefit to glucose control.


Experimental evidence that changing beliefs about mask efficacy and social norms increase mask wearing for COVID-19 risk reduction: Results from the United States and Italy.
In the absence of widespread vaccination for COVID-19, governments and public health officials have advocated for the public to wear masks during the pandemic. The decision to wear a mask in public is likely affected by both beliefs about its efficacy and the prevalence of the behavior. Greater mask use in the community may encourage others to follow this norm, but it also creates an incentive for individuals to free ride on the protection afforded to them by others. We report the results of two vignette-based experiments conducted in the United States (n = 3,100) and Italy (n = 2,659) to examine the causal relationship between beliefs, social norms, and reported intentions to engage in mask promoting behavior. In both countries, survey respondents were quota sampled to be representative of the country's population on key demographics. We find that providing information about how masks protect others increases the likelihood that someone would wear a mask or encourage others to do so in the United States, but not in Italy. There is no effect of providing information about how masks protect the wearer in either country. Additionally, greater mask use increases intentions to wear a mask and encourage someone else to wear theirs properly in both the United States and Italy. Thus, community mask use may be self-reinforcing.


Co-Utilization of Glucose and Xylose for Enhanced Lignocellulosic Ethanol Production with Reverse Membrane Bioreactors.
Integrated permeate channel (IPC) flat sheet membranes were examined for use as a reverse membrane bioreactor (rMBR) for lignocellulosic ethanol production. The fermenting organism, Saccharomyces cerevisiae (T0936), a genetically-modified strain with the ability to ferment xylose, was used inside the rMBR. The rMBR was evaluated for simultaneous glucose and xylose utilization as well as in situ detoxification of furfural and hydroxylmethyl furfural (HMF). The synthetic medium was investigated, after which the pretreated wheat straw was used as a xylose-rich lignocellulosic substrate. The IPC membrane panels were successfully used as the rMBR during the batch fermentations, which lasted for up to eight days without fouling. With the rMBR, complete glucose and xylose utilization, resulting in 86% of the theoretical ethanol yield, was observed with the synthetic medium. Its application with the pretreated wheat straw resulted in complete glucose consumption and 87% xylose utilization; a final ethanol concentration of 30.3 g/L was obtained, which corresponds to 83% of the theoretical yield. Moreover, complete in situ detoxification of furfural and HMF was obtained within 36 h and 60 h, respectively, with the rMBR. The use of the rMBR is a promising technology for large-scale lignocellulosic ethanol production, since it facilitates the co-utilization of glucose and xylose; moreover, the technology also allows the reuse of the yeast for several batches.


From advocacy to austerity: The new role of the U.S. public sector in HIV drug development and access.
Whereas advocacy was once the driving force for U.S. public support for HIV drug development and access, the nation's response to the global epidemic is now shaped by austerity. Extending past scholarship about the role of advocates and governments in support of drug development and access around the world, in this article I identify key shifts in U.S. public sector support over the past 40 years. During the early years of the AIDS epidemic, the U.S. government and civil society expedited drug development for antiretroviral therapy (ART). After the turn of the century, a new wave of advocacy expanded access for ART, including to low- and middle-income countries through the U.S. President's Emergency Plan for AIDS Relief (PEPFAR). On the heels of these accomplishments, advocates and governments set an ambitious agenda to 'End AIDS' by 2030. However, progress toward this goal has been limited by a new era of austerity, as demonstrated by U.S. government spending on HIV.


Isolation of rat renal NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase.
Rat renal NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase was purified to apparent homogeneity in the present study. The purification included ammonium sulfate precipitation, DEAE-Sepharose CL-6B column chromatography, Blue Sepharose CL-6B column chromatography, Sephadex G-100 column chromatography and Mono-P isoelectrofocusing column chromatography. Among the chromatographies used, Mono-P chromatofocusing column of fast protein liquid chromatography gave the most powerful resolution. The enzyme was eluted at pH 6.75 on chromatofocusing column. It indicated that the rat renal enzyme is an acidic protein. Its molecular weight in SDS-polyacrylamide gel electrophoresis was 28 Kd, and the molecular weight of the enzyme having enzyme activity detected by gel filtration column chromatography was 55 Kd. For comparing the characteristics of rat renal enzyme with that of human placental enzyme, polyclonal antibodies and a monoclonal antibody against human placental enzyme were used. The rat renal enzyme did not react with the polyclonal antibodies of human placental enzyme, however, it reacted with a monoclonal antibody of human placental enzyme. The results indicated that the antigenicity of rat renal NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase is different from that of human placental enzyme. The amino acid composition of rat renal enzyme was also different from that of human placental enzyme. Nine tyrosine molecules were observed in the subunit of rat renal enzyme, while no tyrosine has been reported in human placental enzyme.


Evaluation of an Electronic Health Record (EHR) Tool for Integrated Behavioral Health in Primary Care.
Integrating behavioral health into primary care can improve care quality; however, most electronic health records are not designed to meet the needs of integrated teams. We worked with practices and behavioral health (BH) clinicians to design a suite of electronic health record tools to address these needs ("BH e-Suite"). The purpose of this article is to examine whether implementation of the BH e-Suite changes process of care, intermediate clinical outcomes, and patient experiences, and whether its use is acceptable to practice members and BH clinicians. We conducted a convergent mixed-methods proof-of-concept study, implementing the BH e-Suite across 6 Oregon federally qualified community health centers ("intervention clinics"). We matched intervention clinics to 6 control clinics, based on location and patient panel characteristics, to assess whether process of care (Patient Health Questionnaire-9 [PHQ-9] and Generalized Anxiety Disorder-7 screening) and intermediate outcomes (PHQ-9, Generalized Anxiety Disorder-7 scores) changed postimplementation. Prepost patient surveys were used to assess changes in patient experience. To elucidate factors influencing implementation, we merged quantitative findings with structured observations, surveys, and interviews with practice members. Implementation improved process of care (PHQ-9 screening). During the course of the study, change in intermediate outcomes was not observed. Degree of BH e-Suite implementation varied: 2 clinics fully implemented, 2 partially implemented, and 2 practices did not implement at all. Initial practice conditions (eg, low resistance to change, higher capacity), process characteristics (eg, thoughtful planning), and individual characteristics (eg, high self-efficacy) were related to degree of implementation. Health information technology tools designed for behavioral health integration must fit the needs of clinics for the successful uptake and improvement in patient experiences. Research is needed to further assess the effectiveness of this tool in improving patient outcomes and to optimize broader dissemination of this tool among primary care clinics integrating behavioral health.


Re-evaluation of the left atrial to aortic root ratio as a marker of patent ductus arteriosus.
The aim of this study was to re-examine the accuracy of the left atrial aortic root ratio (LA:Ao) as a marker of significant patent ductus arteriosus (PDA) in the preterm infant by comparison with direct Doppler echocardiographic assessment. Fifty six infants (< 1500 g) had 463 serial echocardiograms. Firstly the LA:Ao was measured, then the duct was imaged and classified as wide open, restricting, or closed according to two dimensional and Doppler criteria. Probability analysis was performed to test the ability of the LA:Ao to discriminate between a wide open PDA and a restricting or closed duct. Mean LA:Ao was 1.17 and 1.21 when the duct was respectively closed or restricting compared with 1.61 when wide open. Using a LA:Ao of 1.5 as a cut off gives a sensitivity of 79% and specificity of 95% and increases the accuracy over the recommended levels of 1.3 and 1.4. With this cut off there were 20/94 false negatives, these were associated with scans on day 1 and large interatrial shunts. The sensitivity of the LA:Ao increased to 88% if only scans performed after day 1 were analysed. For diagnosing a PDA after day 1, the positive likelihood ratio of an LA:Ao of 1.5 or more was 17.5, and the negative likelihood ratio of an LA:Ao < 1.5 was 0.13. The LA:Ao is still a useful tool in the diagnosis of PDA. It is a simple method which needs less skill and resources than direct PDA imaging and is feasible on neonatal units without direct access to echocardiographic expertise. Its use on the first postnatal day is not recommended.


Concentrations and Sources of Airborne Particles in a Neonatal Intensive Care Unit.
Premature infants in neonatal intensive care units (NICUs) have underdeveloped immune systems, making them susceptible to adverse health consequences from air pollutant exposure. Little is known about the sources of indoor airborne particles that contribute to the exposure of premature infants in the NICU environment. In this study, we monitored the spatial and temporal variations of airborne particulate matter concentrations along with other indoor environmental parameters and human occupancy. The experiments were conducted over one year in a private-style NICU. The NICU was served by a central heating, ventilation and air-conditioning (HVAC) system equipped with an economizer and a high-efficiency particle filtration system. The following parameters were measured continuously during weekdays with 1-min resolution: particles larger than 0.3 μm resolved into 6 size groups, CO2 level, dry-bulb temperature and relative humidity, and presence or absence of occupants. Altogether, over sixteen periods of a few weeks each, measurements were conducted in rooms occupied with premature infants. In parallel, a second monitoring station was operated in a nearby hallway or at the local nurses' station. The monitoring data suggest a strong link between indoor particle concentrations and human occupancy. Detected particle peaks from occupancy were clearly discernible among larger particles and imperceptible for submicron (0.3-1 μm) particles. The mean indoor particle mass concentrations averaged across the size range 0.3-10 μm during occupied periods was 1.9 μg/m(3), approximately 2.5 times the concentration during unoccupied periods (0.8 μg/m(3)). Contributions of within-room emissions to total PM10 mass in the baby rooms averaged 37-81%. Near-room indoor emissions and outdoor sources contributed 18-59% and 1-5%, respectively. Airborne particle levels in the size range 1-10 μm showed strong dependence on human activities, indicating the importance of indoor-generated particles for infant's exposure to airborne particulate matter in the NICU.


Liposomal bupivacaine provides longer duration analgesia than bupivacaine hydrochloride in an adjustable sole-pressure model of equine lameness.
To compare the efficacy and duration of action for perineural analgesia with liposomal bupivacaine (LB) versus bupivacaine hydrochloride (BHCl) in a sole-pressure induced model of forelimb lameness in horses. 6 healthy adult research horses. In 1 randomly assigned forelimb, grade 3/5 lameness was induced by use of a sole-pressure lameness model. Objective lameness (vector sum [VS]) was determined with an inertial sensor system at 0, 1, 6, and 24 hours after lameness induction to evaluate the model. Mechanical nociceptive thresholds (MNTs) and objective lameness (VS and force platform kinetics) were recorded prior to and at 1, 6, 24, 48, and 72 hours after perineural anesthesia of the palmar nerves at the level of the proximal sesamoid bones with LB or BHCl in random order, with a 1-week washout period between crossover treatments. Data analysis was performed with mixed-model ANOVA. When evaluating the lameness model, there was a decrease in lameness at 24 hours in at least 1 limb of each horse (7/12 limbs); thus, screw length was increased by 1 to 2 mm at each 24-hour interval to maintain lameness. Compared with results at baseline, horses treated with BHCl had significant improvements in median MNT and VS identified at only 1 hour after injection, whereas treatment with LB yielded significantly improved median MNT, VS score, and peak vertical force for up to 24 hours. In this experimental model of forelimb lameness, LB provided longer analgesia when compared with BHCl and should be further investigated for treatment of pain in horses.


Sleepmore in Seattle: Later school start times are associated with more sleep and better performance in high school students.
Most teenagers are chronically sleep deprived. One strategy proposed to lengthen adolescent sleep is to delay secondary school start times. This would allow students to wake up later without shifting their bedtime, which is biologically determined by the circadian clock, resulting in a net increase in sleep. So far, there is no objective quantitative data showing that a single intervention such as delaying the school start time significantly increases daily sleep. The Seattle School District delayed the secondary school start time by nearly an hour. We carried out a pre-/post-research study and show that there was an increase in the daily median sleep duration of 34 min, associated with a 4.5% increase in the median grades of the students and an improvement in attendance.


Binding of ATP to UAP56 is necessary for mRNA export.
The major-histocompatibility-complex protein UAP56 (BAT1) is a DEAD-box helicase that is deposited on mRNA during splicing. UAP56 is retained on spliced mRNA in an exon junction complex (EJC) or, alternatively, with the TREX complex at the 5' end, where it might facilitate the export of the spliced mRNA to the cytoplasm. Using confocal microscopy, UAP56 was found to be concentrated in RNA-splicing speckled domains of nuclei but was also enriched in adjacent nuclear regions, sites at which most mRNA transcription and splicing occur. At speckled domains, UAP56 was in complexes with the RNA-splicing and -export protein SRm160, and, as measured by FRAP, was in a dynamic binding equilibrium. The application of an in vitro FRAP assay, in which fluorescent nuclear proteins are photobleached in digitonin-extracted cells, revealed that the equilibrium binding of UAP56 in complexes at speckled domains was directly regulated by ATP binding. This was confirmed using a point mutant of UAP56 that did not bind ATP. Point mutation of UAP56 to eliminate ATP binding did not affect RNA splicing, but strongly inhibited the export of mRNA to the cytoplasm.


An integrative transcriptomic analysis reveals bisphenol A exposure-induced dysregulation of microRNA expression in human endometrial cells.
Bisphenol A (BPA) are commonly used in the manufacture of polycarbonate plastics. Higher BPA exposure levels have been found in patients with endometrial hyperplasia that is one of risk factors of endometrial cancer (EC). Aberrant microRNAs (miRNAs) regulation has been observed in the development of cancer. Thus, this study investigated whether BPA exposure can disrupt miRNA regulation and its gene expression regarding to EC carcinogenic progress. Microarray experiments of miRNA and mRNA were performed in human endometrial cancer RL95-2 cells with treatment of low-to-moderate (10, 103 and 105nM) BPA to explore the aberrant genes corresponding to human EC progression. According to the analysis of KEGG pathway and Cytoscape gene network, this study identified that BPA exposure reduced miR-149 expression to down-regulate DNA repair gene ARF6 (ADP-ribosylation factor 6) and tumor protein p53 (TP53), and up-regulate CCNE2 (cyclin E2) potentially to interrupt cell cycle. BPA also increased miR-107 to suppress hedgehog signaling factors, suppressor of fused homolog (SUFU) and GLI family zinc finger 3 (GLI3) to activate hedgehog signaling for cell proliferation underlying carcinogenesis. Furthermore, the BPA-induced cell proliferation was attenuated by transfection with miR-149 mimic and miR-107 inhibitor. These findings provided an insight into potential epigenetic mechanism of BPA exposure on the risk of endometrial carcinogenesis.


Structure of the polycystic kidney disease TRP channel Polycystin-2 (PC2).
Mutations in either polycystin-1 (PC1 or PKD1) or polycystin-2 (PC2, PKD2 or TRPP1) cause autosomal-dominant polycystic kidney disease (ADPKD) through unknown mechanisms. Here we present the structure of human PC2 in a closed conformation, solved by electron cryomicroscopy at 4.2-Å resolution. The structure reveals a novel polycystin-specific 'tetragonal opening for polycystins' (TOP) domain tightly bound to the top of a classic transient receptor potential (TRP) channel structure. The TOP domain is formed from two extensions to the voltage-sensor-like domain (VSLD); it covers the channel's endoplasmic reticulum lumen or extracellular surface and encloses an upper vestibule, above the pore filter, without blocking the ion-conduction pathway. The TOP-domain fold is conserved among the polycystins, including the homologous channel-like region of PC1, and is the site of a cluster of ADPKD-associated missense variants. Extensive contacts among the TOP-domain subunits, the pore and the VSLD provide ample scope for regulation through physical and chemical stimuli.


Electrochemically reduced water protects neural cells from oxidative damage.
Aging-related neurodegenerative disorders are closely associated with mitochondrial dysfunction and oxidative stresses and their incidence tends to increase with aging. Brain is the most vulnerable to reactive species generated by a higher rate of oxygen consumption and glucose utilization compared to other organs. Electrochemically reduced water (ERW) was demonstrated to scavenge reactive oxygen species (ROS) in several cell types. In the present study, the protective effect of ERW against hydrogen peroxide (H2O2) and nitric oxide (NO) was investigated in several rodent neuronal cell lines and primary cells. ERW was found to significantly suppress H2O2 (50-200 μM) induced PC12 and SFME cell deaths. ERW scavenged intracellular ROS and exhibited a protective effect against neuronal network damage caused by 200 μM H2O2 in N1E-115 cells. ERW significantly suppressed NO-induced cytotoxicity in PC12 cells despite the fact that it did not have the ability to scavenge intracellular NO. ERW significantly suppressed both glutamate induced Ca(2+) influx and the resulting cytotoxicity in primary cells. These results collectively demonstrated for the first time that ERW protects several types of neuronal cells by scavenging ROS because of the presence of hydrogen and platinum nanoparticles dissolved in ERW.


Magnetic reconnection between colliding magnetized laser-produced plasma plumes.
Observations of magnetic reconnection between colliding plumes of magnetized laser-produced plasma are presented. Two counterpropagating plasma flows are created by irradiating oppositely placed plastic (CH) targets with 1.8-kJ, 2-ns laser beams on the Omega EP Laser System. The interaction region between the plumes is prefilled with a low-density background plasma and magnetized by an externally applied magnetic field, imposed perpendicular to the plasma flow, and initialized with an X-type null point geometry with B=0 at the midplane and B=8 T at the targets. The counterflowing plumes sweep up and compress the background plasma and the magnetic field into a pair of magnetized ribbons, which collide, stagnate, and reconnect at the midplane, allowing the first detailed observations of a stretched current sheet in laser-driven reconnection experiments. The dynamics of current sheet formation are in good agreement with first-principles particle-in-cell simulations that model the experiments.


Microrobots for micrometer-size objects in aqueous media: potential tools for single-cell manipulation.
Conducting polymers are excellent materials for actuators that are operated in aqueous media. Microactuators based on polypyrrole-gold bilayers enable large movement of structures attached to these actuators and are of particular interest for the manipulation of biological objects, such as single cells. A fabrication method for creating individually addressable and controllable polypyrrole-gold microactuators was developed. With these individually controlled microactuators, a micrometer-size manipulator, or microrobotic arm, was fabricated. This microrobotic arm can pick up, lift, move, and place micrometer-size objects within an area of about 250 micrometers by 100 micrometers, making the microrobot an excellent tool for single-cell manipulation.


Prevalence estimates and associated factors for dental pain: a review.
To assess the methodological quality of epidemiological studies on dental pain and review the published literature for its prevalence, and association with age, gender and socio-economic status. Medline and reference lists of relevant articles were searched for observational studies published in English from 1966 to 2001 carried out on humans aged 19 years and over. Articles for reading of the full text were selected by two reviewers independently. Selected articles were assessed independently by the two reviewers according to a set of 8 standardized criteria. Inter-rater agreement was measured using the kappa statistic. Disagreements were discussed and a final score for each study agreed. Data on prevalence estimates and their distribution by age, gender and socio-economic factors were extracted. 422 studies were identified, and 23 selected for review. Inter-rater agreement was high for all 8 criteria used (kappa > 0.6). Methodological quality was poor with the number of criteria fulfilled by each study ranging from 1 to 6, median score 3. The prevalence estimates for 5 case definitions identified were: 'toothache' 7-32%, 'pain in teeth with hot, cold or sweet things' 25-38%, 'pain and discomfort needing medication or treatment' 7-9%, 'pain or discomfort in the mouth, teeth or gums' 19-66%, and 'oral and facial pain'40-44%. Younger subjects and those from lower socio-economic groups were more likely to report pain. Gender was not associated with dental pain. Epidemiological data on dental pain are sparse and of poor quality. There is a need for well-designed surveys using randomly selected community samples and standardized measurement criteria to fill this knowledge gap.


Retinal ganglion cell loss in a rat ocular hypertension model is sectorial and involves early optic nerve axon loss.
Previous analyses of the DBA/2J mouse glaucoma model show a sectorial degeneration pattern suggestive of an optic nerve head insult. In addition, there are large numbers of retinal ganglion cells (RGCs) that cannot be retrogradely labeled but maintain RGC gene expression, and many of these have somatic phosphorylated neurofilament labeling. Here the authors further elucidate these features of glaucomatous degeneration in a rat ocular hypertension model. IOP was elevated in Wistar rats by translimbal laser photocoagulation. Retina whole mounts were analyzed for Sncg mRNA in situ hybridization, fluorogold (FG) retrograde labeling, and immunohistochemistry for phosphorylated neurofilaments (pNF) at 10 and 29 days after IOP increase. A novel automatic method was used to estimate axon numbers in plastic sections of optic nerves. Sncg mRNA was confirmed as a specific marker for RGCs in rat. Loss of RGCs after IOP elevation occurred in sectorial patterns. Sectors amid degeneration contained RGCs that were likely disconnected because these had pNF in their somas and dendrites, were not labeled by FG, and were associated with reactive plasticity within the retina. Most of the axon loss within the optic nerve already occurred by 10 days after the onset of IOP elevation. These data demonstrate that the pattern of RGC loss after laser-induced ocular hypertension in rats is similar to that previously reported in DBA/2J mice. The results support the view that in glaucoma RGC axons are damaged at the optic nerve head and degenerate within the optic nerve before there is loss of RGC somas.


Increased activation in superior temporal gyri as a function of increment in phonetic features.
A common assumption is that phonetic sounds initiate unique processing in the superior temporal gyri and sulci (STG/STS). The anatomical areas subserving these processes are also implicated in the processing of non-phonetic stimuli such as music instrument sounds. The differential processing of phonetic and non-phonetic sounds was investigated in this study by applying a "sound-morphing" paradigm, where the presence of phonetic features were parametrically varied, creating a step-wise transition from a non-phonetic sound into a phonetic sound. The stimuli were presented in an event-related fMRI design. The fMRI-BOLD data were analysed using parametric contrasts. The results showed a higher sensitivity for sounds containing phonetic features compared to non-phonetic sounds in the middle part of STG, and in the anterior part of the planum temporale (PT) bilaterally. Although the same areas were involved in the processing of non-phonetic sounds, a difference in activation was evident in the STG, with an increase in activation related to increment of phonetic features in the sounds. The results indicate a stimulus-driven, bottom-up process that utilizes general auditory resources in the secondary auditory cortex, depending on specific phonetic features in the sounds.


Spectrum control by anisotropy in a cylindrical microcavity.
Spectrum control by anisotropy in a cylindrical microcavity made of electric anisotropic medium was studied. A finite-difference time domain method for electric anisotropic medium and Volume-average Effective Permittivity approximation are applied to calculate the resonant frequencies and quality factors of Whispering-gallery modes. The resonant frequency for different whispering-gallery modes has a similar shift in direct proportion to the relative difference of two principal refractive indices. The quality factors decay exponentially due to directional emission when the difference of two principal refractive indices increases. This novel tuning characteristic of anisotropic cylindrical microcavity will play an important role in many areas, such as light source with tunable wavelength, tunable filter and sensor.


Use of N immobilization to tighten the N cycle in conventional agroecosystems.
Soils in conventional agroecosystems are purposely held in a nitrogen (N)-saturated state to maximize crop yields. Planting winter annual cover crops when fields are usually fallow has been proposed to ameliorate N losses from soils. In this study we introduced winter annual cover crops into an N rate study with plots fertilized at 0, 34, 67, 101, 134, 168, and 202 kg N/ha in maize (Zea mays L.) to determine how winter annual cover crops affect yields, N2O and NO3- fluxes, and N pools. At the six-leaf stage and during flowering, incorporation of cover crop into soil resulted in a 30% reduction in maize biomass. Three weeks after fertilization, KCl-extractable soil mineral N was 75-87% lower in covercropped soils than in no-cover soils, indicating that N had been immobilized in the covercropped soils. At physiological maturity, there was no difference between cover and no-cover treatments in crop yield, which was maximized at 9 Mg/ha in 2006 and 7 Mg/ha in 2007. Where N rates exceed crop requirements, cover crop incorporation may reduce N exports as NO3- and N2O. Tighter N cycling in conventional agroecosystems could be fostered by matching N rates to the amount of N removed with grain and using N immobilization to retain N and support yields. If N immobilization is viewed as a means for efficient fertilizer N use rather than a process that decreases crop productivity, growers might be more willing to adopt cover-cropping practices.


Early Miocene remains of Melissiodon from Mokrá-Quarry (Moravia, Czech Republic) shed light on the evolutionary history of the rare cricetid genus.
Melissiodon is a rare cricetid genus endemic to Europe, known from the Early Oligoceneto the Early Miocene. It is usually a very rare find, and even in the few localities where Melissiodon remains are found, those are scarce and fragmentary. Only a few Central European localities have yielded rich remains of the genus. Currently, two species are known from the Early Miocene: Melissiodon schlosseri, which is based on two teeth from the MN2 German locality of Haslach and only found in two other sites of similar age (Ulm-Uniklinik and La Chaux, from Germany and Switzerland respectively); and Melissiodon dominans, found in MN3 and MN4 localities across Europe, even though the scarce and fragmentary remains make some of these attributions dubious. For that reason, Melissiodon dominans has become a catch-all species. However, Mokrá-Quarry represents one of the best documented findings of Melissiodon remains from MN4 localities of Europe. The Melissiodon assemblage from Mokrá-Quarry has been studied thoroughly, providing metrics and detailed descriptions of all teeth positions, as well as complete comparisons with other MN3 and MN4 localities bearing Melissiodon remains. In this work, new remains of Melissiodon have been identified as a new morphotype that clearly differs from Melissiodon dominans by its unique m1 morphology but still shows some resemblance with Melissiodon schlosseri. Based on that, we here propose the hypothesis of an evolutionary lineage starting from Melissiodon schlosseri, diverging from the lineage leading towards Melissiodon dominans. With this finding, there are at least two different taxa of Melissiodon known during the Early Miocene, prior to the genus extinction. This study arises the certainty that the evolution history of the genus is more complex than previously thought and that more studies are necessary to elucidate it, including a complete revision of the type material of Melissiodon dominans and Melissiodon schlosseri in the light of current knowledge of the genus, which will help to elucidate the attribution of the populations from Mokrá-Quarry. For the time being, the assemblage presented here is referred as Melissiodon aff. schlosseri.


Combustion-derived flame generated ultrafine soot generates reactive oxygen species and activates Nrf2 antioxidants differently in neonatal and adult rat lungs.
Urban particulate matter (PM) has been epidemiologically correlated with multiple cardiopulmonary morbidities and mortalities, in sensitive populations. Children exposed to PM are more likely to develop respiratory infections and asthma. Although PM originates from natural and anthropogenic sources, vehicle exhaust rich in polycyclic aromatic hydrocarbons (PAH) can be a dominant contributor to the PM2.5 and PM0.1 fractions and has been implicated in the generation of reactive oxygen species (ROS). Current studies of ambient PM are confounded by the variable nature of PM, so we utilized a previously characterized ethylene-combusted premixed flame particles (PFP) with consistent and reproducible physiochemical properties and 1) measured the oxidative potential of PFP compared to ambient PM, 2) determined the ability of PFPs to generate oxidative stress and activate the transcription factor using in vitro and ex vivo models, and 3) we correlated these responses with antioxidant enzyme expression in vivo. We compared oxidative stress response (HMOX1) and antioxidant enzyme (SOD1, SOD2, CAT, and PRDX6) expression in vivo by performing a time-course study in 7-day old neonatal and young adult rats exposed to a single 6-hour exposure to 22.4 μg/m3 PFPs. We showed that PFP is a potent ROS generator that induces oxidative stress and activates Nrf2. Induction of the oxidative stress responsive enzyme HMOX1 in vitro was mediated through Nrf2 activation and was variably upregulated in both ages. Furthermore, antioxidant enzyme expression had age and lung compartment variations post exposure. Of particular interest was SOD1, which had mRNA and protein upregulation in adult parenchyma, but lacked a similar response in neonates. We conclude that PFPs are effective ROS generators, comparable to urban ambient PM2.5, that induce oxidative stress in neonatal and adult rat lungs. PFPs upregulate a select set of antioxidant enzymes in young adult animals, that are unaffected in neonates. We conclude that the inability of neonatal animals to upregulate the antioxidant response may, in part, explain enhanced their susceptibility to ultrafine particles, such as PFP.


On-axis non-linear effects with programmable Dammann lenses under femtosecond illumination.
We demonstrate the utilization of Dammann lenses codified onto a spatial light modulator (SLM) for triggering non-linear effects. With continuous wave illumination Dammann lenses are binary phase optical elements that generate a set of equal intensity foci. We theoretically calculate the influence of ultrashort pulse illumination on the uniformity of the generated pattern, which is affected by chromatic aberration for pulses with temporal widths lower than 100 fs. The simulations also indicate that acceptable uniformity can be achieved for pulses of several fs by shortening the distance among foci which can be easily modified with the SLM. Multifocal second-harmonic generation (SHG) and on-axis multiple filamentation are produced and actively controlled in β-BaB2O4 (BBO) and fused silica samples, respectively, with an amplified Ti: Sapphire femtosecond laser of 30 fs pulse duration. Experimental results are in very good agreement with theoretical calculations.


Loss of miRNA biogenesis induces p19Arf-p53 signaling and senescence in primary cells.
Dicer, an enzyme involved in microRNA (miRNA) maturation, is required for proper cell differentiation and embryogenesis in mammals. Recent evidence indicates that Dicer and miRNA may also regulate tumorigenesis. To better characterize the role of miRNA in primary cell growth, we generated Dicer-conditional mice. Ablation of Dicer and loss of mature miRNAs in embryonic fibroblasts up-regulated p19(Arf) and p53 levels, inhibited cell proliferation, and induced a premature senescence phenotype that was also observed in vivo after Dicer ablation in the developing limb and in adult skin. Furthermore, deletion of the Ink4a/Arf or p53 locus could rescue fibroblasts from premature senescence induced by Dicer ablation. Although levels of Ras and Myc oncoproteins appeared unaltered, loss of Dicer resulted in increased DNA damage and p53 activity in these cells. These results reveal that loss of miRNA biogenesis activates a DNA damage checkpoint, up-regulates p19(Arf)-p53 signaling, and induces senescence in primary cells.


The Impact of Clinical Pathways on Antibiotic Prescribing for Acute Otitis Media and Pharyngitis in the Emergency Department.
Although Italian pediatric antimicrobial prescription rates are among the highest in Europe, little action has been taken to improve the appropriateness of antimicrobial prescriptions. The primary aim of this study was to assess changes in antibiotic prescription before and after acute otitis media (AOM) and group A streptococcus (GAS) pharyngitis Clinical Pathway (CP) implementation; secondary aims were to compare treatment failures and to assess change in the total antibiotics costs before and after CP implementation. Pre-post quasi-experimental study comparing the 6-month period before CP implementation (baseline period: October 15, 2014, through April 15, 2015) to the 6 months after intervention (postintervention: October 15, 2015, through April 15, 2016). Two hundred ninety-five pre- and 278 postintervention emergency department visits were associated with AOM. After CP implementation, there was an increase in "wait and see" approach and a decrease in overall prescription of broad-spectrum antibiotics from 53.2% to 32.4% (P < 0.001). One hundred fifty-one pre- and 166 postimplementation clinic visits were associated with GAS pharyngitis, with a decrease in broad-spectrum prescription after CP implementation (46.4% vs. 6.6%; P < 0.001). For both conditions, no difference was found in treatment failure, and total antibiotics cost was significantly reduced after CP implementation, with a decrease especially in broad-spectrum antibiotics costs. A reduction in broad-spectrum antibiotic prescriptions and a reduction in the total cost of antibiotics for AOM and GAS pharyngitis along with an increase in "wait and see" prescribing for AOM indicate effectiveness of CP for antimicrobial stewardship in this setting.


Metrics to assess quality of life after management of early-stage lung cancer.
Quality of life (QOL) is a key clinical outcome in patients with lung cancer because of the debilitating nature of the disease and its treatments. In recent years, advances have been made in the assessment of QOL via patient-reported outcomes. A brief history of the evolution of QOL measures in oncology clinical trials and practice is given with specific reference to early-stage lung cancer. The role that QOL can play as a prognostic factor, especially among lung cancer patients, is delineated. The most commonly seen symptoms among lung cancer patients are listed. This review is intended to provide the clinical researcher with a summary of the alternative measures that are both valid and reasonable to consider when assessing QOL in early-stage lung cancer patients. Suggestions for QOL assessment in both a research setting and clinical environment are considered. A review of the most popular QOL assessments in general application to lung cancer and disease-specific measures is provided. An algorithm for selecting appropriate QOL assessments for lung cancer clinical research is provided. The primary conclusion from this work is that scientifically sound investigations into the QOL of early-stage lung cancer patients are feasible and encouraged so that the care of these patients can be optimized.


Color extended visual cryptography using error diffusion.
Color visual cryptography (VC) encrypts a color secret message into n color halftone image shares. Previous methods in the literature show good results for black and white or gray scale VC schemes, however, they are not sufficient to be applied directly to color shares due to different color structures. Some methods for color visual cryptography are not satisfactory in terms of producing either meaningless shares or meaningful shares with low visual quality, leading to suspicion of encryption. This paper introduces the concept of visual information pixel (VIP) synchronization and error diffusion to attain a color visual cryptography encryption method that produces meaningful color shares with high visual quality. VIP synchronization retains the positions of pixels carrying visual information of original images throughout the color channels and error diffusion generates shares pleasant to human eyes. Comparisons with previous approaches show the superior performance of the new method.


Sex Differences in the Associations between L-Arginine Pathway Metabolites, Skeletal Muscle Mass and Function, and their Responses to Resistance Exercise, in Old Age.
The current study was designed to explore the associations between L-arginine metabolites and muscle mass and function in old age, which are largely unknown. The study used a randomised, double-blind, placebo-controlled design. The study was carried out in a laboratory setting. 50 healthy older adults [median age 70 years (IQR 67-73); 27 males]. Participants undertook an 18-week resistance exercise program, and a nutritional intervention (fish oil vs. placebo). Serum homoarginine, ornithine, citrulline, asymmetric dimethylarginine (ADMA), NG-monomethyl-L-arginine (L-NMMA), and symmetric dimethylarginine (SDMA), maximal voluntary contraction (MVC) and isokinetic torque of the knee extensors at 30° s-1 (MIT), muscle cross sectional area (MCSA) and quality (MQ) were measured at baseline and after the intervention. No significant exercise-induced changes were observed in metabolite concentrations. There were significant sex differences in the associations between metabolites and muscle parameters. After adjusting for age, glomerular filtration rate and fish oil intervention, citrulline (P=0.002) and ornithine (P=0.022) were negatively associated with MCSA at baseline in males but not females. However, baseline citrulline was negatively correlated with exercise-induced changes in MVC (P=0.043) and MQ (P=0.026) amongst females. Furthermore, amongst males, baseline homoarginine was positively associated with exercise-induced changes in MVC (P=0.026), ADMA was negatively associated with changes in MIT (P=0.026), L-NMMA (p=0.048) and ornithine (P<0.001) were both positively associated with changes in MCSA, and ornithine was negatively associated with changes in MQ (P=0.039). Therefore, barring citrulline, there are significant sex differences in the associations between L-arginine metabolites and muscle mass and function in healthy older adults. These metabolites might enhance sarcopenia risk stratification, and the success of exercise programs, in old age.


Biological signal processing with a genetic toggle switch.
Complex gene regulation requires responses that depend not only on the current levels of input signals but also on signals received in the past. In digital electronics, logic circuits with this property are referred to as sequential logic, in contrast to the simpler combinatorial logic without such internal memory. In molecular biology, memory is implemented in various forms such as biochemical modification of proteins or multistable gene circuits, but the design of the regulatory interface, which processes the input signals and the memory content, is often not well understood. Here, we explore design constraints for such regulatory interfaces using coarse-grained nonlinear models and stochastic simulations of detailed biochemical reaction networks. We test different designs for biological analogs of the most versatile memory element in digital electronics, the JK-latch. Our analysis shows that simple protein-protein interactions and protein-DNA binding are sufficient, in principle, to implement genetic circuits with the capabilities of a JK-latch. However, it also exposes fundamental limitations to its reliability, due to the fact that biological signal processing is asynchronous, in contrast to most digital electronics systems that feature a central clock to orchestrate the timing of all operations. We describe a seemingly natural way to improve the reliability by invoking the master-slave concept from digital electronics design. This concept could be useful to interpret the design of natural regulatory circuits, and for the design of synthetic biological systems.


Milk fat content and DGAT1 genotype determine lipid composition of the milk fat globule membrane.
During secretion of milk fat globules, triacylglycerol (TAG) droplets are enveloped by a phospholipid (PL) trilayer. Globule size has been found to be related to polar lipid composition and fat content, and milk fat content and fatty acid composition have been associated with the diacylglycerol acyltransferase 1 (DGAT1) K232A polymorphism; however, the association between the DGAT1 polymorphism and fat globule size and polar lipid composition has not been studied. The ratio between polar and neutral lipids as well as the composition of the polar lipids in milk has industrial as well as nutritional and health implications. Understanding phenotypic and genotypic factors influencing these parameters could contribute to improving milk lipid composition for dairy products. The focus of the present study was to determine the effect of both fat content and DGAT1 polymorphism on PL/TAG ratio, as a marker for milk fat globule size, and detailed PL composition. Milk samples were selected from 200 cows such that there were equal numbers of samples for the different fat contents as well as per DGAT1 genotype. Samples were analyzed for neutral and polar lipid concentration and composition. PL/TAG ratio was significantly associated with both fat content and DGAT1 genotype. Phosphatidylinositol and phosphatidylserine concentrations were associated with fat content*DGAT1 genotype with a stronger association for the AA than the KK genotype. Sphingomyelin concentration tended to interact with fat content*DGAT1 genotype. Phosphatidylethanolamine (PE) concentration showed a biphasic response to fat content, suggesting that multiple biological processes influence its concentration. These results provide a new direction for controlling polar lipid concentration and composition in milk through selective breeding of cows.


Androgen receptor activity modulates responses to cisplatin treatment in bladder cancer.
Cisplatin (CDDP)-based combination chemotherapy remains the mainstream treatment for advanced bladder cancer. However, its efficacy is often limited due to the development of resistance for which underlying mechanisms are poorly understood. Meanwhile, emerging evidence has indicated the involvement of androgen-mediated androgen receptor (AR) signals in bladder cancer progression. In this study, we aimed to investigate whether AR signals have an impact on sensitivity to CDDP in bladder cancer cells. UMUC3-control-short hairpin RNA (shRNA) cells with endogenous AR and AR-negative 647V/5637 cells stably expressing AR were significantly more resistant to CDDP treatment at its pharmacological concentrations, compared with UMUC3-AR-shRNA and 647V-vector/5637-vector control cells, respectively. A synthetic androgen R1881 significantly reduced CDDP sensitivity in UMUC3, 647V-AR, or 5637-AR cells, and the addition of an anti-androgen hydroxyflutamide inhibited the effect of R1881. In these AR-positive cells, R1881 treatment also induced the expression levels of NF-κB, which is known to involve CDDP resistance, and its phosphorylated form, as well as nuclear translocation of NF-κB. In CDDP-resistant bladder cancer sublines established following long-term culture with CDDP, the expression levels of AR as well as NF-κB and phospho-NF-κB were considerably elevated, compared with respective control sublines. In bladder cancer specimens, there was a strong trend to correlate between AR positivity and chemoresistance. These results suggest that AR activation correlates with CDDP resistance presumably via modulating NF-κB activity in bladder cancer cells. Targeting AR during chemotherapy may thus be a useful strategy to overcome CDDP resistance in patients with AR-positive bladder cancer.


Rapid and economical method for species identification of clinically significant coagulase-negative staphylococci.
Four methods for the species identification of coagulase-negative staphylococci in the medical microbiology laboratory were compared with 444 consecutive isolates. The methods included (i) the reference method based on growth tests, (ii) API ID 32 Staph (bioMérieux), (iii) Staph-Zym (Rosco), and (iv) a rapid 4-h method developed in our laboratory (UZA method). The last method is based on the detection within 4 h of enzymatic activity of heavy bacterial suspensions in three substrate solutions (nongrowth tests). For 16.5% of the isolates some supplementary growth tests read after 24 h had to be added to the enzyme data for satisfactory identification. The reference method failed to identify four isolates. Of the 440 isolates identified by the reference method, API ID 32 Staph, Staph-Zym, and the UZA method correctly identified 419 (95.2%), 429 (97.5%), and 430 (97.7%) and misidentified 8 (1.8%), 4 (0.9%), and 1 (0.2%), respectively. Staphylococcus epidermidis, S. haemolyticus, S. lugdunensis, S. schleiferi, and S. capitis were identified with an accuracy of 98 to 100% by all the systems tested. S. capitis subsp. ureolyticus was not recognized by the API ID 32 system because the biochemical profiles for it are not yet included in the corresponding database. Whereas API ID 32 identified all 13 S. warneri isolates, both Staph-Zym and the UZA method missed 2 of these. S. hominis was identified with the least accuracy by the API ID 32 system (26 of 39 isolates), whereas the UZA and Staph-Zym methods identified 36 of the isolates belonging to this species. The UZA method did not identify any of the S. cohnii, S. xylosus, S. lentus, and S. sciuri strains, since it included no discriminatory tests for these species, because they are extremely rarely found in humans. Of all 440 isolates tested, the UZA method failed to identify 9 and misidentified 1 other. Eighty-one percent of the isolates were identified within 4 h and 97.7% were identified after 24 h, at considerably less expense than by the API ID 32 Staph and Staph-Zym methods.


Recommendations for Clinical Decision-making in Children with Type 1 Diabetes and Celiac Disease: Type 1 Diabetes and Celiac Disease Joint Working Group Report
It is well-known that in children with type 1 diabetes (T1D), the frequency of Celiac disease (CD) is increased due to mechanisms which are not fully elucidated but include autoimmune injury as well as shared genetic predisposition. Although histopathologic examination is the gold standard for diagnosis, avoiding unnecessary endoscopy is crucial. Therefore, for both clinicians and patients' families, the diagnosis of CD remains challenging. In light of this, a joint working group, the Type 1 Diabetes and Celiac Disease Joint Working Group, was convened, with the aim of reporting institutional data and reviewing current international guidelines, in order to provide a framework for clinicians. Several controversial issues were discussed: For CD screening in children with T1D, regardless of age, it is recommended to measure tissue transglutaminase-immunoglobulin A (tTG-IgA) and/or endomysial-IgA antibody due to their high sensitivity and specificity. However, the decision-making process based on tTG-IgA titer in children with T1D is still debated, since tTG-IgA titers may fluctuate in children with T1D. Moreover, seronegativity may occur spontaneously. The authors' own data showed that most of the cases who have biopsy-proven CD had tTG-IgA levels 7-10 times above the upper limit. The decision for endoscopy based solely on tTG-IgA levels should be avoided, except in cases where tTG-IgA levels are seven times and above the upper limit. A closer collaboration should be built between divisions of pediatric endocrinology and gastroenterology in terms of screening, diagnosis and follow-up of children with T1D and suspicious CD.


The 9/11 Dust Cloud and Pregnancy Outcomes: A Reconsideration.
The events of 9/11 released a million tons of toxic dust into lower Manhattan, an unparalleled environmental disaster. It is puzzling then that the literature has shown little effect of fetal exposure to the dust. However, inference is complicated by pre-existing differences between the affected mothers and other NYC mothers as well as heterogeneity in effects on boys and girls. Using all births in utero on 9/11 in NYC and comparing them to their siblings, we show that residence in the affected area increased prematurity and low birth weight, especially for boys.


Hydrogen-rich saline reduces oxidative stress and inflammation by inhibit of JNK and NF-κB activation in a rat model of amyloid-beta-induced Alzheimer's disease.
This study is to examine if hydrogen-rich saline reduced amyloid-beta (Aβ) induced neural inflammation and oxidative stress in a rat model by attenuation of activation of JNK and NF-κB. Sprague-Dawley male rats (n=18, 280-330 g) were divided into three groups, sham operated, Aβ1-42 injected and Aβ1-42 plus hydrogen-rich saline treated animals. Hydrogen-rich saline (5 ml/kg, i.p., daily) was injected for 10 days after intraventricular injection of Aβ1-42. The levels of IL-1β were assessed by ELISA analysis, 8-OH-dG by immunohistochemistry in the brain slides, and JNK and NF-κB by immunohistochemistry and western blotting. After Aβ1-42 injection, the level of IL-1β, 8-OH-dG, JNK and NF-κB all increased in brain tissues, while hydrogen-rich saline treatment decreased the level of IL-1β, 8-OH-dG and the activation of JNK and NF-κB. In conclusion, hydrogen-rich saline prevented Aβ-induced neuroinflammation and oxidative stress, possibly by attenuation of activation of c-Jun NH₂-terminal kinase (JNK) and nuclear factor-κB (NF-κB) in this rat model.


Implementation of Digital Radiography during Root Canal Treatments in Saudi Endodontic and General Dental Practice.
To report usage of full-digital-radiography (FDR) during root-canal-treatments (RCTs) in Saudi dental-practice and to explore factors and measures that obstacle/contribute to better implementation. Following a pilot study, questions on demography, types of radiographic systems used during RCTs, advantages and disadvantages of FDR, reasons of not using it and measures that increase its implementation were included. The sample size was calculated considering the total number of general dentists (GDs) in Saudi Arabia and a 50-60% expected response rate. The questionnaire was emailed to 550 GDs and all endodontists in Saudi Arabia (185). A solo a reminder was emailed two months later. Data were analyzed by the Chi-square test at P=0.05. Most participants (64.9%) used FDR for RCTs (P<0.001); with all endodontists (100%) and 52% of GDs (P<0.001). While all who were working in governmental-academia (100%) used FDR, 69.2% in private-academia did so (P<0.001); with no difference between private and governmental-clinics (60.6 and 69.2%). As the weekly-performed RCTs increased and participants' experience decreased, FDR usage increased (P<0.05). While high-cost was the main FDR disadvantage, faster-workflow, better image-quality and less-radiation were the main advantages (P<0.001). The majority (76.1%) of FDR none-users were doing so because of unavailability. Participants reported lower-cost and better undergraduate-education as most effective measures that increase FDR implementation in dental-practice. FDR was adopted to good extent in Saudi dental-practice. Financial aspects were the main concern that should be addressed to increase FDR implementation in private practice. Endodontists showed better perception towards FDR and suggested more attention to educational aspects.


Ethical considerations in conducting surgical research in severe complicated intra-abdominal sepsis.
Severe complicated intra-abdominal sepsis (SCIAS) has high mortality, thought due in part to progressive bio-mediator generation, systemic inflammation, and multiple organ failure. Treatment includes early antibiotics and operative source control. At surgery, open abdomen management with negative-peritoneal-pressure therapy (NPPT) has been hypothesized to mitigate MOF and death, although clinical equipoise for this operative approach exists. The Closed or Open after Laparotomy (COOL) study (https://clinicaltrials.gov/ct2/show/NCT03163095) will prospectively randomize eligible patients intra-operatively to formal abdominal closure or OA with NPTT. We review the ethical basis for conducting research in SCIAS. Research in critically ill incapacitated patients is important to advance care. Conducting research among SCIAS is complicated due to the severity of illness including delirium, need for emergent interventions, diagnostic criteria confirmed only at laparotomy, and obtundation from anaesthesia. In other circumstances involving critically ill patients, clinical experts have worked closely with ethicists to apply principles that balance the rights of patients whilst simultaneously permitting inclusion in research. In Canada, the Tri-Council Policy Statement-2 (TCPS-2) describes six criteria that permit study enrollment and randomization in such situations: (a) serious threat to the prospective participant requires immediate intervention; (b) either no standard efficacious care exists or the research offers realistic possibility of direct benefit; (c) risks are not greater than that involved in standard care or are clearly justified by prospect for direct benefits; (d) prospective participant is unconscious or lacks capacity to understand the complexities of the research; (e) third-party authorization cannot be secured in sufficient time; and (f) no relevant prior directives are known to exist that preclude participation. TCPS-2 criteria are in principle not dissimilar to other (inter)national criteria. The COOL study will use waiver of consent to initiate enrollment and randomization, followed by surrogate or proxy consent, and finally delayed informed consent in subjects that survive and regain capacity. A delayed consent mechanism is a practical and ethical solution to challenges in research in SCIAS. The ultimate goal of consent is to balance respect for patient participants and to permit participation in new trials with a reasonable opportunity for improved outcome and minimal risk of harm.


Duplication analysis in Turkish Charcot-Marie-Tooth type 1A patients using short tandem repeat markers.
Charcot-Marie-Tooth (CMT) is a common inherited peripheral neuropathy with a prevalence of 1 in 2,500. CMT has two distinct forms (CMT1 and CMT2) that can be identified electrophysiologically. A 1.5 Mb tandem microduplication including peripheral myelin protein 22 gene (PMP22) on chromosome 17p11.2-12 causes CMT1A. The increased gene dosage effect of PMP22 is thought to be responsible for the pathogenesis of CMT1A. In this study, 39 Turkish CMT1A patients and 60 unrelated control samples had been examined for the duplication using polymorphic short tandem repeat (STR) markers. Seven STR marker sites (AC005838-4A-, AC0013248-9A-, AC0013248-9B-, D17S2218, D17S2220, D17S2227, and D17S2229) on the duplicated region were amplified via polymerase chain reaction, electrophoresed through 8% polyacrilamide gel and evaluated for the duplication. The rate of duplication was 92.3' (36/39) in the patients whereas it was zero in the control samples. Allele distributions, number of alleles and heterozygosity values of more informative markers (D17S2218, D17S2220, D17S2227, and D17S2229) were assessed. It is found that approximately 85% of duplications in Turkish CMT1A patients were depicted by using D17S2220 and D17S2229 markers together.


Human herpesvirus 6 meningoencephalitis in allogeneic hematopoietic stem cell transplant recipients.
We retrospectively investigated the clinical characteristics of human herpesvirus 6 (HHV-6) meningoencephalitis within 100 days after allogeneic hematopoietic stem cell transplantation (HSCT). Of 1148 patients who received transplants between January 1999 and December 2003, 11 patients (0.96%) with HHV-6 meningoencephalitis were identified. Ten of 11 recipients received hematopoietic stem cells from donors other than HLA-identical siblings. Confusion was the most frequent central nervous system (CNS) symptom, and a skin rash with high-grade fever preceded the CNS symptoms in 9 patients. Magnetic resonance imaging of the brain showed an abnormal increased T2 signal in the hypothalamus of 5 patients. Eight patients were treated with ganciclovir, and an improvement of CNS symptoms was obtained in 3 patients; 3 patients treated with acyclovir showed no improvement. Improvement in the meningoencephalitis seemed less frequent in patients with abnormal findings in the hypothalamus than in those without such findings. Because the symptoms of HHV-6 meningoencephalitis mimicked those of cyclosporine- or tacrolimus-induced encephalopathy, the drugs were withdrawn at the onset of CNS symptoms in 10 patients, resulting in the development of grade IV graft-versus-host disease (GVHD) in 5 patients. Three patients died of HHV-6 meningoencephalitis, and 6 died of other causes, including GVHD. In conclusion, HHV-6 meningoencephalitis is a rare but potentially life-threatening complication in patients who undergo allogeneic HSCT. Careful assessment of the clinical findings and the brain may allow early and precise diagnosis of HHV-6 meningoencephalitis and contribute to improving its prognosis.


Suppression of soft tissue sarcoma growth by a host defense-like lytic peptide.
Soft tissue sarcoma (STS) is an anatomically and histologically heterogeneous neoplasia that shares a putative mesenchymal cell origin. The treatment with common chemotherapeutics is still unsatisfying because of association with poor response rates. Although evidence is accumulating for potent oncolytic activity of host defense peptides (HDPs), their potential therapeutic use is often limited by poor bioavailability and inactivation in serum. Therefore, we tested the designer host defense-like lytic D,L-amino acid peptide [D]-K3H3L9 on two STS cell lines in vitro and also in an athymic and syngeneic mouse model. In recent studies the peptide could show selectivity against prostate carcinoma cells and also an active state in serum. In vitro the human synovial sarcoma cell line SW982, the murine fibrosarcoma cell line BFS-1 and primary human fibroblasts as a control were exposed to [D]-K3H3L9, a 15mer D,L-amino acid designer HDP. Cell vitality in physiological and acidic conditions (MTT-assay), cell growth (BrdU) and DNA-fragmentation (TUNEL) were investigated. Membrane damage at different time points could be analyzed with LDH assay. An antibody against the tested peptide and recordings using scanning electron microscopy could give an inside in the mode of action. In vivo [D]-K3H3L9 was administered intratumorally in an athymic and syngeneic (immunocompetent) mouse model with SW982 and BFS-1 cells, respectively. After three weeks tumor sections were histologically analyzed. The peptide exerts rapid and high significant cytotoxicity and antiproliferating activity against the malignant cell lines, apparently via a membrane disrupting mode of action. The local intratumoral administration of [D]-K3H3L9 in the athymic and syngeneic mice models significantly inhibited tumor progression. The histological analyses of the tumor sections revealed a significant antiproliferative, antiangiogenic activity of the treatment group. These findings demonstrate the in vitro and in vivo oncolytic activity of [D]-K3H3L9 in athymic and syngeneic mouse models.


Dissecting spatial knowledge from spatial choice by hippocampal NMDA receptor deletion.
Hippocampal NMDA receptors (NMDARs) and NMDAR-dependent synaptic plasticity are widely considered crucial substrates of long-term spatial memory, although their precise role remains uncertain. Here we show that Grin1(ΔDGCA1) mice, lacking GluN1 and hence NMDARs in all dentate gyrus and dorsal CA1 principal cells, acquired the spatial reference memory water maze task as well as controls, despite impairments on the spatial reference memory radial maze task. When we ran a spatial discrimination water maze task using two visually identical beacons, Grin1(ΔDGCA1) mice were impaired at using spatial information to inhibit selecting the decoy beacon, despite knowing the platform's actual spatial location. This failure could suffice to impair radial maze performance despite spatial memory itself being normal. Thus, these hippocampal NMDARs are not essential for encoding or storing long-term, associative spatial memories. Instead, we demonstrate an important function of the hippocampus in using spatial knowledge to select between alternative responses that arise from competing or overlapping memories.


QTLs associated with dry matter intake, metabolic mid-test weight, growth and feed efficiency have little overlap across 4 beef cattle studies.
The identification of genetic markers associated with complex traits that are expensive to record such as feed intake or feed efficiency would allow these traits to be included in selection programs. To identify large-effect QTL, we performed a series of genome-wide association studies and functional analyses using 50 K and 770 K SNP genotypes scored in 5,133 animals from 4 independent beef cattle populations (Cycle VII, Angus, Hereford and Simmental×Angus) with phenotypes for average daily gain, dry matter intake, metabolic mid-test body weight and residual feed intake. A total of 5, 6, 11 and 10 significant QTL (defined as 1-Mb genome windows with Bonferroni-corrected P-value<0.05) were identified for average daily gain, dry matter intake, metabolic mid-test body weight and residual feed intake, respectively. The identified QTL were population-specific and had little overlap across the 4 populations. The pleiotropic or closely linked QTL on BTA 7 at 23 Mb identified in the Angus population harbours a promising candidate gene ACSL6 (acyl-CoA synthetase long-chain family member 6), and was the largest effect QTL associated with dry matter intake and mid-test body weight explaining 10.39% and 14.25% of the additive genetic variance, respectively. Pleiotropic or closely linked QTL associated with average daily gain and mid-test body weight were detected on BTA 6 at 38 Mb and BTA 7 at 93 Mb confirming previous reports. No QTL for residual feed intake explained more than 2.5% of the additive genetic variance in any population. Marker-based estimates of heritability ranged from 0.21 to 0.49 for residual feed intake across the 4 populations. This GWAS study, which is the largest performed for feed efficiency and its component traits in beef cattle to date, identified several large-effect QTL that cumulatively explained a significant percentage of additive genetic variance within each population. Differences in the QTL identified among the different populations may be due to differences in power to detect QTL, environmental variation, or differences in the genetic architecture of trait variation among breeds. These results enhance our understanding of the biology of growth, feed intake and utilisation in beef cattle.


How nature covers its bases.
The response of DNA and RNA bases to ultraviolet (UV) radiation has been receiving increasing attention for a number of important reasons: (i) the selection of the building blocks of life on an early earth may have been mediated by UV photochemistry, (ii) radiative damage of DNA depends critically on its photochemical properties, and (iii) the processes involved are quite general and play a role in more biomolecules as well as in other compounds. A growing number of groups worldwide have been studying the photochemistry of nucleobases and their derivatives. Here we focus on gas phase studies, which (i) reveal intrinsic properties distinct from effects from the molecular environment, (ii) allow for the most detailed comparison with the highest levels of computational theory, and (iii) provide isomeric selectivity. From the work so far a picture is emerging of rapid decay pathways following UV excitation. The main understanding, which is now well established, is that canonical nucleobases, when absorbing UV radiation, tend to eliminate the resulting electronic excitation by internal conversion (IC) to the electronic ground state in picoseconds or less. The availability of this rapid "safe" de-excitation pathway turns out to depend exquisitely on molecular structure. The canonical DNA and RNA bases are generally short-lived in the excited state, and thus UV protected. Many closely related compounds are longer lived, and thus more prone to other, potentially harmful, photochemical processes. It is this structure dependence that suggests a mechanism for the chemical selection of the building blocks of life on an early earth. However, the picture is far from complete and many new questions now arise.


Short wavelength sensitive cone acuity: individual differences and clinical use.
Acuity of the short wavelength sensitive (SWS) cone pathways was evaluated in 195 observers ages 5-72. A rapid staircase procedure gave comparable results to a longer frequency-of-seeing procedure. Large and reliable individual differences were found among normal observers. Interindividual variability could not be accounted for by differences in density of prereceptoral filters, differences in sensitivity of the SWS cones, or effects of the macular SWS cone-free region, but could be accounted for in part by differences in the accommodative state. Therefore it is important to control the accommodative state in younger observers. SWS cone acuity can be measured reliably and rapidly in a clinical environment and provides a complement to increment threshold measures of the SWS cone pathways.


Aberrant promoter methylation of laminin-5-encoding genes in prostate cancers and its relationship to clinicopathological features.
Laminin-5 (LN5) is an essential component of the basement membrane (BM) and is composed of three chains that are the products of three distinct genes (LAMA3, LAMB3, and LAMC2). Differential expression of LN5 genes has been reported in prostate and other cancers. Recently, in lung cancers, we developed methylation-specific PCR assays for each gene and demonstrated that the aberrant methylation as the mechanism of inactivation of genes. In this study, we investigated the aberrant promoter methylation of LN5 genes in prostate cancers and correlated the data with clinicopathological features. Promoter methylation of LN5-encoding genes was analyzed in 101 prostate cancer samples by methylation-specific PCR assay. In addition, we analyzed 32 nonmalignant prostate tissue samples. The methylation index (MI) was determined as the methylated fraction of the genes examined. The frequencies of loss of expression for the LAMA3, LAMB3, and LAMC2 genes in six prostate cancer cell lines were 83, 67, and 50%, respectively, whereas the methylation frequencies were 83, 67, and 33%, respectively. The concordances between loss of expression and methylation for the three genes were 100, 100, and 83%, respectively. The frequency of methylation of LN5-encoding genes in prostate cancers and nonmalignant prostate tissues, respectively, were: 44 and 12% for LAMA3 (P = 0.001); 18 and 6% for LAMB3; and 41 and 9% for LAMC2 (P = 0.001). In addition, methylation frequencies of any one or two genes, frequencies of at least one-gene methylation and mean chain MI were significantly higher in prostate cancers than in nonmalignant prostate tissues. For clinicopathological correlations, the high Gleason score (GS) group, high preoperative serum prostate-specific antigen (PSA) group, and high stage group had significantly higher methylation frequencies of LAMA3 than their corresponding low groups. Methylation frequency of at least one gene and mean chain MI was significantly higher in the high PSA group and high-stage group than their respective low groups. There was significant correlation between MI and PSA. The high GS group had higher frequencies of at least one gene methylation and mean chain MI than the low GS group. Our results demonstrate frequent epigenetic silencing of LN5-encoding genes in prostate cancers and it correlates with clinicopathological features of poor prognosis. These findings are of biological interest and potentially of clinical importance.


Cardiac myocyte-specific overexpression of human GTP cyclohydrolase I protects against acute cardiac allograft rejection.
GTP cyclohydrolase I (GTPCH) is the rate-limiting enzyme for tetrahydrobiopterin (BH(4)) synthesis. Decreases in GTPCH activity and expression have been shown in late stages of acute cardiac rejection, suggesting a deficit in BH(4). We hypothesized that increasing intracellular levels of BH(4) by cardiac myocyte-targeted overexpression of GTPCH would diminish acute cardiac allograft rejection. Transgenic mice overexpressing GTPCH in the heart were generated and crossed on C57BL6 background. Wild-type and transgenic mouse donor hearts were transplanted into BALB/c recipient mice. Left ventricular (LV) function, histological rejection, BH(4) levels, and inflammatory cytokine gene expression (mRNA) were examined. Expression of human GTPCH was documented by PCR, Western analysis, and function by a significant (P < 0.001) increase in cardiac BH(4) levels. GTPCH transgene decreased histological rejection (46%; P < 0.003) and cardiac myocyte injury (eosin autofluorescence; 56%; P < 0.0001) independent of changes in inflammatory cytokine expression or nitric oxide content. GTPCH transgene decreased IL-2 (88%; P < 0.002), IL-1R2 (42%; P < 0.0001), and programmed cell death-1 (67%; P < 0.0001) expression, whereas it increased fms-like tyrosine kinase 3 (156%; P < 0.0001) and stromal-derived factor-1 (2; 190%; P < 0.0001) expression. There was no difference in ejection fraction or fractional shortening; however, LV mass was significantly increased (P < 0.05) only in wild-type grafts. The decreases in LV mass, cardiac injury, and histological rejection support a protective role of cardiac GTPCH overexpression and increased BH(4) synthesis in cardiac allografts. The mechanism of the decreased rejection appears related to decreased T cell proliferation and modulation of immune function by higher expression of genes involved in hematopoietic/stromal cell development and recruitment.


Structure and thermomechanical behavior of NiTiPt shape memory alloy wires.
The objective of this work is to understand the structure-property relationships in polycrystalline NiTiPt (Ti 42.7 at.% Ni 7.5 at %Pt) with a composition showing pseudoelasticity at ambient temperatures. Structural characterization of the alloy includes grain size determination and texture analysis while the thermomechanical properties are explored using tensile testing. Variation in heat treatment is used as a vehicle to modify microstructure. The results are compared to experiments on Ni-rich NiTi alloy wires (Ti-51.0 at.% Ni), which are in commercial use in various biomedical applications. With regards to microstructure, both alloys exhibit a <111> fiber texture along the wire drawing axis; however, the NiTiPt alloy grain size is smaller than that of the Ni-rich NiTi wires, while the latter materials contain second-phase precipitates. Given the nanometer-scale grain size in NiTiPt and the dispersed, nanometer-scale precipitate size in NiTi, the overall strength and ductility of the alloys are essentially identical when given appropriate heat treatments. Property differences include a much smaller stress hysteresis and smaller temperature dependence of the transformation stress for NiTiPt alloys compared to NiTi alloys. Potential benefits and implications for use in vascular stent applications are discussed.


[Synchronous male bladder cancer and breast cancer - a case report].
A 74-year-old man complained of blood in his urine over a 1-week period beginning in early October 2013, and was examined in the urology department of our hospital. A thorough examination revealed bladder cancer, and surgery was planned after two cycles of preoperative gemcitabine plus cisplatin chemotherapy. A chest computed tomography (CT) performed to evaluate the response to chemotherapy revealed a mass in the right breast. The patient had previously complained about the same site, and mammography and ultrasonography had suggested the possibility of a malignant mammary gland tumor. The results of aspiration cytology were Class V, and based on that finding, a diagnosis of cancer of the right breast was made. In February 2014, we performed a mastectomy, while preserving the pectoral muscles, along with sentinel node biopsy, total cystectomy, urethrectomy, pelvic lymph node dissection, and ureteroileal anastomosis. The histopathological diagnosis of the right breast tumor was invasive ductal carcinoma[scirrhous carcinoma, ly (+), v (-), g (+), f (+), s (+), nuclear grade 1=atypia 2+mitosis 1, EIC (-), ICT (-), NCAT (-)]. A micrometastatic tumor measuring approximately 1mm was observed in the sentinel lymph node. The breast disease was classified as pT1N1mi(sn)M0, Stage IIA, and the tumor was ER (+), PgR (+), HER2/neu (2+), and FISH (-). The bladder cancer was diagnosed as urothelial carcinoma, non-papillary, invasive G2>G3, pT2a; no pelvic lymph node metastases were detected, and it was classified as pT2aN0M0, Stage II. Synchronous male breast cancer and bladder cancer is a very rare condition, and we report the case with a review of the literature.


Is more better? The impact of extended adjuvant temozolomide in newly diagnosed glioblastoma: a secondary analysis of EORTC and NRG Oncology/RTOG.
Radiation with concurrent and adjuvant (6 cycles) temozolomide (TMZ) is the established standard of postsurgical care for newly diagnosed glioblastoma (GBM). This regimen has been adopted with variations, including extending TMZ beyond 6 cycles. The optimal duration of maintenance therapy remains controversial. We performed pooled analysis of individual patient data from 4 randomized trials for newly diagnosed GBM. All patients who were progression free 28 days after cycle 6 were included. The decision to continue TMZ was per local practice and standards, and at the discretion of the treating physician. Patients were grouped into those treated with 6 cycles and those who continued beyond 6 cycles. Progression-free and overall survival were compared, adjusted by age, performance status, resection extent, and MGMT methylation. A total of 2214 GBM patients were included in the 4 trials. Of these, 624 qualified for analysis 291 continued maintenance TMZ until progression or up to 12 cycles, while 333 discontinued TMZ after 6 cycles. Adjusted for prognostic factors, treatment with more than 6 cycles of TMZ was associated with a somewhat improved progression-free survival (hazard ratio [HR] 0.80 [0.65-0.98], P = .03), in particular for patients with methylated MGMT (n = 342, HR 0.65 [0.50-0.85], P < .01). However, overall survival was not affected by the number of TMZ cycles (HR = 0.92 [0.71-1.19], P = .52), including the MGMT methylated subgroup (HR = 0.89 [0.63-1.26], P = .51). Continuing TMZ beyond 6 cycles was not shown to increase overall survival for newly diagnosed GBM.


A dual-response BODIPY-based fluorescent probe for the discrimination of glutathione from cystein and homocystein.
In situ monitoring of intracellular thiol activity in cell growth and function is highly desirable. However, the discriminative detection of glutathione (GSH) from cysteine (Cys) and homocystein (Hcy) and from common amino acids still remains a challenge due to the similar reactivity of the thiol groups in these amino acids. Here we report a novel strategy for selectively sensing GSH by a dual-response mechanism. Integrating two independent reaction sites with a disulfide linker and a thioether function into a fluorescent BODIPY-based chemsensor can guarantee the synergetic dual-response in an elegant fashion to address the discrimination of GSH. In the first synergetic reaction process, the thiol group in GSH, Cys and Hcy induces disulfide cleavage and subsequent intramolecular cyclization to release the unmasked phenol-based BODIPY (discriminating thiol amino acids from other amino acids). In the second synergetic process, upon the substitution of the thioether with the nucleophilic thiolate to form a sulfenyl-BODIPY, only the amino groups of Cys and Hcy, but not that of GSH, undergo a further intramolecular displacement to yield an amino-substituted BODIPY. In this way, we make full use of the kinetically favorable cyclic transition state in the intramolecular rearrangement, and enable photophysical distinction between sulfenyl- and amino-substituted BODIPY for allowing the discriminative detection of GSH over Cys and Hcy and thiol-lacking amino acids under physiological conditions. Moreover, this probe exhibits a distinguishable ratiometric fluorescence pattern generated from the orange imaging channel to the red channel, which proves the differentiation of GSH from Cys and Hcy in living cells.


Polar and brown bear genomes reveal ancient admixture and demographic footprints of past climate change.
Polar bears (PBs) are superbly adapted to the extreme Arctic environment and have become emblematic of the threat to biodiversity from global climate change. Their divergence from the lower-latitude brown bear provides a textbook example of rapid evolution of distinct phenotypes. However, limited mitochondrial and nuclear DNA evidence conflicts in the timing of PB origin as well as placement of the species within versus sister to the brown bear lineage. We gathered extensive genomic sequence data from contemporary polar, brown, and American black bear samples, in addition to a 130,000- to 110,000-y old PB, to examine this problem from a genome-wide perspective. Nuclear DNA markers reflect a species tree consistent with expectation, showing polar and brown bears to be sister species. However, for the enigmatic brown bears native to Alaska's Alexander Archipelago, we estimate that not only their mitochondrial genome, but also 5-10% of their nuclear genome, is most closely related to PBs, indicating ancient admixture between the two species. Explicit admixture analyses are consistent with ancient splits among PBs, brown bears and black bears that were later followed by occasional admixture. We also provide paleodemographic estimates that suggest bear evolution has tracked key climate events, and that PB in particular experienced a prolonged and dramatic decline in its effective population size during the last ca. 500,000 years. We demonstrate that brown bears and PBs have had sufficiently independent evolutionary histories over the last 4-5 million years to leave imprints in the PB nuclear genome that likely are associated with ecological adaptation to the Arctic environment.


Gay men and other men who have sex with men in West Africa: evidence from the field.
This paper presents a synthesis of lessons learned from field experiences in HIV prevention, treatment and care services for men who have sex with men in the four contiguous West African countries of the Gambia, Guinea-Bissau, Guinea-Conakry and Senegal. Service provision for men who have sex with men in these countries is contextualised by the epidemiology of HIV, as well as the socio-political environment. These countries share notable commonalities in terms of social structures and culture, though past approaches to the needs of men who have sex with men have varied greatly. This synthesis includes three distinct components. The first focuses on what is known about HIV epidemiology among men who have sex with men in these countries and provides an overview of the data gaps affecting the quality of service provision. The second aspect describes the HIV prevention and treatment services currently available and how organisations and strategies have evolved in their approach to working with men who have sex with men. Finally, an examination of the political and cultural climate highlights socio-cultural factors that enable or impede HIV prevention and treatment efforts for men who have sex with men. The review concludes with a series of recommendations for impactful research, advocacy and service provision to improve the health and human rights context for men who have sex with men in West Africa.


Cerebral microbleeds: a guide to detection and interpretation.
Cerebral microbleeds (CMBs) are increasingly recognised neuroimaging findings in individuals with cerebrovascular disease and dementia, and in normal ageing. There has been substantial progress in the understanding of CMBs in recent years, particularly in the development of newer MRI methods for the detection of CMBs and the application of these techniques to population-based samples of elderly people. In this Review, we focus on these recent developments and their effects on two main questions: how CMBs are detected, and how CMBs should be interpreted. The number of CMBs detected depends on MRI characteristics, such as pulse sequence, sequence parameters, spatial resolution, magnetic field strength, and image post-processing, emphasising the importance of taking into account MRI technique in the interpretation of study results. Recent investigations with sensitive MRI techniques have indicated a high prevalence of CMBs in community-dwelling elderly people. We propose a procedural guide for identification of CMBs and suggest possible future approaches for elucidating the role of these common lesions as markers for, and contributors to, small-vessel brain disease.