Difference in response reliability predicted by spectrotemporal tuning in the cochlear nuclei of barn owls.
The brainstem auditory pathway is obligatory for all aural information. Brainstem auditory neurons must encode the level and timing of sounds, as well as their time-dependent spectral properties, the fine structure, and envelope, which are essential for sound discrimination. This study focused on envelope coding in the two cochlear nuclei of the barn owl, nucleus angularis (NA) and nucleus magnocellularis (NM). NA and NM receive input from bifurcating auditory nerve fibers and initiate processing pathways specialized in encoding interaural time (ITD) and level (ILD) differences, respectively. We found that NA neurons, although unable to accurately encode stimulus phase, lock more strongly to the stimulus envelope than NM units. The spectrotemporal receptive fields (STRFs) of NA neurons exhibit a pre-excitatory suppressive field. Using multilinear regression analysis and computational modeling, we show that this feature of STRFs can account for enhanced across-trial response reliability, by locking spikes to the stimulus envelope. Our findings indicate a dichotomy in envelope coding between the time and intensity processing pathways as early as at the level of the cochlear nuclei. This allows the ILD processing pathway to encode envelope information with greater fidelity than the ITD processing pathway. Furthermore, we demonstrate that the properties of the STRFs of the neurons can be quantitatively related to spike timing reliability.


Accrual of Atherosclerotic Vascular Events in a Multicenter Inception Systemic Lupus Erythematosus Cohort.
In previous studies, atherosclerotic vascular events (AVEs) were shown to occur in ~10% of patients with systemic lupus erythematosus (SLE). We undertook this study to investigate the annual occurrence and potential risk factors for AVEs in a multinational, multiethnic inception cohort of patients with SLE. A large 33-center cohort of SLE patients was followed up yearly between 1999 and 2017. AVEs were attributed to atherosclerosis based on SLE being inactive at the time of the AVE as well as typical atherosclerotic changes observed on imaging or pathology reports and/or evidence of atherosclerosis elsewhere. Analyses included descriptive statistics, rate of AVEs per 1,000 patient-years, and univariable and multivariable relative risk regression models. Of the 1,848 patients enrolled in the cohort, 1,710 had ≥1 follow-up visit after enrollment, for a total of 13,666 patient-years. Of these 1,710 patients, 3.6% had ≥1 AVEs attributed to atherosclerosis, for an event rate of 4.6 per 1,000 patient-years. In multivariable analyses, lower AVE rates were associated with antimalarial treatment (hazard ratio [HR] 0.54 [95% confidence interval (95% CI) 0.32-0.91]), while higher AVE rates were associated with any prior vascular event (HR 4.00 [95% CI 1.55-10.30]) and a body mass index of >40 kg/m2 (HR 2.74 [95% CI 1.04-7.18]). A prior AVE increased the risk of subsequent AVEs (HR 5.42 [95% CI 3.17-9.27], P < 0.001). The prevalence of AVEs and the rate of AVE accrual demonstrated in the present study is much lower than that seen in previously published data. This may be related to better control of both the disease activity and classic risk factors.


Application of monoliths for downstream processing of clotting factor IX.
In this paper, the application of monolithic columns for downstream processing of different clotting factor IX concentrates is shown. Determination of basic chromatographic conditions as well as investigations on the regeneration of disk- and tube-shaped monolithic columns using human serum albumin as a model protein, were performed. Separation of factor IX and vitronectin, a possible impurity in commercial factor IX concentrates was accomplished using disk-shaped monolithic columns. These same applications were also carried out with identical results on up-scaled tube-shaped monolithic columns. Since these media allow very fast separations, this method can be successfully applied not only to an in-process control of the purification of factor IX but also to other biopolymers from human plasma. Besides, the same application on the up-scaled tube-shaped monolithic column was successfully carried out.


Challenges and benefits of integrating diverse sampling strategies in the observation of cardiovascular risk factors (ORISCAV-LUX 2) study.
It is challenging to manage data collection as planned and creation of opportunities to adapt during the course of enrolment may be needed. This paper aims to summarize the different sampling strategies adopted in the second wave of Observation of Cardiovascular Risk Factors (ORISCAV-LUX, 2016-17), with a focus on population coverage and sample representativeness. Data from the first nationwide cross-sectional, population-based ORISCAV-LUX survey, 2007-08 and from the newly complementary sample recruited via different pathways, nine years later were analysed. First, we compare the socio-demographic characteristics and health profiles between baseline participants and non-participants to the second wave. Then, we describe the distribution of subjects across different strategy-specific samples and performed a comparison of the overall ORISCAV-LUX2 sample to the national population according to stratification criteria. For the baseline sample (1209 subjects), the participants (660) were younger than the non-participants (549), with a significant difference in average ages (44 vs 45.8 years; P = 0.019). There was a significant difference in terms of education level (P < 0.0001), 218 (33%) participants having university qualification vs. 95 (18%) non-participants. The participants seemed having better health perception (p < 0.0001); 455 (70.3%) self-reported good or very good health perception compared to 312 (58.2%) non-participants. The prevalence of obesity (P < 0.0001), hypertension (P < 0.0001), diabetes (P = 0.007), and mean values of related biomarkers were significantly higher among the non-participants. The overall sample (1558 participants) was mainly composed of randomly selected subjects, including 660 from the baseline sample and 455 from other health examination survey sample and 269 from civil registry sample (constituting in total 88.8%), against only 174 volunteers (11.2%), with significantly different characteristics and health status. The ORISCAV-LUX2 sample was representative of national population for geographical district, but not for sex and age; the younger (25-34 years) and older (65-79 years) being underrepresented, whereas middle-aged adults being over-represented, with significant sex-specific difference (p < 0.0001). This study represents a careful first-stage analysis of the ORISCAV-LUX2 sample, based on available information on participants and non-participants. The ORISCAV-LUX datasets represents a relevant tool for epidemiological research and a basis for health monitoring and evidence-based prevention of cardiometabolic risk in Luxembourg.


Adenosine release during seizures attenuates GABAA receptor-mediated depolarization.
Seizure-induced release of the neuromodulator adenosine is a potent endogenous anticonvulsant mechanism, which limits the extension of seizures and mediates seizure arrest. For this reason several adenosine-based therapies for epilepsy are currently under development. However, it is not known how adenosine modulates GABAergic transmission in the context of seizure activity. This may be particularly relevant as strong activation of GABAergic inputs during epileptiform activity can switch GABA(A) receptor (GABA(A)R) signaling from inhibitory to excitatory, which is a process that plays a significant role in intractable epilepsies. We used gramicidin-perforated patch-clamp recordings to investigate the role of seizure-induced adenosine release in the modulation of postsynaptic GABA(A)R signaling in pyramidal neurons of rat hippocampus. Consistent with previous reports, GABA(A)R responses during seizure activity transiently switched from hyperpolarizing to depolarizing and excitatory. We found that adenosine released during the seizure significantly attenuated the depolarizing GABA(A)R responses and also reduced the extent of the after-discharge phase of the seizure. These effects were mimicked by exogenous adenosine administration and could not be explained by a change in chloride homeostasis mechanisms that set the reversal potential for GABA(A)Rs, or by a change in the conductance of GABA(A)Rs. Rather, A(1)R-dependent activation of potassium channels increased the cell's membrane conductance and thus had a shunting effect on GABA(A)R currents. As depolarizing GABA(A)R signaling has been implicated in seizure initiation and progression, the adenosine-induced attenuation of depolarizing GABA(A)R signaling may represent an important mechanism by which adenosine can limit seizure activity.


Weight loss reduces head motion: Revisiting a major confound in neuroimaging.
Head motion during magnetic resonance imaging (MRI) induces image artifacts that affect virtually every brain measure. In parallel, cross-sectional observations indicate a correlation of head motion with age, psychiatric disease status and obesity, raising the possibility of a systematic artifact-induced bias in neuroimaging outcomes in these conditions, due to the differences in head motion. Yet, a causal link between obesity and head motion has not been tested in an experimental design. Here, we show that a change in body mass index (BMI) (i.e., weight loss after bariatric surgery) systematically decreases head motion during MRI. In this setting, reduced imaging artifacts due to lower head motion might result in biased estimates of neural differences induced by changes in BMI. Overall, our finding urges the need to rigorously control for head motion during MRI to enable valid results of neuroimaging outcomes in populations that differ in head motion due to obesity or other conditions.


Sensitivity analysis of biodiesel blends on Benzo[a]pyrene and main emissions using MOVES: A case study in Temuco, Chile.
Temuco is one of the most highly wood-smoke polluted cities in Chile; however, the diesel mobile sources are growing very fast in the past 10 years and so far very few studies have been done. The main goal of this research was to develop a 2013 emission inventory of criteria pollutants and Benzo[a]pyrene (BaP) and to evaluate the use of six biodiesel blends of 0%, 1%, 4%, 8%, 12%, and 20% by volume of fuel in diesel motors from the vehicle fleet within the mentioned areas using the Motor Vehicle Emission Simulator (MOVES). Input parameters for the base year 2005 were estimated to implement and adapt the model in Chile, while results of NOx, PM10, PM2.5, NH3, CO2 equivalent and SO2 were compared with the Chilean Emission Inventory estimated by the model "Methodology for the Calculation of Vehicle Emissions." The 2013 emissions reduced with respect to 2005, in the majority of the contaminants analyzed, despite the 47% increase in the annual miles traveled. Using biodiesel blends, an emission reduction was estimated at up to 15% in particulate matter, BaP, and CO for the year 2013, as well as an increment of 2% in NOx emissions, attributed to low sulfur content (50 ppm) in the diesel and the antiquity of the vehicle fleet. The results obtained gave evidence of the influence of the biodiesel use in the pollutant emissions to improve the Chilean air quality, as well as providing a strategy for this air quality management.


Sexual and individual foraging segregation in Gentoo penguins Pygoscelis papua from the Southern Ocean during an abnormal winter.
Knowledge about sexual segregation and gender-specific, or indeed individual specialization, in marine organisms has improved considerably in the past decade. In this context, we tested the "Intersexual Competition Hypothesis" for penguins by investigating the feeding ecology of Gentoo penguins during their austral winter non-breeding season. We considered this during unusual environmental conditions (i.e. the year 2009 had observations of high sea surface and air temperatures) in comparison with the long term average at Bird Island, South Georgia. Through conventional (i.e. stomach contents) and stable isotopic values from red blood cells, plasma and feathers of both male and female Gentoo penguins, we showed that there were significant differences between sexes, with males feeding mainly on fish (54% by mass) followed by crustaceans (38%) whereas females fed mainly on crustaceans (89% by mass) followed by fish (4%). Themisto gaudichaudii was the most important crustacean prey for males (64% by mass; 82% by number; 53% by frequency of occurrence) and females (63% by mass; 77% by number; 89% by frequency of occurrence), contrasting with all previous studies that found Antarctic krill Euphausia superba were generally the main prey. Stable isotopic data showed that, in terms of habitat use (based on δ 13C), there were significant differences in short-term carbon signatures between males and females (based on plasma and red blood cells), suggesting that both sexes explored different habitats, with females exploring more offshore pelagic waters and males feeding more in coastal benthic waters. Based on δ 15N, males fed on significantly higher trophic level than females (based on plasma and red blood cells), in agreement with our diet results., Thus, Gentoo penguins behave in a similar manner to other non-breeding penguins species (e.g. king, macaroni and rockhopper penguins), albeit at a smaller spatial scale (as they do not disperse as these other penguins do), in that they have a wider habitat and trophic niche during the Antarctic Winter (in comparison to Summer). We also detected individual specialization in feeding/trophic levels for each gender, with certain males feeding mainly on fish and certain females mainly on crustaceans, which may be driven the prevailing environmental conditions that lead individuals to search for alternative prey, and cause sexual diet segregation. Our results provide further information to help improve understanding about sexual segregation and individual specialization of marine organisms, while contributing valuable information on the winter diet for Antarctic monitoring programs and for modelling Antarctic marine food webs.


A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms.
The objective was to test effects of ethyl eicosapentaenoate (E-E) on persistent ongoing symptoms in patients receiving different types of anti-schizophrenic drugs, typical antipsychotics, new atypical antipsychotics, and clozapine. 115 patients with DSM-IV-defined schizophrenia were studied, 31 on clozapine, 48 on new atypical drugs and 36 on typical antipsychotics. Placebo or 1, 2 or 4 g/day of E-E was given for 12 weeks in addition to the background medication. The main assessment was change from baseline to 12 weeks on the PANSS and its sub-scales. There were no treatment-related side effects or adverse biochemical or haematological effects. Patients on 2 and 4 g/day E-E showed significant reductions in triglyceride levels which had been elevated by clozapine. In patients given 2 g/day E-E there were improvements on the PANSS and its sub-scales, but there was also a large placebo effect in patients on typical and new atypical antipsychotics and no difference between active treatment and placebo. In patients on clozapine, in contrast, there was little placebo response, but a clinically important and statistically significant effect of E-E on all rating scales. This effect was greatest at 2 g/day. There was a positive relationship between improvement on rating scales and rise in red blood cell arachidonic acid concentration.


Diabetogenic effect of cyclosporin.
A young woman given a renal allograft for polycystic kidney disease developed insulin dependent diabetes mellitus 25 days after transplantation. There was no family history of diabetes, plasma glucose concentrations had been normal at presentation and on five subsequent occasions, and at no time were islet cell antibodies detectable. Plasma C peptide concentrations, however, were greatly suppressed after transplantation and remained so for up to six months. The immunosuppressive regimen had included cyclosporin A, which had been difficult to regulate and caused definite signs of toxicity in the patient. By virtue of its reported toxicity for beta cells and the reversal of the diabetes several months after the dose was reduced cyclosporin was incriminated as the probable causative agent. Dose related beta cell toxicity of cyclosporin A may be a risk in recipients of this drug and warrants careful monitoring of drug and glucose concentrations.


Know your medicine: A novel student-led community service learning program.
The objective of this article is to describe the efforts of the student pharmacist organization called Know Your Medicine (KYM) as they conduct medication therapy management (MTM) for older adults and underserved communities. Patients brought medications, immunization records, and health concerns to KYM events during academic years 2012-2013 and 2013-2014. Student pharmacists performed health screenings, created personalized medication records (PMR), made recommendations, created personal action plans (PAP), and conducted follow-up phone calls. Student pharmacists provided MTM services for a total of 107 patients. The mean duration of a KYM appointment was 62±21min, and student pharmacists provided a mean of 3.5±2.1 recommendations per patient. Patients had a mean age of 78±11 years, 4.5±3.2 disease states, 6.9±4.6 prescriptions, 1.9±1.9 OTC medications, and 2.8±2.6 vitamins or herbals. At the time of the follow-up phone call, a mean of 2.6±1.9 recommendations per patient had been followed. Student pharmacists successfully implemented a new MTM program for older adults and underserved communities. This program can serve as an example of how other pharmacy colleges and schools might implement MTM training and real-world MTM experience for their student pharmacists.


Deletion of the Zinc Transporter Lipoprotein AdcAII Causes Hyperencapsulation of Streptococcus pneumoniae Associated with Distinct Alleles of the Type I Restriction-Modification System.
The capsule is the dominant Streptococcus pneumoniae virulence factor, yet how variation in capsule thickness is regulated is poorly understood. Here, we describe an unexpected relationship between mutation of adcAII, which encodes a zinc uptake lipoprotein, and capsule thickness. Partial deletion of adcAII in three of five capsular serotypes frequently resulted in a mucoid phenotype that biochemical analysis and electron microscopy of the D39 adcAII mutants confirmed was caused by markedly increased capsule thickness. Compared to D39, the hyperencapsulated ΔadcAII mutant strain was more resistant to complement-mediated neutrophil killing and was hypervirulent in mouse models of invasive infection. Transcriptome analysis of D39 and the ΔadcAII mutant identified major differences in transcription of the Sp_0505-0508 locus, which encodes an SpnD39III (ST5556II) type I restriction-modification system and allelic variation of which correlates with capsule thickness. A PCR assay demonstrated close linkage of the SpnD39IIIC and F alleles with the hyperencapsulated ΔadcAII strains. However, transformation of ΔadcAII with fixed SpnD39III alleles associated with normal capsule thickness did not revert the hyperencapsulated phenotype. Half of hyperencapsulated ΔadcAII strains contained the same single nucleotide polymorphism in the capsule locus gene cps2E, which is required for the initiation of capsule synthesis. These results provide further evidence for the importance of the SpnD39III (ST5556II) type I restriction-modification system for modulating capsule thickness and identified an unexpected linkage between capsule thickness and mutation of ΔadcAII Further investigation will be needed to characterize how mutation of adcAII affects SpnD39III (ST5556II) allele dominance and results in the hyperencapsulated phenotype.IMPORTANCE The Streptococcus pneumoniae capsule affects multiple interactions with the host including contributing to colonization and immune evasion. During infection, the capsule thickness varies, but the mechanisms regulating this are poorly understood. We have identified an unsuspected relationship between mutation of adcAII, a gene that encodes a zinc uptake lipoprotein, and capsule thickness. Mutation of adcAII resulted in a striking hyperencapsulated phenotype, increased resistance to complement-mediated neutrophil killing, and increased S. pneumoniae virulence in mouse models of infection. Transcriptome and PCR analysis linked the hyperencapsulated phenotype of the ΔadcAII strain to specific alleles of the SpnD39III (ST5556II) type I restriction-modification system, a system which has previously been shown to affect capsule thickness. Our data provide further evidence for the importance of the SpnD39III (ST5556II) type I restriction-modification system for modulating capsule thickness and identify an unexpected link between capsule thickness and ΔadcAII, further investigation of which could further characterize mechanisms of capsule regulation.


Pilot Feasibility Study of Comprehensive Pulmonary Evaluation Following Lung Radiation Therapy.
Symptoms of pulmonary injury following lung irradiation may not manifest clinically in childhood. We performed comprehensive pulmonary evaluation of patients who had received lung irradiation for treatment of cancer. Patients underwent a focused history and physical examination, computed tomography of the chest, pulmonary function test, and cardiopulmonary exercise stress test (CPET). Health-related Quality of Life was also measured. Fourteen patients were recruited with median age of 16 years (range, 6 to 21 y). Median time from pulmonary radiation to testing was 5 years (range, 2 to 11 y). Five patients reported pulmonary symptoms. Twelve patients (85.7%) had at least 1 pulmonary function test abnormality. Nine patients demonstrated CPET abnormalities; 7 patients had abnormal pulmonary limitation to exercise, and 5 patients had exercise-induced bronchospasm. The pulmonary limitations included abnormal ventilatory response to exercise in 5 patients, and gas exchange abnormalities in 4 patients. Chest computed tomography demonstrated grade 1-2 radiation-induced lung changes in 4 patients, and grade 3 abnormalities in 1 patient. Significant pulmonary dysfunction was observed in childhood cancer survivors who had received lung irradiation. CPET is feasible in childhood cancer survivors and can be valuable for assessment of pulmonary function and exercise capacity.


Multiple sodium channel variants in the mosquito Culex quinquefasciatus.
Voltage-gated sodium channels are the target sites of both DDT and pyrethroid insecticides. The importance of alternative splicing as a key mechanism governing the structural and functional diversity of sodium channels and the resulting development of insecticide and acaricide resistance is widely recognized, as shown by the extensive research on characterizing alternative splicing and variants of sodium channels in medically and agriculturally important insect species. Here we present the first comparative study of multiple variants of the sodium channel transcripts in the mosquito Culex quinquefasciatus. The variants were classified into two categories, CxNa-L and CxNa-S based on their distinguishing sequence sizes of ~6.5 kb and ~4.0 kb, respectively, and generated via major extensive alternative splicing with minor small deletions/ insertions in susceptible S-Lab, low resistant HAmCq(G0), and highly resistant HAmCq(G8)Culex strains. Four alternative Cx-Na-L splice variants were identified, including three full length variants with three optional exons (2, 5, and 21i) and one with in-frame-stop codons. Large, multi-exon-alternative splices were identified in the CxNa-S category. All CxNa-S splicing variants in the S-Lab and HAmCq(G0) strains contained in-frame stop codons, suggesting that any resulting proteins would be truncated. The ~1000 to ~3000-fold lower expression of these splice variants with stop codons compared with the CxNa-L splicing variants may support the lower importance of these variants in S-Lab and HAmCq(G0). Interestingly, two alternative splicing variants of CxNa-S in HAmCq(G8) included entire ORFs but lacked exons 5 to18 and these two variants had much higher expression levels in HAmCq(G8) than in S-Lab and HAmCq(G0). These results provide a functional basis for further characterizing how alternative splicing of a voltage-gated sodium channel contributes to diversity in neuronal signaling in mosquitoes in response to pyrethroids, and possibly indicates the role of these variants in the development of pyrethroid resistance.


Altered Cell-Cycle Control, Inflammation, and Adhesion in High-Risk Persistent Bronchial Dysplasia.
Persistent bronchial dysplasia is associated with increased risk of developing invasive squamous cell carcinoma (SCC) of the lung. In this study, we hypothesized that differences in gene expression profiles between persistent and regressive bronchial dysplasia would identify cellular processes that underlie progression to SCC. RNA expression arrays comparing baseline biopsies from 32 bronchial sites that persisted/progressed to 31 regressive sites showed 395 differentially expressed genes [ANOVA, FDR ≤ 0.05). Thirty-one pathways showed significantly altered activity between the two groups, many of which were associated with cell-cycle control and proliferation, inflammation, or epithelial differentiation/cell-cell adhesion. Cultured persistent bronchial dysplasia cells exhibited increased expression of Polo-like kinase 1 (PLK1), which was associated with multiple cell-cycle pathways. Treatment with PLK1 inhibitor induced apoptosis and G2-M arrest and decreased proliferation compared with untreated cells; these effects were not seen in normal or regressive bronchial dysplasia cultures. Inflammatory pathway activity was decreased in persistent bronchial dysplasia, and the presence of an inflammatory infiltrate was more common in regressive bronchial dysplasia. Regressive bronchial dysplasia was also associated with trends toward overall increases in macrophages and T lymphocytes and altered polarization of these inflammatory cell subsets. Increased desmoglein 3 and plakoglobin expression was associated with higher grade and persistence of bronchial dysplasia. These results identify alterations in the persistent subset of bronchial dysplasia that are associated with high risk for progression to invasive SCC. These alterations may serve as strong markers of risk and as effective targets for lung cancer prevention.Significance: Gene expression profiling of high-risk persistent bronchial dysplasia reveals changes in cell-cycle control, inflammatory activity, and epithelial differentiation/cell-cell adhesion that may underlie progression to invasive SCC. Cancer Res; 78(17); 4971-83. ©2018 AACR.


The R-Ras/RIN2/Rab5 complex controls endothelial cell adhesion and morphogenesis via active integrin endocytosis and Rac signaling.
During developmental and tumor angiogenesis, semaphorins regulate blood vessel navigation by signaling through plexin receptors that inhibit the R-Ras subfamily of small GTPases. R-Ras is mainly expressed in vascular cells, where it induces adhesion to the extracellular matrix (ECM) through unknown mechanisms. We identify the Ras and Rab5 interacting protein RIN2 as a key effector that in endothelial cells interacts with and mediates the pro-adhesive and -angiogenic activity of R-Ras. Both R-Ras-GTP and RIN2 localize at nascent ECM adhesion sites associated with lamellipodia. Upon binding, GTP-loaded R-Ras converts RIN2 from a Rab5 guanine nucleotide exchange factor (GEF) to an adaptor that first interacts at high affinity with Rab5-GTP to promote the selective endocytosis of ligand-bound/active β1 integrins and then causes the translocation of R-Ras to early endosomes. Here, the R-Ras/RIN2/Rab5 signaling module activates Rac1-dependent cell adhesion via TIAM1, a Rac GEF that localizes on early endosomes and is stimulated by the interaction with both Ras proteins and the vesicular lipid phosphatidylinositol 3-monophosphate. In conclusion, the ability of R-Ras-GTP to convert RIN2 from a GEF to an adaptor that preferentially binds Rab5-GTP allows the triggering of the endocytosis of ECM-bound/active β1 integrins and the ensuing funneling of R-Ras-GTP toward early endosomes to elicit the pro-adhesive and TIAM1-mediated activation of Rac1.


Bone mineral assessment with tibial ultrasonometry and dual-energy X-ray absorptiometry in long-term survivors of acute lymphoblastic leukemia in childhood.
Acute lymphoblastic leukemia (ALL) in childhood is a serious disease that can affect growth and the attainment of maximal peak bone mass. The latter has recently been recognized as a risk factor for the development of osteoporosis later in life. To determine long-term effects of the disease itself and its treatment, we assessed the bone status of a group of long-term survivors of childhood ALL, all treated with high doses of steroids (dexamethasone) and methotrexate and without cranial irradiation. All 21 subjects enrolled in this cross-sectional study were diagnosed to have non-high-risk precursors acute lymphoblastic leukemia (12 boys and 9 girls, mean age 16.5 yr, range 12.2-25.4 yr). Standard deviation (SD) scores were calculated using a tibial ultrasound device and spinal dual-energy X-ray absorptiometry (DXA) device as bone assessment techniques. SD scores of those two different bone assessment techniques were compared. The mean SOS (speed of sound) SD scores (SDS) of the tibia (mean 0.26, standard deviation [sd] 1.00) were not significantly different from our reference value of 0. There was no significant difference between the SOS SDS in boys and girls. With DXA, no significant difference was seen between the mean BMD SDS and the reference data and no significant difference in BMD between boys and girls was found. The individual mean SDS for bone mineral density (BMD) of lumbar spine are 0.24 (sd 1.02), total body 0.17 (sd 1.00), and apparent BMD (BMAD) 0.07 (sd 1.09). Spearman's correlation between mean SOS SDS and mean BMD of lumbar spine was 0.47, mean SOS SDS and mean BMAD SDS was 0.43, and mean SOS SDS and mean BMD of total body was 0.49. These correlations were significant at the 0.05 level (two tailed). Despite high-dose dexamethasone and methotrexate used for treatment of these children with ALL, no long-term side effects on the bone mineral status of the subjects, measured with DXA or tibial ultrasonometry, could be determined.


Cat Inflicted Eye Injury in a Child.
Ocular injuries, especially corneal abrasions are a common phenomenon noted in the pediatric emergency department. Most of these are minor injuries and are well described in literature. However, there is very limited data on corneal cat scratch injuries and their management. We present the case of a 10-year-old female with cat scratch inflicted superficial corneal laceration. In addition to immediate identification of the injury, it is essential to investigate and evaluate the depth of the ocular injury for prompt management, including route of antibiotics, need for an immediate surgical intervention and future follow-up.


Mauritia flexuosa Presents In Vitro and In Vivo Antiplatelet and Antithrombotic Activities.
Fruit from the palm Mauritia flexuosa is one of the most important species in Peru, Venezuela, Brazil, Colombia, Bolivia, and Guyana. The present study aimed to investigate the antiplatelet and antithrombotic activities of oil extracted from Mauritia flexuosa. The fatty acid contents were determined by gas chromatography-mass spectrometry. Oil extract of peel of Mauritia flexuosa was extracted by soxhlet extraction. The oil extract inhibited platelet secretion and aggregation induced by ADP, collagen, and TRAP-6 by a concentration-dependent way (0.1 to 1 mg/mL) without the participation of the adenylyl cyclase pathway and diminished platelet rolling and firm adhesion under flow conditions. Furthermore, the oil extract induced a marked increase in the rolling speed of leukocytes retained on the platelet surface, reflecting a reduction of rolling and less adhesion. At the concentrations used, the oil extract significantly decreased platelet release of sP-selectin, an atherosclerotic-related inflammatory mediator. Oil extract inhibited thrombus growth at the same concentration as that of aspirin, a classical reference drug. Finally, the data presented herein also demonstrate for the first time to our knowledge the protective effect of oil extracted from Mauritia flexuosa on platelet activation and thrombosis formation.


Ergogenic effects of caffeine and sodium bicarbonate supplementation on intermittent exercise performance preceded by intense arm cranking exercise.
Caffeine and sodium bicarbonate ingestion have been suggested to improve high-intensity intermittent exercise, but it is unclear if these ergogenic substances affect performance under provoked metabolic acidification. To study the effects of caffeine and sodium bicarbonate on intense intermittent exercise performance and metabolic markers under exercise-induced acidification, intense arm-cranking exercise was performed prior to intense intermittent running after intake of placebo, caffeine and sodium bicarbonate. Male team-sports athletes (n = 12) ingested sodium bicarbonate (NaHCO3; 0.4 g.kg(-1) b.w.), caffeine (CAF; 6 mg.kg(-1) b.w.) or placebo (PLA) on three different occasions. Thereafter, participants engaged in intense arm exercise prior to the Yo-Yo intermittent recovery test level-2 (Yo-Yo IR2). Heart rate, blood lactate and glucose as well as rating of perceived exertion (RPE) were determined during the protocol. CAF and NaHCO3 elicited a 14 and 23% improvement (P < 0.05), respectively, in Yo-Yo IR2 performance, post arm exercise compared to PLA. The NaHCO3 trial displayed higher [blood lactate] (P < 0.05) compared to CAF and PLA (10.5 ± 1.9 vs. 8.8 ± 1.7 and 7.7 ± 2.0 mmol.L(-1), respectively) after the Yo-Yo IR2. At exhaustion CAF demonstrated higher (P < 0.05) [blood glucose] compared to PLA and NaHCO3 (5.5 ± 0.7 vs. 4.2 ± 0.9 vs. 4.1 ± 0.9 mmol.L(-1), respectively). RPE was lower (P < 0.05) during the Yo-Yo IR2 test in the NaHCO3 trial in comparison to CAF and PLA, while no difference in heart rate was observed between trials. Caffeine and sodium bicarbonate administration improved Yo-Yo IR2 performance and lowered perceived exertion after intense arm cranking exercise, with greater overall effects of sodium bicarbonate intake.


Reflecting on spirituality in the context of breast cancer diagnosis and treatment.
In this first part of a longitudinal study, women were asked to reflect on the meaning of spirituality in the first year following diagnosis of breast cancer. Twenty-two women were interviewed at approximately one year post-diagnosis. This paper reports on a thematic analysis of these interviews. Participants' responses reflected three higher-order themes: relationship with a higher power, a deepening sense of self, and spiritual connection with others. The findings provide an enhanced understanding of how spirituality frames and impacts (both positively and negatively) the experience of breast cancer immediately following diagnosis and treatment. Most participants in this study found strength and support in their experiences of spirituality. They also spoke at times of feeling disconnected from or abandoned by God. The paper concludes with a discussion of how cancer health professionals might respond to the spiritual needs expressed by women living with cancer.


Comparison of manual therapy and exercise therapy in osteoarthritis of the hip: a randomized clinical trial.
To determine the effectiveness of a manual therapy program compared with an exercise therapy program in patients with osteoarthritis (OA) of the hip. A single-blind, randomized clinical trial of 109 hip OA patients was carried out in the outpatient clinic for physical therapy of a large hospital. The manual therapy program focused on specific manipulations and mobilization of the hip joint. The exercise therapy program focused on active exercises to improve muscle function and joint motion. The treatment period was 5 weeks (9 sessions). The primary outcome was general perceived improvement after treatment. Secondary outcomes included pain, hip function, walking speed, range of motion, and quality of life. Of 109 patients included in the study, 56 were allocated to manual therapy and 53 to exercise therapy. No major differences were found on baseline characteristics between groups. Success rates (primary outcome) after 5 weeks were 81% in the manual therapy group and 50% in the exercise group (odds ratio 1.92, 95% confidence interval 1.30, 2.60). Furthermore, patients in the manual therapy group had significantly better outcomes on pain, stiffness, hip function, and range of motion. Effects of manual therapy on the improvement of pain, hip function, and range of motion endured after 29 weeks. The effect of the manual therapy program on hip function is superior to the exercise therapy program in patients with OA of the hip.


Dialysis and transplantation in Fabry disease: indications for enzyme replacement therapy.
ESRD is a major cause of morbidity and premature mortality in Fabry disease, particularly in classically affected males. The decline of renal function in Fabry nephropathy is adversely affected by male gender, advanced chronic kidney disease (CKD), and severe proteinuria. The diagnosis of Fabry nephropathy may be missed if not specifically addressed in progressive CKD and patients have been first identified in screening programs of dialysis patients. Fabry patients have worse 3-year survival rates on dialysis as compared with nondiabetic controls. The 5-year survival rate of transplanted Fabry patients is also lower than that of controls. However, because Fabry nephropathy does not recur in the allograft and transplanted Fabry patients appear to have better overall outcomes than those maintained on dialysis, kidney transplantation should be recommended as a first choice in renal replacement therapy (RRT) for Fabry disease. Appropriately designed and powered studies are not available to answer the question whether enzyme replacement therapy (ERT) influences outcomes, the course of cardiomyopathy, events, or survival in Fabry patients on RRT. The authors are not aware of compelling indications for ERT in RRT patients because progression of cardiomyopathy was documented during ERT. Whether the excess mortality risk of Fabry patients on RRT can be prevented by ERT is unknown. Despite observational reports of symptomatic improvement, the available evidence supporting ERT for such patients is not compelling enough. To clarify this issue, studies are needed to test the effectiveness of agalsidases in preventing cardiac and cerebrovascular complications in Fabry patients with ESRD.


On the spatial spread of rabies among foxes.
We present a simple model for the spatial spread of rabies among foxes and use it to quantify its progress in England if rabies were introduced. The model is based on the known ecology of fox behaviour and on the assumption that the main vector for the spread of the disease is the rabid fox. Known data and facts are used to determine real parameter values involved in the model. We calculate the speed of propagation of the epizootic front, the threshold for the existence of an epidemic, the period and distance apart of the subsequent cyclical epidemics which follow the main front, and finally we quantify a means for control of the spatial spread of the disease. By way of illustration we use the model to determine the progress of rabies up through the southern part of England if it were introduced near Southampton. Estimates for the current fox density in England were used in the simulations. These suggest that the disease would reach Manchester within about 3.5 years, moving at speeds as high as 100 km per year in the central region. The model further indicates that although it might seem that the disease had disappeared after the wave had passed it would reappear in the south of England after just over 6 years and at periodic times after that. We consider the possibility of stopping the spread of the disease by creating a rabies 'break' ahead of the front through vaccination to reduce the population to a level below the threshold for an epidemic to exist. Based on parameter values relevant to England, we estimate its minimum width to be about 15 km. The model suggests that vaccination has considerable advantages over severe culling.


Targeting fatty acid amide hydrolase (FAAH) to treat pain and inflammation.
The endogenous cannabinoid N-arachidonoyl ethanolamine (anandamide; AEA) produces most of its pharmacological effects by binding and activating CB(1) and CB(2) cannabinoid receptors within the CNS and periphery. However, the actions of AEA are short lived because of its rapid catabolism by fatty acid amide hydrolase (FAAH). Indeed, FAAH knockout mice as well as animals treated with FAAH inhibitors are severely impaired in their ability to hydrolyze AEA as well as a variety of noncannabinoid lipid signaling molecules and consequently possess greatly elevated levels of these endogenous ligands. In this mini review, we describe recent research that has investigated the functional consequences of inhibiting this enzyme in a wide range of animal models of inflammatory and neuropathic pain states. FAAH-compromised animals reliably display antinociceptive and anti-inflammatory phenotypes with a similar efficacy as direct-acting cannabinoid receptor agonists, such as Delta(9)-tetrahydrocannabinol (THC), the primary psychoactive constituent of Cannabis sativa. Importantly, FAAH blockade does not elicit any apparent psychomimetic effects associated with THC or produce reinforcing effects that are predictive of human drug abuse. The beneficial effects caused by FAAH blockade in these models are predominantly mediated through the activation of CB(1) and/or CB(2) receptors, though noncannabinoid mechanisms of actions can also play contributory or even primary roles. Collectively, the current body of scientific literature suggests that activating the endogenous cannabinoid system by targeting FAAH is a promising strategy to treat pain and inflammation but lacks untoward side effects typically associated with Cannabis sativa.


Observational studies in the era of randomized trials: finding the balance.
Randomized controlled trials (RCTs) constitute the gold standard for the generation of evidence-based medicine, but may not always be feasible. Furthermore, randomization alone does not guarantee the utility of the research, as evidenced by thousands of uninformative RCTs documented in the literature. Observational studies, including longitudinal, retrospective, and case-control designs, can contribute to the body of evidence in meaningful ways, provide useful information when an RCT is unethical or not feasible, generate hypotheses for RCTs, or provide preliminary work to better inform design of future RCTs. They can also be used to study rare outcomes, risk factors, and side effects, and to examine whether results from RCTs translate into effective treatment in routine practice. Use of modern statistical techniques, both in the study design and in the analysis stage, can improve the usefulness of the evidence obtained from observational studies.


Plasmodium falciparum Resistance to a Lead Benzoxaborole Due to Blocked Compound Activation and Altered Ubiquitination or Sumoylation.
New antimalarial drugs are needed. The benzoxaborole AN13762 showed excellent activity against cultured Plasmodium falciparum, against fresh Ugandan P. falciparum isolates, and in murine malaria models. To gain mechanistic insights, we selected in vitro for P. falciparum isolates resistant to AN13762. In all of 11 independent selections with 100 to 200 nM AN13762, the 50% inhibitory concentration (IC50) increased from 18-118 nM to 180-890 nM, and whole-genome sequencing of resistant parasites demonstrated mutations in prodrug activation and resistance esterase (PfPARE). The introduction of PfPARE mutations led to a similar level of resistance, and recombinant PfPARE hydrolyzed AN13762 to the benzoxaborole AN10248, which has activity similar to that of AN13762 but for which selection of resistance was not readily achieved. Parasites further selected with micromolar concentrations of AN13762 developed higher-level resistance (IC50, 1.9 to 5.0 μM), and sequencing revealed additional mutations in any of 5 genes, 4 of which were associated with ubiquitination/sumoylation enzyme cascades; the introduction of one of these mutations, in SUMO-activating enzyme subunit 2, led to a similar level of resistance. The other gene mutated in highly resistant parasites encodes the P. falciparum cleavage and specificity factor homolog PfCPSF3, previously identified as the antimalarial target of another benzoxaborole. Parasites selected for resistance to AN13762 were cross-resistant with a close analog, AN13956, but not with standard antimalarials, AN10248, or other benzoxaboroles known to have different P. falciparum targets. Thus, AN13762 appears to have a novel mechanism of antimalarial action and multiple mechanisms of resistance, including loss of function of PfPARE preventing activation to AN10248, followed by alterations in ubiquitination/sumoylation pathways or PfCPSF3.IMPORTANCE Benzoxaboroles are under study as potential new drugs to treat malaria. One benzoxaborole, AN13762, has potent activity and promising features, but its mechanisms of action and resistance are unknown. To gain insights into these mechanisms, we cultured malaria parasites with nonlethal concentrations of AN13762 and generated parasites with varied levels of resistance. Parasites with low-level resistance had mutations in PfPARE, which processes AN13762 into an active metabolite; PfPARE mutations prevented this processing. Parasites with high-level resistance had mutations in any of a number of enzymes, mostly those involved in stress responses. Parasites selected for AN13762 resistance were not resistant to other antimalarials, suggesting novel mechanisms of action and resistance for AN13762, a valuable feature for a new class of antimalarial drugs.


Beyond mean modelling: Bias due to misspecification of dispersion in Poisson-inverse Gaussian regression.
In clinical trials one traditionally models the effect of treatment on the mean response. The underlying assumption is that treatment affects the response distribution through a mean location shift on a suitable scale, with other aspects of the distribution (shape/dispersion/variance) remaining the same. This work is motivated by a trial in Parkinson's disease patients in which one of the endpoints is the number of falls during a 10-week period. Inspection of the data reveals that the Poisson-inverse Gaussian (PiG) distribution is appropriate, and that the experimental treatment reduces not only the mean, but also the variability, substantially. The conventional analysis assumes a treatment effect on the mean, either adjusted or unadjusted for covariates, and a constant dispersion parameter. On our data, this analysis yields a non-significant treatment effect. However, if we model a treatment effect on both mean and dispersion parameters, both effects are highly significant. A simulation study shows that if a treatment effect exists on the dispersion and is ignored in the modelling, estimation of the treatment effect on the mean can be severely biased. We show further that if we use an orthogonal parametrization of the PiG distribution, estimates of the mean model are robust to misspecification of the dispersion model. We also discuss inferential aspects that are more difficult than anticipated in this setting. These findings have implications in the planning of statistical analyses for count data in clinical trials.


Utilization of Ambulatory Physician Encounters, Emergency Room Visits, and Hospitalizations by Systemic Lupus Erythematosus Patients: A 13-Year Population Health Study.
To determine total physician encounters, emergency room (ER) visits, and hospitalizations in an incident cohort of systemic lupus erythematosus (SLE) cases and matched control patients over 13 years. A retrospective cohort study was performed utilizing administrative health care data from approximately 1 million people with access to universal health care. Using International Classification of Diseases, Ninth and Tenth Revisions diagnostic codes, 7 SLE case definitions were used. Each case was matched by age and sex to 4 randomly selected controls. Data included physician billings, ER visits, and hospital discharges over 13 years. The number of incident SLE cases varied from 564 to 4,494 depending on the case definition used. The mean age varied from 47.7 to 50.6 years and the proportion of females from 78.0% to 85.1%. SLE utilization of physicians was highest in the index year, and declined significantly thereafter for all case definitions. By the fourth year, encounters with subspecialty physicians fell by 60% (rheumatologists), 50% (internists), and 31% (other physicians). In contrast, visits to family physicians fell by only 9%. Visits to the ER and hospital admissions for SLE cases were also more frequent early in the disease course and fell significantly over the study for both ER visits (all case definitions) and hospitalizations (2 of 7 case definitions). In SLE patients, health care utilization is highest in the first few years following the diagnosis, which is also the time of maximal involvement by rheumatologists. Utilization declines over time, and encounters with patients' family physicians predominate over those of other physician groups.


Macromolecular-scale resolution in biological fluorescence microscopy.
We demonstrate far-field fluorescence microscopy with a focal-plane resolution of 15-20 nm in biological samples. The 10- to 12-fold multilateral increase in resolution below the diffraction barrier has been enabled by the elimination of molecular triplet state excitation as a major source of photobleaching of a number of dyes in stimulated emission depletion microscopy. Allowing for relaxation of the triplet state between subsequent excitation-depletion cycles yields an up to 30-fold increase in total fluorescence signal as compared with reported stimulated emission depletion illumination schemes. Moreover, it enables the reduction of the effective focal spot area by up to approximately 140-fold below that given by diffraction. Triplet-state relaxation can be realized either by reducing the repetition rate of pulsed lasers or by increasing the scanning speed such that the build-up of the triplet state is effectively prevented. This resolution in immunofluorescence imaging is evidenced by revealing nanoscale protein patterns on endosomes, the punctuated structures of intermediate filaments in neurons, and nuclear protein speckles in mammalian cells with conventional optics. The reported performance of diffraction-unlimited fluorescence microscopy opens up a pathway for addressing fundamental problems in the life sciences.


Polo-like kinase 1: a potential therapeutic option in combination with conventional chemotherapy for the management of patients with triple-negative breast cancer.
Breast cancers are composed of molecularly distinct subtypes with different clinical outcomes and responses to therapy. To discover potential therapeutic targets for the poor prognosis-associated triple-negative breast cancer (TNBC), gene expression profiling was carried out on a cohort of 130 breast cancer samples. Polo-like kinase 1 (PLK1) was found to be significantly overexpressed in TNBC compared with the other breast cancer subtypes. High PLK1 expression was confirmed by reverse phase protein and tissue microarrays. In triple-negative cell lines, RNAi-mediated PLK1 depletion or inhibition of PLK1 activity with a small molecule (BI-2536) induced an increase in phosphorylated H2AX, G(2)-M arrest, and apoptosis. A soft-agar colony assay showed that PLK1 silencing impaired clonogenic potential of TNBC cell lines. When cells were grown in extracellular matrix gels (Matrigel), and exposed to BI-2536, apoptosis was observed specifically in TNBC cancerous cells, and not in a normal cell line. When administrated as a single agent, the PLK1 inhibitor significantly impaired tumor growth in vivo in two xenografts models established from biopsies of patients with TNBC. Most importantly, the administration of BI-2536, in combination with doxorubicin + cyclophosphamide chemotherapy, led to a faster complete response compared with the chemotherapy treatment alone and prevented relapse, which is the major risk associated with TNBC. Altogether, our observations suggest PLK1 inhibition as an attractive therapeutic approach, in association with conventional chemotherapy, for the management of patients with TNBC.


Behavioral and Antennal Responses of Drosophila suzukii (Diptera: Drosophilidae) to Volatiles From Fruit Extracts.
Native to Southeast Asia, the spotted wing drosophila, Drosophila suzukii Matsumura (Diptera: Drosophilidae), has become a serious pest of soft-skinned fruit crops since its introduction into North America and Europe in 2008. Current monitoring strategies use baits based on fermentation products; however, to date, no fruit-based volatile blends attractive to this fly have been identified. This is particularly important because females are able to cut into the epicarp of ripening fruit for oviposition. Thus, we conducted studies to: 1) investigate the behavioral responses of adult D. suzukii to volatiles from blueberry, cherry, raspberry, and strawberry fruit extracts; 2) identify the antennally active compounds from the most attractive among the tested extracts (raspberry) using gas chromatography (GC)-mass spectrometry and coupled gas chromatography -electroantennographic detection (GC-EAD); and 3) test a synthetic blend containing the EAD-active compounds identified from raspberry extract on adult attraction. In olfactometer studies, both female and male D. suzukii were attracted to all four fruit extracts. The attractiveness of the fruit extracts ranks as: raspberry ≥ strawberry > blueberry ≥ cherry. GC analyses showed that the fruit extracts emit distinct volatile compounds. In GC-EAD experiments, 11 raspberry extract volatiles consistently elicited antennal responses in D. suzukii. In choice test bioassays, a synthetic EAD-active blend attracted more D. suzukii than a blank control, but was not as attractive as the raspberry extract. To our knowledge, this is the first report of a behaviorally and antennally active blend of host fruit volatiles attractive to D. suzukii, offering promising opportunities for the development of improved monitoring and behaviourally based management tools.


Universal design of research: inclusion of persons with disabilities in mainstream biomedical studies.
Although persons with disabilities of all kinds have as wide a range of health conditions as the general population, they are profoundly underrepresented in mainstream health research. Such underrepresentation might contribute to the health disparities in this population. We propose the concept of Universal Design of Research (UDR), which would promote routine inclusion of persons with disabilities in mainstream biomedical and psychosocial studies, without the need for adaptation or specialized design. Elements of UDR include the use of multisensory formats for recruiting participants, presenting research instruments and interventions, and data gathering from participants and should promote the inclusion of participants with a wide range of abilities, thus enhancing the generalizability of results.


Narrow-linewidth quantum cascade laser at 8.6 μm.
We report on a narrow-linewidth distributed-feedback quantum cascade laser at 8.6 μm that is optical-feedback locked to a high-finesse V-shaped cavity. The spectral purity of the quantum cascade laser is fully characterized using a high-sensitivity optical frequency discriminator, leading to a 1 ms linewidth of less than 4 kHz and a minimum laser frequency noise spectral density as low as 0.01 Hz2/Hz for Fourier frequencies larger than 100 kHz. The cumulative standard deviation of the laser intensity is better than 0.1% over an integration bandwidth from 2 Hz to 100 MHz.


Defect-mediated relaxation in the random tiling phase of a binary mixture: birth, death and mobility of an atomic zipper.
This paper describes the mechanism of defect-mediated relaxation in a dodecagonal square-triangle random tiling phase exhibited by a simulated binary mixture of soft discs in 2D. We examine the internal transitions within the elementary mobile defect (christened the "zipper") that allow it to move, as well as the mechanisms by which the zipper is created and annihilated. The structural relaxation of the random tiling phase is quantified and we show that this relaxation is well described by a model based on the distribution of waiting times for each atom to be visited by the diffusing zipper. This system, representing one of the few instances where a well defined mobile defect is capable of structural relaxation, can provide a valuable test case for general theories of relaxation in complex and disordered materials.


Satellite-image-derived velocity field of an antarctic ice stream.
The surface velocity of a rapidly moving ice stream has been determined to high accuracy and spatial density with the use of sequential satellite imagery. Variations of ice velocity are spatially related to surface undulations, and transverse velocity variations of up to 30 percent occur. Such large variations negate the concept of plug flow and call into question earlier mass-balance calculations for this and other ice streams where sparse velocity data were used. The coregistration of images with the use of the topographic undulations of the ice stream and the measurement of feature displacement with cross-correlation of image windows provide significant improvements in the use of satellite imagery for ice-flow determination.


The Challenge of Timely, Responsive and Rigorous Ethics Review of Disaster Research: Views of Research Ethics Committee Members.
Research conducted following natural disasters such as earthquakes, floods or hurricanes is crucial for improving relief interventions. Such research, however, poses ethical, methodological and logistical challenges for researchers. Oversight of disaster research also poses challenges for research ethics committees (RECs), in part due to the rapid turnaround needed to initiate research after a disaster. Currently, there is limited knowledge available about how RECs respond to and appraise disaster research. To address this knowledge gap, we investigated the experiences of REC members who had reviewed disaster research conducted in low- or middle-income countries. We used interpretive description methodology and conducted in-depth interviews with 15 respondents. Respondents were chairs, members, advisors, or coordinators from 13 RECs, including RECs affiliated with universities, governments, international organizations, a for-profit REC, and an ad hoc committee established during a disaster. Interviews were analyzed inductively using constant comparative techniques. Through this process, three elements were identified as characterizing effective and high-quality review: timeliness, responsiveness and rigorousness. To ensure timeliness, many RECs rely on adaptations of review procedures for urgent protocols. Respondents emphasized that responsive review requires awareness of and sensitivity to the particularities of disaster settings and disaster research. Rigorous review was linked with providing careful assessment of ethical considerations related to the research, as well as ensuring independence of the review process. Both the frequency of disasters and the conduct of disaster research are on the rise. Ensuring effective and high quality review of disaster research is crucial, yet challenges, including time pressures for urgent protocols, exist for achieving this goal. Adapting standard REC procedures may be necessary. However, steps should be taken to ensure that ethics review of disaster research remains diligent and thorough.


Superimposed signaling inspired channel estimation in full-duplex systems.
Residual self-interference (SI) cancellation in the digital baseband is an important problem in full-duplex (FD) communication systems. In this paper, we propose a new technique for estimating the SI and communication channels in a FD communication system, which is inspired from superimposed signaling. In our proposed technique, we add a constant real number to each constellation point of a conventional modulation constellation to yield asymmetric shifted modulation constellations with respect to the origin. We show mathematically that such constellations can be used for bandwidth efficient channel estimation without ambiguity. We propose an expectation maximization (EM) estimator for use with the asymmetric shifted modulation constellations. We derive a closed-form lower bound for the mean square error (MSE) of the channel estimation error, which allows us to find the minimum shift energy needed for accurate channel estimation in a given FD communication system. The simulation results show that the proposed technique outperforms the data-aided channel estimation method, under the condition that the pilots use the same extra energy as the shift, both in terms of MSE of channel estimation error and bit error rate. The proposed technique is also robust to an increasing power of the SI signal.


Obesogenic behaviors among adolescents: the role of generation and time in the United States.
To examine how obesogenic behaviors (consumption of sugary drinks, physical activity, and/or sedentary behaviors) differ among adolescents within and across generation. Data come from the 2008 Boston Youth Survey, a population-based sample of 9th-12th-graders in 22 public high schools in Boston, MA. We used self-reported information to calculate generation and obesogenic behaviors (i.e. physical activity in past 7 days, consumption of sugar-sweetened beverages in past 7 days, and TV/computer/video game use on an average school day). Multivariable models were conducted to estimate the association between generation and obesogenic behaviors, adjusting for race/ethnicity, sex, age, family structure, and school. Relative to first generation youth, 1.5 generation (RR=1.74, 95% CI=1.10, 2.77) and second generation (RR=1.45, 95% CI=1.02, 2.07) youth were more likely to consume soda. Second (RR=1.60, 95% CI=1.20, 2.14) and third generation (RR=2.29, 95% CI=1.43, 3.65) youth were significantly more likely to consume other sugary drinks. Only third generation youth were more likely to watch ≥2 hours/day of TV when compared to first generation youth (RR=1.53, 95% CI=1.07, 2.18). No differences were seen by generation for levels of moderate-to-vigorous physical activity or computer/video games. Greater consumption of sugary drinks is seen across generation among adolescents. Sugary drinks, which are aggressively marketed to immigrant youth, may contribute to excess weight gain seen among foreign-born youth upon arrival in the United States.


Photo-induced bending in a light-activated polymer laminated composite.
Light activated polymers (LAPs) have attracted increasing attention since these materials change their shape and/or behavior in response to light exposure, which serves as an instant, remote and precisely controllable stimulus that enables non-contact control of the material shape and behavior through simple variation in light intensity, wavelength and spatially controlled exposure. These features distinguish LAPs from other active polymers triggered by other stimuli such as heat, electrical field or humidity. Previous examples have resulted in demonstrations in applications such as surface patterning, photo-induced shape memory behavior, and photo-origami. However, in many of these applications, an undesirable limitation has been the requirement to apply and maintain an external load during light irradiation. In this paper, a laminated structure is introduced to provide a pre-programmed stress field, which is then used for photo-induced deformation. This laminated structure is fabricated by bonding a stretched elastomer (NOA65) sheet between two LAP layers. Releasing the elastomer causes contraction and introduces a compressive stress in the LAPs, which are relaxed optically to trigger the desired deformation. A theoretical model is developed to quantitatively examine the laminated composite system, allowing exploration of the design space and optimum design of the laminate.


Proteomic profiling of non-obese type 2 diabetic skeletal muscle.
Abnormal glucose handling has emerged as a major clinical problem in millions of diabetic patients worldwide. Insulin resistance affects especially one of the main target organs of this hormone, the skeletal musculature, making impaired glucose metabolism in contractile fibres a major feature of type 2 diabetes. High levels of circulating free fatty acids, an increased intramyocellular lipid content, impaired insulin-mediated glucose uptake, diminished mitochondrial functioning and an overall weakened metabolic flexibility are pathobiochemical hallmarks of diabetic skeletal muscles. In order to increase our cellular understanding of the molecular mechanisms that underlie this complex diabetes-associated skeletal muscle pathology, we initiated herein a mass spectrometry-based proteomic analysis of skeletal muscle preparations from the non-obese Goto-Kakizaki rat model of type 2 diabetes. Following staining of high-resolution two-dimensional gels with colloidal Coomassie Blue, 929 protein spots were detected, whereby 21 proteins showed a moderate differential expression pattern. Decreased proteins included carbonic anhydrase, 3-hydroxyisobutyrate dehydrogenase and enolase. Increased proteins were identified as monoglyceride lipase, adenylate kinase, Cu/Zn superoxide dismutase, phosphoglucomutase, aldolase, isocitrate dehydrogenase, cytochrome c oxidase, small heat shock Hsp27/B1, actin and 3-mercaptopyruvate sulfurtransferase. These proteomic findings suggest that the diabetic phenotype is associated with a generally perturbed protein expression pattern, affecting especially glucose, fatty acid, nucleotide and amino acid metabolism, as well as the contractile apparatus, the cellular stress response, the anti-oxidant defense system and detoxification mechanisms. The altered expression levels of distinct skeletal muscle proteins, as documented in this study, might be helpful for the future establishment of a comprehensive biomarker signature of type 2 diabetes. Reliable markers could be used for improving diagnostics, monitoring of disease progression and therapeutic evaluations.


A structure-guided approach for protein pocket modeling and affinity prediction.
Binding affinity prediction is frequently addressed using computational models constructed solely with molecular structure and activity data. We present a hybrid structure-guided strategy that combines molecular similarity, docking, and multiple-instance learning such that information from protein structures can be used to inform models of structure-activity relationships. The Surflex-QMOD approach has been shown to produce accurate predictions of binding affinity by constructing an interpretable physical model of a binding site with no experimental binding site structural information. We introduce a method to integrate protein structure information into the model induction process in order to construct more robust physical models. The structure-guided models accurately predict binding affinities over a broad range of compounds while producing more accurate representations of the protein pockets and ligand binding modes. Structure-guidance for the QMOD method yielded significant performance improvements, both for affinity and pose prediction, especially in cases where predictions were made on ligands very different from those used for model induction.


Proteasome inhibition potentiates antitumor effects of photodynamic therapy in mice through induction of endoplasmic reticulum stress and unfolded protein response.
Photodynamic therapy (PDT) is an approved therapeutic procedure that exerts cytotoxic activity toward tumor cells by inducing production of reactive oxygen species such as singlet oxygen. PDT leads to oxidative damage of cellular macromolecules, including proteins that undergo multiple modifications such as fragmentation, cross-linking, and carbonylation that result in protein unfolding and aggregation. Because the major mechanism for elimination of carbonylated proteins is their degradation by proteasomes, we hypothesized that a combination of PDT with proteasome inhibitors might lead to accumulation of carbonylated proteins in endoplasmic reticulum (ER), aggravated ER stress, and potentiated cytotoxicity toward tumor cells. We observed that Photofrin-mediated PDT leads to robust carbonylation of cellular proteins and induction of unfolded protein response. Pretreatment of tumor cells with three different proteasome inhibitors, including bortezomib, MG132, and PSI, gave increased accumulation of carbonylated and ubiquitinated proteins in PDT-treated cells. Proteasome inhibitors effectively sensitized tumor cells of murine (EMT6 and C-26) as well as human (HeLa) origin to PDT-mediated cytotoxicity. Significant retardation of tumor growth with 60% to 100% complete responses was observed in vivo in two different murine tumor models (EMT6 and C-26) when PDT was combined with either bortezomib or PSI. Altogether, these observations indicate that combination of PDT with proteasome inhibitors leads to potentiated antitumor effects. The results of these studies are of immediate clinical application because bortezomib is a clinically approved drug that undergoes extensive clinical evaluations for the treatment of solid tumors.


Inhibition of growth and metastasis of human gastric cancer implanted in nude mice by d-limonene.
To investigate the effects and mechanism of d-limonene on the growth and metastasis of gastric cancer in vivo. Metastatic model simulating human gastric cancer was established by orthotopic implantation of histologically intact human tumor tissue into gastric wall of nude mice. One percent d-limonene was orally administered at dose of 15 ml/kg every other day for seven weeks. Eight weeks after implantation, tumor weight, inhibition rate, apoptotic index (AI), microvessel density (MVD), vascular endothelial growth factor (VEGF), variation of ultrastructure, and the presence of metastasis were evaluated, respectively, after the mice were sacrificed. The tumor weight was significantly reduced in 5-FU group (2.55+/-0.28 g), d-limonene group (1.49+/-0.09 g) and combined treatment group (1.48+/-0.21 g) compared with the control group(2.73+/-0.23 g, P<0.05). In 5-FU group, d-limonene group, combined treatment group, the inhibition rates were 2.60%,47.58% and 46.84% and 0, respectively; AI was (3.31+/-0.33)%, (8.26+/-1.21)%, (20.99+/-1.84)% and (19.34+/-2.19)%, respectively; MVD was (8.64+/-2.81), (16.77+/-1.39), (5.32+/-4.26) and (5.86+/-2.27), respectively; VEGF expression was (45.77+/-4.79), (41.34+/-5.41), (29.71+/-8.92) and (28.24+/-8.55), respectively. The incidences of peritoneal metastasis also decreased significantly in 5-FU group(77.8%), d-limonene group (20.0%) and combined group (22.2%) compared with control group (100%) versus 62.5%,30% and 22.2%) (P<0.05). Liver metastasis was also inhibited and the incidences decreased significantly in 5-FU group, d-limonene group and combined group than that in control group (87.5% vs 55.5%, 20.0% and 22.2% respectively)(P<0.05). The incidence of ascites in control group, 5-FU group, d-limonene group and combined group was 25.0%, 22.2%, 0, 0, respectively and 12.5%, 11.1% 0, 0, with respect to the metastasis rate to other organs. d-limonene has antiangiogenic and proapoptotic effects on gastric cancer, thereby inhibits tumor growth and metastasis. Combination of d-limonene with cytotoxic agents may be more effective.


Quality of life and independent living and working levels of farmers and ranchers with disabilities.
The status of farmers and ranchers with disabilities has been understudied. Understanding this population's quality of life (QOL) and independent living and working (ILW) levels have the potential to be informative for changes in public policy and service provision. To assess QOL levels among farmers and ranchers with disabilities as well as explore a conceptual model of ILW accounting for variance in QOL levels. Participants (N = 398) included farmers and ranchers with varying disabilities. Descriptive information was gathered using the McGill Quality of Life (MQOL) and ILW measures. The MQOL measure produces an objective and comprehensive profile of one's QOL across several domains. ILW was used to account for variance in QOL scores. We also examined whether there were any differences in QOL and or ILW based on type of disability. There were no differences in type of disability and QOL levels. The mean QOL level was 5.50 (SD = 1.67; N = 398). The sample rated support and existential well-being the highest among the QOL subscales, which confounds previous research. Further, age group and ILW accounted for 16.2% of the variance in QOL levels, P < .001. With this sample of farmers and ranchers with disabilities, age group and ILW account for significant variance in QOL. Health professionals can use these findings to support and assess improvements in clients' ILW, self-determination, and QOL. Future research is needed to explore further the effects of QOL and ILW in this population.


Biomarkers of inflammation in HIV-infected Peruvian men and women before and during suppressive antiretroviral therapy.
Inflammatory biomarkers associated with cardiovascular disease are elevated in HIV-infected persons. These biomarkers improve with antiretroviral therapy (ART) but do not normalize to values observed in HIV-uninfected adults. Little is known regarding biomarkers of inflammation in HIV-infected Peruvians, in whom an increased burden of infectious diseases may exacerbate inflammation, and women, in whom sex difference may alter inflammation compared with men. Peruvians initiating first-line ART were enrolled in a prospective observational study. Individuals with suppression of HIV RNA plasma loads to less than 30 copies/ml when determined quarterly over 24 months of ART, had biomarkers of inflammation and cellular activation measured pre-ART and at 24-months of ART, and evaluated for associations with sex and clinical parameters. Pre-ART high-sensitivity C-reactive protein (hsCRP) values of men were in the high-risk cardiovascular disease category (>3.0 mg/l) more frequently compared with women (P = 0.02); most women's values were in the low/average-risk categories. At 24 months of suppressive ART, hsCRP concentrations decreased in men (P = 0.03), but tended to increase in women, such that the proportion with high-risk hsCRP did not differ by sex. Pre-ART, soluble CD163 concentrations were higher in women compared with men (P = 0.02), and remained higher after 24 months of suppressive ART (P = 0.02). All other inflammatory biomarkers (P < 0.03) decreased across sexes. Biomarker concentrations were not associated with BMI or coinfections. Elevated inflammatory biomarkers persisted despite 24 months of suppressive ART in a subset of Peruvians, and to a greater extent in women compared with men. These findings suggest that lifestyle or pharmacologic interventions may be required to optimize the health of HIV-infected Peruvians, particularly women.


Toxicology and Carcinogenesis Studies of C.I. Acid Red 114 (CAS No. 6459-94-5) in F344/N Rats (Drinking Water Studies).
C.I. Acid Red 114 is one of five chemicals being evaluated in 2-year carcinogenicity and toxicity studies as part of the NTP's Benzidine Dye Initiative. This Initiative was designed to evaluate representative benzidine congeners, benzidine congener-derived dyes, and benzidine-derived dyes. C.I. Acid Red 114 was nominated for study because of the potential for human exposure during production of bisazobiphenyl dyes and because benzidine, a structurally related chemical, is a known human carcinogen. Toxicology and carcinogenesis studies were conducted by administering desalted, industrial grade C.I. Acid Red 114 in drinking water to groups of F344/N rats of each sex for 13 days, 13 weeks, 9 or 15 months, or 2 years. These studies were performed only in rats because studies of benzidine congeners were being performed in mice at the National Center for Toxicological Research (NCTR). Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary cells, and Drosophila melanogaster. 13-Day Studies: Rats were exposed to C.I. Acid Red 114 in drinking water at doses of 0, 10,000, 20,000, or 30,000 ppm. All control and dosed rats survived except one male rat in the 20,000 ppm dose group. Final mean body weights in the three dosed groups were 94%, 83%, or 77% of controls for males and 92%, 88%, or 80% of controls for females. Water consumption declined with increased dose. Clinical findings included red stained fur, ears, and tail in all test animals. On gross necropsy, organs and tissues were also stained red. 13-Week Studies: C.I. Acid Red 114 was administered in drinking water at doses of 0, 600, 1,200, 2,500, 5,000, or 10,000 ppm. All control and dosed animals survived until the end of the study. Final mean body weights in the five dosed groups were 97%, 89%, 87%, 87%, or 85% of controls for males and 97%, 94%, 94%, 92%, or 89% of controls for females. Water consumption was decreased in dosed animals. As was seen in the 13-day studies, major organs and tissues from treated animals were stained red. Kidney toxicity characterized by regeneration and karyomegaly of tubule epithelial cells with chronic inflammation was observed in female rats at doses of 1,200 ppm or above. Treatment-related increases in relative liver weights and elevated liver enzyme levels were seen in males and females, centrilobular pallor in the liver was seen in all male dose groups. Because of these body weight differences, decreases in water consumption, and organ toxicity, the doses chosen for the 2-year studies were 70,150, and 300 ppm for males and 150, 300, and 600 for females. 2-Year Studies: Male rats received doses of 0, 70, 150, or 300 ppm of C.I. Acid Red 114, and female rats received 0, 150, 300, or 600 ppm. Seventy animals were in the control and high-dose groups, 45 in the low-dose groups, and 75 in the mid-dose groups. Ten animals were evaluated from the control and high-dose groups at 9 months, and ten animals from all dose groups were evaluated at 15 months. The average amount of compound consumed per day was 4, 8, or 20 mg/kg for males and 9, 20, or 70 mg/kg for females. Survival and Body Weights: Survival at 105 weeks for male rats receiving 0, 70, 150, or 300 ppm was 24/50, 15/35, 26/65, and 1/50; for females receiving 0, 150, or 300 ppm, survival was 36/50, 13/35, and 6/64. All female rats receiving 600 ppm died by week 89. The decreased survival in treated groups was due primarily to the development of chemical-related neoplasms. Of the surviving animals, the final mean body weights for males receiving 70 or 150 ppm were 94% and 90% of control and for females receiving 150 or 300 ppm, 99% and 84% of control. These weight differences began in the second year of the studies and were attributed in part to the development of neoplasms in the dosed groups. Histopathologic Effects in the 2-Year Studies: At 9 and 15 months, a few neoplasms were seen in the liver, lung, clitoral gland, skin, Zymbal's gland, oral cavity epithelium, and small and large intestine, and the number of neoplasms at these sites increased as gland, skin, Zymbal's gland, oral cavity epithelium, and small and large intestine, and the number of neoplasms at these sites increased as the studies progressed. At 2 years, there was a clear carcinogenic response in the skin, Zymbal's gland, and liver of male and female rats, and in the clitoral gland, oral cavity epithelium, small and large intestine, and lung in female rats. Treatment-related increases were also seen in the incidence in neoplasms of the oral cavity epithelium, adrenal gland, and lung of male rats, and in mononuclear cell leukemia and in neoplasms of the mammary gland and adrenal gland in female rats. The incidence of these neoplasms was generally lower, but was significant and considered to be marginally related to chemical treatment. The same neoplastic effects have been previously observed in some or all of the NTP studies with dimethoxybenzidine, dimethylbenzidine, or C.I. Direct Blue 15. Genetic Toxicology: In a standard preincubation protocol, C.I. Acid Red 114 was mutagenic in Salmonella typhimurium strain TA98 in the presence of induced hamster liver S9, and an equivocal response was noted in strain TA100 with hamster liver S9. However, no significant mutagenic activity was noted in strains TA1535 or TA1537 with or without S9 activation. In a modified S. typhimurium gene mutation test which employed reductive metabolism followed by oxidative metabolism with S9 liver enzymes, C.I. Acid Red 114 was strongly mutagenic in strain TA1538. C.I. Acid Red 114 did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells with or without S9 activation; reductive metabolism was not used in these cytogenetic tests. No increase in sex-linked recessive lethal mutations was observed in germ cells of male Drosophila melanogaster administered C.I. Acid Red 114 by feeding or injection. Conclusions: Under the conditions of these 2-year drinking water studies, there was clear evidence of carcinogenic activity of C.I. Acid Red 114 for male F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, and liver. Increased incidences of neoplasms of the oral cavity epithelium, adrenal gland, and lung may have been related to chemical administration. There was clear evidence of carcinogenic activity for female F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, clitoral gland, liver, oral cavity epithelium, small and large intestines, and lung. Increased incidences of mononuclear cell leukemia, mammary gland adenocarcinoma, and adrenal gland pheochromocytomas may have been related to chemical administration. Synonyms: 1,3-Naphthalenedisulfonic acid, 8-((3,3'-dimethyl-4'-((4-(((4-methylphenyl)sulfonyl)oxy)phenyl)azo)(1,1'-bipheny)-4-yl)azo)-7-hydroxy, disodium salt, Acid Leather Red BG, Acid Red 114, Amacid Milling Red PRS, Benzyl Fast Red BG, Benzyl Red BR, Cerven Kysela, C.I. 23635, Erionyl Red RS, Folan Red B, Kayanol Milling Red RS, Leather Fast Red B, Levanol Red GG, Midlon Red PRS, Milling Red B, Milling Red BB, Milling Red SWB, NCI C61096, Polar Red RS, Sandolan Red N-RS, Sella Fast Red RS, Sulphonol Fast Red R, Supranol Fast Red GG, Supranol Red PBX-CF, Supranol Red R, Telon Fast Red GG, Tertracid Milling Red B, Vondamol Fast Red RS


Ticks infesting captive and free-roaming wild animal species at the São Paulo Zoo, São Paulo, Brazil.
Ticks are ectoparasites of worldwide distribution that affect vertebrates and can transmit pathogens to animals and humans. The Zoological Park Foundation of São Paulo (FPZSP) is located in a Conservation Unit in one of the most important remaining fragments of the Atlantic Rainforest biome in the suburbs of São Paulo, Brazil. The FPZSP houses more than 3,000 wild animals on exhibit, in breeding programs and in environmental education programs, and also attracts migratory birds and free-roaming wildlife. This study focused on identifying the diversity of tick species that infest captive and free-roaming animals at the FPZSP. The collection of ticks kept at the FPZSP contains 523 specimens that were collected from different host species between 1990 and 2017. Ten tick species were found. In addition, Amblyomma aureolatum (Pallas) was found on stray cats living in the Atlantic forest fragment in the FPZSP. This study reveals a low occurrence of parasitism in captive animals and a high diversity of tick species collected from hosts in this Atlantic forest fragment, contributing information about host-parasite relationships and potential vectors of zoonotic diseases, since the vectors of Brazilian spotted fever, A. aureolatum and Amblyomma sculptum Berlese, were found in some hosts.


Familial tumoral calcinosis: a forty-year follow-up on one family.
Familial tumoral calcinosis is a rare autosomal recessive disorder that was first described well in a report on four patients from one family in 1969. The disease leads to periarticular ectopic calcifications. The original report described patients from black, healthy, unrelated parents with sixteen children, seven of whom had the disease. On the basis of retrospective chart reviews and interviews with surviving family members, we describe the long-term follow-up of this one family, encompassing as long as forty years. Of the sixteen siblings, seven had tumoral calcinosis. All seven affected children had hyperphosphatemia. There were two subsequent generations comprising thirteen children and seven grandchildren with no instances of tumoral calcinosis. The seven affected patients were followed for as many as forty years and underwent an average of twenty-one operations (range, four to thirty-six operations) for the treatment of calcified lesions. The genetic defect has been identified as the GALNT3 gene, thus leading to the hyperphosphatemic form of the disease. Although two of the patients had died by the time of the present study, the remaining five provided accounts of the disease course, the response to surgery and to medical therapy, and the effect of therapy on their lives. Some members had relatively few lesions and surgical procedures (as few as four), whereas others had an unrelenting course of lesions, recurrences, and surgical procedures (as many as thirty-six, with numerous other procedures). Three patients had multiyear periods with few symptoms--one for seven years, one for twelve years, and one for fifteen years. No effective medical therapy was found to control the lesions, and operations were associated with a high recurrence rate. Familial tumoral calcinosis has a varied natural history; some patients have an unrelenting course, while others may experience quiescent periods. The GALNT3 gene is responsible for the hyperphosphatemic form as seen in this family. Molecular testing may be of benefit to members of affected families, and future studies may help to explain the phenotypic variability among affected individuals. No medical or surgical treatment plan seemed to be effective for controlling the lesions in this family.


Microcephaly gene links trithorax and REST/NRSF to control neural stem cell proliferation and differentiation.
Microcephaly is a neurodevelopmental disorder causing significantly reduced cerebral cortex size. Many known microcephaly gene products localize to centrosomes, regulating cell fate and proliferation. Here, we identify and characterize a nuclear zinc finger protein, ZNF335/NIF-1, as a causative gene for severe microcephaly, small somatic size, and neonatal death. Znf335 null mice are embryonically lethal, and conditional knockout leads to severely reduced cortical size. RNA-interference and postmortem human studies show that ZNF335 is essential for neural progenitor self-renewal, neurogenesis, and neuronal differentiation. ZNF335 is a component of a vertebrate-specific, trithorax H3K4-methylation complex, directly regulating REST/NRSF, a master regulator of neural gene expression and cell fate, as well as other essential neural-specific genes. Our results reveal ZNF335 as an essential link between H3K4 complexes and REST/NRSF and provide the first direct genetic evidence that this pathway regulates human neurogenesis and neuronal differentiation.


Assessing Sexually Intrusive Thoughts: Parsing Unacceptable Thoughts on the Dimensional Obsessive-Compulsive Scale.
Sexual obsessions are a common symptom of obsessive-compulsive disorder (OCD), often classified in a broader symptom dimension that includes aggressive and religious obsessions, as well. Indeed, the Dimensional Obsessive-Compulsive Scale (DOCS) Unacceptable Thoughts Scale includes obsessional content relating to sexual, violent, and religious themes associated with rituals that are often covert. However, there is reason to suspect that sexual obsessions differ meaningfully from other types of unacceptable thoughts. We conducted two studies to evaluate the factor structure, initial psychometric characteristics, and associated clinical features of a new DOCS scale for sexually intrusive thoughts (SIT). In the first study, nonclinical participants (N=475) completed the standard DOCS with additional SIT questions and we conducted an exploratory factor analysis on all items and examined clinical and cognitive correlates of the different scales, as well as test-retest reliability. The SIT Scale was distinct from the Unacceptable Thoughts Scale and was predicted by different obsessional cognitions. It had good internal consistency and there was evidence for convergent and divergent validity. In the second study, we examined the relationships among the standard DOCS and SIT scales, as well as types of obsessional cognitions and symptom severity, in a clinical sample of individuals with OCD (N=54). There were indications of both convergence and divergence between the Unacceptable Thoughts and SIT scales, which were strongly correlated with each other. Together, the studies demonstrate the potential utility of assessing sexually intrusive thoughts separately from the broader category of unacceptable thoughts.


Tetrachelate porphyrin chromophores for metal oxide semiconductor sensitization: effect of the spacer length and anchoring group position.
Four Zn(II)-tetra(carboxyphenyl)porphyrins in solution and bound to metal oxide (TiO2, ZnO, and ZrO2) nanoparticle films were studied to determine the effect of the spacer length and anchoring group position (para or meta) on their binding geometry and photoelectrochemical and photophysical properties. The properties of three types of anchoring groups (COOH and COONHEt3) for four Zn(II)-porphyrins (Zn(II)-5,10,15,20-tetra(4-carboxyphenyl)porphyrin (p-ZnTCPP), Zn(II)-5,10,15,20-tetra(3-carboxyphenyl)porphyrin (m-ZnTCPP), Zn(II)-5,10,15,20-tetra(3-(4-carboxyphenyl)phenyl)porphyrin (m-ZnTCP2P), and Zn(II)-5,10,15,20-tetra(3-ethynyl(4-carboxyphenyl)phenyl)porphyrin (m-ZnTC(PEP)P)) were compared. In m-ZnTCPP, m-ZnTCP2P, and m-ZnTC(PEP)P the four anchoring groups are in the meta position on the meso-phenyl rings of the porphyrin macrocycle, thus favoring a planar binding mode to the metal oxide surfaces. The three meta-substituted porphyrin salts have rigid spacer units of increasing length (phenyl (P), biphenyl (P2), and diphenylethynyl (PEP)) between the porphyrin ring and the carboxy anchoring groups, thus raising the macrocycle from the metal oxide surface. All porphyrins studied here, when bound to TiO2 and ZnO, exhibited quenching of the fluorescence emission, consistent with electron injection into the conduction band of the semiconductor. Steady-state UV-vis and fluorescence studies of p-ZnTCPP on insulating ZrO2 showed evidence of aggregation and exciton coupling. This was not observed in any of the meta-substituted porphyrins. The photoelectrochemical properties (IPCE, Voc, and Isc) of the porphyrins bound to TiO2 films in solar cells have been measured and rationalized with respect to the sensitizer binding geometry and distance from the surface.


Treatment of obesity: should we target the individual or society?
Obesity is a heritable disease that affects millions of people, is disproportionately prevalent in some ethnic groups, and has serious health consequences. Molecular mechanisms causing excessive adiposity are being discovered at an unprecedented rate in animal models. The same cannot be said for humans and, in fact, the etiology of obesity in the majority of people remains unknown. Furthermore, we are far from fully understanding how an obesogenic environment increases the severity of the disease in people who are genetically susceptible to weight gain. Due to these uncertainties, it is perhaps not surprising that current antiobesity treatments are moderately effective at best. This manuscript provides a brief review of current and future strategies for the treatment of obesity and how they relate to our current knowledge of its pathophysiology. It is concluded that there are reasons to be moderately optimistic that effective pharmacological means to palliate obesity will eventually be identified. However, reversing the current pandemic will require a greater understanding not only of the molecular and physiological underpinnings, but also social and political causes of this disease.


Functional connectivity with the hippocampus during successful memory formation.
Although it is well established that the hippocampus is critical for episodic memory, little is known about how the hippocampus interacts with cortical regions during successful memory formation. Here, we used event-related functional magnetic resonance imaging (fMRI) to identify areas that exhibited differential functional connectivity with the hippocampus during processing of novel objects that were subsequently remembered or forgotten on a postscan test. Functional connectivity with the hippocampus was enhanced during successful, as compared with unsuccessful, memory formation, in a distributed network of limbic cortical areas-including perirhinal, orbitofrontal, and retrosplenial/posterior cingulate cortex-that are anatomically connected with the hippocampal formation. Increased connectivity was also observed in lateral temporal, medial parietal, and medial occipital cortex. These findings demonstrate that successful memory formation is associated with transient increases in cortico-hippocampal interaction.


Microsurgical endoscopy-assisted presigmoid retrolabyrinthine approach as a minimally invasive surgical option for the treatment of medium to large vestibular schwannomas.
Treatment of vestibular schwannomas presents many controversial aspects, from the indication to the selection of the best treatment option. In the era of stereotactic radiotherapy, microsurgery has to be competitive in terms of providing the best chances of functional preservation and complete tumor removal. The two most commonly used surgical approaches are the retrosigmoid suboccipital and the presigmoid translabyrinthine. We describe the endoscopy-assisted presigmoid retrolabyrinthine approach (EAPRA) aiming at combining the advantages of the retrosigmoid and translabyrinthine techniques. For 2 years (from May 2009 to June 2011), the EAPRA was used to remove medium to large sporadic vestibular schwannomas in ten patients. Complete tumor removal was obtained in eight patients, postoperative transient facial nerve function impairment or worsening was observed in two, and one had hearing deterioration postoperatively. No threatening complications occurred after surgery, and the length of hospitalization was usually less than 10 days. The EAPRA can provide direct access to the CPA along with labyrinthine complex conservation, allowing hearing function preservation and minimal cerebellar retraction. Endoscopic assistance is a crucial adjunct in the presigmoid retrolabyrinthine approach in order to address the limits imposed by labyrinthine complex preservation. It ensures complete visualization of the intracanalicular portion of the schwannoma, thus improving the rate of a radical tumor resection. The EAPRA could represent a valid surgical option in vestibular schwannoma surgery.


Medical electives in sub-Saharan Africa: a host perspective.
Electives are part of most Western medical school curricula. It is estimated that each year 3000-4000 undergraduate medical students from the UK alone undertake an elective in a developing country. The impact of these electives has given some cause for concern, but the views of elective hosts are largely missing from the debate. The purpose of this study was to evaluate the organisation, outcomes and impacts of medical electives in sub-Saharan Africa from a host perspective. A qualitative analysis of 14 semi-structured interviews with elective hosts at seven elective sites in Malawi, Zambia and Tanzania was carried out. A framework analysis approach was used to analyse 483 minutes of audio-recorded data. Hosts were committed to providing elective experiences but their reasons for doing so varied considerably, in particular between urban or teaching hospitals and rural or mission hospitals. Nurturing a group of professionals who will understand the provision of health care from a global perspective was the main reason reported for hosting an elective, along with generating potential future staff. Hosts argued that the quality of supervision should be judged according to local context. Typical concerns cited in the literature with reference to clinical activities, safety and ethics did not emerge as issues for these hosts. However, in under-resourced clinical contexts, the training of local students sometimes had to take priority. Electives could be improved with greater student preparation and some contribution from sending institutions to support teaching, supervision or patient care. The challenge to both students and their sending institutions is to progress towards giving something proportionate back in return for the learning experiences received. There is clearly room to improve electives from the hosts' perspective, but individually host institutions lack the opportunity or ability to achieve change.