Tuning ubiquinone position in biomimetic monolayer membranes.
Artificial lipid bilayers have been extensively studied as models that mimic natural membranes (biomimetic membranes). Several attempts of biomimetic membranes inserting ubiquinone (UQ) have been performed to enlighten which the position of UQ in the lipid layer is, although obtaining contradictory results. In this work, pure components (DPPC and UQ) and DPPC:UQ mixtures have been studied using surface pressure-area isotherms and Langmuir-Blodgett (LB) films of the same compounds have been transferred onto solid substrates being topographically characterized on mica using atomic force microscopy and electrochemically on indium tin oxide slides. DPPC:UQ mixtures present less solid-like physical state than pure DPPC indicating a higher-order degree for the latter. UQ influences considerably DPPC during the fluid state, but it is mainly expelled after the phase transition at [Formula: see text] 26 mN·m^-1 for the 5:1 ratio and at [Formula: see text] 21 mN·m^-1 for lower UQ content. The thermodynamic studies confirm the stability of the DPPC:UQ mixtures before that event, although presenting a non-ideal behaviour. The results indicate that UQ position can be tuned by means of the surface pressure applied to obtain LB films and the UQ initial content. The UQ positions in the biomimetic membrane are distinguished by their formal potential: UQ located in "diving" position with the UQ placed in the DPPC matrix in direct contact with the electrode surface ( -0.04±0.02 V), inserted between lipid chains without contact to the substrate ( 0.00±0.01 V) and parallel to the substrate, above the lipid chains ( 0.09±0.02 V).


An up-converting phosphor technology-based lateral flow assay for point-of-collection detection of morphine and methamphetamine in saliva.
Morphine (Mop) and methamphetamine (Met) are highly addictive drugs worldwide. Point-of-collection testing (POCT) for drug-of-abuse screening is important in abuse/rehabilitation clinics and law-enforcement agencies. We established an up-converting phosphor technology-based lateral flow assay (UPT-LFA) as a point-of-collection testing (POCT) method, namely Mop-UPT-LFA and Met-UPT-LFA, for the detection of morphine and methamphetamine without complicated sample pre-treatment, respectively, in saliva. The sensitivities of the Mop-UPT-LFA and the Met-UPT-LFA were 5 and 10 ng mL-1 with accurate quantitation of 5-100 ng mL-1 and 10-250 ng mL-1 for morphine and methamphetamine, respectively, for a detection time of 15 min. In reference to the detection limits of 20 and 25 ng mL-1 for morphine and methamphetamine, respectively, in the Driving Under the Influence of Drugs, Alcohol and Medicines (DRUID) program of the European Union, the percentage test/control (T/C) ratio of the UPT-LFA between 2 and 15 min reached 101% and 86%, and the UPT-LFA produced accurate qualitative results in 2 min for 100 simulated-saliva samples with the exception of a few weakly positive samples. The sample and sample treating buffer were mixed and added to the test strip, and the test was conducted 15 min later. Although we found no significant difference between the UPT-LFA quantitative test and the liquid chromatography tandem mass spectrometry (LC-MS) test, compared with the latter, the UPT-LFA was substantially faster and had higher detection efficiency. The UPT-LFA showed more accurate qualitative results than the LC-MS for 50 simulated-saliva samples. The ease of operation, high sensitivity, and accuracy of the UPT-LFA make it a valid candidate POCT method for drug-of-abuse screening.


Capacitor blocks for linear transformer driver stages.
In the Linear Transformer Driver (LTD) technology, the low inductance energy storage components and switches are directly incorporated into the individual cavities (named stages) to generate a fast output voltage pulse, which is added along a vacuum coaxial line like in an inductive voltage adder. LTD stages with air insulation were recently developed, where air is used both as insulation in a primary side of the stages and as working gas in the LTD spark gap switches. A custom designed unit, referred to as a capacitor block, was developed for use as a main structural element of the transformer stages. The capacitor block incorporates two capacitors GA 35426 (40 nF, 100 kV) and multichannel multigap gas switch. Several modifications of the capacitor blocks were developed and tested on the life time and self breakdown probability. Blocks were tested both as separate units and in an assembly of capacitive module, consisting of five capacitor blocks. This paper presents detailed design of capacitor blocks, description of operation regimes, numerical simulation of electric field in the switches, and test results.


Storage-induced change in platelet transfusion response evaluated by serial transfusions from one donor to one patient.
Storage of platelet concentrates (PCs) results in storage lesions with possible detrimental effects on platelet recovery after transfusion, which might affect their ability to prevent or arrest bleeding. The aim of this study was to compare the quality of PCs stored for 1 to 3 or 5 to 7 days by assessing the corrected count increment (CCI) after transfusion. To isolate the effects of storage time, we studied serial transfusions of PCs obtained from one donor and one donation, and transfused to one single recipient after storage for 1 to 3 days and 5 to 7 days. Platelets were obtained from one donor by apheresis, divided into two units (>240 × 109 platelets/unit) and stored for 1 to 3 and 5 to 7 days, respectively, before transfusion. The PCs were transfused on normal indications to patients undergoing treatment at the hematology ward. Platelet count was measured before and after transfusion. Thirty patients concluded the study according to the protocol. The mean storage time was 2.4 ± 0.7 and 5.7 ± 0.8 days for platelets transfused on Days 1 to 3 and 5 to 7, respectively. Storage for 5 to 7 days decreased the 1-hour transfusion response as compared to platelets stored 1 to 3 days, from a CCI of 17 ± 7 to 13 ± 5. Despite this decrease, 86% of the 5 to 7 days stored PCs resulted in a CCI above the cutoff value for a successful transfusion of 7.5, which was not significantly different to PCs stored for 1 to 3 days. Storage of PCs for 5 to 7 days only slightly altered the transfusion response.


Oral amino acid load mimicking hemoglobin results in reduced regional cerebral perfusion and deterioration in memory tests in patients with cirrhosis of the liver.
This study tests the hypothesis that administration of an oral amino acid load mimicking hemoglobin in patients with cirrhosis of the liver causes deterioration in neuropsychological function and a reduction in regional cerebral perfusion. Eight overnight fasted, metabolically stable cirrhotic patients with no evidence of overt hepatic encephalopathy were studied prior to and 4 h after simulating an upper gastrointestinal bleed by oral administration of 75 g of a solution mimicking the amino acid composition of hemoglobin. Neuropsychological function was measured using a test battery. Peripheral venous blood was collected for the measurement of ammonia and amino acid concentrations. Regional cerebral perfusion was measured using a head SPECT scanner following intravenous administration of technetium-99m hexamethyl propylamineoxime. The amino acid solution resulted in significant deterioration in the immediate and delayed story recall tests. Ammonia concentration increased from a median of 87 (range 67-94) micromol/L to 105 (98-112) micromol/L at 4 h after the simulated bleed (p < 0.01). The concentration of almost all amino acids increased; only isoleucine levels decreased following the upper gastrointestinal bleed. SPECT analysis showed a significant reduction in cerebral perfusion after the simulated bleed in both temporal lobes, left superior frontal gyrus, and right parietal and cingulate gyrus. An oral amino acid load mimicking hemoglobin in cirrhotic patients produces hyperammonemia and hypoisoleucinemia and causes a significant deterioration in memory tests, probably due to a reduction in regional cerebral perfusion. The model of simulating the metabolic effects of an upper gastrointestinal bleed in patients with cirrhosis of the liver seems to be useful in studying the metabolism of hepatic encephalopathy.


Assessment of acute injuries, exposure to environmental toxins, and five-year health surveillance of New York Police Department working dogs following the September 11, 2001, World Trade Center terrorist attack.
To determine deployment logistics of New York Police Department (NYPD) working dogs that assisted in relief efforts at the World Trade Center (WTC) site following the September 11, 2001, terrorist attack; establish types and rates of related acute injuries and illnesses; identify environmental toxin exposures; and determine long-term (ie, 5-year) health effects of deployment. Prospective cohort study. 27 working dogs. Deployment logistics for the period from September 11, 2001, through May 30, 2002, were determined, and acute health disorders were identified by means of physical examination; a questionnaire; interviews with dog handlers; and toxicologic (blood and hair samples), clinicopathologic, microbiologic (nasal swab specimens submitted for Bacillus anthracis culture), and radiographic methods. Long-term health surveillance ended September 21, 2006. Dogs worked a total of 1,428 days (15,148 hours) at the site. Seventeen of the 27 (62.9%) dogs had health disorders during the first week. Specific conditions included fatigue (incidence rate [events/1,000 active deployment hours], 13.1), conjunctival irritation (13.1), respiratory tract problems (12.4), decreased appetite (10.8), dehydration (10), and cuts (9.3). Only minor hematologic and serum biochemical abnormalities were identified. Bacterial culture of nasal swab specimens did not yield B anthracis. Only mild and infrequent health conditions were identified during the 5-year follow-up period. None of the dogs were identified as having chronic respiratory tract disease. Six dogs died of various causes. Results suggested that acute injuries and illnesses were common among NYPD working dogs deployed to the WTC disaster site, but that longterm health complications were minimal.


Costs associated with instrument sterilization in gynecologic surgery.
With rising health care expenditures, hospitals must contain costs in ways that maintain high-quality patient care. A significant portion of perioperative costs are associated with materials and supplies; many reusable instruments on surgical trays go unused, which may account for significant annual excess processing costs. Reorganizing gynecologic trays to contain fewer instruments can result in significant cost savings. In the field of operative gynecology, there has been considerable attention to the various costs and surgical outcomes that are associated with hysterectomy performed in the abdominal, vaginal, and laparoscopic approaches; however, little research has been done on the cost differences that are associated with the reusable instruments that are used in these approaches. This study aimed to identify the percent usage of instruments within gynecologic surgery and to identify differences by surgical approach. We further aimed to estimate the costs of sterilizing surgical instruments and estimate the excess costs that are associated with processing unused instruments. This was a single site observational study. Specific instruments that were used from incision to closure were recorded on operating room count sheets via direct observation of surgeries that were performed in the gynecologic operating rooms by a trained investigator. Cost data on instrument transportation, employee wages, and instrument replacement was obtained from institutional supply chain management. In total, 28 surgical cases (5 abdominal, 11 laparoscopic, and 12 vaginal) were analyzed, with an average of 2 hours 37 minutes operating room time and 5.4 instrument trays for each case. One hundred fifty trays were observed. Trays had an average of 38 instruments per tray (range, 1-141). Surgeons used an average of 36.7 instruments of 184 available instruments per case, for a usage rate of 20.5±2.8%. A significant difference was noted between usage rates in abdominal cases (26.3±6.5%) and vaginal cases (13.6±3.3%) but not between laparoscopic (19.4±4.2%) vs other approaches. Instrument use was correlated inversely with the number of instruments, with an average usage rate of 18.7% for trays that contained ≥10 instruments. Total annual institutional cost associated with instrument processing was estimated at $3.19 per instrument. Instrument usage in the gynecologic operating room is low, and the cost of processing instruments is significant. Availability of certain instruments is necessary for patient safety in the event of rare unexpected events. However, given that less than one quarter of the instruments pulled for surgery are used and that total processing cost per instrument exceeds $3.00, careful review of what instruments are included in each tray is warranted. Clearly, significant cost-savings are possible while concurrently balancing safety concerns.


Evaluation of eating and rumination behaviour in cows using a noseband pressure sensor.
An automated technique for recording eating and rumination behaviour was evaluated in ten lactating Brown Swiss cows by comparing data obtained from a pressure sensor with data obtained via direct observation over a 24-hour period. The recording device involved a pressure sensor integrated in the noseband of a halter. The analysed variables included number and duration of individual rumination, eating and resting phases, total daily length of these phases and number of cuds chewed per day. Eating and rumination phases were readily differentiated based on characteristic pressure profiles. Chewing movements during rumination were regular and generated regular waveforms with uniform amplitudes, whereas eating generated irregular waveforms with variable amplitudes. There was complete or almost complete agreement and no significant differences between data obtained via direct observation and pressure sensor technique. Both methods yielded an average of 16 daily eating phases with a mean duration of 28.3 minutes. Total time spent eating was 445.0 minutes for direct observation and 445.4 minutes for the pressure sensor technique. Both techniques recorded an average of 13.3 rumination phases with a mean duration of 30.3 (direct observation) and of 30.2 (pressure sensor) minutes. Total time spent ruminating per day, number of cuds per day and chewing cycles per cud were 389.3 and 388.3 minutes, 410.1 and 410.0 and 60.0 and 60.3 for direct observation and pressure sensor technique, respectively. There was a significant difference between the two methods with respect to mean number of chewing cycles per day (24'669, direct observation vs. 24'751, pressure sensor, P < 0.05, paired t-test). There were strong correlations between the two recording methods with correlation coefficients ranging from 0.98 to 1.00. The results confirmed that measurements of eating and rumination variables obtained via the pressure sensor technique are in excellent agreement with data obtained via direct observation.


Early radiotherapy after radical prostatectomy improves cancer-specific survival only in patients with highly aggressive prostate cancer: validation of recently released criteria.
To test the effect of radiotherapy administered within 6 months after radical prostatectomy on cancer-specific mortality in prostate cancer patients after stratification according to a risk score. Overall, 7616 patients with pT3/4 N0/1 prostate cancer treated with radical prostatectomy between 1995 and 2009 within the Surveillance Epidemiology and End Results Medicare-linked database were included in the study. Competing-risks regression models were carried out to test the effect of early radiotherapy on cancer-specific mortality in the entire cohort, and after stratifying patients according to the risk score based on the number and nature of adverse pathological characteristics (Gleason score 8-10; pT3b/4, lymph node invasion). The risk score was associated with increasing 5- and 10-year cancer-specific mortality rates (P < 0.001). When considering only patients with a risk score ≥ 2, 5- and 10-year cancer-specific mortality rates were significantly lower for individuals undergoing early radiotherapy compared with their counterparts not receiving early radiotherapy (2.9 and 6.9 vs 5.7 and 16.2%, respectively; P = 0.002). The corresponding number required to treat to prevent one death from prostate cancer at 10-year follow up was 10. Early radiotherapy was not associated with lower cancer-specific mortality rates overall and in patients with a risk score <2. This was confirmed in multivariable analyses, where early radiotherapy decreased the risk of cancer-specific mortality only in patients with a risk score ≥ 2 (P ≤ 0.02). The presence of two or more of the following pathological features might be used to identify patients who benefit from early radiotherapy: Gleason score 8-10, pT3b/4 and lymph node invasion.


Disrupting the ventral premotor cortex interferes with the contribution of action observation to use-dependent plasticity.
Action observation (AO), observing another individual perform an action, has been implicated in several higher cognitive processes including forming basic motor memories. Previous work has shown that physical practice (PP) results in cortical motor representational changes, referred to as use-dependent plasticity (UDP), and that AO combined with PP potentiates UDP in both healthy adults and stroke patients. In humans, AO results in activation of the ventral premotor cortex (PMv), however, whether this PMv activation has a functional contribution to UDP is not known. Here, we studied the effects disruption of PMv has on UDP when subjects performed PP combined with AO (PP + AO). Subjects participated in two randomized crossover sessions measuring the amount of UDP resulting from PP + AO while receiving disruptive (1 Hz) TMS over the fMRI-activated PMv or over frontal cortex (Sham). We found that, unlike the sham session, disruptive TMS over PMv reduced the beneficial contribution of AO to UDP. To ensure that disruption of PMv was specifically interfering with the contribution of AO and not PP, subjects completed two more control sessions where they performed only PP while receiving disruptive TMS over PMv or frontal cortex. We found that the magnitude of UDP for both control sessions was similar to PP + AO with TMS over PMv. These findings suggest that the fMRI activation found in PMv during AO studies is functionally relevant to task performance, at least for the beneficial effects that AO exerts over motor training.


Distribution of carbon-14 labeled C60 ([14C]C60) in the pregnant and in the lactating dam and the effect of C60 exposure on the biochemical profile of urine.
This study was conducted to determine the distribution of [(14)C]C60 in the pregnant rat and fetuses, and in the lactating rat and offspring. Pregnant rats were dosed on gestation day (gd) 15 and lactating rats were dosed on postnatal day (pnd) 8 via tail vein injection with a suspension of approximately 0.3 mg [(14)C]C60 kg(-1) body weight prepared in polyvinylpyrrolidone (PVP), or with PVP alone. Tissues were collected at 24 and 48 h after dosing. The largest portion of the administered dose was detected in the liver (approximately 43%, pregnant dam; approximately 35%, lactating dam) and lung (approximately 25%, lactating dam). Radioactivity (approximately 6%) was distributed to the reproductive tract, placenta and fetuses of the pregnant dam. Lactating rats had radioactivity distributed to the milk (3140 dpm g(-1) tissue, 24 h; 1620 dpm g(-1) tissue, 48 h), and to the pups' GI tract (2.8%, 24 h; 4.4% 48 h) and liver (<1%). Blood radioactivity was significant at 24 h (14-19%) and at 48 h (7%) after dosing; largely accounted for in the plasma fraction. Less that 4% of the dose was recovered in the maternal spleen, heart, brain, urine or feces. Metabolomics analysis of urine indicated that dams exposed to [(14)C]C60 had decreased metabolites derived from the Krebs cycle and increased metabolites derived from the urea cycle or glycolysis, as well as alterations in the levels of some sulfur-containing amino acids and purine/pyrimidine metabolites. This study demonstrated that [(14)C]C60 crosses the placenta and is transmitted to offspring via the dam's milk and subsequently systemically absorbed.


Health related quality of life and emergency department visits in adults of age ≥ 66 years: a prospective cohort study.
Age increases the risk of emergency department [ED] visits. Health related quality of life (HRQoL) is often estimated as an outcome of ED visits, but it can be a risk factor of ED visits. This study aims to assess the association of HRQoL with time to first ED visit and/or frequent ED use in older adults during four-year period and if this association differs in 66-80 and 80+ age groups. Data from the Swedish National Study on Aging and Care-Blekinge of wave 2007-2009 was used in combination with electronic health records on ED visits. The analytical sample included 673 participants of age 66 years and older with information on HRQoL. Cox proportional hazard model was used to assess the association between HRQoL and time to first ED visit. Logistic regression analysis was performed to estimate the association of HRQoL with frequent ED use. During the study period, 55.3% of older adults visited the ED and 28.8% had a frequent ED use. Poor physical HRQoL was independently associated with first ED visit both in total sample (p < 0.001) and in 66-80 (p < 0.001) and 80+ (p = 0.038) age groups. Poor mental HRQoL had no significant association with first ED visit and frequent ED use. Findings suggest that poor physical HRQoL is associated with time to first ED visit in older adults. Therefore, physical HRQoL should be considered while planning interventions on the reduction of ED utilisation in older adults. Explanatory factors of frequent ED use may differ in age groups. Further studies are needed to identify associated factors of frequent ED visits in 80+ group.


Arm span and ulnar length are reliable and accurate estimates of recumbent length and height in a multiethnic population of infants and children under 6 years of age.
Surrogate measures are needed when recumbent length or height is unobtainable or unreliable. Arm span has been used as a surrogate but is not feasible in children with shoulder or arm contractures. Ulnar length is not usually impaired by joint deformities, yet its utility as a surrogate has not been adequately studied. In this cross-sectional study, we aimed to examine the accuracy and reliability of ulnar length measured by different tools as a surrogate measure of recumbent length and height. Anthropometrics [recumbent length, height, arm span, and ulnar length by caliper (ULC), ruler (ULR), and grid (ULG)] were measured in 1479 healthy infants and children aged <6 y across 8 study centers in the United States. Multivariate mixed-effects linear regression models for recumbent length and height were developed by using ulnar length and arm span as surrogate measures. The agreement between the measured length or height and the predicted values by ULC, ULR, ULG, and arm span were examined by Bland-Altman plots. All 3 measures of ulnar length and arm span were highly correlated with length and height. The degree of precision of prediction equations for length by ULC, ULR, and ULG (R(2) = 0.95, 0.95, and 0.92, respectively) was comparable with that by arm span (R(2) = 0.97) using age, sex, and ethnicity as covariates; however, height prediction by ULC (R(2) = 0.87), ULR (R(2) = 0.85), and ULG (R(2) = 0.88) was less comparable with arm span (R(2) = 0.94). Our study demonstrates that arm span and ULC, ULR, or ULG can serve as accurate and reliable surrogate measures of recumbent length and height in healthy children; however, ULC, ULR, and ULG tend to slightly overestimate length and height in young infants and children. Further testing of ulnar length as a surrogate is warranted in physically impaired or nonambulatory children.


The interleukin-6 -174G/C promoter polymorphism is not associated with endometriosis in South Indian women.
To investigate the association of the -174 G/C promoter polymorphism of the interleukin-6 (IL-6) gene with endometriosis in South Indian women. The genotype frequencies of the common IL-6 -174 G/C polymorphism were compared in infertility patients with (n = 232) and without (n = 210) endometriosis using polymerase chain reaction (PCR) and sequencing analysis. The genotype frequencies among the cases and controls were G/G 62.9% and 71.9%, G/C 34.1% and 25.2%, and C/C 3.0% and 2.9%. The G and C allele frequencies were 80% and 84.6%, and 20% and 15.4%, respectively. There were no statistically significant differences in the genotype distributions or allele frequencies between the cases and controls (P = .12). The present study demonstrates no significant association between the IL-6 -174 G/C promoter polymorphism and endometriosis in South Indian women.


Client-centred occupational therapy with children: A critical perspective.
Client-centredness is a central theme within occupational therapy; however, its application within clinical practice has not been thoroughly examined within the literature. The aim of this practice reflection is to provide a critical perspective on client-centredness in occupational therapy practice with children. Two action points of the Canadian Practice Process Framework (CPPF): Set the Stage and Agree on Objectives and Plan are applied to examine the concept of client-centred practice using a common practice example. There are multiple benefits to using a client-centred approach to goal setting and developing a therapy plan. Practical challenges to client-centred practice include a lack of time, organizational support, and professional autonomy. Therapists may exert power over clients by enforcing institutional policies that prioritize the client diagnosis and organizational processes. The authors support a client-centred approach to occupational therapy practice with children but suggest that therapists may feel conflicted in trying to apply these principles within the current context of rehabilitation for children. Occupational therapists are encouraged to identify opportunities where they can advocate for a client-centred approach to services.


A Combined Experimental and First-Principles Based Assessment of Finite-Temperature Thermodynamic Properties of Intermetallic Al3Sc.
We present a first-principles assessment of the finite-temperature thermodynamic properties of the intermetallic Al3Sc phase including the complete spectrum of excitations and compare the theoretical findings with our dilatometric and calorimetric measurements. While significant electronic contributions to the heat capacity and thermal expansion are observed near the melting temperature, anharmonic contributions, and electron-phonon coupling effects are found to be relatively small. On the one hand, these accurate methods are used to demonstrate shortcomings of empirical predictions of phase stabilities such as the Neumann-Kopp rule. On the other hand, their combination with elasticity theory was found to provide an upper limit for the size of Al3Sc nanoprecipitates needed to maintain coherency with the host matrix. The chemo-mechanical coupling being responsible for the coherency loss of strengthening precipitates is revealed by a combination of state-of-the-art simulations and dedicated experiments. These findings can be exploited to fine-tune the microstructure of Al-Sc-based alloys to approach optimum mechanical properties.


TE-mode coplanar imaging using weakly anisotropic metasurface.
We analyze and experimentally realize coplanar imaging of transverse-electric (TE) modes surface waves using weakly anisotropic metasurface consisting of non-periodic subwavelength U-shaped metallic structures. Such metallic structures with the exciting coplanar dipole are integrated on the top surface of a thin dielectric board. A circuit model is utilized to analyze the characteristics of the surface waves supported by the metasurface. By varying the geometrical parameters of the U-shaped metallic structures, the phases of surface waves are modulated, from which a planar lens is presented for the TE-mode coplanar imaging. The analyses and measurements show that anisotropies of the U-shaped metallic structures have little influence on the imaging properties of the planar lens. The measurement results have good agreements to numerical simulations.


Mental health visits to complementary and alternative medicine providers.
The objective of this study was to examine the characteristics of mental health visits to Complementary and Alternative Medicine (CAM) providers. A representative sample of acupuncturists, chiropractors, massage therapists, and naturopathic physicians in four states reported on 8933 consecutive visits, including demographic characteristics; presenting complaints; referral source; treatments provided; disposition; and other sources of care for the presenting problem. The proportion of visits for a mental health complaint ranged from 7% to 11% for acupuncture, massage, and naturopathic physicians to less than 1% for chiropractors. For acupuncturists, massage therapists, and naturopaths, 69-87% of patients making mental health visits were self-referred. The CAM provider discussed care with a conventional medical provider in 6-20% of cases and was aware of concomitant conventional medical care in an additional 10-30%. Only 1-5% were subsequently referred to conventional providers. For acupuncturists, massage therapists, and naturopaths, the proportion of visits for mental health concerns is similar to that in conventional primary care. Mental health visits to chiropractors are much less common, but this may reflect differences in true prevalence or differences in presentation. Among those seeking CAM care for mental disorders, concomitant treatment by conventional medical providers is common, but communication or coordination of care is rare.


Results of treatment of stage IA and IIA Hodgkin's disease.
This study analyzed the 5 year actuarial survival and disease-free survival of 122 patients with Stage IA and IIA Hodgkin's disease, (108 patients laparotomy staged) treated with mantle and paraaortic irradiation from 1975 to 1981. Prognostic subgroups and patterns of treatment failure were investigated. The 5 year actuarial survival and disease-free survival was 91% and 75% respectively for the entire group. For Stage IA patients, the 5 year survival and disease-free survival was 92% and 86% respectively, whereas for those in Stage IIA the respective figures were 86% and 65%. Individuals with greater than four sites of involvement at initial presentation; extensive mediastinal adenopathy; hilar or extramediastinal extension to lung, pleura or pericardium, had a poorer 5 year actuarial disease-free survival (43%-60%) than those without these factors (70%-85%). Of the 122 patients, there were 26 relapses: nine infield failures; two concurrent infield and systemic failures; nine marginal recurrences, and three relapses occurring systemically and three in nodal groups not irradiated. Following relapse, 17 patients were salvaged with chemotherapy. Two patients are alive with disease and seven patients died of Hodgkin's disease. Patients with less extensive mediastinal adenopathy and supradiaphragmatic nonmediastinal presentations can be satisfactorily treated with mantle and paraaortic irradiation, whereas patients with extensive mediastinal adenopathy receive six cycles of multiagent chemotherapy before irradiation.


Molecular mechanism of phosphoinositides' specificity for the inwardly rectifying potassium channel Kir2.2.
Phosphoinositides are essential signaling lipids that play a critical role in regulating ion channels, and their dysregulation often results in fatal diseases including cardiac arrhythmia and paralysis. Despite decades of intensive research, the underlying molecular mechanism of lipid agonism and specificity remains largely unknown. Here, we present a systematic study of the binding mechanism and specificity of a native agonist, phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and two of its variants, PI(3,4)P2 and PI(3,4,5)P3, on inwardly rectifying potassium channel Kir2.2, using molecular dynamics simulations and free energy perturbations (FEPs). Our results demonstrate that the major driving force for the PI(4,5)P2 specificity on Kir2.2 comes from the highly organized salt-bridge network formed between the charged inositol head and phosphodiester linker of PI(4,5)P2. The unsaturated arachidonic chain is also shown to contribute to the stable binding through hydrophobic interactions with nearby Kir2.2 hydrophobic residues. Consistent with previous experimental findings, our FEP results confirmed that non-native ligands, PI(3,4)P2 and PI(3,4,5)P3, show significant loss in binding affinity as a result of the substantial shift from the native binding mode and unfavorable local solvation environment. However, surprisingly, the underlying molecular pictures for the unfavorable binding of both ligands are quite distinctive: for PI(3,4)P2, it is due to a direct destabilization in the bound state, whereas for PI(3,4,5)P3, it is due to a relative stabilization in its free state. Our findings not only provide a theoretical basis for the ligand specificity, but also generate new insights into the allosteric modulation of ligand-gated ion channels.


Excess success for psychology articles in the journal science.
This article describes a systematic analysis of the relationship between empirical data and theoretical conclusions for a set of experimental psychology articles published in the journal Science between 2005-2012. When the success rate of a set of empirical studies is much higher than would be expected relative to the experiments' reported effects and sample sizes, it suggests that null findings have been suppressed, that the experiments or analyses were inappropriate, or that the theory does not properly follow from the data. The analyses herein indicate such excess success for 83% (15 out of 18) of the articles in Science that report four or more studies and contain sufficient information for the analysis. This result suggests a systematic pattern of excess success among psychology articles in the journal Science.


Structural basis for CRISPR RNA-guided DNA recognition by Cascade.
The CRISPR (clustered regularly interspaced short palindromic repeats) immune system in prokaryotes uses small guide RNAs to neutralize invading viruses and plasmids. In Escherichia coli, immunity depends on a ribonucleoprotein complex called Cascade. Here we present the composition and low-resolution structure of Cascade and show how it recognizes double-stranded DNA (dsDNA) targets in a sequence-specific manner. Cascade is a 405-kDa complex comprising five functionally essential CRISPR-associated (Cas) proteins (CasA(1)B(2)C(6)D(1)E(1)) and a 61-nucleotide CRISPR RNA (crRNA) with 5'-hydroxyl and 2',3'-cyclic phosphate termini. The crRNA guides Cascade to dsDNA target sequences by forming base pairs with the complementary DNA strand while displacing the noncomplementary strand to form an R-loop. Cascade recognizes target DNA without consuming ATP, which suggests that continuous invader DNA surveillance takes place without energy investment. The structure of Cascade shows an unusual seahorse shape that undergoes conformational changes when it binds target DNA.


Evaluation of systemic involvement of Coronavirus disease 2019 through spleen; size and texture analysis
To investigate the changes in the spleen size, parenchymal heterogeneity, and computed tomography (CT) texture analysis features of patients diagnosed with Coronavirus disease 2019 (COVID-19) The size and parenchymal structure of the spleen in 91 patients who underwent thoracic CT examination due to COVID-19 were evaluated. For the evaluation of parenchymal heterogeneity, CT texture analysis was performed using dedicated software (Olea Medical, France). The texture analysis of each case consisted of 15 first-order intensity-based features, 17 gray level co- occurrence matrix-based features, and 9 gray level run length matrix-based features. A total of 91 patients (45 males, 46 females) with a mean age of 54.31 ± 16.33 years (range: 18–81) were included in the study. A statistically significant decrease in spleen size was seen in the follow-up CT examinations (p < 0.001) whereas no statistically significant difference was found between the Hounsfield unit (HU) values. The radiomics consisted of first-order intensity-based features such as 90th percentile, maximum, interquartile range, range, mean absolute deviation, standard deviation, and variance, all of which showed statistically significant differences (p-values: < 0.001, < 0.001, 0.001, 0.003, 0.001, 0.001, and 0.004, respectively). "Correlation" as a gray level co-occurrence matrix-based feature and "gray level nonuniformity" as a gray level run length matrix-based feature showed statistically differences (p-values: 0.033 and < 0.001, respectively). Although COVID-19 manifests with lung involvement in the early stage, it can also cause systemic involvement, and the spleen may be one of its target organs. A decrease in the spleen size and parenchymal microstructure changes can be observed in the short follow-up time. It is hoped that the changes in the parenchymal microstructure will be demonstrated by a noninvasive method: texture analysis.


Extension of the AMBER force field to cyclic α,α dialkylated peptides.
The popular biomolecular AMBER (ff99SB) force field (FF) has been extended with new parameters for the simulations of peptides containing α,α dialkylated residues with cyclic side chains. Together with the recent set of nitroxide parameters [E. Stendardo, A. Pedone, P. Cimino, M. C. Menziani, O. Crescenzi and V. Barone, Phys. Chem. Chem. Phys., 2010, 12, 11697] this extension allows treating the TOAC residue (TOAC, 2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid) widely used as a spin label in protein studies. All the conformational minima of the Ac-Ac(6)C-NMe (Ac = acetyl, Ac(6)C = 1-aminocyclohexaneacetic acid, NMe = methylamino) and Ac-TOAC-NMe dipeptides have been examined in terms of geometry and relative energy stability by Quantum Mechanical (QM) computations employing an hybrid density functional (PBE0) for an extended training set of conformers with various folds. A very good agreement between QM and MM (molecular mechanics) data has been obtained in most of the investigated properties, including solvent effects. Finally, the new set of parameters has been validated by comparing the conformational and dynamical behavior of TOAC-labeled polypeptides investigated by means of classical molecular dynamics (MD) simulations with QM data and experimental evidence. The new FF accurately describes the tuning of conformational and dynamical behavior of the Ac-TOAC-NMe dipeptide and double spin-labeled heptapeptide Fmoc-(Aib-Aib-TOAC)(2)-Aib-OMe (Fmoc, fluorenyl-9-methoxycarbonyl; Aib, α-aminoisobutyric acid; OMe, methoxy) by solvents with different polarity. In particular, we found that the 3(10) helical structure of heptapeptide is the most stable one in vacuo, with a geometry very similar to the X-ray crystallographic structure, whereas a conformational equilibrium between the 3(10)- and α-helical structures is established in aqueous solution, in agreement with EPR data.


The molecular era of the mitochondrial calcium uniporter.
The mitochondrial calcium uniporter is an evolutionarily conserved calcium channel, and its biophysical properties and relevance to cell death, bioenergetics and signalling have been investigated for decades. However, the genes encoding this channel have only recently been discovered, opening up a new 'molecular era' in the study of its biology. We now know that the uniporter is not a single protein but rather a macromolecular complex consisting of pore-forming and regulatory subunits. We review recent studies that harnessed the power of molecular biology and genetics to characterize the mechanism of action of the uniporter, its evolution and its contribution to physiology and human disease.


High fever after sublingual administration of misoprostol for treatment of post-partum haemorrhage: a hospital-based, prospective observational study in Argentina.
To characterise the occurrence of fever (≥38.0°C) after treatment for post-partum haemorrhage (PPH) with sublingual misoprostol 800 mcg in Latin America, where elevated rates of misoprostol's thermoregulatory effects and recipients' increased susceptibility to high fever have been documented. A prospective observational study in hospitals in Argentina enrolled consenting women with atonic PPH after vaginal delivery, eligible to receive misoprostol. Corporal temperature was assessed at 30, 60, 90 and 120 min post-treatment; other effects were recorded. The incidence of high fever ≥ 40.0°C (primary outcome) was compared to the rate observed previously in Ecuador. Logistic regressions were performed to identify clinical and population-based predictors of misoprostol-induced fever. Transient shivering and fever were experienced by 75.5% (37/49) of treated participants and described as acceptable by three-quarters of women interviewed (35/47). The high fever rate was 12.2% (6/49), [95% Confidence Interval (CI) 4.6, 24.8], compared to Ecuador's rate following misoprostol treatment (35.6% (58/163) [95% CI 28.3, 43.5], P = 0.002). Significant predictors of misoprostol-induced fever (model dependent) were as follows: pre-delivery haemoglobin < 11.0g/dl, rapid placental expulsion, and higher age of the woman. No serious outcomes were reported prior to discharge. Misoprostol to treat PPH in Argentina resulted in a significantly lower rate of high fever than in Ecuador, although both are notably higher than rates seen elsewhere. A greater understanding of misoprostol's side effects and factors involved in their occurrence, including genetics, will help alleviate concerns. The onset of shivering may be the simplest way to know if fever can also be expected.


High Areal Capacity Li-Ion Storage of Binder-Free Metal Vanadate/Carbon Hybrid Anode by Ion-Exchange Reaction.
Storing more energy in a limited device area is very challenging but crucial for the applications of flexible and wearable electronics. Metal vanadates have been regarded as a fascinating group of materials in many areas, especially in lithium-ion storage. However, there has not been a versatile strategy to synthesize flexible metal vanadate hybrid nanostructures as binder-free anodes for Li-ion batteries so far. A convenient and versatile synthesis of Mx Vy Ox+2.5y @carbon cloth (M = Mn, Co, Ni, Cu) composites is proposed here based on a two-step hydrothermal route. As-synthesized products demonstrate hierarchical proliferous structure, ranging from nanoparticles (0D), and nanobelts (1D) to a 3D interconnected network. The metal vanadate/carbon hybrid nanostructures exhibit excellent lithium storage capability, with a high areal specific capacity up to 5.9 mAh cm-2 (which equals to 1676.8 mAh g-1 ) at a current density of 200 mA g-1 . Moreover, the nature of good flexibility, mixed valence states, and ultrahigh mass loading density (over 3.5 mg cm-2 ) all guarantee their great potential in compact energy storage for future wearable devices and other related applications.


Adrenergic receptors and metabolism: role in development of cardiovascular disease.
Activation of the adrenergic system has a profound effects on metabolism. Increased circulating catecholamine and activation of the different adrenergic receptors deployed in the various organs produce important metabolic responses which include: (1) increased lipolysis and elevated levels of fatty acids in plasma, (2) increased gluconeogenesis by the liver to provide substrate for the brain, and (3) moderate inhibition of insulin release by the pancreas to conserve glucose and to shift fuel metabolism of muscle in the direction of fatty acid oxidation. These physiological responses, typical of the stress conditions, are demonstrated to be detrimental for the functioning of different organs like the cardiac muscle when they become chronic. Indeed, a common feature of many pathological conditions involving over-activation of the adrenergic system is the development of metabolic alterations which can include insulin resistance, altered glucose and lipid metabolism and mitochondrial dysfunction. These patterns are involved with a variably extent among the different pathologies, however, they are in general strictly correlated to the level of activation of the adrenergic system. Here we will review the effects of the different adrenergic receptors subtypes on the metabolic variation observed in important disease like Heart Failure.


Increased dopamine transmission and adult neurogenesis in trace amine-associated receptor 5 (TAAR5) knockout mice.
Trace amine-associated receptors (TAARs) are a class of sensory G protein-coupled receptors that detect biogenic amines, products of decarboxylation of amino acids. The majority of TAARs (TAAR2-TAAR9) have been described mainly in the olfactory epithelium and considered to be olfactory receptors sensing innate odors. However, there is recent evidence that one of the members of this family, TAAR5, is expressed also in the limbic brain areas receiving projection from the olfactory system and involved in the regulation of emotions. In this study, we further characterized a mouse line lacking TAAR5 (TAAR5 knockout, TAAR5-KO mice) that express beta-galactosidase mapping TAAR5 expression. We found that in TAAR5-KO mice the number of dopamine neurons, the striatal levels of dopamine and its metabolites, as well as striatal levels of GDNF mRNA, are elevated indicating a potential increase in dopamine neuron proliferation. Furthermore, an analysis of TAAR5 beta-galactosidase expression revealed that TAAR5 is present in the major neurogenic areas of the brain such as the subventricular zone (SVZ), the subgranular zone (SGZ) and the less characterized potentially neurogenic zone surrounding the 3rd ventricle. Direct analysis of neurogenesis by using specific markers doublecortin (DCX) and proliferating cell nuclear antigen (PCNA) revealed at least 2-fold increase in the number of proliferating neurons in the SVZ and SGZ of TAAR5-KO mice, but no such markers were detected in mutant or control mice in the areas surrounding the 3rd ventricle. These observations indicate that TAAR5 involved not only in regulation of emotional status but also adult neurogenesis and dopamine transmission. Thus, future TAAR5 antagonists may exert not only antidepressant and/or anxiolytic action but may also provide new treatment opportunity for neurodegenerative disorders such as Parkinson's disease.


Contact Lens Correction of Aphakia in Children: A Report by the American Academy of Ophthalmology.
To review the published literature to assess the visual outcomes and adverse events associated with the 2 most commonly used contact lenses for treating aphakia in children: silicone elastomer (SE) and rigid gas permeable (RGP). Literature searches were last conducted in January 2018 in the PubMed, Cochrane Library, and ClinicalTrials.gov databases with no date or language restrictions. These combined searches yielded 167 citations, 27 of which were reviewed in full text. Of these, 10 articles were deemed appropriate for inclusion in this assessment and subsequently assigned a level of evidence rating by the panel methodologist. The literature search identified 4 level II studies and 6 level III studies. There were insufficient data to compare visual outcomes for eyes treated using SE lenses versus RGP lenses. Silicone elastomer lenses have the advantage that they can be worn on an extended-wear basis, but they were associated with more adverse events than RGP lenses. These adverse events included microbial keratitis, corneal infiltrates, corneal edema, corneal scars, lenses adhering to the cornea, superficial punctate keratopathy, lid swelling, and conjunctival hyperemia. The lens replacement rate was approximately 50% higher for RGP lenses in the only study that directly compared SE and RGP lenses. Limited evidence was found in the literature on this topic. Silicone elastomer and RGP contact lenses were found to be effective for treating aphakia in children. Silicone elastomer lenses are easier to fit and may be worn on an extended-wear basis. Rigid gas permeable lenses must be removed every night and require a more customized fit, but they are associated with fewer adverse events. The choice of which lens a practitioner prescribes should be based on the particular needs of each patient.


Abnormal avoidance learning in mice lacking functional high-affinity nicotine receptor in the brain.
Nicotine affects many aspects of behaviour including learning and memory through its interaction with neuronal nicotinic acetylcholine receptors (nAChR). Functional nAChRs are pentameric proteins containing at least one type of alpha-subunit and one type of beta-subunit. The involvement of a particular neuronal nicotinic subunit in pharmacology and behaviour was examined using gene targeting to mutate beta 2, the most widely expressed nAChR subunit in the central nervous system. We report here that high-affinity binding sites for nicotine are absent from the brains of mice homozygous for the beta 2-subunit mutation. Further, electrophysiological recording from brain slices reveals that thalamic neurons from these mice do not respond to nicotine application. Finally, behavioural tests demonstrate that nicotine no longer augments the performance of beta 2-1- mice on passive avoidance, a test of associative memory. Paradoxically, mutant mice are able to perform better than their non-mutant siblings on this task.


Three-dimensional piezoelectric fibrous scaffolds selectively promote mesenchymal stem cell differentiation.
The discovery of electric fields in biological tissues has led to efforts in developing technologies utilizing electrical stimulation for therapeutic applications. Native tissues, such as cartilage and bone, exhibit piezoelectric behavior, wherein electrical activity can be generated due to mechanical deformation. Yet, the use of piezoelectric materials have largely been unexplored as a potential strategy in tissue engineering, wherein a piezoelectric biomaterial acts as a scaffold to promote cell behavior and the formation of large tissues. Here we show, for the first time, that piezoelectric materials can be fabricated into flexible, three-dimensional fibrous scaffolds and can be used to stimulate human mesenchymal stem cell differentiation and corresponding extracellular matrix/tissue formation in physiological loading conditions. Piezoelectric scaffolds that exhibit low voltage output, or streaming potential, promoted chondrogenic differentiation and piezoelectric scaffolds with a high voltage output promoted osteogenic differentiation. Electromechanical stimulus promoted greater differentiation than mechanical loading alone. Results demonstrate the additive effect of electromechanical stimulus on stem cell differentiation, which is an important design consideration for tissue engineering scaffolds. Piezoelectric, smart materials are attractive as scaffolds for regenerative medicine strategies due to their inherent electrical properties without the need for external power sources for electrical stimulation.


Dupilumab improves patient-reported symptoms of atopic dermatitis, symptoms of anxiety and depression, and health-related quality of life in moderate-to-severe atopic dermatitis: analysis of pooled data from the randomized trials SOLO 1 and SOLO 2.
Background: Atopic dermatitis (AD) profoundly affects quality of life (QoL). Dupilumab significantly improves clinical outcomes, is well tolerated, and approved to treat inadequately controlled moderate-to-severe AD in adults; however, its effect on patient-reported outcomes (PROs) is not fully characterized.Objective: To evaluate the impact of dupilumab on patient-reported AD symptoms and QoL.Methods: Pooled data were analyzed from two identically designed phase 3 studies, LIBERTY AD SOLO 1 (NCT02277743) and SOLO 2 (NCT02277769), assessing the following PROs: Peak Pruritus Numerical Rating Scale (NRS), Pruritus Categorical Scale, SCORing AD (SCORAD), Dermatology Life Quality Index (DLQI), Patient-Oriented Eczema Measure (POEM), Hospital Anxiety and Depression Scale (HADS), five-dimension EuroQoL questionnaire (EQ-5D), and patient-assessed disease status and treatment effectiveness.Results: Dupilumab rapidly improved (vs. placebo) Peak Pruritus NRS scores by day 2 (p < .05), anxiety and depression (HADS), and QoL (DLQI) by week 2, and maintained through week 16 (p < .0001). At week 16, more dupilumab-treated than placebo-treated patients reported improvement in SCORAD itch and sleep, and no pain/discomfort (EQ-5D) (p < .0001).Limitations: Cultural differences of translated PROs.Conclusion: Dupilumab had a significant, positive impact on AD symptoms, including itch, sleep, pain, anxiety and depression, and QoL in adults with moderate-to-severe AD.


Improved diagnosis of spinal cord disorders with contact heat evoked potentials.
To evaluate the sensitivity of contact heat evoked potentials (CHEPs) compared with dermatomal somatosensory evoked potentials (dSSEPs) and clinical sensory testing in myelopathic spinal cord disorders (SCDs). In a prospective cohort study, light-touch (LT) and pinprick (PP) testing was complemented by dermatomal CHEPs and dSSEPs in patients with a confirmed SCD as defined by MRI. Patients with different etiologies (i.e., traumatic and nontraumatic) and varying degrees of spinal cord damage (i.e., completeness) were included. SCD was distinguished into 3 categories according to MRI pattern and neurologic examination: a) complete, b) incomplete-diffuse, and c) central or anterior cord damage. Seventy-five patients were included (complete n = 7, incomplete-diffuse n = 33, central/anterior n = 35). In total, 319 dermatomes were tested with combined CHEPs and dSSEPs. CHEPs, dSSEPs, and clinical sensory testing were comparably sensitive to detect the myelopathy in complete (CHEPs 100%, dSSEPs 91%, PP and LT 82%) and incomplete-diffuse (CHEPs 92%, dSSEPs and PP 86%, LT 81%, p > 0.05 for all comparisons) cord damage. In central/anterior cord damage, CHEPs showed a significantly higher sensitivity than dSSEPs (89% compared with 24%, p < 0.001) and clinical sensory testing (PP 62%, LT 57%, p < 0.05). A subclinical sensory impairment was detected more frequently by CHEPs than dSSEPs (60% compared with 29%, p = 0.001). Assessment of spinothalamic pathways with CHEPs is reliable and revealed the highest sensitivity in all SCDs. Specifically in incomplete lesions that spare dorsal pathways, CHEPs are sensitive to complement the clinical diagnosis.


Inactivated Eyedrop Influenza Vaccine Adjuvanted with Poly(I:C) Is Safe and Effective for Inducing Protective Systemic and Mucosal Immunity.
The eye route has been evaluated as an efficient vaccine delivery routes. However, in order to induce sufficient antibody production with inactivated vaccine, testing of the safety and efficacy of the use of inactivated antigen plus adjuvant is needed. Here, we assessed various types of adjuvants in eyedrop as an anti-influenza serum and mucosal Ab production-enhancer in BALB/c mice. Among the adjuvants, poly (I:C) showed as much enhancement in antigen-specific serum IgG and mucosal IgA antibody production as cholera toxin (CT) after vaccinations with trivalent hemagglutinin-subunits or split H1N1 vaccine antigen in mice. Vaccination with split H1N1 eyedrop vaccine antigen plus poly(I:C) showed a similar or slightly lower efficacy in inducing antibody production than intranasal vaccination; the eyedrop vaccine-induced immunity was enough to protect mice from lethal homologous influenza A/California/04/09 (H1N1) virus challenge. Additionally, ocular inoculation with poly(I:C) plus vaccine antigen generated no signs of inflammation within 24 hours: no increases in the mRNA expression levels of inflammatory cytokines nor in the infiltration of mononuclear cells to administration sites. In contrast, CT administration induced increased expression of IL-6 cytokine mRNA and mononuclear cell infiltration in the conjunctiva within 24 hours of vaccination. Moreover, inoculated visualizing materials by eyedrop did not contaminate the surface of the olfactory bulb in mice; meanwhile, intranasally administered materials defiled the surface of the brain. On the basis of these findings, we propose that the use of eyedrop inactivated influenza vaccine plus poly(I:C) is a safe and effective mucosal vaccine strategy for inducing protective anti-influenza immunity.


[In vitro antimicrobial susceptibility of Helicobacter pylori strains: isolation of strains resistant to clarithromycin].
Our laboratory has carried out an epidemiological surveillance of Helicobacter pylori antimicrobial susceptibility since 1997. To report the antimicrobial susceptibility of H pylori strains, isolated in Chile from August 1997 to August 2000. Ninety one H pylori strains, obtained from antral gastric biopsies during upper gastrointestinal endoscopies were studied. Susceptibility towards clarithromycin, amoxicillin, bismuth subcitrate and metronidazole was studied by an agar diffusion technique. All strains were susceptible to amoxicillin and two strains were resistant to clarithromycin. Forty two percent of strains were resistant to metronidazole and 13% were resistant to bismuth subcitrate. These results underscore the need to maintain an epidemiological surveillance of H pylori antimicrobial susceptibility, to modify its eradication therapy accordingly.


Ets-1-dependent expression of vascular endothelial growth factor receptors is activated by latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus through interaction with Daxx.
Vascular endothelial growth factor (VEGF) and its receptors are highly expressed in Kaposi's sarcoma (KS) lesion and play a key role in angiogenesis. Latency-associated nuclear antigen (LANA) of Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) has multiple functions related to viral latency and KSHV-induced oncogenesis. In this report, we have identified Daxx as a LANA-binding protein by co-immunoprecipitation analysis of HeLa cells stably expressing LANA. LANA associated with Daxx in a PEL cell line infected with KSHV. LANA and Daxx also bound in vitro, suggesting direct interaction. From the results of binding assays, a region containing the Glu/Asp-rich domain within LANA, and a central region including the second paired amphipathic helix within Daxx contributed to the interaction. To address the physiological significance of this interaction, we focused on a Daxx-mediated VEGF receptor gene regulation. We found that Daxx repressed Ets-1-dependent Flt-1/VEGF receptor-1 gene expression, and that LANA inhibited the repression by Daxx in a reporter assay. Analyses of flow cytometry and real-time PCR revealed that expression of VEGF receptor-1 and -2 in LANA-expressing human umbilical vein endothelial cells (HUVECs) significantly increased. Co-immunoprecipitation and immunoblotting experiments suggested that LANA-bound Daxx to inhibit the interaction between Daxx and Ets-1. Chromatin immunoprecipitation assays showed that Daxx associated with VEGF receptor-1 promoter in HUVECs, and that LANA expression reduced this association. These results suggested that LANA contributes to a high expression of VEGF receptors in KS lesion by interfering with the interaction between Daxx and Ets-1.


Expression of full-length polyglutamine-expanded Huntingtin disrupts growth factor receptor signaling in rat pheochromocytoma (PC12) cells.
We reported previously that normal Huntingtin is associated with epidermal growth factor receptor (EGF) signaling complex (Liu, Y. F., Deth, C. R., and Devys, D. (1997) J. Biol. Chem. 272, 8121-8124). To investigate the potential role of normal and polyglutamine-expanded Huntingtin in the regulation of growth factor receptor-mediated cellular signaling and biological function, we stably transfected full-length Huntingtin containing 16, 48, or 89 polyglutamine repeats into PC12 cells where cellular signaling mechanisms, mediated by nerve growth factor (NGF) or EGF receptors, are well characterized. Expression of polyglutamine-expanded Huntingtin, but not normal Huntingtin, leads to a dramatic morphological change. In clones carrying the mutated Huntingtin, both NGF and EGF receptor-mediated activation of mitogen-activated protein kinase, c-Jun N-terminal kinase, and Akt are significantly attenuated, and NGF receptor-mediated neurite outgrowth is blocked. Co-immunoprecipitation studies show that the associations of NGF or EGF receptors with growth factor receptor-binding protein 2 (Grb2) and phosphoinositide 3-kinase are significantly inhibited. NGF-induced tyrosine phosphorylation of NGF receptors (TrkA) is also consistently suppressed. Our data demonstrate that polyglutamine-expanded Huntingtin disrupts cellular signaling mediated by both EGF and NGF receptors in PC12 cells. It is known that Huntington's disease patients exhibit an extremely low incidence of a variety of cancers and are deficient in glucose metabolism. Thus, our results may reflect an important molecular mechanism for the pathogenesis of the disease.


Gelastic epilepsy.
A case of retinitis pigmentosa with laughing epilepsy is described. Stereotyped repetitive episodes of limb movement, rigidity, and cackling laughter responding to diazepam are recorded. One episode is presented as gelastic status epilepticus and the clinical and EEG features are reported. Features of gelastic epilepsy are discussed and briefly compared with other laughing disorders. A short history of the condition is accompanied by a relevant review of the literature. The possible importance of hypothalamic lesions in laughing epilepsy is discussed and the absence of consistent EEG findings is noted.


Matrix metalloproteinases vary with airway microbiota composition and lung function in non-cystic fibrosis bronchiectasis.
Despite growing evidence for the roles of airway remodeling and bacterial infection in the progression of non-cystic fibrosis bronchiectasis, relationships between collagen-degrading proteases and chronic airway infection are poorly understood. The aim of this study was to determine which matrix metalloproteinases (MMPs) are elevated in bronchiectasis, whether these MMP levels vary based on patients' dominant infective microbe, and how these levels correlate with clinical measures of disease severity. We determined concentrations of nine MMPs and four tissue inhibitors of metalloproteinases (TIMPs) in induced sputum from 86 patients with bronchiectasis and 8 healthy control subjects by Luminex protein assay. Concentrations were then assessed in relation to lung function, inflammatory markers, and airway microbiota composition, determined by 16S rRNA gene amplicon sequencing. Airway microbiota composition was classified as Pseudomonas aeruginosa-dominated, Haemophilus influenzae-dominated, or dominated by another species. MMP-8 and MMP-9 activity levels were also measured in a subset of patients. MMP-1, -3, -7, -8, and -9 and TIMP-2 and -4 levels, as well as MMP-8/TIMP-1 and MMP-9/TIMP-1 ratios, were significantly higher in patients with bronchiectasis than in healthy control subjects (all: P < 0.001, except MMP-7: P < 0.05). Patients with bronchiectasis with H. influenzae-dominated airway infections demonstrated higher MMP-2 levels (P < 0.01) and MMP-8 activity (P < 0.05) than those with P. aeruginosa-dominated airway infections. Among patients with bronchiectasis, there were significant inverse correlations between FEV1 as a percentage of predicted value, MMP-8 and MMP-1 levels, and MMP-8/TIMP-1 and MMP-9/TIMP-1 ratios (P < 0.01). Increased MMP levels (particularly MMP-8 and MMP-1) and MMP/TIMP ratios in patients with bronchiectasis compared with healthy control subjects correlated with lower lung function and higher levels of inflammatory markers. Further, MMP profiles differed in patients with bronchiectasis according to the dominant pathogen determined by gene sequencing, raising the possibility of differential airway remodeling according to airway microbiology.


The management of clival chordomas: an Italian multicentric study.
In the last 2 decades, the endoscopic endonasal approach in the treatment of clival chordomas has evolved to be a viable strategy to achieve maximal safe resection of this tumor. Here, the authors present a multicentric national study, intending to analyze the evolution of this approach over a 20-year time frame and its contribution in the treatment of clival chordomas. Clival chordoma cases surgically treated between 1999 and 2018 at 10 Italian neurosurgical departments were included in this retrospective study. Clinical, radiological, and surgical findings, adjuvant therapy, and outcomes were evaluated and compared according to classification in the treatment eras from 1999 to 2008 and from 2009 to 2018. One hundred eighty-two surgical procedures were reviewed, with an increase in case load since 2009. The endoscopic endonasal transclival approach (EETA) was performed in 151 of 182 cases (83.0%) and other approaches were performed in 31 cases (17%). There was an increment in the use of EETA, neuronavigation, and Doppler ultrasound after 2008. The overall postoperative complication rate was 14.3% (26 of 182 cases) consisting of 9 CSF leaks (4.9%), 7 intracranial hemorrhages (3.8%), 5 cases of meningitis (2.7%), and 5 cerebral ischemic injuries (2.7%). Gross-total resection (GTR) was achieved in 93 of 182 cases (51.1%). Extent of resection (EOR) improved in the second era of the study. Signs and/or symptoms at presentation worsened in 27 cases (14.8%), and the Katz Index worsened in 10 cases (5.5%). Previous treatment, dural involvement, EETA, and intraoperative Doppler ultrasound correlated with GTR. Patients received adjuvant proton beam radiation in 115 of 182 cases (63.2%), which was administered more in the latter era. Five-year progression-free survival (PFS) and overall survival (OS) were 62.3% and 73.5%, respectively. GTR, EETA, proton beam therapy, and the chondroid subtype correlated with a better survival rate. The mean follow-up was 62 months. Through multicentric data collection, this study encompasses the largest series in the literature of clival chordomas surgically treated through an EETA. An increase in the use of this approach was found among Italian neurosurgical departments together with an improved extent of resection over time. The satisfactory rate of GTR was marked by low surgical morbidity and the preservation of patient quality of life. Surgical outcome was reinforced, in terms of PFS and OS, by the use of proton beam therapy, which was increasingly performed along the period of study.


Multiplicity of morphologies in poly (l-lactide) bioresorbable vascular scaffolds.
Poly(l-lactide) (PLLA) is the structural material of the first clinically approved bioresorbable vascular scaffold (BVS), a promising alternative to permanent metal stents for treatment of coronary heart disease. BVSs are transient implants that support the occluded artery for 6 mo and are completely resorbed in 2 y. Clinical trials of BVSs report restoration of arterial vasomotion and elimination of serious complications such as late stent thrombosis. It is remarkable that a scaffold made from PLLA, known as a brittle polymer, does not fracture when crimped onto a balloon catheter or during deployment in the artery. We used X-ray microdiffraction to discover how PLLA acquired ductile character and found that the crimping process creates localized regions of extreme anisotropy; PLLA chains in the scaffold change orientation from the hoop direction to the radial direction on micrometer-scale distances. This multiplicity of morphologies in the crimped scaffold works in tandem to enable a low-stress response during deployment, which avoids fracture of the PLLA hoops and leaves them with the strength needed to support the artery. Thus, the transformations of the semicrystalline PLLA microstructure during crimping explain the unexpected strength and ductility of the current BVS and point the way to thinner resorbable scaffolds in the future.


Meta-mining of neuroblastoma and neuroblast gene expression profiles reveals candidate therapeutic compounds.
Neuroblastoma is a heterogeneous childhood tumor with poor survival outcome for the aggressive type despite intensive multimodal therapies. In this study, we aimed to identify new treatment options for neuroblastoma based on integrative genomic analysis. The Connectivity Map is a database comprising expression profiles in response to known therapeutic compounds. This renders it a useful tool in the search for potential therapeutic compounds based on comparison of gene expression profiles of diseased cells and a database of profiles in response to known therapeutic compounds. We have used this strategy in the search for new therapeutic molecules for neuroblastoma based on data of an integrative meta-analysis of gene copy number and expression profiles from 146 primary neuroblastoma tumors and normal fetal neuroblasts. In a first step, a 132-gene classifier was established that discriminates three major genomic neuroblastoma subgroups, reflecting inherent differences in gene expression between these subgroups. Subsequently, we screened the Connectivity Map database using gene lists generated by comparing expression profiles of fetal adrenal neuroblasts and the genomic subgroups of neuroblastomas. A putative therapeutic effect was predicted for several compounds of which six were empirically tested. A significant reduction in cell viability was shown for five of these molecules: 17-allylamino-geldanamycin, monorden, fluphenazine, trichostatin, and rapamycin. This proof-of-principle study indicates that an integrative genomic meta-analysis approach with inclusion of neuroblast data enables the identification of promising compounds for treatment of children with neuroblastoma. Further studies are warranted to explore in detail the therapeutic potential of these compounds.


A young white dwarf companion to pulsar B1620-26: evidence for early planet formation.
The pulsar B1620-26 has two companions, one of stellar mass and one of planetary mass. We detected the stellar companion with the use of Hubble Space Telescope observations. The color and magnitude of the stellar companion indicate that it is an undermassive white dwarf (0.34 +/- 0.04 solar mass) of age 480 x 10(6) +/- 140 x 10(6) years. This places a constraint on the recent history of this triple system and supports a scenario in which the current configuration arose through a dynamical exchange interaction in the cluster core. This implies that planets may be relatively common in low-metallicity globular clusters and that planet formation is more widespread and has happened earlier than previously believed.


Thermo-Sensitive Alternative Splicing of FLOWERING LOCUS M Is Modulated by Cyclin-Dependent Kinase G2.
The ability to sense environmental temperature and to coordinate growth and development accordingly, is critical to the reproductive success of plants. Flowering time is regulated at the level of gene expression by a complex network of factors that integrate environmental and developmental cues. One of the main players, involved in modulating flowering time in response to changes in ambient temperature is FLOWERING LOCUS M (FLM). FLM transcripts can undergo extensive alternative splicing producing multiple variants, of which FLM-β and FLM-δ are the most representative. While FLM-β codes for the flowering repressor FLM protein, translation of FLM-δ has the opposite effect on flowering. Here we show that the cyclin-dependent kinase G2 (CDKG2), together with its cognate cyclin, CYCLYN L1 (CYCL1) affects the alternative splicing of FLM, balancing the levels of FLM-β and FLM-δ across the ambient temperature range. In the absence of the CDKG2/CYCL1 complex, FLM-β expression is reduced while FLM-δ is increased in a temperature dependent manner and these changes are associated with an early flowering phenotype in the cdkg2 mutant lines. In addition, we found that transcript variants retaining the full FLM intron 1 are sequestered in the cell nucleus. Strikingly, FLM intron 1 splicing is also regulated by CDKG2/CYCL1. Our results provide evidence that temperature and CDKs regulate the alternative splicing of FLM, contributing to flowering time definition.


Replicable association between human cytomegalovirus infection and reduced white matter fractional anisotropy in major depressive disorder.
Major depressive disorder (MDD) is associated with reductions in white matter microstructural integrity as measured by fractional anisotropy (FA), an index derived from diffusion tensor imaging (DTI). The neurotropic herpesvirus, human cytomegalovirus (HCMV), is a major cause of white matter pathology in immunosuppressed populations but its relationship with FA has never been tested in MDD despite the presence of inflammation and weakened antiviral immunity in a subset of depressed patients. We tested the relationship between FA and HCMV infection in two independent samples consisting of 176 individuals with MDD and 44 healthy controls (HC) (Discovery sample) and 88 participants with MDD and 48 HCs (Replication sample). Equal numbers of HCMV positive (HCMV+) and HCMV negative (HCMV-) groups within each sample were balanced on ten different clinical/demographic variables using propensity score matching. Anti-HCMV IgG antibodies were measured using a solid-phase ELISA. In the Discovery sample, significantly lower FA was observed in the right inferior fronto-occipital fasciculus (IFOF) in HCMV+ participants with MDD compared to HCMV- participants with MDD (cluster size 1316 mm3; pFWE < 0.05, d = -0.58). This association was confirmed in the replication sample by extracting the mean FA from this exact cluster and applying the identical statistical model (p < 0.05, d = -0.45). There was no significant effect of diagnosis or interaction between diagnosis and HCMV in either sample. The effect of chronic HCMV infection on white matter integrity may-in at-risk individuals-contribute to the psychopathology of depression. These findings may provide a novel target of intervention for a subgroup of patients with MDD.


SETD1B Activates iNOS Expression in Myeloid-Derived Suppressor Cells.
Inducible nitric oxide synthase (iNOS) generates nitric oxide (NO) in myeloid cells that acts as a defense mechanism to suppress invading microorganisms or neoplastic cells. In tumor-bearing mice, elevated iNOS expression is a hallmark of myeloid-derived suppressor cells (MDSC). MDSCs use NO to nitrate both the T-cell receptor and STAT1, thus inhibiting T-cell activation and the antitumor immune response. The molecular mechanisms underlying iNOS expression and regulation in tumor-induced MDSCs are unknown. We report here that deficiency in IRF8 results in diminished iNOS expression in both mature CD11b+Gr1- and immature CD11b+Gr1+ myeloid cells in vivo Strikingly, although IRF8 was silenced in tumor-induced MDSCs, iNOS expression was significantly elevated in tumor-induced MDSCs, suggesting that the expression of iNOS is regulated by an IRF8-independent mechanism under pathologic conditions. Furthermore, tumor-induced MDSCs exhibited diminished STAT1 and NF-κB Rel protein levels, the essential inducers of iNOS in myeloid cells. Instead, tumor-induced MDSCs showed increased SETD1B expression as compared with their cellular equivalents in tumor-free mice. Chromatin immunoprecipitation revealed that H3K4me3, the target of SETD1B, was enriched at the nos2 promoter in tumor-induced MDSCs, and inhibition or silencing of SETD1B diminished iNOS expression in tumor-induced MDSCs. Our results show how tumor cells use the SETD1B-H3K4me3 epigenetic axis to bypass a normal role for IRF8 expression in activating iNOS expression in MDSCs when they are generated under pathologic conditions. Cancer Res; 77(11); 2834-43. ©2017 AACR.


The frequency of absence of palmaris longus in a South African population of mixed race.
The palmaris longus (PL) is a weak flexor of the wrist that may be harvested as a tendon graft and used in surgical procedures for reconstructive purposes. The PL is congenitally absent in 15% of the worldwide population. However, the frequency of absence varies considerably among different population groups, being as high as 63.9% in the Turkish population and as low as 3% in the black population in the Republic of Congo. In this study, South African persons of mixed race (n = 201) were assessed by two anatomists for the presence of the PL tendon using three clinical tests, namely the Traditional Test, Mishra's Test II, and the Gangata Test. The most reliable of the three tests used was determined using Kendall's coefficient of concordance. Of the total number of subjects used, 11.5% had absence (either bilaterally or unilaterally) of the PL tendon. There was a 5.5% bilateral absence of the PL. The study revealed that the PL tendon may present in six different patterns according to the clinical assessment tests applied, the presence or absence of the PL alongside the flexor capi radialis, and the degree of prominence of PL, if present. Using the Kendall's coefficient of concordance, the Mishra's Test II, and the Gangata Test, both involving abduction of the thumb, were found to be most effective in revealing the PL. The frequency of absence of the PL in South Africans of mixed race has been determined.


Emergence of self-organised oscillatory domains in fungal mycelia.
Fungi play a central role in the nutrient cycles of boreal and temperate forests. In these biomes, the saprotrophic wood-decay fungi are the only organisms that can completely decompose woody plant litter. In particular, cord-forming basidiomycete fungi form extensive mycelial networks that scavenge scarce mineral nutrients and translocate them over long distances to exploit new food resources. Despite the importance of resource allocation, there is limited information on nutrient dynamics in these networks, particularly for nitrogen, as there is no suitable radioisotope available. We have mapped N-translocation using photon-counting scintillation imaging of the non-metabolised amino acid analogue, (14)C-aminoisobutyrate. We describe a number of novel phenomena, including rapid, preferential N-resource allocation to C-rich sinks, induction of simultaneous bi-directional N-transport, abrupt switching between different pre-existing transport routes, and emergence of locally synchronised, oscillatory phase domains. It is possible that such self-organised oscillatory behaviour is a mechanism to achieve global co-ordination in the mycelium.


Influence of a short-time antioxidant application on the dentin bond strength after intracoronal bleaching.
This study evaluated the effects of an antioxidant application on the compromised bond strength of an adhesive to dentin bleached with 35% hydrogen peroxide. The dentin surfaces of the pulp chambers of 70 human third molars were ground, and the specimens were assigned randomly into seven groups, as follows: (a) control (unbleached); (b) bleached for 45 min, bonded immediately; (c) bleached for 45 min, treated with sodium ascorbate (SA) for 2 min, and bonded; (d) bleached for 45 min, bonded after 2 weeks; (e) bleached for 12 days, bonded immediately; (f) bleached for 12 days, treated with SA for 10 min, and bonded; and (g) bleached for 12 days, bonded after 2 weeks. In each group, the multimode adhesive was applied in etch-and-rinse and self-etch modes. The dentin surfaces were covered with a resin-based composite, and the bonded specimens were sectioned to produce composite-dentin sticks. The sticks were attached to a testing machine and subjected to a tensile force, and the representative specimens were examined via scanning electron microscopy. The bond strength was not affected by the application period of the bleaching agent. Both bleaching treatments significantly reduced the bond strength to the dentin in the self-etch or etch-and-rinse mode when compared with the control group. The bond strengths returned to normal levels with the SA applications or by waiting 2 weeks, regardless of the application period of the bleaching gel. The adhesive revealed a higher bond strength in the etch-and-rinse mode than in the self-etch mode.


Directed differentiation of dendritic cells from mouse embryonic stem cells.
Dendritic cells (DCs) are uniquely capable of presenting antigen to naive T cells, either eliciting immunity [1] or ensuring self-tolerance [2]. This property identifies DCs as potential candidates for enhancing responses to foreign [3] and tumour antigens [4], and as targets for immune intervention in the treatment of autoimmunity and allograft rejection [1]. Realisation of their therapeutic potential would be greatly facilitated by a fuller understanding of the function of DC-specific genes, a goal that has frequently proven elusive because of the paucity of stable lines of DCs that retain their unique properties, and the inherent resistance of primary DCs to genetic modification. Protocols for the genetic manipulation of embryonic stem (ES) cells are, by contrast, well established [5], as is their capacity to differentiate into a wide variety of cell types in vitro, including many of hematopoietic origin [6]. Here, we report the establishment, from mouse ES cells, of long-term cultures of immature DCs that share many characteristics with macrophages, but acquire, upon maturation, the allostimulatory capacity and surface phenotype of classical DCs, including expression of CD11c, major histocompatibility complex (MHC) class II and co-stimulatory molecules. This novel source should prove valuable for the generation of primary, untransformed DCs in which candidate genes have been overexpressed or functionally ablated, while providing insights into the earliest stages of DC ontogeny.


Detection of Intratumor Heterogeneity in Modern Pathology: A Multisite Tumor Sampling Perspective.
Current sampling protocols of neoplasms along the digestive tract and in the urinary bladder have to be updated, as they do not respond to the necessities of modern personalized medicine. We show here that an adapted version of multisite tumor sampling (MSTS) is a sustainable model to overcome current deficiencies in digestive and bladder tumors when they are large enough so as to make unaffordable a total sampling. The new method is based on the divide-and-conquer algorithm and includes a slight modification of the MSTS, which proved to be useful very recently in clear cell renal cell carcinoma. This in silico analysis confirms the usefulness of MSTS for detecting intratumor heterogeneity (ITH) in tumors arising in hollow viscera. However, MSTS does not seem to improve routine traditional sampling in detecting tumor budding, extramural venous invasion, and perineural invasion. We conclude that (1) MSTS is the best method for tumor sampling to detect ITH balancing high performance and sustainable cost, (2) MSTS must be adapted to tumor shape and tumor location for an optimal performance.


Effects of strontium ions with potential antibacterial activity on in vivo bone regeneration.
Bioactive glasses (BGs) have attracted added attention in the structure of the scaffolds for bone repair applications. Different metal ions could be doped in BGs to induce specific biological responses. Among these ions, strontium (Sr) is considered as an effective and safe doping element with promising effects on bone formation and regeneration. In this experiment, we evaluated the antibacterial activities of the gelatin-BG (Gel-BG) and Gel-BG/Sr scaffolds in vitro. The osteogenic properties of the prepared scaffolds were also assessed in rabbit calvarial bone defects for 12 weeks. Both scaffolds showed in vivo bone formation during 12 weeks with the newly formed bone area in Gel-BG/Sr scaffold was higher than that in Gel-BG scaffolds after the whole period. Based on the histological results, Gel-BG/Sr exhibited acceleration of early-stage bone formation in vivo. The results of antibacterial investigation for both scaffolds showed complete growth inhibition against Escherichia coli (E. coli). Although Gel-BG revealed no antibacterial effect on Staphylococcus aureus (S. aureus), the Gel-BG/Sr was able to partially inhibit the growth of S. aureus, as detected by threefold reduction in growth index. Our results confirmed that Sr doped BG is a favorable candidate for bone tissue engineering with superior antibacterial activity and bone regeneration capacity compared with similar counterparts having no Sr ion.


Hematopoietic cells express two forms of lyn kinase differing by 21 amino acids in the amino terminus.
cDNAs for the murine lyn protein tyrosine kinase gene were cloned from mouse bone marrow-derived monocytic cells. Comparison of the human and murine genes demonstrated a 94% homology in peptide sequence. Comparable to the human gene, murine lyn was found to be expressed in myeloid and B-lymphoid lineage cells. During the cloning, two types of cDNAs were obtained that differed by the presence (lynA) or absence (lynB) of 63 bp within the amino-terminal coding region of the gene. The genomic structure of the murine lyn gene demonstrates that the two types of lyn transcripts are derived from alternative splicing utilizing an internal splice donor site. Transcripts for both forms were found to be expressed in myeloid cells. lyn-specific antisera detected comparable levels of proteins of 56 and 53 kDa in hematopoietic cells. these 56- and 53-kDa proteins comigrated with proteins produced by in vitro translation or in vivo expression of the lynA and lynB cDNAs, respectively. The two forms had comparable in vitro kinase activities in immunoprecipitates and showed similar peptide patterns, with partial V8 digestion of the in vitro-phosphorylated proteins. The potential significance of the two lyn proteins is discussed.


Women's fertility across the cycle increases the short-term attractiveness of creative intelligence.
Male provisioning ability may have evolved as a "good dad" indicator through sexual selection, whereas male creativity may have evolved partly as a "good genes" indicator. If so, women near peak fertility (midcycle) should prefer creativity over wealth, especially in short-term mating. Forty-one normally cycling women read vignettes describing creative but poor men vs. uncreative but rich men. Women's estimated fertility predicted their short-term (but not long-term) preference for creativity over wealth, in both their desirability ratings of individual men (r=.40, p<.01) and their forced-choice decisions between men (r=.46, p<.01). These preliminary results are consistent with the view that creativity evolved at least partly as a good genes indicator through mate choice.


Statin prescription in patients with chronic obstructive pulmonary disease and risk of exacerbations: a retrospective cohort study in the Clinical Practice Research Datalink.
Observational studies have suggested a beneficial effect of taking statins on frequency of chronic obstructive pulmonary disease (COPD) exacerbations. However, clinical trials of statins in people with COPD did not confirm those results. This study aimed to investigate this association using a methodological approach, which reduces the biases associated with some previous observational study designs. Retrospective cohort study comparing new-users of statins with non-users. General practices in England contributing to the Clinical Practice Research Datalink in 2007-2017, with linkage to data on Hospital Episode Statistics inpatient episodes. 48 124 people with COPD, aged over 40 years, who had not been prescribed statin in the previous year. Participants became new-users of statins at their first prescription for a statin during follow-up. They were then assumed to remain statin users. Statin users were compared with non-users. Primary outcomes were COPD exacerbation, or severe exacerbation requiring hospitalisation. Secondary outcomes were death from any cause (for comparison with other studies) and urinary tract infection (negative-control). Maximum follow-up was 3 years. Adjusted HR were calculated using time-dependent Cox regression. The Andersen-Gill model was used for recurrent exacerbations. Covariates included demographic variables, variables related to COPD severity, cardiovascular comorbidities as time-dependent variables, and other comorbidities at baseline. 7266 participants became new-users of statins over an average 2.5 years of follow-up. In total, 30 961 people developed an exacerbation, 8110 severe exacerbation, 3650 urinary tract infection and 5355 died. Adjusted HR (95% CI) in statin users compared with non-users were first exacerbation 1.01 (0.96-1.06), severe exacerbation 0.92 (0.84-0.99), number of exacerbations 1.00 (0.97-1.04), urinary tract infection 1.10 (0.98-1.23) and death 0.63 (0.57-0.70). In this study of health records from a Primary Care database, statin use in people with COPD was not associated with a lower risk of COPD exacerbation.


Neurological injuries associated with regional anesthesia.
A peripheral nerve or spinal cord injury is a rare but significant complication of regional anesthesia. Evaluation of acute nerve injury includes a focused history and examination to localize the lesion. Confirmatory testing should include electromyography and appropriate imaging. In most cases magnetic resonance imaging (MRI) is preferred to computed tomography (CT) or ultrasound given the better resolution of the nerves and soft tissue. Most cases of peripheral nerve injury will improve and resolve without deficit. In mild cases reassurance and observation is all that is necessary. In more severe cases, if the deficit is progressive or complete, surgical exploration should be considered. If there is no recovery by 2 to 5 months then referral to a peripheral nerve surgeon should be considered. The prognosis for cauda equina or spinal cord lesions is more guarded. Recovery from these is commonly incomplete. Early diagnosis and intervention is the key to preventing catastrophic neurological outcomes.


Dysregulation of synaptic plasticity precedes appearance of morphological defects in a Pten conditional knockout mouse model of autism.
The phosphoinositide signaling system is a crucial regulator of neural development, cell survival, and plasticity. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) negatively regulates phosphatidylinositol 3-kinase signaling and downstream targets. Nse-Cre Pten conditional knockout mice, in which Pten is ablated in granule cells of the dentate gyrus and pyramidal neurons of the hippocampal CA3, but not CA1, recapitulate many of the symptoms of humans with inactivating PTEN mutations, including progressive hypertrophy of the dentate gyrus and deficits in hippocampus-based social and cognitive behaviors. However, the impact of Pten loss on activity-dependent synaptic plasticity in this clinically relevant mouse model of Pten inactivation remains unclear. Here, we show that two phosphatidylinositol 3-kinase- and protein synthesis-dependent forms of synaptic plasticity, theta burst-induced long-term potentiation and metabotropic glutamate receptor (mGluR)-dependent long-term depression, are dysregulated at medial perforant path-to-dentate gyrus synapses of young Nse-Cre Pten conditional knockout mice before the onset of visible morphological abnormalities. In contrast, long-term potentiation and mGluR-dependent long-term depression are normal at CA3-CA1 pyramidal cell synapses at this age. Our results reveal that deletion of Pten in dentate granule cells dysregulates synaptic plasticity, a defect that may underlie abnormal social and cognitive behaviors observed in humans with Pten inactivating mutations and potentially other autism spectrum disorders.


Shape-controlled electrodeposition of single Pt nanocrystals onto carbon nanoelectrodes.
In this paper, we report the electrosynthesis and characterization of individual, shape-controlled Pt nanocrystals (NCs) electrodeposited on carbon nanoelectrodes (CNEs). Single Pt NCs were deposited onto the CNEs using an empirically developed square-wave potential program. Characterization by scanning electron microscopy indicates that the sizes of Pt NCs are remarkably reproducible (relative standard deviation = 6%). Electrochemically active surface areas, determined by Cu underpotential deposition and H adsorption/desorption analyses, are also reproducible. Selected area electron diffraction indicates that each Pt NC is comprised of just one single crystal (no grain boundaries). Although different square-wave potential programs lead to different types of crystals, the Pt NCs discussed here have a concave hexoctahedral geometry bound primarily by {13 6 2} surface facets. The results in this report represent a first step toward our ultimate goal of studying electrocatalysis at individual, shape-controlled, single-crystal nanoparticles.


Development of an innovative 3D cell culture system to study tumour--stroma interactions in non-small cell lung cancer cells.
We describe a novel 3D co-culture model using non-small cell lung cancer (NSCLC) cell lines in combination with lung fibroblasts. This model allows the investigation of tumour-stroma interactions and addresses the importance of having a more in vivo like cell culture model. Automation-compatible multi-well hanging drop microtiter plates were used for the production of 3D mono- and co-cultures. In these hanging drops the two NSCLC cell lines A549 and Colo699 were cultivated either alone or co-cultured with lung fibroblasts. The viability of tumour spheroids was confirmed after five and ten days by using Annexin V/Propidium Iodide staining for flow-cytometry. Tumour fibroblast spheroid formation was characterized by scanning electron microscope (SEM), semi-thin sections, fluorescence microscope and immunohistochemistry (IHC). In addition to conventional histology, protein expression of E-Cadherin, vimentin, Ki67, fibronectin, cytokeratin 7 and α-smooth muscle actin (α-SMA) was investigated by IHC. Lower viability was observed in A549 monocultures compared to co-cultures, whereas Colo699 monocultures showed better viability compared to co-cultures. Ki67 expression varied significantly between mono- and co-cultures in both tumour cell lines. An increase of vimentin and decreased E-Cadherin expression could be detected during the course of the cultivation suggesting a transition to a more mesenchymal phenotype. Furthermore, the fibroblast cell line showed an expression of α-SMA only in co-culture with the cancer cell line A549, thereby indicating a mesenchymal to mesenchymal shift to an even more myofibroblast phenotype. We demonstrate that our method is a promising tool for the generation of tumour spheroid co-cultures. Furthermore, these spheroids allow the investigation of tumour-stroma interactions and a better reflection of in vivo conditions of cancer cells in their microenvironment. Our method holds potential to contribute to the development of anti-cancer agents and support the search for biomarkers.


Neuroimaging in cerebral palsy: Patterns of brain dysgenesis and injury.
Despite advances in obstetric and neonatal care, the overall prevalence of cerebral palsy has remained stable, supporting the belief that pathogenesis is primarily due to prenatal brain dysgenesis and injury. Neuroimaging studies have consistently shown abnormalities in 70% to 90% of affected children, facilitating clinical classification into groups with early brain malformations, white-matter injury, neonatal encephalopathies, and a heterogeneous group of postnatally acquired disorders. White-matter injury, well seen on conventional magnetic resonance imaging (MRI), is the leading cause of cerebral palsy in children born preterm. As many as 20% of very low birthweight infants have cystic and/or diffuse white-matter injury, termed periventricular leukomalacia, with evidence of associated pathology in other cortical and subcortical structures. In the group with acute, term perinatal pathology, a variety of imaging modalities, in addition to MRI, have diagnostic utility. In general, when added to conventional MRI, advanced techniques, such as diffusion tensor imaging, diffusion-weighted imaging, and magnetic resonance spectroscopy, provide a more complete picture of structural and functional brain abnormalities. The results have led to improved understanding of pathogenesis, especially in regard to periventricular leukomalacia and hypoxic-ischemic encephalopathy. This information might lead to interventions preventing brain injury in preterm infants and asphyxiated term newborns.