Functional connectivity modeling of consistent cortico-striatal degeneration in Huntington's disease.
Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by a complex neuropsychiatric phenotype. In a recent meta-analysis we identified core regions of consistent neurodegeneration in premanifest HD in the striatum and middle occipital gyrus (MOG). For early manifest HD convergent evidence of atrophy was most prominent in the striatum, motor cortex (M1) and inferior frontal junction (IFJ). The aim of the present study was to functionally characterize this topography of brain atrophy and to investigate differential connectivity patterns formed by consistent cortico-striatal atrophy regions in HD. Using areas of striatal and cortical atrophy at different disease stages as seeds, we performed task-free resting-state and task-based meta-analytic connectivity modeling (MACM). MACM utilizes the large data source of the BrainMap database and identifies significant areas of above-chance co-activation with the seed-region via the activation-likelihood-estimation approach. In order to delineate functional networks formed by cortical as well as striatal atrophy regions we computed the conjunction between the co-activation profiles of striatal and cortical seeds in the premanifest and manifest stages of HD, respectively. Functional characterization of the seeds was obtained using the behavioral meta-data of BrainMap. Cortico-striatal atrophy seeds of the premanifest stage of HD showed common co-activation with a rather cognitive network including the striatum, anterior insula, lateral prefrontal, premotor, supplementary motor and parietal regions. A similar but more pronounced co-activation pattern, additionally including the medial prefrontal cortex and thalamic nuclei was found with striatal and IFJ seeds at the manifest HD stage. The striatum and M1 were functionally connected mainly to premotor and sensorimotor areas, posterior insula, putamen and thalamus. Behavioral characterization of the seeds confirmed that experiments activating the MOG or IFJ in conjunction with the striatum were associated with cognitive functions, while the network formed by M1 and the striatum was driven by motor-related tasks. Thus, based on morphological changes in HD, we identified functionally distinct cortico-striatal networks resembling a cognitive and motor loop, which may be prone to early disruptions in different stages of the disease and underlie HD-related cognitive and motor symptom profiles. Our findings provide an important link between morphometrically defined seed-regions and corresponding functional circuits highlighting the functional and ensuing clinical relevance of structural damage in HD.


Short-term lung function decline in tunnel construction workers.
Tunnel construction workers are exposed to particulate and gaseous air contaminants. Previous studies carried out in the 1990s showed that tunnel construction workers were at increased risk of both short-term and long-term lung function decline. Since then, efforts have been made to reduce exposure. The objective of the present study was to investigate if current exposure may still cause short-term lung function impairment. Tunnel workers work 12 days consecutively, and then they are off for 9 days. Ninety tunnel workers and 51 referents were examined with spirometry and questionnaires before their work period started and again 11 days later. Personal exposure to particles and α-quartz in the thoracic aerosol subfraction, elemental carbon and organic carbon, oil mist, nitrogen dioxide and ammonia was assessed on two consecutive days between the two health examinations. The geometric means air concentrations for particulate matter in the thoracic mass aerosol subfraction, α-quartz, oil mist, organic carbon and elemental carbon for all workers were 561, 63, 210, 146 and 35 μg/m(3), respectively. After 11 days of work, the mean forced expiratory volume in 1 s (FEV1) in healthy participants had declined 73 mL (SD 173), p<0.001 in the tunnel workers, compared to 3 mL (SD 21), p=0.9 in the referents. Also, forced vital capacity (FVC) had declined significantly. Declines in FVC and FEV1 were significantly associated with exposure to organic carbon. In spite of reduced levels of exposure in modern tunnelling operations, a negative impact on lung function was still observed.


Bayesian inference of hub nodes across multiple networks.
Hub nodes within biological networks play a pivotal role in determining phenotypes and disease outcomes. In the multiple network setting, we are interested in understanding network similarities and differences across different experimental conditions or subtypes of disease. The majority of proposed approaches for joint modeling of multiple networks focus on the sharing of edges across graphs. Rather than assuming the network similarities are driven by individual edges, we instead focus on the presence of common hub nodes, which are more likely to be preserved across settings. Specifically, we formulate a Bayesian approach to the problem of multiple network inference which allows direct inference on shared and differential hub nodes. The proposed method not only allows a more intuitive interpretation of the resulting networks and clearer guidance on potential targets for treatment, but also improves power for identifying the edges of highly connected nodes. Through simulations, we demonstrate the utility of our method and compare its performance to current popular methods that do not borrow information regarding hub nodes across networks. We illustrate the applicability of our method to inference of co-expression networks from The Cancer Genome Atlas ovarian carcinoma dataset.


Economic analysis of opportunities to accelerate Alzheimer's disease research and development.
The development of disease-modifying treatments for Alzheimer's disease (AD) faces a number of barriers. Among these are the lack of surrogate biomarkers, the exceptional size and duration of clinical trials, difficulties in identifying appropriate populations for clinical trials, and the limitations of monotherapies in addressing such a complex multifactorial disease. This study sets out to first estimate the consequent impact on the expected cost of developing disease-modifying treatments for AD and then to estimate the potential benefits of bringing together industry, academic, and government stakeholders to co-invest in, for example, developing better biomarkers and cognitive assessment tools, building out advanced registries and clinical trial-readiness cohorts, and establishing clinical trial platforms to investigate combinations of candidate drugs and biomarkers from the portfolios of multiple companies. Estimates based on interviews with experts on AD research and development suggest that the cost of one new drug is now $5.7 billion (95% confidence interval (CI) $3.7-9.5 billion) and could be reduced to $2.0 billion (95% CI $1.5-2.9 billion). The associated acceleration in the arrival of disease-modifying treatments could reduce the number of case years of dementia by 7.0 million (95% CI 4.4-9.4 million) in the United States from 2025 through 2040.


Screening Instruments for Developmental and Behavioral Concerns in Pediatric Hispanic Populations in the United States: A Systematic Literature Review.
Racial and ethnic disparities in the identification of developmental and behavioral concerns in children are public health problems in the United States. Early identification of developmental delay using validated screening instruments provides a pathway to prevention and intervention in pediatric health care settings. However, the validity of Spanish-language screening instruments, used in clinical settings in the United States, has not been systematically examined. This study aims to review the literature of clinically administered developmental and behavioral instruments with Hispanic caregivers to investigate implementation variation due to language and cultural factors. A systematic literature review using PubMed and PsycINFO was conducted of articles published from January 1, 2006 to December 12, 2017. Abstract, full-text, and critical appraisal resulted in 11 studies that met criteria for inclusion. Five different instruments were used to screen Hispanic or Spanish-speaking caregivers of children younger than 6 years. None of the instruments established validity and reliability apart from Spanish translation. Two studies identified differences in screening results with Spanish-speaking caregivers due to language and 6 described cultural differences that impacted screening implementation. Two studies reported differential item functioning in Spanish-translated instruments. Language and cultural considerations are critical to the administration of valid and reliable screening in pediatric health care settings. Available developmental and behavioral Spanish-language-screening instruments function differently because of both language and culture, suggesting the tools are not as psychometrically valid when administered to Spanish-speaking families. Validation of translated screening instruments is essential to eliminate the possibility of detection bias or misidentification of developmental risk, improving early access to clinical services for Hispanic and Spanish-speaking families.


Improvement of the validity of the simplified modal method for designing a subwavelength dielectric transmission grating.
To accurately and easily design the diffraction characteristics of a rectangular transmission grating under the illumination of Littrow mounting, the validity and limitation of the simplified modal method is evaluated by a comparison of diffraction efficiencies predicted by the modal approach to exact results calculated with rigorous coupled-wave analysis. The influence of the grating normalized period, the normalized groove depth, and the fill factor on the accuracy of the modal method is quantitatively determined. More importantly, the reflection effect of two propagating grating modes with the optical thin-film model and the nonsymmetrical Fabry-Perot model is proposed and applied in the modal method to improve the accuracy of the calculated diffraction efficiencies. Generally, it is found that the thin-film model of reflection loss is valid at the smaller normalized period, but the Fabry-Perot model can exactly calculate the reflection loss of grating modes at the larger normalized period. Based on the fact that the validity of the modal approach is determined independently of the incident wavelength, the exact design and analysis of grating diffraction elements can be implemented at different wavelengths by simply scaling the grating parameters. Moreover, the polarization effect of diffraction properties on the limitation of the modal method without and with the reflection loss of grating modes is clearly demonstrated.


Comparison of infectious complications between incident hemodialysis and peritoneal dialysis patients.
The impact of dialysis modality on infection, especially early in the course of dialysis, has not been well studied. This study compared infection between hemodialysis (HD) and peritoneal dialysis (PD) from the start of dialysis and evaluated factors that have an impact on infection risk. In this observational cohort study, all incident dialysis patients (n = 181; HD 119 and PD 62) at a single center from 1999 to 2005 had data collected prospectively beginning day 1 of dialysis. Excluded were those with any previous ESRD therapy. Infection rates were evaluated using multivariate Poisson regression. Overall infection rates were similar (HD 0.77 versus PD 0.86/yr; P = 0.24). Only HD patients had bacteremia (0.16/yr), and only PD patients had peritonitis (0.24/yr). Bacteremia that occurred < or =90 d after start of HD was 0.44/yr, increased compared with overall rate of 0.16/yr (P < 0.004). HD catheters, used in 67% of patients who started HD, were associated with a strikingly increased rate of bacteremia. Peritonitis < or =90 d was 0.22/yr, no different from the overall rate. Modality was not an independent predictor of overall infections (PD versus HD: relative risk 1.30; 95% confidence interval 0.93 to 1.8; P = 0.12) using multivariate analysis. PD and HD patients had similar infection rates overall, but type of infection and risk over time varied. HD patients had an especially high risk for bacteremia in the first 90 d, whereas the risk for peritonitis for the PD cohort was not different over time. These results support the placement of permanent accesses (fistula or PD catheter) before the start of dialysis to avoid use of HD catheters.


Climate change effects on plant disease: genomes to ecosystems.
Research in the effects of climate change on plant disease continues to be limited, but some striking progress has been made. At the genomic level, advances in technologies for the high-throughput analysis of gene expression have made it possible to begin discriminating responses to different biotic and abiotic stressors and potential trade-offs in responses. At the scale of the individual plant, enough experiments have been performed to begin synthesizing the effects of climate variables on infection rates, though pathosystem-specific characteristics make synthesis challenging. Models of plant disease have now been developed to incorporate more sophisticated climate predictions. At the population level, the adaptive potential of plant and pathogen populations may prove to be one of the most important predictors of the magnitude of climate change effects. Ecosystem ecologists are now addressing the role of plant disease in ecosystem processes and the challenge of scaling up from individual infection probabilities to epidemics and broader impacts.


Cell-cycle-specific transcription termination within the human histone H3.3 gene is correlated with specific protein-DNA interactions.
In vitro studies using highly purified calf thymus RNA polymerase II and a fragment spanning the first intron of H3.3 as template DNA have demonstrated the existence of a strong transcription termination site consisting of thymidine stretches. In this study, nuclear run-on experiments have been performed to assess the extent to which transcription elongation is blocked in vivo using DNA probes corresponding to region 5' and 3' of the in vitro termination sites. These studies suggest that H3.3 expression is stimulated following the inhibition of DNA synthesis through the elimination of the transcription elongation block. Interestingly, both the in vivo and in vitro experiments have revealed that the transcriptional block/termination sites are positioned immediately downstream of a 73 bp region that has been over 90% conserved between the chicken and human H3.3 genes. The extreme conservation of this intronic region suggests a possible role in maintaining cis-acting function. Electrophoretic mobility shift experiments show that HeLa cell nuclear extracts contain protein factors that bind specifically to the region of transcription elongation block. Furthermore, we demonstrate a correlation between the protein binding activity and the transcriptional block in cells that have been either arrested at the initiation of S phase or were replication-interrupted by hydroxyurea. DNA footprinting experiments indicate that the region of protein binding is at the 3' end of the conserved region and overlaps with one of the three in-vitro-mapped termination sites.


Survival and quality of life for patients with COPD or asthma admitted to intensive care in a UK multicentre cohort: the COPD and Asthma Outcome Study (CAOS).
Non-invasive ventilation is first-line treatment for patients with acutely decompensated chronic obstructive pulmonary disease (COPD), but endotracheal intubation, involving admission to an intensive care unit, may sometimes be required. Decisions to admit to an intensive care unit are commonly based on predicted survival and quality of life, but the information base for these decisions is limited and there is some evidence that clinicians tend to be pessimistic. This study examined the outcomes in patients with COPD admitted to the intensive care unit for decompensated type II respiratory failure. A prospective cohort study was carried out in 92 intensive care units and 3 respiratory high dependency units in the UK. Patients aged 45 years and older with breathlessness, respiratory failure or change in mental status due to an exacerbation of COPD, asthma or a combination of the two were recruited. Outcomes included survival and quality of life at 180 days. Of the 832 patients recruited, 517 (62%) survived to 180 days. Of the survivors, 421 (81%) responded to a questionnaire. Of the respondents, 73% considered their quality of life to be the same as or better than it had been in the stable period before they were admitted, and 96% would choose similar treatment again. Function during the stable pre-admission period was a reasonable indicator of function reported by those who survived 180 days. Most patients with COPD who survive to 180 days after treatment in an intensive care unit have a heavy burden of symptoms, but almost all of them-including those who have been intubated-would want similar intensive care again under similar circumstances.


Kir6.2 polymorphisms sensitize beta-cell ATP-sensitive potassium channels to activation by acyl CoAs: a possible cellular mechanism for increased susceptibility to type 2 diabetes?
The commonly occurring E23K and I337V Kir6.2 polymorphisms in the ATP-sensitive potassium (KATP) channel are more frequent in Caucasian type 2 diabetic populations. However, the underlying cellular mechanisms contributing to the pathogenesis of type 2 diabetes remain uncharacterized. Chronic elevation of plasma free fatty acids observed in obese and type 2 diabetic subjects leads to cytosolic accumulation of long-chain acyl CoAs (LC-CoAs) in pancreatic beta-cells. We postulated that the documented stimulatory effects of LC-CoAs on KATP channels might be enhanced in polymorphic KATP channels. Patch-clamp experiments were performed on inside-out patches containing recombinant KATP channels (Kir6.2/SUR1) to record macroscopic currents. KATP channels containing Kir6.2 (E23K/I337V) showed significantly increased activity in response to physiological palmitoyl-CoA concentrations (100-1,000 nmol/l) compared with wild-type KATP channels. At physiological intracellular ATP concentrations (mmol/l), E23K/I337V polymorphic KATP channels demonstrated significantly enhanced activity in response to palmitoyl-CoA. The observed increase in KATP channel activity may result in multiple defects in glucose homeostasis, including impaired insulin and glucagon-like peptide-1 secretion and increased glucagon release. In summary, these results suggest that the E23K/I337V polymorphism may have a diabetogenic effect via increased KATP channel activity in response to endogenous levels of LC-CoAs in tissues involved in the maintenance of glucose homeostasis.


Dipstick proteinuria as a predictor of all-cause and cardiovascular disease mortality in Bangladesh: A prospective cohort study.
Baseline, persistent, incident, and remittent dipstick proteinuria have never been tested as predictors of mortality in an undeveloped country. The goal of this study was to determine which of these four types of proteinuria (if any) predict mortality. Baseline data was collected from 2000 to 2002 in Bangladesh from 11,121 adults. Vital status was ascertained over 11-12years. Cox models were used to evaluate proteinuria in relation to all-cause and cardiovascular disease (CVD) mortality. CVD mortality was evaluated only in those with baseline proteinuria. Persistent, remittent, and incident proteinuria were determined at the 2-year exam. Baseline proteinuria of 1+ or greater was significantly associated with all-cause (hazard ratio (HR) 2.87; 95% C.I., 1.71-4.80) and CVD mortality (HR: 3.55; 95% C.I., 1.81-6.95) compared to no proteinuria, adjusted for age, gender, arsenic well water concentration, education, hypertension, BMI, smoking, and diabetes mellitus. Persistent 1+ proteinuria had a stronger risk of death, 3.49 (1.64-7.41)-fold greater, than no proteinuria. Incident 1+ proteinuria had a 1.87 (0.92-3.78)-fold greater mortality over 9-10years. Remittent proteinuria revealed no increased mortality. Baseline, persistent, and incident dipstick proteinuria were predictors of all-cause mortality with persistent proteinuria having the greatest risk. In developing countries, those with 1+ dipstick proteinuria, particularly if persistent, should be targeted for definitive diagnosis and treatment. The two most common causes of proteinuria to search for are diabetes mellitus and hypertension.


Modelling heat conduction in polycrystalline hexagonal boron-nitride films.
We conducted extensive molecular dynamics simulations to investigate the thermal conductivity of polycrystalline hexagonal boron-nitride (h-BN) films. To this aim, we constructed large atomistic models of polycrystalline h-BN sheets with random and uniform grain configuration. By performing equilibrium molecular dynamics (EMD) simulations, we investigated the influence of the average grain size on the thermal conductivity of polycrystalline h-BN films at various temperatures. Using the EMD results, we constructed finite element models of polycrystalline h-BN sheets to probe the thermal conductivity of samples with larger grain sizes. Our multiscale investigations not only provide a general viewpoint regarding the heat conduction in h-BN films but also propose that polycrystalline h-BN sheets present high thermal conductivity comparable to monocrystalline sheets.


Main concerns of patients regarding the most common complications in the post-anesthetic care unit.
'Minor' events have a fundamental role in the determination of the quality of the Anesthesiology service. The objective of the present study was to evaluate the main concerns of patients regarding the post-anesthetic period and to test the hypothesis that the most undesirable effects can be influenced by demographic characteristics. Four hundred and forty patients answered a questionnaire immediately before the pre-anesthetic evaluation. Possible undesirable effects in the immediate postoperative period, based on data gathered in the literature considering the criterion of frequency but not severity were listed. Demographic data and the nine more frequent occupations were evaluated. The information gathered from the analysis of the questionnaires was related with anthropometric, socioeconomic, and educational data of the patients to assess their influence on the answer profile. Among the undesirable effects, the fear of being intubated upon waking up was mentioned more often as the most important factor, followed by 'severe pain at the surgery site'. Analysis of the three most frequent undesirable effects according to the demographic data did not show significant statistical differences, except for 'pain at the surgery site' (which was less common among male patients). The main post-anesthetic concerns of patients included: waking up with a tube in the throat, severe pain at the surgery site, and remembering being conscious during the surgery. Age, schooling, and family income did not determine differences in the concerns of patients.


Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort.
Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously. We analyzed DNA from the largest reported international cohort of patients with DSD (278 patients with 46,XY DSD and 48 with 46,XX DSD). Our targeted gene panel compares favorably with other sequencing platforms. We found a total of 28 diagnostic genes that are implicated in DSD, highlighting the genetic spectrum of this disorder. Sequencing revealed 93 previously unreported DSD gene variants. Overall, we identified a likely genetic diagnosis in 43% of patients with 46,XY DSD. In patients with 46,XY disorders of androgen synthesis and action the genetic diagnosis rate reached 60%. Surprisingly, little difference in diagnostic rate was observed between singletons and trios. In many cases our findings are informative as to the likely cause of the DSD, which will facilitate clinical management. Our massively parallel sequencing targeted DSD gene panel represents an economical means of improving the genetic diagnostic capability for patients affected by DSD. Implementation of this panel in a large cohort of patients has expanded our understanding of the underlying genetic etiology of DSD. The inclusion of research candidate genes also provides an invaluable resource for future identification of novel genes.


Analysis of GNAQ mutations, proliferation and MAPK pathway activation in uveal melanomas.
To study the GNAQ mutational status in a series of uveal melanomas and evaluate possible associations with mitogen-activated protein kinase (MAPK) pathway protein expression and tumour proliferation markers. Mutational analysis was performed by PCR/sequencing of exon 5 of the GNAQ gene in a series of 22 uveal melanomas in which total and phosphorylated extracellular signal-regulated kinase (ERK) 1/2 overexpression without coexistent BRAF and NRAS mutations had previously been observed. Expression of the cell cycle markers (Ki-67, cyclin D1 and p27) was evaluated by immunohistochemistry. The association between GNAQ mutational status, ERK1/2, phospho-ERK1/2, Ki-67, cyclin D1 and p27 expression levels and the clinicopathological prognostic parameters of uveal melanomas was also assessed. GNAQ mutations were found in 36% of uveal melanomas. No associations were found between the GNAQ mutational status and prognostic parameters, the expression of ERK1/2, pERK1/2 and cell cycle markers. The results of this study suggest that GNAQ mutated uveal melanomas do not exhibit a higher deregulation of proliferation or higher activation of the MAPK signalling pathway than uveal melanomas without GNAQ overactivation.


Antibiotic use and other risk factors at hospital level for outbreaks with Clostridium difficile PCR ribotype 027.
The first Dutch outbreak due to Clostridium difficile ribotype 027 was observed in mid-2005; by the end of that year, eight hospitals were affected. To study the relationship between hospital-wide antibiotic use and the incidence of 027-linked C. difficile-associated disease (CDAD) three study groups were made: group A, all eight hospitals with an 027-associated epidemic; group B, five of a total of six hospitals with occasional 027 cases, without an increase in CDAD; and group C, ten randomly selected hospitals with no reported 027 epidemics or isolated 027 cases. Quarterly data on CDAD incidences, hygiene measures and the use of fluoroquinolones, second- and third-generation cephalosporins, extended-spectrum penicillins, penicillins with beta-lactamase inhibitors, carbapenems, lincomycins and macrolides were collected for 2004 and 2005, and divided into pre-epidemic and epidemic periods. Using a multilevel Poisson regression analysis, CDAD incidence was linked to antibiotic use in the previous quarter and to certain hygiene measures. In the pre-epidemic period, the total use of the studied antibiotics was comparable between affected and unaffected hospitals. Higher use of second-generation cephalosporins, macrolides and all of the studied antibiotics were independently associated with a small increase in CDAD incidence [relative risk (95% confidence interval): 1.14 per increase of 100 defined daily doses per 10,000 bed days (1.06-1.23), 1.10 (1.01-1.19) and 1.02 (1.01-1.03), respectively]. However the effect was too small to predict which hospitals might be more prone to 027-associated outbreaks.


Therapeutic monitoring of anti-seizure medications in low- and middle-income countries: a systematic review.
Background: The treatment gap for epilepsy is large in low- and middle-income countries (LMICs) and the effectiveness and safety of the available anti-seizure medication (ASMs) is not fully understood. We systematically reviewed available evidence on therapeutic drug monitoring (TDM) of ASM in LMIC. Methods: We searched four main databases (PubMed, Psych-Info, CINAHL and Embase) up to 31 st December 2020, with eligible articles screened using a PRISMA checklist and a set of exclusion and inclusion criteria. Full texts were examined to evaluate the extent and practice of TDM in LMICs. Analyses were performed using Stata 13 and descriptive statistics were used to pool median distribution of TDM across studies. Results: Of the 6,309 articles identified in the initial search, 65 (1.0%) met the eligibility criteria. TDM of ASMs was mostly done to assess toxicity (42.8%), but rarely to monitor adherence (9.0%). TDM differed by economic status and infrastructural status with majority of the studies coming from Europe (53.8%) and upper-middle-income countries (87.6%). First generation ASMs (82.3%) were more likely to be monitored than second generation ASMs (17.6%) and carbamazepine was the most frequently monitored drug. Fluorescence Polarization Immunoassay (FPIA) was the most common technique used for TDM (41.5%) followed by High-Performance Liquid Chromatography (HPLC) (16.9%). In addition, FPIA was the cheapest method of TDM based on approximated costs ($1000, TDx system). Assay validation and quality control were reported variably, and reference ranges used during TDM of ASMs were relatively uniform. Conclusions: TDM is mostly done to evaluate ASM toxicity, but rarely for other reasons such as evaluating adherence or assessing clinical efficacy. There is a need for more investment in comprehensive and targeted TDM in LMICs when initiating treatment, switching therapies, adding or removing ASM and evaluating treatment response and safety of both first generation and second generation ASMs.


Ground-plane-less bidirectional terahertz absorber based on omega resonators.
We present a new ultrathin metamaterial that acts as a frequency-selective absorber of terahertz radiation. The absorber is a square array of pairs of omega-shaped micro-resonators made of high-ohmic-loss metal. The metamaterial provides significant suppression of transmitted and reflected radiation in a bidirectional regime (that is, for both forward and backward propagating radiation). The absorber is efficient in a wide range of angles of incidence. The absence of a ground plane makes the absorber unique in comparison with numerous analogs with a ground plane that operate in a unidirectional regime. The novel metamaterial potentially enables controllable transmission of terahertz radiation in imaging systems. Analytical calculations as well as finite-element electromagnetic modeling are presented for an exemplary case with peak absorption at ∼3 THz.


Testing the role of genetic background in parallel evolution using the comparative experimental evolution of antibiotic resistance.
Parallel evolution is the independent evolution of the same phenotype or genotype in response to the same selection pressure. There are examples of parallel molecular evolution across divergent genetic backgrounds, suggesting that genetic background may not play an important role in determining the outcome of adaptation. Here, we measure the influence of genetic background on phenotypic and molecular adaptation by combining experimental evolution with comparative analysis. We selected for resistance to the antibiotic rifampicin in eight strains of bacteria from the genus Pseudomonas using a short term selection experiment. Adaptation occurred by 47 mutations at conserved sites in rpoB, the target of rifampicin, and due to the high diversity of possible mutations the probability of within-strain parallel evolution was low. The probability of between-strain parallel evolution was only marginally lower, because different strains substituted similar rpoB mutations. In contrast, we found that more than 30% of the phenotypic variation in the growth rate of evolved clones was attributable to among-strain differences. Parallel molecular evolution across strains resulted in divergent phenotypic evolution because rpoB mutations had different effects on growth rate in different strains. This study shows that genetic divergence between strains constrains parallel phenotypic evolution, but had little detectable impact on the molecular basis of adaptation in this system.


Hypogonadism in chronic liver disease: impaired release of luteinising hormone.
Alcohol abuse leads to impotence, infertility, and feminisation. Patients with chronic alcoholism may have impaired hypothalamic-pituitary function. The release of luteinising hormone was investigated in men with alcoholic cirrhosis with and without hypogonadism and controls. Blood was sampled every 15 minutes for six or eight hours and luteinising hormone concentrations measured by radioimmunoassay. Data were analysed by iterative computerised analysis and spectral analysis to assess pulsatile release and the length of the cycle, respectively. Pulsatile release of luteinising hormone was shown in all the control subjects; in the men with alcoholic liver disease it was normal in those with subclinical primary testicular failure but absent or grossly attenuated in those with overt combined central and primary gonadal failure. The impaired release of luteinising hormone in the men with overt gonadal failure might be due to a hypothalamic defect.


The properties of intracellular calcium stores in cultured rat cerebellar neurons.
Cerebellar Purkinje neurons contain a remarkable array of cellular components potentially concerned with regulation of the free cytoplasmic Ca2+ concentration, [Ca2+]i. These include high concentrations of Ca(2+)-binding proteins, inositol 1,4,5-triphosphate receptors (IP3R), and ryanodine receptors (RyR). The latter two molecules are thought to be associated with intracellular Ca2+ stores. We have examined the properties of such stores in cultured rat cerebellar neurons taken from 16 d rat embryos. In this system, about half of the neurons could be identified as Purkinje-like cells, as indicated by staining for the Ca(2+)-binding protein calbindin D-28k, as well as for IP3R and RyR. In double immunofluorescent staining, the IP3R and RyR immunoreactivity primarily colocalized with the staining for calbindin. The cells responded to glutamate, kainate, and quisqualate with large increases in the somatic [Ca2+]i but failed to respond directly to NMDA (10-50 microM). Furthermore, the neurons expressed active membrane conductances, repetitive action potential firing, and spontaneous firing patterns similar to those reported for cerebellar Purkinje neurons in vivo. Action potential firing produced changes in somatic [Ca2+]i that were quite small or absent in most cells. However, blocking spike repolarization with tetraethylammonium (5 mM) produced substantial transient elevations in somatic [Ca2+]i, suggesting the expression of some Ca2+ channels in the somatic membrane. Caffeine (10 mM) released Ca2+ from intracellular stores in about one-half of the cultured neurons. This effect could be repeated if the stores were first reloaded by a depolarization-induced elevation in [Ca2+]i. The effects of caffeine were reduced by prolonged application of ryanodine (10 microM). We were also able to demonstrate that the caffeine-sensitive Ca2+ stores could regulate electrophysiological events in some cells, altering patterns of spontaneous activity. Furthermore, in the presence of caffeine, [Ca2+]i signals induced by an evoked spike train were larger and accompanied by long-lasting after hyperpolarizations. We conclude that in addition to providing a releasable pool of Ca2+, the caffeine-sensitive stores also influence cellular events by their contribution to Ca2+ buffering.


Dnmt3b ablation impairs fracture repair through upregulation of Notch pathway.
We previously established that DNA methyltransferase 3b (Dnmt3b) is the sole Dnmt responsive to fracture repair and that Dnmt3b expression is induced in progenitor cells during fracture repair. In the current study, we confirmed that Dnmt3b ablation in mesenchymal progenitor cells (MPCs) resulted in impaired endochondral ossification, delayed fracture repair, and reduced mechanical strength of the newly formed bone in Prx1-Cre;Dnmt3bf/f (Dnmt3bPrx1) mice. Mechanistically, deletion of Dnmt3b in MPCs led to reduced chondrogenic and osteogenic differentiation in vitro. We further identified Rbpjκ as a downstream target of Dnmt3b in MPCs. In fact, we located 2 Dnmt3b binding sites in the murine proximal Rbpjκ promoter and gene body and confirmed Dnmt3b interaction with the 2 binding sites by ChIP assays. Luciferase assays showed functional utilization of the Dnmt3b binding sites in murine C3H10T1/2 cells. Importantly, we showed that the MPC differentiation defect observed in Dnmt3b deficiency cells was due to the upregulation of Rbpjκ, evident by restored MPC differentiation upon Rbpjκ inhibition. Consistent with in vitro findings, Rbpjκ blockage via dual antiplatelet therapy reversed the differentiation defect and accelerated fracture repair in Dnmt3bPrx1 mice. Collectively, our data suggest that Dnmt3b suppresses Notch signaling during MPC differentiation and is necessary for normal fracture repair.


Glow discharge plasma deposition of tetraethylene glycol dimethyl ether for fouling-resistant biomaterial surfaces.
The glow discharge plasma deposition (GDPD) of tetraethylene glycol dimethyl ether is introduced as a novel method for obtaining surfaces that are resistant to protein adsorption and cellular attachment. Analysis of films by x-ray photoelectron spectroscopy and several biological assays indicate the formation of a fouling-resistant, PEO-like surface on several substrata (e.g., glass, polytetrafluoroethylene, polyethylene). Adsorption of 125I-radiolabelled proteins (fibrinogen, albumin and IgG) from buffer and plasma was very low (typically less than 20 ng/cm2) when compared to the untreated substrata, which exhibited much higher levels of protein adsorption. Not all coated substrata adsorbed equal amounts of protein (e.g., coated glass samples typically adsorbed more protein than coated polyethylene or coated polytetrafluoroethylene samples), suggesting that the substratum used may affect the amount of protein adsorbed. Measurement of dynamic platelet adhesion, using epifluorescent video microscopy, and endothelial cell attachment further demonstrates the short-term nonadhesiveness of these surfaces.


Effects of chronotropic incompetence and beta-blocker use on the exercise treadmill test in men.
Our purpose was to assess the diagnostic characteristics of the exercise test in patients who fail to reach conventional target heart rates and in patients on beta-blockers. Exercise test results are often considered "inadequate" or "nondiagnostic" in patients taking beta-blockers and in patients who do not achieve 85% of their age-predicted maximal heart rate. The results of exercise tests and coronary angiography performed to evaluate chest pain in 1282 male patients without a prior history of myocardial infarction, coronary revascularization, diagnostic Q wave on the baseline electrocardiogram, or previous cardiac catheterization were analyzed with respect to beta-blocker exposure and failure to reach 85% age-predicted maximal heart rate. Sensitivity, specificity, and predictive accuracy of exercise testing, as well as area under the curve for the receiver operating characteristic plots were calculated for these subgroups with use of coronary angiography as the reference. The angiographic criterion for significant coronary artery disease was 50% narrowing or greater in one or more major coronary arteries. The population was divided into 4 exclusive groups on the basis of whether they reached their target heart rates and whether they were receiving beta-blockers. Sixty to 40 percent of this clinical population failed to reach target heart rate, of which 24% (n = 303) were receiving beta-blockers and 40% (n = 518) were not. The group of patients who reached target heart rate and were not taking beta-blockers was taken as the reference group (n = 409). The group of patients supposedly beta-blocked but who reached the target heart rate (n = 52) had hemodynamic and test characteristics similar to those of the reference group and most likely were not taking their beta-blockers or were not adequately dosed. The prevalence of angiographic coronary disease was significantly higher in the 2 groups failing to reach target heart rate, both in the presence and absence of beta-blockers, compared with the reference group (68% and 64%, respectively, vs 49%, P <.01). Although the areas under the curve of the receiver operating characteristic curves for ST depression of the groups failing to reach target heart rate were not significantly different from the reference group, the predictive accuracy and sensitivity were significantly lower for 1 mm of ST depression in the beta-blocked group who did not reach target heart rate (predictive accuracy of 56% vs 67%, sensitivity of 44% vs 58%, P <.01). The only way to maintain sensitivity with the standard exercise test in the beta-blocker group who failed to reach target heart rate was to use a treadmill score or 0.5-mm ST depression as the criteria for abnormal. Sensitivity and predictive accuracy of standard ST criteria for exercise-induced ST depression are significantly decreased in male patients who are taking beta-blockers and do not reach target heart rate. In those who fail to reach target heart rate and are not beta-blocked, sensitivity and predictive accuracy are maintained.


Risk of invasive cancer of the cervix in relation to the use of injectable progestogen contraceptives and combined estrogen/progestogen oral contraceptives (South Africa).
Cervical cancer is caused by specific types of the human papilloma virus (HPV), but not all infected women develop cancer. It has been hypothesized that hormonal contraceptives may potentiate the oncogenicity of HPV infection. In a case-control study of colored and black women in the Western Cape Province, South Africa, 524 incident cases of clinically evident invasive cervical cancer (stages 1b-1V) were compared with 1541 controls, and with a subgroup of 254 HPV-positive controls. For injectable progestogen contraceptives (95% of which were depot medroxyprogesterone acetate) the overall relative risk, adjusted for confounding, was 1.0 (95% confidence interval 0.8-1.3); for combined estrogen/progestogen oral contraceptives the corresponding estimate was 0.8 (0.7-1.1). When the data were divided into categories of duration of use extending to > or = 15 years, or according to age, ethnic group, or recency of use, there was no consistent evidence of an increased risk. The findings were unchanged when the cases were compared with the HPV-positive controls. The present findings suggest that neither injectable progestogen-only nor combined estrogen/ progestogen oral contraceptives increase the risk of clinically evident invasive cancer of the cervix.


Development of a Community-Based Rehabilitation Intervention for People with Schizophrenia in Ethiopia.
Community-based rehabilitation (CBR) is a multi-sectoral strategy to improve the functioning and quality of life of people with disabilities. The RISE (Rehabilitation Intervention for people with Schizophrenia in Ethiopia) trial will evaluate the effectiveness of CBR for people with schizophrenia in Ethiopia. Nevertheless, the components of CBR that are both feasible and likely to prove effective in low and middle-income countries such as Ethiopia are unclear. In this study intervention development work was undertaken to design a CBR intervention that is acceptable and feasible in the local context. The development work consisted of five phases. 1: Identify potential components of CBR for schizophrenia, 2: Situational analysis, 3: Determine feasibility of CBR (Theory of Change workshops with experts and local stakeholders), 4: Determine acceptability of CBR (16 in-depth interviews and five focus group discussions with people with schizophrenia, caregivers, health workers and community leaders) and 5: Synthesise results to finalise intervention. A Theory of Change map was constructed showing the causal pathway for how we expect CBR to achieve its impact. People with schizophrenia in rural Ethiopia experience family conflict, difficulty participating in work and community life, and stigma. Stakeholders perceived CBR to be acceptable and useful to address these problems. The focus of CBR will be on the individual developing the skills and confidence to perform their previous or desired roles and activities. To ensure feasibility, non-health professionals will be trained to deliver CBR and provide supervision, rather than mental health specialists. Novel components of CBR for schizophrenia included family intervention and dealing with distressing symptoms. Microfinance was excluded due to concerns about stress and exploitation. Community mobilisation was viewed as essential to ensure the effectiveness and sustainability of CBR. Extensive formative research using a variety of methods has enabled the design of a culturally appropriate CBR intervention for people with schizophrenia that is acceptable and feasible.


Can overall results of clinical trials be applied to all patients?
It is generally assumed that the overall results of a clinical trial are generalisable to all patients in the trial and all similar future patients; in other words, that the relative treatment effect in individual patients is similar to the overall trial result. Although this assumption underpins the application of trial results to clinical practice, it has rarely been tested. By independently derived prognostic models, the results of the European Carotid Surgery Trial and the UK-TIA Aspirin Trial were reanalysed to find out whether relative treatment effect varied with absolute baseline risk of stroke. There was significant heterogeneity of relative treatment effect in both trials, resulting in substantial variation in absolute treatment effect with predicted baseline risk. Although, on average, the application of overall trial results to all patients will do more good than harm, a knowledge of the association between relative treatment effect and absolute baseline risk will increase the cost-effectiveness of healthcare interventions by identifying those patients in whom treatment is ineffective and those patients who are most likely to benefit.


Profiling of the Causative Bacteria in Infected Lymphocysts after Lymphadenectomy for Gynecologic Cancer by Pyrosequencing the 16S Ribosomal RNA Gene Using Next-Generation Sequencing Technology.
Surgery for gynecologic cancer with lymphadenectomy and pelvic radiotherapy can produce lymphoceles that sometimes complicate with infection, resulting in abscesses. The true pathogenic bacteria of abscesses are not always found because of false-negative results due to administered antibiotics and difficulty with detection, including for anaerobic bacteria. Analyzing bacteria flora by next-generation sequencing (NGS) using 16S ribosomal DNA may reveal the true pathogenic bacteria in abscesses. This is the first report on causative pathogens for infectious lymphocele using this technology. The subjects were patients who developed infectious lymphocele after surgery for gynecologic cancer at our hospital from July 2015 to September 2016. NGS analyses of bacterial flora were performed using specimens preserved at -80°C. Two steps of PCR were performed for purified DNA samples to obtain sequence libraries. Processing of sequence data, including operational taxonomic unit (OTU) definition, taxonomy assignment, and an OTU BLAST search were performed. All patients gave written informed consent and the study was approved by the institutional research ethics committee. Six patients underwent puncture and drainage. The result in most cases indicated a single causative pathogen, including Staphylococcus lugdunensis, Streptococcus dysgalactiae, Streptococcus equinus, Enterococcus saccharolyticus, and Escherichia coli. Conclusions. NGS revealed that the causative bacteria in lymphocele infection are normally a single strain, such as a surface Gram-positive coccus or enteric bacteria. Antibiotics should be chosen as appropriate for elimination of these respective bacteria.


Body Composition and Perceived Stress through a Calendar Year in NCAA I Female Volleyball Players.
The aim of the study was to track changes of perceived stress and body composition across an entire calendar year in National Collegiate Athletic Association (NCAA) division I female volleyball players. We hypothesized that perceived stress and body composition would vary between the competitive season and off-season, with the largest changes occurring during time points prior to the onset and after the end of the competitive season. Eight female volleyball players participated in a longitudinal study. Body mass, body mass index (BMI), percent body fat, fat mass, and fat free mass were obtained during the early, mid, late, and off season and during the pre, early, mid, and late competitive season. The perceived stress scale-10 was used to appraise stress levels. BMI and body mass were significantly higher in pre-season compared to early-offseason. Changes in BMI between these points were due to increase in fat mass. Fat mass and percent body fat were significantly higher in pre-season compared to late off-season, mid-season, and late season. Perceived stress was significantly higher at the mid-season compared to early offseason. A significant positive correlation existed between BMI and body fat (p<0.05, r=0.69), while a significant negative correlation existed between percent body fat and perceived stress (p<0.05, r=0.34). Tracking body composition and perceived stress in collegiate female volleyball players can provide informative feedback on the training status and well-being of female collegiate athletes. Interestingly, it appears stress in these athletes may be more dependent upon the school session rather than participation in competitive sports.


Mono-functional aminosilanes as primers for peptide functionalization.
When covalently attaching biomolecules to surfaces such as titanium, trifunctional silanes are commonly used as primers to produce surface amine groups. However, these primed surfaces are rarely uniform in structure due to networking of the silane. Mono-functional aminosilanes may result in more uniform structures, although their long-term stability and effect on osteoblast cell responses are possible issues for orthopedic applications. This study examines for the first time the optimization of peptide coupling to titanium using mono-functional aminosilane reaction chemistry. The resultant surface topography, chemistry, and thicknesses were characterized showing improved surface uniformity compared with trifunctional silanized surfaces. The stability of the coatings was examined over a period of 8 days in environments of varying pH, temperature, and humidity. In addition, human osteosarcoma (HOS) cell adhesion and spreading on the samples was examined; adhesion was minimal on silanized surfaces, but after functionalization with cysteine the cell density was greater than the titanium control and showed no overall detrimental effect on initial cell responses.


Essentiality of boron for healthy bones and joints.
Since 1963, evidence has accumulated that suggests boron is a safe and effective treatment for some forms of arthritis. The initial evidence was that boron supplementation alleviated arthritic pain and discomfort of the author. This was followed by findings from numerous other observations epidemiologic and controlled animal and human experiments. These findings included a) analytical evidence of lower boron concentrations in femur heads, bones, and synovial fluid from people with arthritis than from those without this disorder; b) observation evidence that bones of patients using boron supplements are much harder to cut than those of patients not using supplements; c) epidemiologic evidence that in areas of the world where boron intakes usually are 1.0 mg or less/day the estimated incidence of arthritis ranges from 20 to 70%, whereas in areas of the world where boron intakes are usually 3 to 10 mg, the estimated incidence of arthritis ranges from 0 to 10%; d) experimental evidence that rats with induced arthritis benefit from orally or intraperitoneally administered boron; e) experimental evidence from a double-blind placebo-boron supplementation trial with 20 subjects with osteoarthritis. A significant favorable response to a 6 mg boron/day supplement was obtained; 50% of subjects receiving the supplement improved compared to only 10% receiving the placebo. The preceding data indicate that boron is an essential nutrient for healthy bones and joints, and that further research into the use of boron for the treatment or prevention of arthritis is warranted.


Observing learned object-specific functional grasps preferentially activates the ventral stream.
In one popular account of the human visual system, two streams are distinguished, a ventral stream specialized for perception and a dorsal stream specialized for action. The skillful use of familiar tools, however, is likely to involve the cooperation of both streams. Using functional magnetic resonance imaging, we scanned individuals while they viewed short movies of familiar tools being grasped in ways that were either consistent or inconsistent with how tools are typically grasped during use. Typical-for-use actions were predicted to preferentially activate parietal areas important for tool use. Instead, our results revealed several areas within the ventral stream, as well as the left posterior middle temporal gyrus, as preferentially active for our typical-for-use actions. We believe these findings reflect sensitivity to learned semantic associations and suggest a special role for these areas in representing object-specific actions. We hypothesize that during actual tool use a complex interplay between the two streams must take place, with ventral stream areas providing critical input as to how an object should be engaged in accordance with stored semantic knowledge.


PCNA monoubiquitylation and DNA polymerase eta ubiquitin-binding domain are required to prevent 8-oxoguanine-induced mutagenesis in Saccharomyces cerevisiae.
7,8-Dihydro-8-oxoguanine (8-oxoG) is an abundant and mutagenic DNA lesion. In Saccharomyces cerevisiae, the 8-oxoG DNA N-glycosylase (Ogg1) acts as the primary defense against 8-oxoG. Here, we present evidence for cooperation between Rad18-Rad6-dependent monoubiquitylation of PCNA at K164, the damage-tolerant DNA polymerase eta and the mismatch repair system (MMR) to prevent 8-oxoG-induced mutagenesis. Preventing PCNA modification at lysine 164 (pol30-K164R) results in a dramatic increase in GC to TA mutations due to endogenous 8-oxoG in Ogg1-deficient cells. In contrast, deletion of RAD5 or SIZ1 has little effect implying that the modification of PCNA relevant for preventing 8-oxoG-induced mutagenesis is monoubiquitin as opposed to polyubiquitin or SUMO. We also report that the ubiquitin-binding domain (UBZ) of Pol eta is essential to prevent 8-oxoG-induced mutagenesis but only in conjunction with a functional PCNA-binding domain (PIP). We propose that PCNA is ubiquitylated during the repair synthesis reaction after the MMR-dependent excision of adenine incorporated opposite to 8-oxoG. Monoubiquitylation of PCNA would favor the recruitment of Pol eta thereby allowing error-free incorporation of dCMP opposite to 8-oxoG. This study suggests that Pol eta and the post-replication repair (PRR) machinery can also prevent mutagenesis at DNA lesions that do not stall replication forks.


Effectiveness and safety of bevacizumab for unresectable non-small-cell lung cancer: a meta-analysis.
Non-small-cell lung cancer (NSCLC) accounts for more than 85% of all cases of lung cancer. The 5-year survival of patients presenting with advanced stage NSCLC is less than 15%, indicating that additional treatment options are needed. Bevacizumab is a recombinant humanized version of the murine anti-human vascular endothelial growth factor (VEGF) monoclonal antibody with a high binding specificity for VEGF. The aim of this meta-analysis was to evaluate the effectiveness and safety of bevacizumab in patients with unresectable non-small-cell lung cancer (NSCLC) on the basis of evidence-based methodology. The electronic database PubMed was searched to identify randomized, controlled trials (RCTs) of bevacizumab for the treatment of unresectable NSCLC. Other databases such as the Cochrane Library Trials Register, the WHO Trial Registration, the National Cancer Institute, ClinicalTrials.gov, the European Organization for Research and Treatment of Cancer, the Southwest Oncology Group, the Eastern Cooperative Oncology Group, the European Society of Clinical Oncology and the American Society of Clinical Oncology were also searched. The meta-analysis was performed using Reviewer Manager Version 5.0 software provided by the Cochrane Collaboration. Outcome measures were overall survival rates, progression-free survival, tumour response rate, incidence of severe adverse events (SAEs) and treatment-related death. Four eligible studies that included 2101 patients were found; in these studies, bevacizumab was administered to 1237 patients. Neither high-dose (15 mg/kg) nor low-dose (7.5 mg/kg) bevacizumab increased 1-year overall survival rates compared with patients not treated with bevacizumab. However, high-dose bevacizumab, rather than low-dose, increased 2-year overall survival rate (risk ratio [RR] = 1.24; 95% confidence interval [CI] 1.04, 1.49) and tumour response rate (RR = 1.69; 95% CI 1.21, 2.35) compared with patients not treated with bevacizumab. Progression-free survival was also significantly improved in both the low- (hazard ratio [HR] = 0.76; 95% CI 0.64, 0.90) and high-dose groups (HR = 0.73; 95% CI 0.65, 0.81). There was a clear and significant increase in the rate of treatment-related death in the high-dose group (RR = 2.07; 95% CI 1.19, 3.59) compared with patients not treated with bevacizumab. No significant differences were noted in the rate of treatment-related death in the low-dose group or in the incidences of SAE in the low- or high-dose groups compared with patients not treated with bevacizumab. Neutropenia was easily induced in both the low- and high-dose bevacizumab groups. Patients who received high-dose bevacizumab tended to experience hypertension, neutropenia, haemoptysis, rash and headache more frequently than patients not treated with bevacizumab. Low-dose bevacizumab may significantly improve progression-free survival in patients with unresectable NSCLC, whereas high-dose bevacizumab may increase 2-year overall survival rates, prolong progression-free survival and improve tumour response rate but at the cost of higher treatment-related death. Larger well designed RCTs should be carried out in the future to clarify the role of bevacizumab in the treatment of NSCLC.


Detection of Alzheimer's disease amyloid-beta plaque deposition by deep brain impedance profiling.
Alzheimer disease (AD) is the most common form of neurodegenerative disease in elderly people. Toxic brain amyloid-beta (Aß) aggregates and ensuing cell death are believed to play a central role in the pathogenesis of the disease. In this study, we investigated if we could monitor the presence of these aggregates by performing in situ electrical impedance spectroscopy measurements in AD model mice brains. In this study, electrical impedance spectroscopy measurements were performed post-mortem in APPPS1 transgenic mice brains. This transgenic model is commonly used to study amyloidogenesis, a pathological hallmark of AD. We used flexible probes with embedded micrometric electrodes array to demonstrate the feasibility of detecting senile plaques composed of Aß peptides by localized impedance measurements. We particularly focused on deep brain structures, such as the hippocampus. Ex vivo experiments using brains from young and old APPPS1 mice lead us to show that impedance measurements clearly correlate with the percentage of Aβ plaque load in the brain tissues. We could monitor the effects of aging in the AD APPPS1 mice model. We demonstrated that a localized electrical impedance measurement constitutes a valuable technique to monitor the presence of Aβ-plaques, which is complementary with existing imaging techniques. This method does not require prior Aβ staining, precluding the risk of variations in tissue uptake of dyes or tracers, and consequently ensuring reproducible data collection.


Amplification of MDS1/EVI1 and EVI1, located in the 3q26.2 amplicon, is associated with favorable patient prognosis in ovarian cancer.
Increased copy number involving chromosome 3q26 is a frequent and early event in cancers of the ovary, lung, head and neck, cervix, and BRCA1 positive and basal breast cancers. The p110alpha catalytic subunit of phosphoinositide-3-kinase (PI3KCA) and protein kinase Ciota (PKCiota) have previously been shown as functionally deregulated by 3q copy number increase. High-resolution array comparative genomic hybridization of 235 high-grade serous epithelial ovarian cancers using contiguous bacterial artificial chromosomes across 3q26 delineated an approximately 2 Mb-wide region at 3q26.2 encompassing PDCD10 to MYNN (chr3:168722613-170908630). Ecotropic viral integration site-1 (EVI1) and myelodysplastic syndrome 1 (MDS1) are located at the center of this region, and their DNA copy number increases are associated with at least 5-fold increased RNA transcript levels in 83% and 98% of advanced ovarian cancers, respectively. Moreover, MDS1/EVI1 and EVI1 protein levels are increased in ovarian cancers and cancer cell lines. EVI1 and MDS1/EVI1 gene products increased cell proliferation, migration, and decreased transforming growth factor-beta-mediated plasminogen activator inhibitor-1 promoter activity in ovarian epithelial cells. Intriguingly, the increases in EVI1 DNA copy number and MDS1/EVI1 transcripts are associated with improved patient outcomes, whereas EVI1 transcript levels are associated with a poor patient survival. Thus, the favorable patient prognosis associated with increased DNA copy number seems to be as a result of high-level expression of the fusion transcript MDS1/EVI1. Collectively, these studies suggest that MDS1/EVI1 and EVI1, previously implicated in acute myelogenous leukemia, contribute to the pathophysiology of epithelial ovarian cancer.


Computer-assisted analysis of heterogeneity on B-mode imaging predicts instability of asymptomatic carotid plaque.
Computerized assessment of plaque echogenicity by B-mode ultrasonography has demonstrated that the gray-scale median (GSM) pixel intensity of the entire plaque predicts future ischemic stroke in patients with symptomatic carotid stenosis, but not those with asymptomatic stenosis. This study investigated whether plaque heterogeneity (i.e., the distribution of pixel intensities) could predict the instability of asymptomatic plaque. By comparison with carotid endarterectomy specimens and the GSM values of known tissues on B-mode images, the GSM values for blood, lipid, muscle/fibrous tissue, and calcification were determined. Then we estimated the percent area of each tissue component for 297 asymptomatic plaques causing 40-99% carotid artery stenosis in 250 patients, and monitored the incidence of atherothrombotic cerebral infarction due to carotid stenosis during follow-up. Eight infarcts occurred during a follow-up period of 22 +/- 15 months. Plaques in the top tertile for the percent area of lipid-like echogenicity (p < 0.05) and in the lowest tertile for calcification (p = 0.06) showed an association with future infarction according to Kaplan-Meier analysis. This association remained significant after adjustment for the severity of carotid stenosis (hazard ratio 4.4 for lipid-like and 0.24 for calcification-like component, both p < 0.05) according to Cox proportional hazards analysis. The distribution of pixel intensities in carotid plaque on B-mode ultrasonography can be employed to predict instability of asymptomatic plaque and possibly to select patients for interventional procedures. A large-scale investigation will be needed to confirm that estimating the percentage of plaque components relative to the total plaque area can predict ischemic stroke.


Prebiotic effects of resistant starch from purple yam (Dioscorea alata L.) on the tolerance and proliferation ability of Bifidobacterium adolescentis in vitro.
The in vitro prebiotic effects of resistant starch (RS), prepared by different treatments from purple yam, on Bifidobacterium adolescentis (bifidobacteria for short), were investigated. Tolerance tests indicated that bifidobacteria in PDS (prepared by debranching combined with autoclaving) and PDS.H (PDS further treated by double enzyme hydrolysis) media adapted better to simulated upper gastrointestinal conditions (at pH 1.5-3.0 and 0.3% and 1.0% bile acid) than those in GLU (glucose) and DAS (prepared by autoclaving) media. PDS.H, which had the highest digestion resistibility, exhibited significant effects on the OD600 nm value (1.544) and the pH value (4.21) when the carbohydrate concentration was 20 g L-1. Additionally, the exponential growth phase of bifidobacteria was 2 h in the PDS or PDS.H media, whereas it was 4 h in the GLU or DAS media. A higher content of short-chain fatty acids (SCFAs) was obtained in the PDS.H medium. Analysis of the structural features of RS and fermented RS indicated that PDS, especially PDS.H, had a rougher surface and higher crystallinity than DAS. Fermented RS in a simulated large bowel environment showed an eroded surface and decreased crystallinity. All of these findings suggest that RS with a rough surface and perfect crystalline structure could protect bifidobacteria from gastrointestinal conditions and enhance the proliferation of bifidobacteria.


Relationship between baseline brain metabolism measured using [¹⁸F]FDG PET and memory and executive function in prodromal and early Alzheimer's disease.
Differences in brain metabolism as measured by FDG-PET in prodromal and early Alzheimer's disease (AD) have been consistently observed, with a characteristic parietotemporal hypometabolic pattern. However, exploration of brain metabolic correlates of more nuanced measures of cognitive function has been rare, particularly in larger samples. We analyzed the relationship between resting brain metabolism and memory and executive functioning within diagnostic group on a voxel-wise basis in 86 people with AD, 185 people with mild cognitive impairment (MCI), and 86 healthy controls (HC) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We found positive associations within AD and MCI but not in HC. For MCI and AD, impaired executive functioning was associated with reduced parietotemporal metabolism, suggesting a pattern consistent with known AD-related hypometabolism. These associations suggest that decreased metabolic activity in the parietal and temporal lobes may underlie the executive function deficits in AD and MCI. For memory, hypometabolism in similar regions of the parietal and temporal lobes were significantly associated with reduced performance in the MCI group. However, for the AD group, memory performance was significantly associated with metabolism in frontal and orbitofrontal areas, suggesting the possibility of compensatory metabolic activity in these areas. Overall, the associations between brain metabolism and cognition in this study suggest the importance of parietal and temporal lobar regions in memory and executive function in the early stages of disease and an increased importance of frontal regions for memory with increasing impairment.


Energy and nutrient intakes of young children in the UK: findings from the Gemini twin cohort.
Data on the diets of young children in the UK are limited, despite growing evidence of the importance of early diet for long-term health. We used the largest contemporary dietary data set to describe the intake of 21-month-old children in the UK. Parents of 2336 children aged 21 months from the UK Gemini twin cohort completed 3-d diet diaries in 2008/2009. Family background information was obtained from questionnaires completed 8 months after birth. Mean total daily intakes of energy, macronutrients (g and %E) and micronutrients from food and beverages, including and excluding supplements, were derived. Comparisons with UK dietary reference values (DRV) were made using t tests and general linear regression models, respectively. Daily energy intake (kJ), protein (g) and most micronutrients exceeded DRV, except for vitamin D and Fe, where 96 or 84 % and 70 or 6 % of children did not achieve the reference nutrient intake or lower reference nutrient intake (LRNI), respectively, even with supplementation. These findings reflect similar observations in the smaller sample of children aged 18-36 months in the National Diet and Nutrition Survey. At a population level, young children in the UK are exceeding recommended daily intakes of energy and protein, potentially increasing their risk of obesity. The majority of children are not meeting the LRNI for vitamin D, largely reflecting inadequate use of the supplements recommended at this age. Parents may need more guidance on how to achieve healthy energy and nutrient intakes for young children.


Victim service and justice system representative responses about partner stalking: what do professionals recommend?
Research suggests that partner stalking is associated with reassault and lethality as well as increased psychological distress for victims. However, there is a significant gap in information about stalking interventions and the responses of health, mental health, law enforcement, social services, and criminal justice professionals to women experiencing partner stalking. The purpose of this study is to examine the ideas about appropriate and effective responses to stalking victims from professionals in victim services and the justice system. The study also examined differences among rural and urban representatives because prior studies have shown significant differences between rural and urban areas on experiences and responses to partner violence. A total of 152 key informants (38 urban and 114 rural) were interviewed. Study results suggest a need for more training for victim services and justice system professionals on stalking and service needs of women who experience stalking in the context of partner violence.


The effect of income question design in health surveys on family income, poverty and eligibility estimates.
To compare systematic differences between an "omnibus" income measure that asks for total family income amounts with a central survey item and an aggregated income measure that sums specific amounts of income obtained from multiple income sources from everyone within a family. The 2001 Current Population Survey-Demographic Supplement (CPS-DS). Data were collected from 78,000 households from February through April 2001. First, we compare the omnibus family income to the aggregated family income amounts for each family. Second, we use the various aggregated family income sources to predict whether there is a mismatch between the omnibus and aggregated family income amounts. Finally, we assign a new aggregated amount of income that is restricted to be within the range of the omnibus amount to observe differences in poverty rates. Data were extracted from University of Michigan's ICPSR website. There is a great deal of variation between the omnibus family income measure and the aggregated family income measure, with the omnibus amount generally being lower than the aggregated. As a result, the percent of people estimated to be in poverty is higher using the omnibus income item. Health surveys generally rely on an omnibus income measure and analysts should be aware that the income estimates derived from it are limited with respect to poverty determination, and the related concept of eligibility estimation. Analysts of health surveys should also consider matching respondents or multiple imputation to improve the usability of the data.


Involuntary smoking and head and neck cancer risk: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium.
Although active tobacco smoking has been identified as a major risk factor for head and neck cancer, involuntary smoking has not been adequately evaluated because of the relatively low statistical power in previous studies. We took advantage of data pooled in the International Head and Neck Cancer Epidemiology Consortium to evaluate the role of involuntary smoking in head and neck carcinogenesis. Involuntary smoking exposure data were pooled across six case-control studies in Central Europe, Latin America, and the United States. Adjusted odds ratios (OR) and 95% confidence interval (95% CI) were estimated for 542 cases and 2,197 controls who reported never using tobacco, and the heterogeneity among the study-specific ORs was assessed. In addition, stratified analyses were done by subsite. No effect of ever involuntary smoking exposure either at home or at work was observed for head and neck cancer overall. However, long duration of involuntary smoking exposure at home and at work was associated with an increased risk (OR for >15 years at home, 1.60; 95% CI, 1.12-2.28; P(trend) < 0.01; OR for >15 years at work, 1.55; 95% CI, 1.04-2.30; P(trend) = 0.13). The effect of duration of involuntary smoking exposure at home was stronger for pharyngeal and laryngeal cancers than for other subsites. An association between involuntary smoking exposure and the risk of head and neck cancer, particularly pharyngeal and laryngeal cancers, was observed for long duration of exposure. These results are consistent with those for active smoking and suggest that elimination of involuntary smoking exposure might reduce head and neck cancer risk among never smokers.


Increased chemiluminescence of polymorphonuclear leucocytes from patients with progressive systemic sclerosis.
Chemiluminescence (CL) of whole blood and isolated polymorphonuclear leucocytes (PMN) from patients with systemic sclerosis (SS) and from age and sex matched controls was measured. CL was induced by the addition of particles (zymosan, latex beads), or phorbol myristate acetate (PMA) or chemotactic peptide (FMLP). Whole blood CL (induced by PMA, zymosan or latex particles) was significantly greater in SS patients than in normal controls. Isolated PMN CL (induced by PMA, FMLP or latex particles) was also significantly greater in the SS patients compared with controls. Increased CL or PMN from patients with SS was mainly observed when luminol was used as amplifier (which detects hydrogen peroxide formation). In most cases, lucigenin-amplified CL of PMN from patients with SS (which detects the primary superoxide anion radical formation) did not differ from the controls. Sera from patients with SS significantly increased both spontaneous and induced CL of normal PMN. Enhanced excitability of PMN to phagocytosis-related stimuli may provide a mechanism for the (leucocyte-mediated) endothelial injury in SS.


Assessing the origin of high-grade serous ovarian cancer using CRISPR-modification of mouse organoids.
High-grade serous ovarian cancer (HG-SOC)-often referred to as a "silent killer"-is the most lethal gynecological malignancy. The fallopian tube (murine oviduct) and ovarian surface epithelium (OSE) are considered the main candidate tissues of origin of this cancer. However, the relative contribution of each tissue to HG-SOC is not yet clear. Here, we establish organoid-based tumor progression models of HG-SOC from murine oviductal and OSE tissues. We use CRISPR-Cas9 genome editing to introduce mutations into genes commonly found mutated in HG-SOC, such as Trp53, Brca1, Nf1 and Pten. Our results support the dual origin hypothesis of HG-SOC, as we demonstrate that both epithelia can give rise to ovarian tumors with high-grade pathology. However, the mutated oviductal organoids expand much faster in vitro and more readily form malignant tumors upon transplantation. Furthermore, in vitro drug testing reveals distinct lineage-dependent sensitivities to the common drugs used to treat HG-SOC in patients.


Diphtheria toxin-epidermal growth factor fusion protein DAB389EGF for the treatment of bladder cancer.
The novel fusion protein, DAB(389)EGF, is composed of both the catalytic and the translocation domains of diphtheria toxin that are fused to the human EGF, providing a targeting and a toxicity component. We tested DAB(389)EGF for antitumor activity in both in vitro and in vivo urinary bladder cancer models. Human bladder cancer lines were treated with DAB(389)EGF and assessed for growth inhibition and clonogenic suppression. Using 6- to 8-week-old female athymic nude mice implanted orthotopically with HTB9 cells, DAB(389)EGF was administered intravesically twice weekly for 2 weeks. The response of the luciferase-expressing HTB9 cells was monitored via bioluminescence as the primary endpoint. Treatment response with DAB(389)EGF was specific and robust, with an IC(50) ranging from 0.5 to 15 ng/mL in eight tested bladder cancer cell lines, but greater than 50 ng/mL in the EGF receptor (EGFR)-negative H520 control cell line. Simulating short-duration intravesical therapy used clinically, a 2-hour treatment exposure of DAB(389)EGF (10 ng/mL) produced clonogenic suppression in three selected bladder cancer cell lines. In vivo, luciferase activity was suppressed in five of six mice treated with DAB(389)EGF [70 μL (1 ng/μL) per mouse], as compared with only one of six mice treated with a control diphtheria toxin (DT) fusion protein. Histologic assessment of tumor clearance correlated with the bioluminescent changes observed with DAB(389)EGF treatment. Immunocompetent mice treated with intravesical DAB(389)EGF did not show any nonspecific systemic toxicity. The intravesical delivery of targeted toxin fusion proteins is a novel treatment approach for non-muscle-invasive urinary bladder cancer. With appropriate targeting, the treatments are effective and well-tolerated in vivo.


Broadband Tm-doped superfluorescent fiber source with 11 W single-ended output power.
High-power operation of a cladding-pumped Tm-doped broadband superfluorescent fiber source in the two-micron wavelength regime is described. Predominately single-ended operation was achieved using a simple all-fiber geometry without the use of a high reflectivity mirror or fiber Bragg gratings. The source produced >11 W of single-ended amplified spontaneous emission output spanning the wavelength range from approximately 1930 nm to 1988 nm for a launched diode pump power of approximately 40 W at approximately 790 nm, corresponding to a slope efficiency of 38% with respect to launched pump power. The wavelength spectrum of the superfluorescent source spanned the range from approximately 1650 to 2100 nm with a bandwidth (FWHM) of > 100 nm for output power levels of < 20 mW.


Sex specificity of kidney markers to assess prognosis in cirrhotic patients with TIPS.
Renal function assessed by creatinine is a key prognostic factor in cirrhotic patients. However, creatinine is influenced by several factors, rendering interpretation difficult in some situations. This is especially important in early stages of renal dysfunction where renal impairment might not be accompanied by an increase in creatinine. Other parameters, such as cystatin C (CysC) and beta-trace protein (BTP), have been evaluated to fill this gap. However, none of these studies have considered the role of the patient's sex. The present study analysed CysC and BTP to evaluate their prognostic value and differentiate them according to sex. CysC and BTP were measured in 173 transjugular intrahepatic portosystemic shunt (TIPS)-patients from the NEPTUN-STUDY(NCT03628807) and analysed their relationship with mortality and sex. Propensity score for age, MELD, etiology and TIPS indication was used. Cystatin C and BTP showed excellent correlations with creatinine values at baseline and follow-up. CysC was an independent predictor of overall mortality (HR = 1.66(1.33-2.06)) with an AUC of 0.75 and identified a cut-off of 1.55 mg/L in the whole cohort. Interestingly, CysC was significantly lower in females, also after propensity score matching. In males, the only independent predictor was the creatinine level (HR = 1.54(1.25-1.58)), while in females CysC levels independently predicted mortality (HR = 3.17(1.34-7.52)). This study demonstrates for the first time that in TIPS-patients creatinine predicts mortality in males better than in females, whereas CysC is a better predictor of mortality in females. These results may influence future clinical decisions on therapeutic options for example, allocation for liver transplantation in TIPS-patients.


Lingering effects of contraception management on feral mare (Equus caballus) fertility and social behavior.
Due to the extirpation of their natural predators, feral horse populations have expanded across the United States, necessitating their management. Contraception of females (mares) with porcine zona pellucida (PZP) is a popular option; however, effects to physiology and behavior can be substantial. On Shackleford Banks, North Carolina, USA, treated mares have exhibited cycling during the non-breeding season and demonstrated decreased fidelity to the band stallion, but PZP's long-term effects on mare physiology and behavior remain largely unexplored. After the contraception program was suspended in this population, we examined how prior exposure to varying levels of PZP treatment impacted (1) foaling probability and foaling dates (a proxy for ovulatory cycling) from 2009 to 2014 and (2) mare fidelity to the band stallion and reproductive behavior during 2013 and 2015. Additionally, we evaluated the effects of time since the mares' last treatment on these factors. Mares receiving any level of prior PZP treatment were less likely to foal than were untreated mares. Among mares that received 1-3 PZP applications, foaling probability increased with time since last treatment before declining, at ~6 years post-treatment. Mares that received 4+ applications did not exhibit a significant increase in foaling probability with time since last treatment. Moreover, previously treated mares continued to conceive later than did untreated mares. Finally, mares previously receiving 4+ treatments changed groups more often than did untreated mares, though reproductive behavior did not differ with contraception history. Our results suggest that although PZP-induced subfertility and its associated behavioral effects can persist after the cessation of treatment, these effects can be ameliorated for some factors with less intense treatment. Careful consideration to the frequency of PZP treatment is important to maintaining more naturally functioning populations; the ability to manage populations adaptively may be compromised if females are kept subfertile for extended periods of time.


The utility of a drainage needle for percutaneous abscess drainage.
In this article, I describe a percutaneous drainage needle that consists of six side holes in its cannula. The needle is specially designed for effective evacuation of complex abscess collections consisting of internal solid components, including floating debris, that tend to block the needle aperture during aspiration. The characteristic features of the needle and its performance in both in vitro and in vivo environments are described. An in vitro experiment was performed with the use of a model of a fluid collection containing floating sheets of gelatin sponge to mimic a complex body collection consisting of floating fibrinous strands. Five radiologists were asked to perform aspiration from two collections of normal saline and 5% methylcellulose of two different volumes using an ordinary aspiration needle and the drainage needle. The needle was evaluated in a prospective in vivo study of 30 postoperative abdominal collections in 29 consecutive patients that were drained by a single radiologist. Complete evacuation was attempted initially with a conventional aspiration needle. When there was sonographic evidence of residual fluid collection, a repeat aspiration using a drainage needle was performed during the same session. In the in vitro experiment, the median percentage of fluid aspirated with the conventional needle from the 10- and 15-mL collections of saline was 10% and 15% and from the 10 mL and 15 mL of methylcellulose solution was 20% and 26.67%, respectively, whereas the drainage needle was able to remove 100% of fluid in all attempts. In the in vivo study, the conventional needle was able to remove all drainable fluid from the 12 simple collections. For the 18 complex collections, the drainage needle was always able to remove some residual fluid from the collection after aspiration with the conventional needle. The median percentage of fluid volume aspirated with the conventional needle was 55.6%, whereas that aspirated with both the conventional and drainage needles was 95.5%, with a significant difference by Wilcoxon's signed rank test (p < 0.001). This drainage needle was effective in evacuating fluid from complex abdominal collections that could not be drained with conventional end-hole needles.


Auxin signal transduction.
The plant hormone auxin (indole-3-acetic acid, IAA) controls growth and developmental responses throughout the life of a plant. A combination of molecular, genetic and biochemical approaches has identified several key components involved in auxin signal transduction. Rapid auxin responses in the nucleus include transcriptional activation of auxin-regulated genes and degradation of transcriptional repressor proteins. The nuclear auxin receptor is an integral component of the protein degradation machinery. Although auxin signalling in the nucleus appears to be short and simple, recent studies indicate that there is a high degree of diversity and complexity, largely due to the existence of multigene families for each of the major molecular components. Current studies are attempting to identify interacting partners among these families, and to define the molecular mechanisms involved in the interactions. Future goals are to determine the levels of regulation of the key components of the transcriptional complex, to identify higher-order complexes and to integrate this pathway with other auxin signal transduction pathways, such as the pathway that is activated by auxin binding to a different receptor at the outer surface of the plasma membrane. In this case, auxin binding triggers a signal cascade that affects a number of rapid cytoplasmic responses. Details of this pathway are currently under investigation.


Assessment of the healing process in distal radius fractures by high resolution peripheral quantitative computed tomography.
In clinical practice, fracture healing is evaluated by clinical judgment in combination with conventional radiography. Due to limited resolution, radiographs don't provide detailed information regarding the bone micro-architecture and bone strength. Recently, assessment of in vivo bone density, architectural and mechanical properties at the microscale became possible using high resolution peripheral quantitative computed tomography (HR-pQCT) in combination with micro finite element analysis (μFEA). So far, such techniques have been used mainly to study intact bone. The aim of this study was to explore whether these techniques can also be used to assess changes in bone density, micro-architecture and bone stiffness during fracture healing. Therefore, the fracture region in eighteen women, aged 50 years or older with a stable distal radius fracture, was scanned using HR-pQCT at 1-2 (baseline), 3-4, 6-8 and 12weeks post-fracture. At 1-2 and 12 weeks post-fracture the distal radius at the contra-lateral side was also scanned as control. Standard bone density, micro-architectural and geometric parameters were calculated and bone stiffness in compression, torsion and bending was assessed using μFEA. A linear mixed effect model with time post-fracture as fixed effect was used to detect significant (p-value ≤0.05) changes from baseline. Wrist pain and function were scored using the patient-rated wrist evaluation (PRWE) questionnaire. Correlations between the bone parameters and the PRWE score were calculated by Spearman's correlation coefficient. At the fracture site, total and trabecular bone density increased by 11% and 20%, respectively, at 6-8 weeks, whereas cortical density was decreased by 4%. Trabecular thickness increased by 23-31% at 6-8 and 12 weeks and the intertrabecular area became blurred, indicating intertrabecular bone formation. Compared to baseline, calculated bone stiffness in compression, torsion and bending was increased by 31% after 12 weeks. A moderate negative correlation was found between the stiffness and the PRWE score. No changes were observed at the contra-lateral side. The results demonstrate that it is feasible to assess clinically relevant and significant longitudinal changes in bone density, micro-architecture and mechanical properties at the fracture region during the healing process of stable distal radius fractures using HR-pQCT.


Non-genomic actions of estrogens and their interaction with genomic actions in the brain.
Ligands for the nuclear receptor superfamily have at least two mechanisms of action: (a) classical transcriptional regulation of target genes (genomic mechanisms); and (b) non-genomic actions, which are initiated at the cell membrane, which could also impact transcription. Though transcriptional mechanisms are increasingly well understood, membrane-initiated actions of these ligands are incompletely understood. This has led to considerable debate over the physiological relevance of membrane-initiated actions of hormones versus genomic actions of hormones, with genomic actions predominating in the endocrine field. There is good evidence that the membrane-limited actions of hormones, particularly estrogens, involve the rapid activation of kinases and the release of calcium and that these are linked to physiologically relevant scenarios in the brain. We show evidence in this review, that membrane actions of estrogens, which activate these rapid signaling cascades, can also potentiate nuclear transcription in both the central nervous system and in non-neuronal cell lines. We present a theoretical scenario which can be used to understand this phenomenon. These signaling cascades may occur in parallel or in series but subsequently, converge at the modification of transcriptionally relevant molecules such as nuclear receptors and/or coactivators. In addition, other non-cognate hormones or neurotransmitters may also activate cascades to crosstalk with estrogen receptor-mediated transcription, though the relevance of this is less clear. The idea that coupling between membrane-initiated and genomic actions of hormones is a novel idea in neuroendocrinology and provides us with a unified view of hormone action in the central nervous system.


Can drug-drug interactions be predicted from in vitro studies?
Potential drug-drug interactions as well as drug-xenobiotic interactions are a major source of clinical problems, sometimes with dramatic consequences. Investigation of drug-drug interactions during drug development is a major concern for the drug companies while developing new drugs. Our knowledge of the drug-metabolising enzymes, their mechanism of action, and their regulation has made considerable progress during the last decades. Various efficient in vitro approaches have been developed during recent years and powerful computer-based data handling is becoming widely available. All these tools allow us to initiate, early in the development of new chemical entities, large-scale studies on the interactions of drugs with selective cytochrome P-450 (CYP) isozymes, drug receptors, and other cellular entities. Standardisation and validation of these methodological approaches significantly improve the quality of the data generated and the reliability of their interpretation. The simplicity and the low costs associated with the use of in vitro techniques have made them a method of choice to investigate drug-drug interactions. Promising successes have been achieved in the extrapolation of in vitro data to the in vivo situation and in the prediction of drug-drug interaction. Nevertheless, linking in vitro and in vivo studies still remains fraught with difficulties and should be made with great caution.


Complete hyperentangled-Bell-state analysis for photon systems assisted by quantum-dot spins in optical microcavities.
Bell-state analysis (BSA) is essential in quantum communication, but it is impossible to distinguish unambiguously the four Bell states in the polarization degree of freedom (DOF) of two-photon systems with only linear optical elements, except for the case in which the BSA is assisted with hyperentangled states, the simultaneous entanglement in more than one DOF. Here, we propose a scheme to distinguish completely the 16 hyperentangled Bell states in both the polarization and the spatial-mode DOFs of two-photon systems, by using the giant nonlinear optics in quantum dot-cavity systems. This scheme can be applied to increase the channel capacity of long-distance quantum communication based on hyperentanglement, such as entanglement swapping, teleportation, and superdense coding. We use hyperentanglement swapping as an example to show the application of this HBSA.


Loss of lordosis and clinical outcomes after anterior cervical fusion with dynamic rotational plates.
The cervical dynamic rotational plating system may induce bone graft subsidence, so it may cause loss of cervical lordosis. However there were few studies for alignments of cervical spines influencing the clinical results after using dynamic rotational plates. The purpose is to evaluate the effect of graft subsidence on cervical alignments due to the dynamic rotational cervical plates and correlating it with the clinical outcomes of patients undergoing anterior cervical fusion. Thirty-three patients with disease or fracture underwent anterior cervical decompression and fusion using a dynamic rotational plate. The presence and extent of implant complications, graft subsidence, loss of lordosis were identified and Visual Analog Scale score (VAS score), Japanese Orthopaedic Association score (JOA score), clinical outcomes based on Odom's criteria were recorded. Fusion was achieved without implant complications in all cases. The mean graft subsidence at 6 months after the surgery was 1.46 mm. The lordotic changes in local cervical angles were 5.85° which was obtained postoperatively. VAS score for radicular pain was improved by 5.19 and the JOA score was improved by 3. Clinical outcomes based on Odom's criteria showed sixteen excellent, ten good and two satisfactory results. There was no significant relationship between clinical outcomes and changes in the cervical angles. Dynamic rotational anterior cervical plating provides comparable clinical outcomes to that of the reports of former static cervical platings. The loss of lordosis is related to the amount of graft settling but it is not related to the clinical outcomes.


Disclosure of pharmacokinetic drug results to understand nonadherence.
In VOICE, a phase IIB trial of daily oral and vaginal tenofovir for HIV prevention, at least 50% of women receiving active products had undetectable tenofovir in all plasma samples tested. MTN-003D, an ancillary study using in-depth interviews (IDIs) and focus group discussions (FGDs), together with retrospective disclosure of plasma tenofovir pharmacokinetic results, explored adherence challenges during VOICE. We systematically recruited participants with pharmacokinetic data (median six plasma samples), categorized as low (0%, N = 79), inconsistent (1-74%, N = 28) or high (≥75%; N = 20) on the basis of frequency of tenofovir detection. Following disclosure of pharmacokinetic results, reactions were captured and adherence challenges systematically elicited; IDIs and FGDs were audio-recorded, transcribed, coded and thematically analysed. We interviewed 127 participants from South Africa, Uganda and Zimbabwe. The most common reactions to pharmacokinetic results included surprise (41%; low pharmacokinetic), acceptance (39%; inconsistent pharmacokinetic) and happiness (65%; high pharmacokinetic). On the basis of participants' explanations, we developed a typology of adherence patterns: noninitiation, discontinuation, misimplementation (resulting from visit-driven use, variable taking, modified dosing or regimen) and adherence. Fear of product side effects/harm was a frequent concern, fuelled by stories shared among participants. Although women with high pharmacokinetic levels reported similar concerns, several described strategies to overcome challenges. Women at all pharmacokinetic levels suggested real-time drug monitoring and feedback to improve adherence and reporting. Retrospective provision of pharmacokinetic results seemingly promoted candid discussions around nonadherence and study participation. The effect of real-time drug monitoring and feedback on adherence and accuracy of reporting should be evaluated in trials.


Biosynthetic Plasticity Enables Production of Fluorinated Aurachins.
Enzyme promiscuity has important implications in the field of biocatalysis. In some cases, structural analogues of simple metabolic building blocks can be processed through entire pathways to give natural product derivatives that are not readily accessible by chemical means. In this study, we explored the plasticity of the aurachin biosynthesis pathway with regard to using fluoro- and chloroanthranilic acids, which are not abundant in the bacterial producers of these quinolone antibiotics. The incorporation rates of the tested precursor molecules disclosed a regiopreference for halogen substitution as well as steric limitations of enzymatic substrate tolerance. Three previously undescribed fluorinated aurachin derivatives were produced in preparative amounts by fermentation and structurally characterized. Furthermore, their antibacterial activities were evaluated in comparison to their natural congener aurachin D.