Cost-effectiveness of pneumococcal conjugate vaccination in Latin America and the Caribbean: a regional analysis.
In Latin America and the Caribbean, routine vaccination of infants against Streptococcus pneumoniae would need substantial investment by governments and donor organizations. Policymakers need information about the projected health benefits, costs, and cost-effectiveness of vaccination when considering these investments. Our aim was to incorporate vaccine, demographic, epidemiologic, and cost data into an economic analysis of pneumococcal vaccination of infants in Latin America and the Caribbean. We previously used a structured literature review to develop regional estimates of the incidence of disease. Cost data were collected from physician interviews and public fee schedules. We then constructed a decision analytic model to compare pneumococcal conjugate vaccination of infants with no vaccination across this region, examining only vaccine's direct effects on children. Pneumococcal vaccination at the rate of diphtheria-tetanus-pertussis vaccine coverage was projected to prevent 9 500 deaths per year in children aged 0 to 5 years in the region, or approximately one life saved per 1 100 infants vaccinated. These saved lives as well as averted cases of deafness, motor deficit, and seizure result in 321 000 disability-adjusted life years (DALYs) being averted annually. At vaccine prices between US$5 and US$53 per dose, the cost per DALY averted from a societal perspective would range from US$154 to US$5 252. Pneumococcal conjugate vaccine was highly cost-effective up to $40 per dose. Introduction of pneumococcal vaccine in the Latin American and Caribbean region is projected to reduce childhood mortality and to be highly cost-effective across a range of possible costs.


Meta-studies in land use science: Current coverage and prospects.
Land use science has traditionally used case-study approaches for in-depth investigation of land use change processes and impacts. Meta-studies synthesize findings across case-study evidence to identify general patterns. In this paper, we provide a review of meta-studies in land use science. Various meta-studies have been conducted, which synthesize deforestation and agricultural land use change processes, while other important changes, such as urbanization, wetland conversion, and grassland dynamics have hardly been addressed. Meta-studies of land use change impacts focus mostly on biodiversity and biogeochemical cycles, while meta-studies of socioeconomic consequences are rare. Land use change processes and land use change impacts are generally addressed in isolation, while only few studies considered trajectories of drivers through changes to their impacts and their potential feedbacks. We provide a conceptual framework for linking meta-studies of land use change processes and impacts for the analysis of coupled human-environmental systems. Moreover, we provide suggestions for combining meta-studies of different land use change processes to develop a more integrated theory of land use change, and for combining meta-studies of land use change impacts to identify tradeoffs between different impacts. Land use science can benefit from an improved conceptualization of land use change processes and their impacts, and from new methods that combine meta-study findings to advance our understanding of human-environmental systems.


Risk Factors of In-Hospital Mortality in Patients Treated for Pneumonia at a Tertiary Care Centre in Switzerland.
Little is known about risk factors upon hospital admission that are associated with in-hospital death of patients hospitalized for bacterial pneumonia. Identifying such factors may help to optimize the treatment and lower the mortality of these patients. The aim of the study was to characterize baseline characteristics of patients hospitalized for bacterial pneumonia in Switzerland and to identify risk factors associated with all-cause in-hospital mortality. Routinely collected electronic health record data of patients discharged from a large Swiss tertiary care hospital between August 2009 and 2017 were analysed. Potential risk factors such as patient demographics, physical examination findings, vital signs, laboratory results, and comorbidities were considered within ±24 h of admission. Univariable and multivariable logistic regression models identified risk factors for in-hospital death. The area under the receiver operating characteristic (ROC) curve was used to compare the identified factors to existing pneumonia scoring systems. Out of 1,781 hospital stays with initial and main diagnosis of bacterial pneumonia, 85 patients (4.85%) died (33.9% female, median age 62.3 years [interquartile range, 52-75]). Age, low systolic blood pressure, underweight, a missing value for body mass index, decreased haemoglobin level, raised C-reactive protein, high urea, high lactate dehydrogenase, concomitant pleural effusion, and cancer were independently associated with in-hospital death. The area under the ROC curve was 0.89 for the multivariable model containing the identified predictors. Our data are consistent with previous trials characterizing patients hospitalized for pneumonia. Additionally, we identified new and independent risk factors associated with in-hospital death among patients treated for bacterial pneumonia. Findings need to be further validated in larger multicentre cohorts.


Growing together and growing apart: regional and sex differences in the lifespan developmental trajectories of functional homotopy.
Functional homotopy, the high degree of synchrony in spontaneous activity between geometrically corresponding interhemispheric (i.e., homotopic) regions, is a fundamental characteristic of the intrinsic functional architecture of the brain. However, despite its prominence, the lifespan development of the homotopic resting-state functional connectivity (RSFC) of the human brain is rarely directly examined in functional magnetic resonance imaging studies. Here, we systematically investigated age-related changes in homotopic RSFC in 214 healthy individuals ranging in age from 7 to 85 years. We observed marked age-related changes in homotopic RSFC with regionally specific developmental trajectories of varying levels of complexity. Sensorimotor regions tended to show increasing homotopic RSFC, whereas higher-order processing regions showed decreasing connectivity (i.e., increasing segregation) with age. More complex maturational curves were also detected, with regions such as the insula and lingual gyrus exhibiting quadratic trajectories and the superior frontal gyrus and putamen exhibiting cubic trajectories. Sex-related differences in the developmental trajectory of functional homotopy were detected within dorsolateral prefrontal cortex (Brodmann areas 9 and 46) and amygdala. Evidence of robust developmental effects in homotopic RSFC across the lifespan should serve to motivate studies of the physiological mechanisms underlying functional homotopy in neurodegenerative and psychiatric disorders.


Real-world practice of conversion surgery for unresectable hepatocellular carcinoma - a single center data of 26 consecutive patients.
To understand the proportion of uHCC (unresectable hepatocellular carcinoma) patients who achieve successful conversion resection in a high-volume setting with state of the art treatment options. We retrospectively reviewed all HCC patients hospitalized to our center from June 1st, 2019 to June 1st, 2022. Conversion rate, clinicopathological features, response to systemic and/or loco-regional therapy and surgical outcomes were analyzed. A total of 1,904 HCC patients were identified, with 1672 patients receiving anti-HCC treatment. 328 patients were considered up-front resectable. Of the remaining 1344 uHCC patients, 311 received loco-regional treatment, 224 received systemic treatment, and the remainder (809) received combination systemic plus loco-regional treatment. Following treatment, one patient from the systemic group and 25 patients from the combination group were considered to have resectable disease. A high objective response rate (ORR) was observed in these converted patients (42.3% under RECIST v1.1 and 76.9% under mRECIST criteria). The disease control rate (DCR) reached 100%. 23 patients underwent curative hepatectomy. Major post-operative morbidity was equivalent in the both groups (P=0.76). Pathologic complete response (pCR) was 39.1%. During conversion treatment, grade 3 or higher treatment-related adverse events (TRAEs) were observed in 50% of patients. The median follow-up time was 12.9 months (range, 3.9~40.6) from index diagnosis and 11.4 months (range, 0.9~26.9) from resection. Three patients experienced disease recurrence following conversion surgery. By intensive treatment, a small sub-group of uHCC patients (2%) may potentially be converted to curative resection. Loco-regional combined with systemic modality was relative safe and effective in the conversion therapy. Short-term outcomes are encouraging, but long-term follow-up in a larger patient population are required to fully understand the utility of this approach.


Understanding the evolutionary relationships and major traits of Bacillus through comparative genomics.
The presence of Bacillus in very diverse environments reflects the versatile metabolic capabilities of a widely distributed genus. Traditional phylogenetic analysis based on limited gene sampling is not adequate for resolving the genus evolutionary relationships. By distinguishing between core and pan-genome, we determined the evolutionary and functional relationships of known Bacillus. Our analysis is based upon twenty complete and draft Bacillus genomes, including a newly sequenced Bacillus isolate from an aquatic environment that we report for the first time here. Using a core genome, we were able to determine the phylogeny of known Bacilli, including aquatic strains whose position in the phylogenetic tree could not be unambiguously determined in the past. Using the pan-genome from the sequenced Bacillus, we identified functional differences, such as carbohydrate utilization and genes involved in signal transduction, which distinguished the taxonomic groups. We also assessed the genetic architecture of the defining traits of Bacillus, such as sporulation and competence, and showed that less than one third of the B. subtilis genes are conserved across other Bacilli. Most variation was shown to occur in genes that are needed to respond to environmental cues, suggesting that Bacilli have genetically specialized to allow for the occupation of diverse habitats and niches. The aquatic Bacilli are defined here for the first time as a group through the phylogenetic analysis of 814 genes that comprise the core genome. Our data distinguished between genomic components, especially core vs. pan-genome to provide insight into phylogeny and function that would otherwise be difficult to achieve. A phylogeny may mask the diversity of functions, which we tried to uncover in our approach. The diversity of sporulation and competence genes across the Bacilli was unexpected based on previous studies of the B. subtilis model alone. The challenge of uncovering the novelties and variations among genes of the non-subtilis groups still remains. This task will be best accomplished by directing efforts toward understanding phylogenetic groups with similar ecological niches.


The HAART cell phone adherence trial (WelTel Kenya1): a randomized controlled trial protocol.
The objectives are to compare the effectiveness of cell phone-supported SMS messaging to standard care on adherence, quality of life, retention, and mortality in a population receiving antiretroviral therapy (ART) in Nairobi, Kenya. A multi-site randomized controlled open-label trial. A central randomization centre provided opaque envelopes to allocate treatments. Patients initiating ART at three comprehensive care clinics in Kenya will be randomized to receive either a structured weekly SMS ('short message system' or text message) slogan (the intervention) or current standard of care support mechanisms alone (the control). Our hypothesis is that using a structured mobile phone protocol to keep in touch with patients will improve adherence to ART and other patient outcomes. Participants are evaluated at baseline, and then at six and twelve months after initiating ART. The care providers keep a weekly study log of all phone based communications with study participants. Primary outcomes are self-reported adherence to ART and suppression of HIV viral load at twelve months scheduled follow-up. Secondary outcomes are improvements in health, quality of life, social and economic factors, and retention on ART. Primary analysis is by 'intention-to-treat'. Sensitivity analysis will be used to assess per-protocol effects. Analysis of covariates will be undertaken to determine factors that contribute or deter from expected and determined outcomes. This study protocol tests whether a novel structured mobile phone intervention can positively contribute to ART management in a resource-limited setting.


Infant VEPs reveal neural correlates of implicit naming: Lateralized differences between lexicalized versus name-unknown pictures.
Recent behavioural studies with toddlers have demonstrated that simply viewing a picture in silence triggers a cascade of linguistic processing which activates a representation of the picture's name (Mani and Plunkett, 2010, 2011). Electrophysiological studies have also shown that viewing a picture modulates the auditory evoked potentials (AEPs) triggered by later speech, from early in the second year of life (Duta et al., 2012; Friedrich and Friederici, 2005; Mani et al., 2011) further supporting the notion that picture viewing gives rise to a representation of the picture's name against which later speech can be matched. However, little is known about how and when the implicit name arises during picture viewing, or about the electrophysiological activity which supports this linguistic process. We report differences in the visual evoked potentials (VEPs) of fourteen-month-old infants who saw photographs of animals and objects, some of which were name-known (lexicalized), while waiting for an auditory label to be presented. During silent picture viewing, lateralized neural activity was selectively triggered by lexicalized items, as compared to nameless items. Lexicalized items generated a short-lasting negative-going deflection over frontal, left centro-temporal, and left occipital regions shortly after the picture appeared (126-225 ms). A positive deflection was also observed over the right hemisphere (particularly centro-temporal regions) in a later, longer-lasting window (421-720 ms). The lateralization of these differences in the VEP suggests the possible involvement of linguistic processes during picture viewing, and may reflect activity involved in the implicit activation of the picture's name.


Power calculation of wavelength tunable Yb3+:LSO laser.
A theoretical model is presented describing continuous-wave operation about wavelength tunable Yb(3+):LSO (Yb(3+):Lu(2)SiO(5)) laser. In LSO host, Yb(3+) ion occupies two different Lu(3+) sites and the spectrum exhibits the inhomogeneously broadened property. Working as a computable model, it takes into account the pump absorption saturation, the re-absorption of laser, and the full spectral information of the laser transition. The calculated results are compared with the experimental results, and it verifies the validity of the model. Then the laser performances for different Yb(3+) concentration, crystal length, and the transmission of the output mirror are predicted.


Genotype variation in bark texture drives lichen community assembly across multiple environments.
A major goal of community genetics is to understand the influence of genetic variation within a species on ecological communities. Although well-documented for some organisms, additional research is necessary to understand the relative and interactive effects of genotype and environment on biodiversity, identify mechanisms through which tree genotype influences communities, and connect this emerging field with existing themes in ecology. We employ an underutilized but ecologically significant group of organisms, epiphytic bark lichens, to understand the relative importance of Populus angustifolia (narrowleaf cottonwood) genotype and environment on associated organisms within the context of community assembly and host ontogeny. Several key findings emerged. (1) In a single common garden, tree genotype explained 18-33% and 51% of the variation in lichen community variables and rough bark cover, respectively. (2) Across replicated common gardens, tree genotype affected lichen species richness, total lichen cover, lichen species composition, and rough bark cover, whereas environment only influenced composition and there were no genotype by environment interactions. (3) Rough bark cover was positively correlated with total lichen cover and richness, and was associated with a shift in species composition; these patterns occurred with variation in rough bark cover among tree genotypes of the same age in common gardens and with increasing rough bark cover along a -40 year tree age gradient in a natural riparian stand. (4) In a common garden, 20-year-old parent trees with smooth bark had poorly developed lichen communities, similar to their 10-year-old ramets (root suckers) growing in close proximity, while parent trees with high rough bark cover had more developed communities than their ramets. These findings indicate that epiphytic lichens are influenced by host genotype, an effect that is robust across divergent environments. Furthermore, the response to tree genotype is likely the result of genetic variation in the timing of the ontogenetic shift from smooth to rough bark allowing communities on some genotypes to assemble faster than those on other genotypes. Organisms outside the typical sphere of community genetics, such as lichens, can help address critical issues and connect plant genotype effects to long-established streams of biological research, such as ontogeny and community assembly.


Behavioral and endocrinological correlates of social status in the male sugar glider (Petaurus breviceps Marsupialia: Petauridae).
Socially dominant male sugar gliders are heavier than socially subordinate males, have higher plasma testosterone and lower cortisol concentrations, win more social encounters, scan the arena more, scent-mark more, and are more active and move more quickly, even though they spend more time in the colony nesting box. When they are transferred into a foreign stable colony there is an impressive reversal of behavioral measures and a concomitant decrease in concentration of plasma testosterone and rise in cortisol that is apparent over the first 3 weeks of observation.


Comparing 3 Suture Techniques After Muscle Laceration Repair.
Background: Skeletal muscle lacerations are a relatively common injury. Compared with nonrepaired lacerations, surgically repaired muscle lacerations regenerate faster, develop less scar tissue, have a higher return to baseline strength, and have lower incidence of hematomas. Despite the benefits of repair, the optimal repair technique is still unknown. The purpose of this study was to examine the biomechanical properties of common muscle repair techniques to determine the optimal repair. Methods: Forty-two fusiform porcine muscle specimens were dissected and used for this study. Three suture techniques were used for comparative analysis: Figure-eight, Mason Allen, and Perimeter. Each muscle was transected and then repaired using one of the 3 techniques. Fourteen muscle-tendon specimens were prepared for each group and tested for tensile failure using a material testing system. Biomechanical properties, including peak failure point and stiffness, were compared for differences between the suture groups by 1-way analysis of variance. The average time per repair technique was also recorded. Results: The Perimeter technique showed a statistically significant higher peak failure point than the Mason Allen technique (P = .03). Both the Figure-eight (P = .047) and Perimeter techniques (P < .001) were significantly stiffer than the Mason Allen technique. The repair time was comparable across all 3 techniques. Conclusions: The Figure-eight and Perimeter repairs were found to be similar in peak failure point and stiffness, whereas the Mason Allen technique showed significantly lower stiffness and peak failure point. The Figure-eight was the quickest repair to perform. The Figure-eight technique may be strongly considered for muscle laceration repairs due to its simplicity and efficiency.


Expression of HER2/erbB-2 correlates with survival in osteosarcoma.
In osteosarcoma, prognostic factors at diagnosis other than clinical stage have not been clearly identified. The aim of this study was to determine whether human epidermal growth factor receptor 2 (HER2)/erbB-2, p-glycoprotein, or p53 expression correlated with histologic response to preoperative chemotherapy or event-free survival. We performed a retrospective immunohistochemical study on material obtained from patients treated on the Memorial Sloan-Kettering Cancer Center T12 protocol between 1986 and 1993. Paraffin-embedded tissue was identified from 53 patients (73% of patients enrolled onto protocol) and stained for HER2/erbB-2, p53, and p-glycoprotein expression using standard monoclonal antibodies and methods. At the time of initial biopsy, 20 (42.6%) of 47 samples demonstrated high levels of HER2/erbB-2 expression. Higher frequencies of expression were observed in samples from patients with metastatic disease at presentation and at the time of relapse. Expression of HER2/erbB-2 correlated with a significantly worse histologic response (P =.03). In patients presenting with nonmetastatic disease, expression of HER2/erbB-2 at the time of initial biopsy was associated with a significantly decreased event-free survival (47% v 79% at 5 years, P =.05). p53 and p-glycoprotein expression did not correlate with histologic response or patient event-free survival. The correlation of HER2/erbB-2 expression with histologic response to preoperative chemotherapy and event-free survival in this study suggests that HER2/erbB-2 should be evaluated prospectively as a prognostic indicator. The correlation also suggests that clinical trials of antibodies that target this receptor, such as recombinant humanized anti-HER2 monoclonal antibody (Herceptin; Genentech, San Francisco, CA), should be considered for the treatment of osteosarcoma.


Nanoshells for photothermal therapy: a Monte-Carlo based numerical study of their design tolerance.
The optimization of the coated metallic nanoparticles and nanoshells is a current challenge for biological applications, especially for cancer photothermal therapy, considering both the continuous improvement of their fabrication and the increasing requirement of efficiency. The efficiency of the coupling between illumination with such nanostructures for burning purposes depends unevenly on their geometrical parameters (radius, thickness of the shell) and material parameters (permittivities which depend on the illumination wavelength). Through a Monte-Carlo method, we propose a numerical study of such nanodevice, to evaluate tolerances (or uncertainty) on these parameters, given a threshold of efficiency, to facilitate the design of nanoparticles. The results could help to focus on the relevant parameters of the engineering process for which the absorbed energy is the most dependant. The Monte-Carlo method confirms that the best burning efficiency are obtained for hollow nanospheres and exhibit the sensitivity of the absorbed electromagnetic energy as a function of each parameter. The proposed method is general and could be applied in design and development of new embedded coated nanomaterials used in biomedicine applications.


Vitamin D receptor gene polymorphisms in children with kidney stone disease.
Subaşı B, Gökçe İ, Delil K, Alpay H. Vitamin D receptor gene polymorphisms in children with kidney stone disease. Turk J Pediatr 2017; 59: 404-409. Kidney stone disease has a multifactorial etiology involving the interaction of genetic and environmental factors. There is an increased risk of stone formation in the relatives of idiopathic stone patients, which can be explained up to 60% by genetic factors. This study was conducted to explore the association of vitamin D receptor (VDR) gene polymorphisms with the risk of urolithiasis (UL) in Turkish children. We investigated the VDR gene polymorphisms: ApaI, BsmI, TagI, Cdx2, FokI, in 52 children (26 boys, 26 girls) with UL and in 51 healthy children (22 boys, 29 girls) without UL. Apa I, BsmI, TagI, Cdx2, FokI genotypes were analyzed by Apa I, BsmI, TagI, Cdx2, FokI restriction enzyme digestion, respectively. The resulting alleles are designated as ABTCF (ApaI, BsmI, TagI, Cdx2, and FokI restriction site is absent), or abtcf (ApaI, BsmI, TagI, Cdx2, FokI restriction site is present), respectively. Genotype and allele frequencies were calculated, and the association with UL, hypercalciuria and hypocitraturia was investigated. Our data provide no statistically significant evidence for an association between UL and VDR ApaI, BsmI, TagI, Cdx2, and FokI genotype and allele frequencies. Patients with hypocitraturia and hypercalciuria were compared with the control group and no statistically significant difference was detected in terms of VDR gene ApaI, BsmI, TagI, Cdx2, and FokI polymorphisms and allele frequencies. Our data suggest that the VDR ApaI, BsmI, TagI, Cdx2, and FokI polymorphisms do not indicate a significant risk for UL.


Vasoregulation by the beta1 subunit of the calcium-activated potassium channel.
Small arteries exhibit tone, a partially contracted state that is an important determinant of blood pressure. In arterial smooth muscle cells, intracellular calcium paradoxically controls both contraction and relaxation. The mechanisms by which calcium can differentially regulate diverse physiological responses within a single cell remain unresolved. Calcium-dependent relaxation is mediated by local calcium release from the sarcoplasmic reticulum. These 'calcium sparks' activate calcium-dependent potassium (BK) channels comprised of alpha and beta1 subunits. Here we show that targeted deletion of the gene for the beta1 subunit leads to a decrease in the calcium sensitivity of BK channels, a reduction in functional coupling of calcium sparks to BK channel activation, and increases in arterial tone and blood pressure. The beta1 subunit of the BK channel, by tuning the channel's calcium sensitivity, is a key molecular component in translating calcium signals to the central physiological function of vasoregulation.


Practice brief: adolescents and HIV clinical trials: ethics, culture, and context.
One quarter of HIV infections globally occur among young people 15 to 24 years of age, and more than half of all new infections are in people younger than 25 years. Clearly, there is a need to identify and implement effective HIV prevention strategies among at-risk teens. Some of the most effective options for slowing the epidemic are biomedical, and several promising methods are in development, including microbicides, vaccines, and preexposure prophylaxis (PREP, or the daily use of antiretrovirals to prevent the acquisition of HIV). There is widespread reluctance to enroll minors in such biomedical prevention trials because of concerns about vulnerability related to physical maturity, experiential maturity, and diminished autonomy as well as legal and social challenges that vary across and within nations. However, excluding minors from trials misses an important opportunity to evaluate the effectiveness, acceptability, and safety of innovative interventions under the best conditions for identifying and resolving potential problems. The challenges of including minors in HIV prevention trials are highlighted through the example of one rural South African community that has been particularly devastated by the HIV epidemic.


Genetic Biomarkers of Barrett's Esophagus Susceptibility and Progression to Dysplasia and Cancer: A Systematic Review and Meta-Analysis.
Barrett's esophagus (BE) is a common and important precursor lesion of esophageal adenocarcinoma (EAC). A third of patients with BE are asymptomatic, and our ability to predict the risk of progression of metaplasia to dysplasia and EAC (and therefore guide management) is limited. There is an urgent need for clinically useful biomarkers of susceptibility to both BE and risk of subsequent progression. This study aims to systematically identify, review, and meta-analyze genetic biomarkers reported to predict both. A systematic review of the PubMed and EMBASE databases was performed in May 2014. Study and evidence quality were appraised using the revised American Society of Clinical Oncology guidelines, and modified Recommendations for Tumor Marker Scores. Meta-analysis was performed for all markers assessed by more than one study. A total of 251 full-text articles were reviewed; 52 were included. A total of 33 germline markers of susceptibility were identified (level of evidence II-III); 17 were included. Five somatic markers of progression were identified; meta-analysis demonstrated significant associations for chromosomal instability (level of evidence II). One somatic marker of progression/relapse following photodynamic therapy was identified. However, a number of failings of methodology and reporting were identified. This is the first systematic review and meta-analysis to evaluate genetic biomarkers of BE susceptibility and risk of progression. While a number of limitations of study quality temper the utility of those markers identified, some-in particular, those identified by genome-wide association studies, and chromosomal instability for progression-appear plausible, although robust validation is required.


Physiological relevance of cell cycle kinases.
The basic biology of the cell division cycle and its control by protein kinases was originally studied through genetic and biochemical studies in yeast and other model organisms. The major regulatory mechanisms identified in this pioneer work are conserved in mammals. However, recent studies in different cell types or genetic models are now providing a new perspective on the function of these major cell cycle regulators in different tissues. Here, we review the physiological relevance of mammalian cell cycle kinases such as cyclin-dependent kinases (Cdks), Aurora and Polo-like kinases, and mitotic checkpoint regulators (Bub1, BubR1, and Mps1) as well as other less-studied enzymes such as Cdc7, Nek proteins, or Mastl and their implications in development, tissue homeostasis, and human disease. Among these functions, the control of self-renewal or asymmetric cell division in stem/progenitor cells and the ability to regenerate injured tissues is a central issue in current research. In addition, many of these proteins play previously unexpected roles in metabolism, cardiovascular function, or neuron biology. The modulation of their enzymatic activity may therefore have multiple therapeutic benefits in human disease.


Method for Electrochemical Detection of Brain Derived Neurotrophic Factor (BDNF) in Plasma.
Currently, a blood test for the diagnosis of endometriosis, a common estrogen-dependent gynecological disease, does not exist. Recent studies suggest that circulating concentrations of brain-derived neurotrophic factor (BDNF) have potential for the diagnosis of endometriosis. However, at present, BDNF can only be measured by ELISA, which requires a clinic visit, a routine blood sample, and laboratory testing. Therefore, we developed a point-of-care device (EndoChip) for use with small blood volumes that can be collected through a finger prick. Specifically, the presented device is a polymer-based chip with a nanoporous, wrinkled gold film acting as the electrode/sensing layer, allowing for the electrochemical detection of BDNF in plasma. Increasing concentrations of BDNF (0.1-2.0 ng/mL) induced significant differences in redox current. The biosensor produces a signal readout in a matter of seconds, and is ideal for realizing multiplexing. Blood samples were collected from women ( n = 20) with chronic pelvic pain undergoing a diagnostic laparoscopy. Plasma BDNF concentrations measured by commercial ELISA were positively correlated ( r2 = 0.8033; p < 0.001) with results from the EndoChip. Our results demonstrate a quick and reliable method for point-of-care quantification of circulating concentrations of BDNF and a promising diagnostic tool for endometriosis.


Validation of the Rheumatoid and Arthritis Outcome Score (RAOS) for the lower extremity.
Patients with inflammatory joint diseases tend due to new treatments to be more physically active; something not taken into account by currently used outcome measures. The Rheumatoid and Arthritis Outcome Score (RAOS) is an adaptation of the Knee injury and Osteoarthritis Outcome Score (KOOS) and evaluates functional limitations of importance to physically active people with inflammatory joint diseases and problems from the lower extremities. The aim of the study was to test the RAOS for validity, reliability and responsiveness. 119 in-patients with inflammatory joint disease (51% RA) admitted to multidisciplinary care, mean age 56 (+/-13), 73% women, mean disease duration 18 (+/-14) yr were consecutively enrolled. They all received the RAOS, the SF-36, the HAQ and four subscales of the AIMS2 twice during their stay for test of validity and responsiveness. Test-retest reliability of the RAOS questionnaire was calculated on 52 patients using the first or second administration and an additional mailed questionnaire. The RAOS met set criteria of reliability and validity. The random intraclass correlation coefficient (ICC 2,1) for the five subscales ranged from 0.76 to 0.92, indicating that individual comparisons were possible except for the subscale Sport and Recreation Function. Inter-item correlation measured by Cronbach's alpha ranged from 0.78 to 0.95. When measuring construct validity the highest correlations occurred between subscales intended to measure similar constructs. Change over time (24 (+/- 7) days) due to multidisciplinary care was significant for all subscales (p < 0.001). The effect sizes ranged from 0.30-0.44 and were considered small to medium. All the RAOS subscales were more responsive than the HAQ. Some of the SF-36 subscales and the AIMS2 subscales were more responsive than the RAOS subscales. It is possible to adapt already existing outcome measures to assess other groups with musculoskeletal difficulties in the lower extremity. The RAOS is a reliable, valid and responsive outcome instrument for assessment of multidisciplinary care. To fully validate the RAOS further studies are needed in other populations.


Analysis of the relationship between smokeless tobacco and cancer based on data from the National Mortality Followback Survey.
This study investigates the potential link between the use of smokeless tobacco and oral cancer and cancer of digestive organs. The combined data of the National Mortality Followback Survey (NMFS), a probability sample of the U.S. deaths, and the coincident National Health Interview Survey (NHIS), a probability sample of the living, non-institutionalized U.S. population, are used to compute risk estimates for cancer, oral cancer, and cancer of the digestive organs associated with use of smokeless tobacco based on a cross sectional study design, simultaneously controlled for potential confounding from active smoking, alcohol consumption, and occupational exposure. Use of smokeless tobacco (either as snuff or chewing tobacco) does not increase the risk of oral cancer or cancer of the digestive organs. Alcohol emerges as a major risk factor for oral cancer with a strong dose-response relationship between the amount of drinking and risk. The same is true to a lesser extent for cancer of the digestive organs. Smoking is associated with increased risk of oral cancer but not of cancer of the digestive organs. Blue collar, technical, and service workers have significantly increased risk of cancer of the digestive organs relative to professional, managerial, and clerical workers, but not of oral cancer. Differences between findings based on the NMFS/NHIS and those obtained from other data very likely are due to inadequate control for confounding. Other reasons for differences between the NMFS/NHIS data and other studies are discussed.


Reducing bias in bacterial community analysis of lower respiratory infections.
High-throughput pyrosequencing and quantitative PCR (Q-PCR) analysis offer greatly improved accuracy and depth of characterisation of lower respiratory infections. However, such approaches suffer from an inability to distinguish between DNA derived from viable and non-viable bacteria. This discrimination represents an important step in characterising microbial communities, particularly in contexts with poor clearance of material or high antimicrobial stress, as non-viable bacteria and extracellular DNA can contribute significantly to analyses. Pre-treatment of samples with propidium monoazide (PMA) is an effective approach to non-viable cell exclusion (NVCE). However, the impact of NVCE on microbial community characteristics (abundance, diversity, composition and structure) is not known. Here, adult cystic fibrosis (CF) sputum samples were used as a paradigm. The effects of PMA treatment on CF sputum bacterial community characteristics, as analysed by pyrosequencing and enumeration by species-specific (Pseudomonas aeruginosa) and total bacterial Q-PCR, were assessed. At the local community level, abundances of both total bacteria and of P. aeruginosa were significantly lower in PMA-treated sample portions. Meta-analysis indicated no overall significant differences in diversity; however, PMA treatment resulted in a significant alteration in local community membership in all cases. In contrast, at the metacommunity level, PMA treatment resulted in an increase in community evenness, driven by an increase in diversity, predominately representing rare community members. Importantly, PMA treatment facilitated the detection of both recognised and emerging CF pathogens, significantly influencing 'core' and 'satellite' taxa group membership. Our findings suggest failure to implement NVCE may result in skewed bacterial community analyses.


Development and characterisation of acoustofluidic devices using detachable electrodes made from PCB.
Acoustofluidics has been increasingly applied in biology, medicine and chemistry due to its versatility in manipulating fluids, cells and nano-/micro-particles. In this paper, we develop a novel and simple technology to fabricate a surface acoustic wave (SAW)-based acoustofluidic device by clamping electrodes made using a printed circuit board (PCB) with a piezoelectric substrate. The PCB-based SAW (PCB-SAW) device is systematically characterised and benchmarked with a SAW device made using the conventional photolithography process with the same specifications. Microparticle manipulations such as streaming in droplets and patterning in microchannels were demonstrated in the PCB-SAW device. In addition, the PCB-SAW device was applied as an acoustic tweezer to pattern lung cancer cells to form three or four traces inside the microchannel in a controllable manner. Cell viability of ∼97% was achieved after acoustic manipulation using the PCB-SAW device, which proved its ability as a suitable tool for acoustophoretic applications.


Explanation for the signs and symptoms of tooth eruption: mast cells.
This study contributes to the understanding of the mechanisms associated with signs and symptoms of tooth eruption, by investigating the presence of mast cells in pericoronal tissues during the intraosseous (Group 1) and submucosal (Group 2) phases of eruption. We compared findings for these two groups with each other and with those for the oral mucosa (Group 3). In each group, 14 specimens were analyzed microscopically after hematoxylin and eosin staining and immunohistochemical analysis of c-Kit and tryptase expression. Results revealed that the number and density of mast cells is different in follicular tissues according to the eruption phase, which may mean that: 1) masticatory trauma of the oral mucosa and dental follicles in the submucosa may explain why reduced enamel epithelium exposes enamel to the cells of the connective tissue; 2) exposure of antigenic enamel proteins might correspond to the release of sequestered antigens, which may lead to the interaction of IgE and a greater number of mast cells in the region; and 3) the consequent degranulation and the local release of mediators, such as histamine, leukotrienes, prostaglandins, proteases, cytokines and growth factors, contribute to the understanding of signs and symptoms associated with tooth eruption.


In vitro-reassembled plant virus-like particles for loading of polyacids.
The coat protein (CP) of certain plant viruses may reassemble into empty virus-like particles (VLPs) and these protein cages may serve as potential drug delivery platforms. In this paper, the production of novel VLPs from the Hibiscus chlorotic ringspot virus (HCRSV) is reported and the capacity to load foreign materials was characterized. VLPs were readily produced by destabilizing the HCRSV in 8 M urea or Tris buffer pH 8, in the absence of calcium ions, followed by removal of viral RNA by ultrahigh-speed centrifugation and the reassembly of the CP in sodium acetate buffer pH 5. The loading of foreign materials into the VLPs was dependent on electrostatic interactions. Anionic polyacids, such as polystyrenesulfonic acid and polyacrylic acid, were successfully loaded but neutrally charged dextran molecules were not. The molecular-mass threshold for the polyacid cargo was about 13 kDa, due to the poor retention of smaller molecules, which readily diffused through the holes between the S domains present on the surface of the VLPs. These holes precluded the entry of large molecules, but allowed smaller molecules to enter or exit. The polyacid-loaded VLPs had comparable size, morphology and surface-charge density to the native HCRSV, and the amount of polyacids loaded was comparable to the weight of the native genomic materials. The conditions applied to disassembly-reassembly of the virions did not change the structural conformation of the CP. HCRSV-derived VLPs may provide a promising nano-sized protein cage for delivery of anionic drug molecules.


Phantom and Clinical Evaluation of the Bayesian Penalized Likelihood Reconstruction Algorithm Q.Clear on an LYSO PET/CT System.
Q.Clear, a Bayesian penalized-likelihood reconstruction algorithm for PET, was recently introduced by GE Healthcare on their PET scanners to improve clinical image quality and quantification. In this work, we determined the optimum penalization factor (beta) for clinical use of Q.Clear and compared Q.Clear with standard PET reconstructions. A National Electrical Manufacturers Association image-quality phantom was scanned on a time-of-flight PET/CT scanner and reconstructed using ordered-subset expectation maximization (OSEM), OSEM with point-spread function (PSF) modeling, and the Q.Clear algorithm (which also includes PSF modeling). Q.Clear was investigated for β (B) values of 100-1,000. Contrast recovery (CR) and background variability (BV) were measured from 3 repeated scans, reconstructed with the different algorithms. Fifteen oncology body (18)F-FDG PET/CT scans were reconstructed using OSEM, OSEM PSF, and Q.Clear using B values of 200, 300, 400, and 500. These were visually analyzed by 2 scorers and scored by rank against a panel of parameters (overall image quality; background liver, mediastinum, and marrow image quality; noise level; and lesion detectability). As β is increased, the CR and BV decreases; Q.Clear generally gives a higher CR and lower BV than OSEM. For the smallest sphere reconstructed with Q.Clear B400, CR is 28.4% and BV 4.2%, with corresponding values for OSEM of 24.7% and 5.0%. For the largest hot sphere, Q.Clear B400 yields a CR of 75.2% and a BV of 3.8%, with corresponding values for OSEM of 64.4% and 4.0%. Scorer 1 and 2 ranked B400 as the preferred reconstruction in 13 of 15 (87%) and 10 of 15 (73%) cases. The least preferred reconstruction was OSEM PSF in all cases. In most cases, lesion detectability was highest ranked for B200, in 9 of 15 (67%) and 10 of 15 (73%), with OSEM PSF ranked lowest. Poor lesion detectability on OSEM PSF was seen in cases of mildly (18)F-FDG-avid mediastinal nodes in lung cancer and small liver metastases due to background noise. Conversely, OSEM PSF was ranked second highest for lesion detectability in most pulmonary nodule evaluation cases. The combined scores confirmed B400 to be the preferred reconstruction. Our phantom measurement results demonstrate improved CR and reduced BV when using Q.Clear instead of OSEM. A β value of 400 is recommended for oncology body PET/CT using Q.Clear.


Antibacterial Activity and Mechanism of Action of Aspidinol Against Multi-Drug-Resistant Methicillin-Resistant Staphylococcus aureus.
This study aimed at investigating the antibacterial activity of aspidinol, an extract from Dryopteris fragrans (L.) Schott, against methicillin-resistant Staphylococcus aureus (MRSA). MRSA isolates were treated with aspidinol to determine the differential expression of genes and associated pathways following the drug treatment. Aspidinol displayed significant anti-MRSA activity, both in vivo (minimum inhibitory concentration = 2 μg/mL) and in vitro, and achieved an antibacterial effect comparable to that of vancomycin. In the lethal septicemic mouse study, a dose of 50 mg/kg of either aspidinol or vancomycin provided significant protection from mortality. In the non-lethal septicemic mouse study, aspidinol and vancomycin produced a significant reduction in mean bacterial load in murine organs, including the spleen, lung, and liver. After treatment with aspidinol, we found through RNA-seq and RT-PCR experiments that the inhibition of the formation of ribosomes was the primary S. aureus cell-killing mechanism, and the inhibition of amino acid synthesis and the reduction of virulence factors might play a secondary role.


Big spleens and hypersplenism: fix it or forget it?
Hypersplenism is a common manifestation of portal hypertension in the cirrhotic. More than half of cirrhotics will have low platelet counts, but neutropenia is much less common. Despite being common in the cirrhotic population, the presence of hypersplenism is of little clinical consequence. The presence of hypersplenism suggests more advanced liver disease and an increase in risk of complications, but there is no data showing that correcting the hypersplenism improves patient survival. In most series, the most common indications for treating the hypersplenism is to increase platelet and white blood cell counts to allow for use of drugs that suppress the bone marrow such as interferon alpha and chemotherapeutic agents. There are several approaches used to treat hypersplenism. Portosystemic shunts are of questionable benefit. Splenectomy, either open or laparoscopically, is the most effective but is associated with a significant risk of portal vein thrombosis. Partial splenic artery embolization and radiofrequency ablation are effective methods for treating hypersplenism, but counts tend to fall back to baseline long-term. Pharmacological agents are also effective in increasing platelet counts. Development of direct acting antivirals against hepatitis C will eliminate the most common indication for treatment. We lack controlled trials designed to determine if treating the hypersplenism has benefits other than raising the platelet and white blood cell counts. In the absence of such studies, hypersplenism in most patients should be considered a laboratory abnormality and not treated, in other words forget it.


Validation of smoke inhalation therapy to treat microbial infections.
In traditional healing, the burning of selected indigenous medicinal plants and the inhalation of the liberated smoke are widely accepted and a practiced route of administration. This study elucidated the rationale behind this commonly practiced treatment by examining the antimicrobial activity for five indigenous South African medicinal plants commonly administered through inhalation (Artemisia afra, Heteropyxis natalensis, Myrothamnus flabellifolius, Pellaea calomelanos and Tarchonanthus camphoratus). An apparatus was designed to simulate the burning process that occurs in a traditional setting and the smoke fraction was captured for analysis and bioassay. Methanol and acetone extracts as well as the essential oil (for the aromatic species) were prepared and assayed in parallel with the smoke fraction. Antimicrobial data revealed that in most cases, the 'smoke-extract' obtained after burning had lower minimum inhibitory concentration (MIC) values than the corresponding solvent extracts and essential oils. The combustion, acetone and methanol extracts produced different chromatographic profiles as demonstrated for Pellaea calomelanos where several compounds noted in the smoke fraction were not present in the other extracts. These results suggest that the combustion process produces an 'extract' with superior antimicrobial activity and provides in vitro evidence for inhalation of medicinal smoke as an efficient mode of administration in traditional healing.


The mechanical waveform of the basilar membrane. I. Frequency modulations ("glides") in impulse responses and cross-correlation functions.
The purpose of this investigation is to present evidence from experimental as well as model results on temporal variations of the frequency of oscillation in the basilar membrane's impulse response. Stimuli were either clicks leading to a direct estimate of the impulse response, or bands of pseudo-random noise (one or two octaves wide) which lead to an indirect estimate of the impulse response via a cross-correlation procedure. The noise bands were centered at the best frequency of the BM location under observation. Responses were obtained from the basal turn of the guinea-pig cochlea, from a location with a best frequency (for the weakest stimuli) between 17.0 and 18.5 kHz. Data acquisition was done with a sample frequency of 208 kHz. Input-output cross-correlation functions were found to share with impulse responses the property that the initial oscillations have a noticeably lower frequency than the later ones. During the impulse response the frequency of oscillation increases gradually. This increase occurs and continues to beyond the time that the oscillations reach the largest amplitude. This frequency variation is called a "glide." Using the "analytic signal" method the frequency of oscillation is found to increase continually throughout the duration of the main lobe of oscillation, even at the lowest tested stimulus intensities (about 20 dB SPL). At high stimulus intensity both the direct and indirect impulse response change their appearance drastically but the glide retains its basic form. In the case of the direct impulse response estimate the glide can be attributed to temporal variation of the degree of nonlinearity. For the indirect impulse response this is not true, because with a constant level noise stimulus there is no regular temporal variation of nonlinearity. In this case the glide should be interpreted as an intrinsic property of the cochlear system. From our and others' data the glide was found to exist over a topographic frequency range of best frequencies of at least from 1.76 to 18 kHz. Two examples of present-day models of the cochlea are discussed of which one is found to demonstrate the glide phenomenon in its response, and the other one does not.


Estrogen-calcium interactions in the postmenopause: a quantitative description.
Accumulated data describing the time course of bone loss in postmenopausal women were combined with metabolic data on estrogen-calcium interactions to produce a comprehensive, quantitative model of involutional bone loss. The model was shown to be able to mimic results of published intervention studies with considerable fidelity. Implicit in existing understanding, and made explicit by the model, are such relationships as: (1) calcium deficiency, if present in a woman, is masked during the early years of estrogen withdrawal bone loss; (2) accordingly, except in severe deficiency states, it is unlikely that calcium supplementation can confer much benefit in the immediate postmenopause; (3) however, by 5-8 years postmenopause, an underlying calcium deficiency, if present, becomes manifest, and if uncorrected will greatly augment the bone loss produced by estrogen withdrawal; (4) estrogen replacement therapy, if stopped, does not produce a sustained difference in bone mass in calcium-replete women; however, (5) estrogen, by effectively reducing the level of any calcium deficiency that may be present, does produce a permanent benefit in women with such deficiency. These relationships suggest that late fracture protection from earlier estrogen therapy is either confined to women with calcium deficiency, or has a non-mass basis (or both).


Fluorescence Chemicals To Detect Insoluble and Soluble Amyloid-β Aggregates.
Misfolded amyloid-β (Aβ) is the key biomarker of Alzheimer's disease (AD), and discoveries of fluorescence chemicals visualizing such Aβ aggregates in the brain have made major contributions in postmortem and antemortem diagnosis of the disorder. Insoluble senile plaques of Aβ in brain tissues are commonly stained with thioflavin and congo red dyes and observed through microscopy, while those in living patient brains are detected via radioisotope-labeled fluorescence chemicals for positron emission tomography. Clinical evidence strongly supports the view that plaques are well-associated with the onset but not with the progression of AD. Plaques could accumulate while cognitive functions of at-risk individuals are still intact, and thus, another biomarker is needed to monitor neurodegeneration. Soluble Aβ oligomers are considered to have strong correlation with neuronal loss and brain atrophy as they are the most neurotoxic forms of misfolded Aβ. However, oligomer-targeting probes encounter several major difficulties in development. There is a significant structural distinction between two Aβ species-plaques are β-sheet-rich while oligomers are unordered-and it is still difficult to isolate and stabilize the oligomeric forms of Aβ. Due to these challenges, soluble oligomer-detecting imaging probes are relatively rare compared to the plaque-targeting chemical probes. This Review describes biochemical and optical characteristics of up-to-date fluorescence chemicals targeting insoluble plaques and soluble oligomers of Aβ. We also highlight the contributions of Aβ fluorescence chemicals to the clinical diagnosis of AD and technical challenges in searching for enhanced imaging probes.


Cdc42 promotes transendothelial migration of cancer cells through β1 integrin.
Cancer cells interact with endothelial cells during the process of metastatic spreading. Here, we use a small interfering RNA screen targeting Rho GTPases in cancer cells to identify Cdc42 as a critical regulator of cancer cell-endothelial cell interactions and transendothelial migration. We find that Cdc42 regulates β1 integrin expression at the transcriptional level via the transcription factor serum response factor (SRF). β1 integrin is the main target for Cdc42-mediating interaction of cancer cells with endothelial cells and the underlying extracellular matrix, as exogenous β1 integrin expression was sufficient to rescue the Cdc42-silencing phenotype. We show that Cdc42 was required in vivo for cancer cell spreading and protrusion extension along blood vessels and retention in the lungs. Interestingly, transient Cdc42 depletion was sufficient to decrease experimental lung metastases, which suggests that its role in endothelial attachment is important for metastasis. By identifying β1 integrin as a transcriptional target of Cdc42, our results provide new insight into Cdc42 function.


The search for Pleiades in trait constellations: functional integration and phenotypic selection in the complex flowers of Morrenia brachystephana (Apocynaceae).
Pollinator-mediated natural selection on single traits, such as corolla tube or spur length, has been well documented. However, flower phenotypes are usually complex, and selection is expected to act on several traits that functionally interact rather than on a single isolated trait. Despite the fact that selection on complex phenotypes is expectedly widespread, multivariate selection modelling on such phenotypes still remains under-explored in plants. Species of the subfamily Asclepiadoideae (Apocynaceae) provide an opportunity to study such complex flower contrivances integrated by fine-scaled organs from disparate developmental origin. We studied the correlation structure among linear floral traits (i) by testing a priori morphological, functional or developmental hypotheses among traits and (ii) by exploring the organization of flower covariation, considering alternative expectations of modular organization or whole flower integration through conditional dependence analysis (CDA) and integration matrices. The phenotypic selection approach was applied to determine whether floral traits involved in the functioning of the pollination mechanism were affected by natural selection. Floral integration was low, suggesting that flowers are organized in more than just one correlation pleiad; our hypothetical functional correlation matrix was significantly correlated with the empirical matrix, and the CDA revealed three putative modules. Analyses of phenotypic selection showed significant linear and correlational gradients, lending support to expectations of functional interactions between floral traits. Significant correlational selection gradients found involved traits of different floral whorls, providing evidence for the existence of functional integration across developmental domains.


Postexercise Dietary Protein Ingestion Increases Whole-Body Leucine Balance in a Dose-Dependent Manner in Healthy Children.
Background: Protein ingestion is important in enhancing whole-body protein balance in children. The effect of discrete bolus protein ingestion on acute postexercise recovery has yet to be determined.Objective: This study determined the effect of increasing doses of ingested protein on postexercise whole-body leucine balance in healthy, active children.Methods: Thirty-five children (26 boys, 9 girls; age range: 9-13 y; weight mean ± SD: 44.9 ± 10.6 kg) underwent a 5-d adaptation diet (0.95 g protein ⋅ kg-1 ⋅ d-1) before performing 20 min of cycling 3 times with a concurrent, primed, constant infusion of [13C]leucine. After exercise, participants consumed an isoenergetic beverage (140 kcal) containing variable amounts of bovine skim-milk protein and carbohydrates (sucrose) (0, 5, 10, and 15 g protein made up with 35, 30, 25, and 20 g carbohydrates, respectively). Blood and breath samples were taken over the 3 h of recovery to determine non-steady state whole-body leucine oxidation (LeuOX) and net leucine balance (LeuBAL).Results: LeuOX (secondary outcome) peaked 60 min after beverage ingestion and demonstrated a relative dose-response over the 3 h of recovery (15 g = 10 > 5 > 0 g; P < 0.001). LeuBAL (primary outcome) demonstrated a dose-response over the 3 h [15 g (24.2 ± 8.2 mg/kg) > 10 g (11.6 ± 4.3 mg/kg) > 5 g (5.7 ± 1.9 mg/kg) > 0 g (-3.0 ± 1.7 mg/kg); all P < 0.01] with all conditions different from zero (all P < 0.001).Conclusions: Over the 3-h postexercise period, LeuBAL was negative with carbohydrate ingestion alone; however, the co-ingestion of carbohydrates and 5 g high-quality dietary protein was sufficient to promote a positive postexercise whole-body protein balance in healthy, active children. Moreover, LeuBAL increased in a dose-dependent manner within the protein range studied. Children should consider consuming a source of dietary protein after physical activity to enhance whole-body anabolism. This trial was registered at clinicaltrials.gov as NCT01598935.


Genomic characterization of a large plasmid containing a bla NDM-1 gene carried on Salmonella enterica serovar Indiana C629 isolate from China.
The bla NDM-1 gene in Salmonella species is mostly reported in clinical cases, but is rarely isolated from red and white meat in China. A Salmonella Indiana (S. Indiana) isolate was cultured from a chicken carcass procured from a slaughterhouse in China. Antimicrobial susceptibility was tested against a panel of agents. Whole-genome sequencing of the isolate was carried out and data was analyzed. A large plasmid, denoted as plasmid pC629 (210,106 bp), containing a composite cassette, consisting of IS26-bla NDM-1-ble MBL -△trpF-tat-cutA-ISCR1-sul1-qacE△1-aadA2-dfrA12-intI1-IS26 was identified. The latter locus was physically linked with bla OXA-1, bla CTX-M-65, bla TEM-1-encoding genes. A mercury resistance operon merACDEPTR was also identified; it was flanked on the proximal side, among IS26 element and the distally located on the bla NDM-1 gene. Plasmid pC629 also contained 21 other antimicrobial resistance-encoding genes, such as aac(6')-Ib-cr, aac(3)-VI, aadA5, aph(4)-Ia, arr-3, blmS, brp, catB3, dfrA17, floR, fosA, mph(A), mphR, mrx, nimC/nimA, oqxA, oqxB, oqxR, rmtB, sul1, sul2. Two virulence genes were also identified on plasmid pC629. To the best of our knowledge, this is the first report of bla NDM-1 gene being identified from a plasmid in a S. Indiana isolate cultured from chicken carcass in China.


Light beam coupling between standard single mode fibers and highly nonlinear photonic crystal fibers based on the fused biconical tapering technique.
We propose and experimentally demonstrate light beam coupling between a single-mode fiber (SMF) and a highly nonlinear photonic crystal fiber (HN-PCF) based on the fused biconical tapering (FBT) technique. In our experiment, a standard SMF is pre-tapered to match its propagation constant to that of a HN-PCF. In order to remove the condensation in the air holes, the temperature is increased gradually to preheat the fibers. An appropriate level of hydrogen flow is administered to avoid the air-hole collapse. As a result, coupling ratio exceeding 90% between the SMF and HN-PCF is achieved. This technique avoids back Fresnel reflection, mode-field diameter (MFD) mismatch and fiber-core misalignment, bubble generation and air-hole collapse in the interface fusion splice.


High throughput protein nanocrystal fractionation in a microfluidic sorter.
Protein crystallography is transitioning into a new generation with the introduction of the X-ray free electron laser, which can be used to solve the structures of complex proteins via serial femtosecond crystallography. Sample characteristics play a critical role in successful implementation of this new technology, whereby a small, narrow protein crystal size distribution is desired to provide high quality diffraction data. To provide such a sample, we developed a microfluidic device that facilitates dielectrophoretic sorting of heterogeneous particle mixtures into various size fractions. The first generation device demonstrated great potential and success toward this endeavor; thus, in this work, we present a comprehensive optimization study to improve throughput and control over sorting outcomes. First, device geometry was designed considering a variety of criteria, and applied potentials were modeled to determine the scheme achieving the largest sorting efficiency for isolating nanoparticles from microparticles. Further, to investigate sorting efficiency within the nanoparticle regime, critical geometrical dimensions and input parameters were optimized to achieve high sorting efficiencies. Experiments revealed fractionation of nanobeads from microbeads in the optimized device with high sorting efficiencies, and protein crystals were sorted into submicrometer size fractions as desired for future serial femtosecond crystallography experiments.


Preparation and evaluation of microemulsion-based transdermal delivery of total flavone of rhizoma arisaematis.
The aims of the present study were to investigate the skin permeation and cellular uptake of a microemulsion (ME) containing total flavone of rhizoma arisaematis (TFRA), and to evaluate its effects on skin structure. Pseudo-ternary phase diagrams were constructed to evaluate ME regions with various surfactants and cosurfactants. Eight formulations of oil-in-water MEs were selected as vehicles, and in vitro skin-permeation experiments were performed to optimize the ME formulation and to evaluate its permeability, in comparison to that of an aqueous suspension. Laser scanning confocal microscopy and fluorescent-activated cell sorting were used to explore the cellular uptake of rhodamine 110-labeled ME in human epidermal keratinocytes (HaCaT) and human embryonic skin fibroblasts (CCC-ESF-1). The structure of stratum corneum treated with ME was observed using a scanning electron microscope. Furthermore, skin irritation was tested to evaluate the safety of ME. ME formulated with 4% ethyl oleate (weight/weight), 18% Cremophor EL (weight/weight), and 18% Transcutol P, with 1% Azone to enhance permeation, showed good skin permeability. ME-associated transdermal fluxes of schaftoside and isoschaftoside, two major effective constituents of TFRA, were 3.72-fold and 5.92-fold higher, respectively, than those achieved using aqueous suspensions. In contrast, in vitro studies revealed that uptake by HaCaT and CCC-ESF-1 cells was lower with ME than with an aqueous suspension. Stratum corneum loosening and shedding was observed in nude mouse skin treated with ME, although ME produced no observable skin irritation in rabbits. These findings indicated that ME enhanced transdermal TFRA delivery effectively and showed good biocompatibility with skin tissue.


Constrictive external nitinol meshes inhibit vein graft intimal hyperplasia in nonhuman primates.
External mesh support of vein grafts has been shown to mitigate the formation of intimal hyperplasia. The aim of the present study was to address the issue of optimal mesh size in a nonhuman primate model that mimics the dimensional mismatch typically encountered between clinical vein grafts and their target arteries. The effect of mesh size on intimal hyperplasia and endothelial preservation was assessed in bilateral femoral interposition grafts in Chacma baboons (n(Sigma) = 32/n = 8 per mesh size). No mesh support (group I) was compared with external nitinol meshes at three different sizes: loose fitting (group II), 25% diameter constricting (group III), and 50% diameter constricting (group IV). Mesh sizes were seen not only in isolation but also against the background of anastomotic size mismatch at implantation, expressed as quotient of cross-sectional area of host artery to vein graft (Q(C)). Significant amounts of intimal hyperplasia were found in group I (Q(C) median 0.20; intimal hyperplasia 6 weeks = 1.63 +/- 0.34 mm(2); intimal hyperplasia 12 weeks = 1.73 +/- 0.5 mm(2)) and group II (Q(C) median 0.25; intimal hyperplasia 6 weeks = 1.96 +/- 1.64 mm(2); intimal hyperplasia 12 weeks = 2.88 +/- 1.69 mm(2)). In contrast, group III (Q(C) median 0.45; intimal hyperplasia 6 weeks = 0.08 +/- 0.13 mm(2); intimal hyperplasia 12 weeks = 0.18 +/- 0.32 mm(2)) and IV (Q(C) median 1.16; intimal hyperplasia 6 weeks = 0.02 +/- 0.03 mm(2); intimal hyperplasia 12 weeks = 0.11 +/- 0.10 mm(2)) showed dramatically suppressed intimal hyperplasia (P < .01) at both time points. Endothelial integrity was only preserved in group IV (P < .05). There were no significant differences in vascularization and inflammation in either interlayer or intergroup comparisons. By using an animal model that addressed the clinical phenomenon of diameter discrepancy between vein graft and bypassed artery, we could demonstrate that suppression of intimal hyperplasia required constrictive mesh sizes.


Demographic and clinical characteristics of deaths associated with influenza A(H1N1) pdm09 in Central America and Dominican Republic 2009-2010.
The demographic characteristics of pandemic influenza decedents among middle and low-income tropical countries are poorly understood. We explored the demographics of persons who died with influenza A (H1N1)pdm09 infection during 2009-2010, in seven countries in the American tropics. We used hospital-based surveillance to identify laboratory-confirmed influenza deaths in Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, Panama and Dominican Republic. An influenza death was defined as a person who died within two weeks of a severe acute respiratory infection (SARI) defined as sudden onset of fever >38 °C, cough or sore-throat, and shortness of breath, or difficulty breathing requiring hospitalization, and who tested positive for influenza A (H1N1)pdm09 virus by real time polymerase chain reaction. We abstracted the demographic and clinical characteristics of the deceased from their medical records. During May 2009-June 2010, we identified 183 influenza deaths. Their median age was 32 years (IQR 18-46 years). One-hundred and one (55 %) were female of which 20 (20 %) were pregnant and 7 (7 %) were in postpartum. One-hundred and twelve decedents (61 %) had pre-existing medical conditions, (15 % had obesity, 13 % diabetes, 11 % asthma, 8 % metabolic disorders, 5 % chronic obstructive pulmonary disease, and 10 % neurological disorders). 65 % received oseltamivir but only 5 % received it within 48 h of symptoms onset. The pandemic killed young adults, pregnant women and those with pre-existing medical conditions. Most sought care too late to fully benefit from oseltamivir. We recommend countries review antiviral treatment policies for people at high risk of developing complications.


The effects of fatigue on soccer skills performed during a soccer match simulation.
This study examined the effects of exercise-induced fatigue on soccer skills performed throughout simulated match play. Fifteen academy soccer players completed a soccer match simulation (SMS) including passing, dribbling, and shooting skills. Precision, success rate, and ball speed were determined via video analysis for all skills. Blood samples were obtained before exercise (preexercise), every 15 min during the simulation (15, 30, 45, 60, 75, and 90 min), and 10 min into half-time. Preliminary testing confirmed test-retest repeatability of performance, physiological, and metabolic responses to 45 min of the SMS. Exercise influenced shooting precision (timing effect: P = .035) and passing speed (timing effect: P = .011), such that shots taken after exercise were 25.5 ± 4.0% less accurate than those taken before exercise and passes in the last 15 min were 7.8 ± 4.3% slower than in the first 15 min. Shot and pass speeds were slower during the second half compared with the first half (shooting: 17.3 ± 0.3 m·s-1 vs 16.6 ± 0.3 m·s-1, P = 0.012; passing: 13.0 ± 0.5 m·s-1 vs 12.2 ± 0.5 m·s-1, P = 0.039). Dribbling performance was unaffected by exercise. Blood lactate concentrations were elevated above preexercise values throughout exercise (time of sample effect: P < .001). These findings demonstrate that soccer-specific exercise influenced the quality of performance in gross motor skills, such as passing and shooting. Therefore, interventions to maintain skilled performance during the second half of soccer match play are warranted.


Discovery of 1-(phenylsulfonyl)-1H-indole-based multifunctional ligands targeting cholinesterases and 5-HT6 receptor with anti-aggregation properties against amyloid-beta and tau.
Multifunctional ligands as an essential variant of polypharmacology are promising candidates for the treatment of multi-factorial diseases like Alzheimer's disease. Based on clinical evidence and following the paradigm of multifunctional ligands we have rationally designed and synthesized a series of compounds targeting processes involved in the development of the disease. The biological evaluation led to the discovery of two compounds with favorable pharmacological characteristics and ADMET profile. Compounds 17 and 35 are 5-HT6R antagonists (Ki = 13 nM and Ki = 15 nM respectively) and cholinesterase inhibitors with distinct mechanisms of enzyme inhibition. Compound 17, a tacrine derivative is a reversible inhibitor of acetyl- and butyrylcholinesterase (IC50 = 8 nM and IC50 = 24 nM respectively), while compound 35 with rivastigmine-derived phenyl N-ethyl-N-methylcarbamate fragment is a selective, pseudo-irreversible inhibitor of butyrylcholinesterase (IC50 = 455 nM). Both compounds inhibit aggregation of amyloid β in vitro (75% for compound 17 and 68% for 35 at 10 μM) moreover, compound 35 is a potent tau aggregation inhibitor in cellulo (79%). In ADMET in vitro studies both compounds showed acceptable metabolic stability on mouse liver microsomes (28% and 60% for compound 17 and 35 respectively), no or little effect on CYP3A4 and 2D6 up to a concentration of 10 μM and lack of toxicity on HepG2 cell line (IC50 values of 80 and 21 μM, for 17 and 35 respectively). Based on the pharmacological characteristics and favorable pharmacokinetic properties, we propose compounds 17 and 35 as an excellent starting point for further optimization and in-depth biological studies.


Structure and dynamics of water in nanoscopic spheres and tubes.
We study the reorientation dynamics of liquid water confined in nanometer-sized reverse micelles of spherical and cylindrical shape. The size and shape of the micelles are characterized in detail using small-angle x-ray scattering, and the reorientation dynamics of the water within the micelles is investigated using GHz dielectric relaxation spectroscopy and polarization-resolved infrared pump-probe spectroscopy on the OD-stretch mode of dilute HDO:H2O mixtures. We find that the GHz dielectric response of both the spherical and cylindrical reverse micelles can be well described as a sum of contributions from the surfactant, the water at the inner surface of the reversed micelles, and the water in the core of the micelles. The Debye relaxation time of the core water increases from the bulk value τ(H2O) of 8.2 ± 0.1 ps for the largest reverse micelles with a radius of 3.2 nm to 16.0 ± 0.4 ps for the smallest micelles with a radius of 0.7 nm. For the nano-spheres the dielectric response of the water is approximately ∼6 times smaller than expected from the water volume fraction and the bulk dielectric relaxation of water. We find that the dielectric response of nano-spheres is more attenuated than that of nano-tubes of identical composition (water-surfactant ratio), whereas the reorientation dynamics of the water hydroxyl groups is identical for the two geometries. We attribute the attenuation of the dielectric response compared to bulk water to a local anti-parallel ordering of the molecular dipole moments. The difference in attenuation between nano-spheres and nano-cylinders indicates that the anti-parallel ordering of the water dipoles is more pronounced upon spherical than upon cylindrical nanoconfinement.


Assessing urban and rural neighborhood characteristics using audit and GIS data: derivation and reliability of constructs.
Measures to assess neighborhood environments are needed to better understand the salient features that may enhance outdoor physical activities, such as walking and bicycling for transport or leisure. The purpose of this study was to derive constructs to describe neighborhoods using both primary (neighborhood audit) and secondary (geographic information systems) data. We collected detailed information on 10,770 road segments using an audit and secondary data. The road segment sample was randomly split into an exploratory (60%) and validation sample (40%) for cross-validation. Using the exploratory sample (n = 6,388), seven a priori constructs were assessed separately (functionality, safety, aesthetics, destinations, incivilities, territorality, social spaces) by urbanicity using multi-group confirmatory factor analysis (CFA). Additionally, new a posteriori constructs were derived using exploratory factor analysis (EFA). For cross-validation (n = 4,382), we tested factor loadings, thresholds, correlated errors, and correlations among a posteriori constructs between the two subsamples. Two-week test-retest reliability of the final constructs using a subsample of road segments (n = 464) was examined using Spearman correlation coefficients. CFA indicated the a priori constructs did not hold in this geographic area, with the exception of physical incivilities. Therefore, we used EFA to derive a four-factor solution on the exploratory sample: arterial or thoroughfare, walkable neighborhood, physical incivilities, and decoration. Using CFA on the validation sample, the internal validity for these a posteriori constructs was high (range 0.43 to 0.73) and the fit was acceptable. Spearman correlations indicated the arterial or thoroughfare factor displayed near perfect reliability in both urban and rural segments (r = 0.96). Both the physical incivilities factor and the walkable neighborhood factor had substantial to near perfect reliability in both urban and rural segments (r = 0.77 to 0.78 and r = 0.79 to 0.82, respectively). The decoration factor displayed moderate reliability in urban segments (r = 0.50; 95% CI: 0.38-0.60) and lower reliability in rural segments (r = 0.39; 95% CI: 0.25-0.52). The results of our analyses yielded four reliably and objectively measured constructs that will be used to explore associations with physical activity in urban and rural North Carolina. These constructs should be explored in other geographic areas to confirm their usefulness elsewhere.


Ranking adverse drug reactions with crowdsourcing.
There is no publicly available resource that provides the relative severity of adverse drug reactions (ADRs). Such a resource would be useful for several applications, including assessment of the risks and benefits of drugs and improvement of patient-centered care. It could also be used to triage predictions of drug adverse events. The intent of the study was to rank ADRs according to severity. We used Internet-based crowdsourcing to rank ADRs according to severity. We assigned 126,512 pairwise comparisons of ADRs to 2589 Amazon Mechanical Turk workers and used these comparisons to rank order 2929 ADRs. There is good correlation (rho=.53) between the mortality rates associated with ADRs and their rank. Our ranking highlights severe drug-ADR predictions, such as cardiovascular ADRs for raloxifene and celecoxib. It also triages genes associated with severe ADRs such as epidermal growth-factor receptor (EGFR), associated with glioblastoma multiforme, and SCN1A, associated with epilepsy. ADR ranking lays a first stepping stone in personalized drug risk assessment. Ranking of ADRs using crowdsourcing may have useful clinical and financial implications, and should be further investigated in the context of health care decision making.


Phase Behavior of Mixed Lipid Monolayers on Perfluorocarbon Nanoemulsions and its Effect on Acoustic Contrast.
Lipid-stabilized nanoemulsions containing a volatile liquid perfluorocarbon core have been studied as ultrasound contrast agents owing to their ability to transform into high-contrast microbubbles when subjected to high intensity focused ultrasound (HIFU). However, while there have been several studies on the effect of acoustic parameters on contrast, the effect of the droplet's stabilizing shell has not been studied as extensively. Inspired by previous studies showing lateral phase separation in microbubbles and vesicles, nanodroplets were formulated with a perfluorohexane core and a shell composed of varying amounts of saturated (DPPC) phospholipids, unsaturated (DOPC) phospholipids, and cholesterol, which were fractionated to obtain nanodroplets of mean diameter 300-400 nm and were stable over one week. When the DOPC content was increased to 40 mol%, ultrasound contrast increased by about one order of magnitude over DPPC-only droplets. Based on fluorescence microscopy results of lateral lipid phase separation on the droplet surface, the various combinations of DPPC, DOPC, and cholesterol were assigned to three regimes on the ternary phase diagram: solid-liquid ordered (low contrast), liquid ordered-liquid disordered (medium contrast), and solid-liquid disordered (high contrast). These regimes were confirmed by TEM analysis of nanoscale droplets. Droplets containing mixed lipid monolayers were also found to produce a significantly greater yield than single-component droplets. The discovery of the dependence of acoustic response on lipid phase separation will help to understand the formulation, behavior, and vaporization mechanism of acoustically-responsive nanoemulsions.


The induction of tomato leucine aminopeptidase genes (LapA) after Pseudomonas syringae pv. tomato infection is primarily a wound response triggered by coronatine.
Tomato plants constitutively express a neutral leucine aminopeptidase (LAP-N) and an acidic LAP (LAP-A) during floral development and in leaves in response to insect infestation, wounding, and Pseudomonas syringae pv. tomato infection. To assess the physiological roles of LAP-A, a LapA-antisense construct (35S:asLapA1) was introduced into tomato. The 35S:asLapA1 plants had greatly reduced or showed undetectable levels of LAP-A and LAP-N proteins in healthy and wounded leaves and during floral development. Despite the loss of these aminopeptidases, no global changes in protein profiles were noted. The 35S:asLapA1 plants also exhibited no significant alteration in floral development and did not impact the growth and development of Manduca sexta and P. syringae pv. tomato growth rates during compatible or incompatible infections. To investigate the mechanism underlying the strong induction of LapA upon P. syringae pv. tomato infection, LapA expression was monitored after infection with coronatine-producing and -deficient P. syringae pv. tomato strains. LapA RNA and activity were detected only with the coronatine-producing P. syringae pv. tomato strain. Coronatine treatment of excised shoots caused increases in RNAs for jasmonic acid (JA)-regulated wound-response genes (LapA and pin2) but did not influence expression of a JA-regulated pathogenesis-related protein gene (PR-1). These results indicated that coronatine mimicked the wound response but was insufficient to activate JA-regulated PR genes.


Induction of DNA polymerase activities in the regenerating rat liver.
The levels of DNA polymerase alpha, DNA polymerase delta, and its accessory protein, proliferating cell nuclear antigen (PCNA) were examined in the regenerating rat liver. The levels of DNA polymerase alpha and delta activities in regenerating liver extracts were determined by the use of the DNA polymerase alpha specific inhibitor, BuAdATP [2-(p-n-butylanilino)-9-(2-deoxy-beta-D-ribofuranosyl) adenine 5'-triphosphate], and monoclonal antibodies. These reagents showed that the total DNA polymerase activities increased ca. 4-fold during regeneration and that the fraction of DNA polymerase delta activity at the peak was 40% of the total DNA polymerase activity. Immunoblots and inhibition studies using specific antibodies showed that DNA polymerase delta and epsilon and PCNA were concomitantly induced after partial hepatectomy. The levels of both DNA polymerase delta and epsilon and PCNA reached their maxima at 24-36 h post hepatectomy, i.e., at the same time that in vivo DNA synthesis reached its peak. Partial purification and characterization of DNA polymerases delta and epsilon from the regenerating rat liver were also performed. These observations suggest that the variation of DNA polymerase delta and epsilon and PCNA during liver regeneration is closely related to DNA synthesis and is consistent with their involvement in DNA replication.


Influence of false-positive mammography results on subsequent screening: do physician recommendations buffer negative effects?
Cancer screening guidelines often include discussion about the unintended negative consequences of routine screening. This prospective study examined effects of false-positive mammography results on women's adherence to subsequent breast cancer screening and psychological well-being. We also assessed whether barriers to screening exacerbated the effects of false-positive results. We conducted secondary analyses of data from telephone interviews and medical claims records for 2406 insured women. The primary outcome was adherence to screening guidelines, defined as adherent (10-14 months), delayed (15-34 months), or no subsequent mammogram on record. About 8% of women reported that their most recent screening mammograms produced false-positive results. In the absence of self-reported advice from their physicians to be screened, women were more likely to have no subsequent mammograms on record if they received false-positive results than if they received normal results (18% vs. 7%, OR = 3.17, 95% CI = 1.30, 7.70). Receipt of false-positive results was not associated with this outcome for women who said their physicians had advised regular screening in the past year (7% vs. 10%, OR = 0.74, 95% CI = 0.38, 1.45). False-positive results were associated with greater breast cancer worry (P < .01), thinking more about the benefits of screening (P < .001), and belief that abnormal test results do not mean women have cancer (P < .01), regardless of physicians' screening recommendations. False-positive mammography results, coupled with reports that women's physicians did not advise regular screening, could lead to non-adherence to future screening. Abnormal mammograms that do not result in cancer diagnoses are opportunities for physicians to stress the importance of regular screening.


Endothelin antagonism normalizes VEGF signaling and cardiac function in STZ-induced diabetic rat hearts.
Abnormal alterations in cardiac expression of vascular endothelial growth factor (VEGF) as well as its receptors and impairment in the development of coronary collaterals have recently been reported in diabetic subjects. However, the presence of pharmacological intervention on these defects in diabetes remains unsettled. Here, we studied the effect of endothelin (ET) receptor blockade on cardiac VEGF signaling pathways and cardiac function in Sprague-Dawley rats 5 wk after induction of type I diabetes with streptozotocin (65 mg/kg ip) in comparison with age-matched control rats. After streptozotocin (1 wk), some diabetic rats were treated with the ET receptor antagonist SB-209670 (1 mg/day) for 4 wk. VEGF, its receptors, and its angiogenic signaling molecules [phosphorylated Akt and endothelial nitric-oxide synthase (eNOS)] were analyzed by Western blot, ELISA, real-time PCR, and immunohistochemistry, and cardiac function was evaluated by echocardiography. Coronary capillary morphology was assessed by lectin and enzymatic double staining. We found significant decreases in cardiac expression of VEGF, its receptors, phosphorylation of Akt and eNOS, and coronary capillary density in diabetic rats compared with controls. Treatment of diabetic rats with SB-209670 reversed these alterations to the control levels and ameliorated impairment of cardiac function. From a molecular point of view, the present study is the first to indicate the potential usefulness of an ET receptor antagonist in the treatment of cardiac dysfunction in type I diabetes.


Alternative carbon price trajectories can avoid excessive carbon removal.
The large majority of climate change mitigation scenarios that hold warming below 2 °C show high deployment of carbon dioxide removal (CDR), resulting in a peak-and-decline behavior in global temperature. This is driven by the assumption of an exponentially increasing carbon price trajectory which is perceived to be economically optimal for meeting a carbon budget. However, this optimality relies on the assumption that a finite carbon budget associated with a temperature target is filled up steadily over time. The availability of net carbon removals invalidates this assumption and therefore a different carbon price trajectory should be chosen. We show how the optimal carbon price path for remaining well below 2 °C limits CDR demand and analyze requirements for constructing alternatives, which may be easier to implement in reality. We show that warming can be held at well below 2 °C at much lower long-term economic effort and lower CDR deployment and therefore lower risks if carbon prices are high enough in the beginning to ensure target compliance, but increase at a lower rate after carbon neutrality has been reached.


Multicenter Outcomes of Endoscopic Pubic Symphysectomy for Osteitis Pubis Associated With Femoroacetabular Impingement.
To investigate outcomes of athletic patients treated with concurrent femoroacetabular impingement (FAI) and osteitis pubis (OP) surgery including endoscopic pubic symphysectomy. We performed a multicenter retrospective case series of 7 consecutive adult patients (4 men) with a mean age of 33 years with symptomatic FAI and OP who underwent arthroscopic surgery for the former and endoscopic pubic symphysectomy for the latter with a mean follow-up period of 2.9 years (range, 2.0 to 5.0 years). The visual analog scale (VAS) score, the Non-Arthritic Hip Score (NAHS), and patient satisfaction were measured. Complications and revision surgical procedures were reported, and preoperative and postoperative radiographs were assessed. The mean preoperative VAS score of 6.7 (range, 4 to 8) improved to a mean postoperative VAS score of 1.5 (range, 0 to 7) (P = .03). The mean preoperative NAHS of 50.2 points (range, 21 to 78 points) improved to a mean postoperative NAHS of 84.7 points (range, 41 to 99 points) (P = .03). The mean patient satisfaction rating was 8.3 (range, 3 to 10). Two male patients had postoperative scrotal swelling that resolved spontaneously. There were no other complications. Preoperative and postoperative radiographs showed no anterior or posterior pelvic ring instability. One patient underwent pubic symphyseal arthrodesis because of continued pain. Endoscopic pubic symphysectomy is a minimally invasive treatment for athletic OP with encouraging early outcomes that may be performed concurrently with surgery for FAI in co-afflicted patients. Level IV, therapeutic case series.


Postoperative suprachoroidal hemorrhage following filtration procedures.
We reviewed the charts of 500 patients who underwent filtration procedures and found ten patients who developed postoperative suprachoroidal hemorrhage (PSCH) following surgery. The incidence (2% overall) is especially high in those patients who were aphakic (6.6%) or who had high myopia (10%). Nine patients developed PSCH within the first four postoperative days. Pain, nausea, and vomiting were common presenting symptoms of PSCH although not invariably present. Postoperative suprachoroidal hemorrhage is related to prolonged hypotonia and inflammation; prevention centers on proper case selection and on avoiding a precipitous rise in postoperative intravascular pressure. Initial treatment consisted of anterior chamber reformation and drainage of suprachoroidal blood, often followed by vitrectomy and scleral buckling procedures. Four eyes (40%) obtained final visual acuities of 20/200 or better, four (40%) were reduced to counting fingers or hand motions, and two (20%) lost all light perception.


Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer.
The primary purpose of this study was to evaluate the effect of CYP2C8*3 and three genetic ABCB1 variants on the elimination of paclitaxel. We studied 93 Caucasian women with ovarian cancer treated with paclitaxel and carboplatin. Using sparse sampling and nonlinear mixed effects modeling, the individual clearance of unbound paclitaxel was estimated from total plasma paclitaxel and Cremophor EL. The geometric mean of clearance was 385 l h⁻¹ (range 176-726 l h⁻¹). Carriers of CYP2C8*3 had 11% lower clearance than non-carriers, P=0.03. This has not been shown before in similar studies; the explanation is probably the advantage of using both unbound paclitaxel clearance and a population of patients of same gender. No significant association was found for the ABCB1 variants C1236T, G2677T/A and C3435T. Secondarily, other candidate single-nucleotide polymorphisms were explored with possible associations found for CYP2C8*4 (P=0.04) and ABCC1 g.7356253C>G (P=0.04).


Differential effects of fasting vs food restriction on liver thyroid hormone metabolism in male rats.
A variety of illnesses that leads to profound changes in the hypothalamus-pituitary-thyroid (HPT) are axis collectively known as the nonthyroidal illness syndrome (NTIS). NTIS is characterized by decreased tri-iodothyronine (T3) and thyroxine (T4) and inappropriately low TSH serum concentrations, as well as altered hepatic thyroid hormone (TH) metabolism. Spontaneous caloric restriction often occurs during illness and may contribute to NTIS, but it is currently unknown to what extent. The role of diminished food intake is often studied using experimental fasting models, but partial food restriction might be a more physiologically relevant model. In this comparative study, we characterized hepatic TH metabolism in two models for caloric restriction: 36 h of complete fasting and 21 days of 50% food restriction. Both fasting and food restriction decreased serum T4 concentration, while after 36-h fasting serum T3 also decreased. Fasting decreased hepatic T3 but not T4 concentrations, while food restriction decreased both hepatic T3 and T4 concentrations. Fasting and food restriction both induced an upregulation of liver D3 expression and activity, D1 was not affected. A differential effect was seen in Mct10 mRNA expression, which was upregulated in the fasted rats but not in food-restricted rats. Other metabolic pathways of TH, such as sulfation and UDP-glucuronidation, were also differentially affected. The changes in hepatic TH concentrations were reflected by the expression of T3-responsive genes Fas and Spot14 only in the 36-h fasted rats. In conclusion, limited food intake induced marked changes in hepatic TH metabolism, which are likely to contribute to the changes observed during NTIS.


Iron Oxide Nanoparticles Coated with a Phosphorothioate Oligonucleotide and a Cationic Peptide: Exploring Four Different Ways of Surface Functionalization.
The superparamagnetic iron oxide nanoparticles (SPIONs) have great potential in therapeutic and diagnostic applications. Due to their superparamagnetic behavior, they are used clinically as a Magnetic Resonance Imaging (MRI) contrast agent. Iron oxide nanoparticles are also recognized todays as smart drug-delivery systems. However, to increase their specificity, it is essential to functionalize them with a molecule that effectively targets a specific area of the body. Among the molecules that can fulfill this role, peptides are excellent candidates. Oligonucleotides are recognized as potential drugs for various diseases but suffer from poor uptake and intracellular degradation. In this work, we explore four different strategies, based on the electrostatic interactions between the different partners, to functionalize the surface of SPIONs with a phosphorothioate oligonucleotide (ODN) and a cationic peptide labeled with a fluorophore. The internalization of the nanoparticles has been evaluated in vitro on RAW 264.7 cells. Among these strategies, the "«one-step assembly»", i.e., the direct complexation of oligonucleotides and peptides on iron oxide nanoparticles, provides the best way of coating for the internalization of the nanocomplexes.


Family history, ethnicity, and relative risk of breast cancer in a prospective cohort study of older women.
In a cohort of 27,578 postmenopausal Iowa women, we examined whether the risk with a family history of breast cancer differs by self-reported ethnicity. A total of 1042 breast cancer cases occurred over 10 years of follow-up. Using a phylogenetic tree, ethnicities were combined into five groups: Scandinavian; English, Scottish, Welsh, and Dutch (ESWD); Irish; German; and Other European. The incidence of breast cancer did not differ significantly by ethnicity, although the highest rates were observed among Scandinavian women (488 per 100,000 per year) and the lowest among Irish women (353 per 100,000 per year). The prevalence of a family history of breast cancer was not significantly associated with ethnicity when only first-degree relatives were considered (P = 0.17), but inclusion of data on second-degree relatives increased the statistical significance of the association (P = 0.003). Differences in mean levels of breast cancer risk factors between ethnicities were generally small but statistically significant. Proportional hazards regression was performed to evaluate potential interactions of family history with ethnicity on breast cancer incidence. A family history of breast cancer was associated with increased relative risks among ESWD, Germans, and Other Europeans but not among Irish and Scandinavians. Relative risk estimates were not attenuated upon addition of known breast cancer risk factors to the model, implying that the distribution of these risk factors by ethnicity is unlikely to explain some of the observed ethnic-specific differences between family history and risk of breast cancer. Results of this study could have implications for studies of common genetic polymorphisms and cancer risk.