Oxygenation Threshold Derived from Near-Infrared Spectroscopy: Reliability and Its Relationship with the First Ventilatory Threshold.
Near-infrared spectroscopy (NIRS) measurements of oxygenation reflect O2 delivery and utilization in exercising muscle and may improve detection of a critical exercise threshold. First, to detect an oxygenation breakpoint (Δ[O2HbMb-HHbMb]-BP) and compare this breakpoint to ventilatory thresholds during a maximal incremental test across sexes and training status. Second, to assess reproducibility of NIRS signals and exercise thresholds and investigate confounding effects of adipose tissue thickness on NIRS measurements. Forty subjects (10 trained male cyclists, 10 trained female cyclists, 11 endurance trained males and 9 recreationally trained males) performed maximal incremental cycling exercise to determine Δ[O2HbMb-HHbMb]-BP and ventilatory thresholds (VT1 and VT2). Muscle haemoglobin and myoglobin O2 oxygenation ([HHbMb], [O2HbMb], SmO2) was determined in m. vastus lateralis. Δ[O2HbMb-HHbMb]-BP was determined by double linear regression. Trained cyclists performed the maximal incremental test twice to assess reproducibility. Adipose tissue thickness (ATT) was determined by skinfold measurements. Δ[O2HbMb-HHbMb]-BP was not different from VT1, but only moderately related (r = 0.58-0.63, p<0.001). VT1 was different across sexes and training status, whereas Δ[O2HbMb-HHbMb]-BP differed only across sexes. Reproducibility was high for SmO2 (ICC = 0.69-0.97), Δ[O2HbMb-HHbMb]-BP (ICC = 0.80-0.88) and ventilatory thresholds (ICC = 0.96-0.99). SmO2 at peak exercise and at occlusion were strongly related to adipose tissue thickness (r2 = 0.81, p<0.001; r2 = 0.79, p<0.001). Moreover, ATT was related to asymmetric changes in Δ[HHbMb] and Δ[O2HbMb] during incremental exercise (r = -0.64, p<0.001) and during occlusion (r = -0.50, p<0.05). Although the oxygenation threshold is reproducible and potentially a suitable exercise threshold, VT1 discriminates better across sexes and training status during maximal stepwise incremental exercise. Continuous-wave NIRS measurements are reproducible, but strongly affected by adipose tissue thickness.


Topoisomerase II-mediated DNA breaks and cytotoxicity in relation to cell proliferation and the cell cycle in NIH 3T3 fibroblasts and L1210 leukemia cells.
The DNA intercalator, 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) and the nonintercalator, etoposide (VP-16) produce topoisomerase II-mediated protein-linked DNA strand breaks. This function of topoisomerase II was investigated in relation to cell proliferation and cell cycle. Mouse fibroblasts NIH 3T3 and mouse leukemia L1210 cells stop proliferation when they reach a certain density. Nuclei were isolated from proliferative or quiescent cells and then treated with drug for 30 min. DNA modifications were assayed by alkaline elution. We found that the frequencies of m-AMSA- or VP-16-induced DNA-protein links were higher in nuclei from exponentially growing than in those from quiescent cells in both the 3T3 and the L1210 lines. Drug-induced protein-associated DNA breaks were also studied as a function of the cell cycle in 3T3 cells that had been arrested by contact inhibition in medium containing 1% calf serum and then stimulated to proliferate by raplating at a lower cell density in medium containing 10% serum. In these synchronized cells, a large peak of [3H]thymidine incorporation occurred 18-30 h after replating. The yield of DNA-protein cross-links produced by 30-min drug treatments of nuclei isolated at various times after growth initiation increased concomitantly with the peak of the DNA synthesis. The topoisomerase II activity of nuclear extracts, as measured by kinetoplast DNA decatenation followed a similar pattern. Using colony-forming assays, we also observed that m-AMSA and VP-16 were most cytotoxic in proliferative cells and during DNA synthesis. These results suggest that alkaline elution measurement of m-AMSA- or VP-16-induced protein-linked DNA breaks reflects the association of topoisomerase II with DNA. This association is increased during DNA replication, making the cells more vulnerable to m-AMSA and VP-16 at this time.


Silicon on ultra-low-loss waveguide photonic integration platform.
We demonstrate a novel integrated silicon and ultra-low-loss Si3N4 waveguide platform. Coupling between layers is achieved with (0.4 ± 0.2) dB of loss per transition and a 20 nm 3-dB bandwidth for one tapered coupler design and with (0.8 ± 0.2) dB of loss per transition and a 100 nm 3-dB bandwidth for another. The minimum propagation loss measured in the ultra-low-loss waveguides is 1.2 dB/m in the 1590 nm wavelength regime.


Vascular access related septicemia in hemodialysis: a focus on bacterial flora and antibiotic access salvage.
A good vascular access is the lifeline of patients on long-term hemodialysis (HD) and anteriovenous fistula is considered the ideal access. Vascular access related septicemia (VARS) is the second most common cause of mortality among HD patients. Such infections could also lead to loss of vascular access unless specific measures are taken to preserve the accesses. The present study was designed to determine the incidence of septicemia, common bacterial flora involved, and impact of early, empirical antibiotic therapy on vascular access salvage among HD patients. This prospective study, involved 209 patients, undergoing long-term HD, from June 1996 to June 2000. A total of 85 (40.6%) developed VARS with predominance in females (63.7%), patients above 50 years of age (37.0%) and those having diabetes mellitus (25.1%). A total of 124 episodes of septicemia were recorded with an average of 1.23 episodes per 100 patient-months during the four year (10032 patient-months) study period. Peripheral blood samples for culture and sensitivity were collected and the patients were started empirically on amikacin-vancomycin combination which was modified after obtaining culture and sensitivity results. A cure was defined as 45 days symptom-free interval after antibiotic therapy was completed. Staphylococcus aureus was the commonest (29.0%) organism associated with VARS, followed by Pseudomonas aeruginosa (15.3%). The temporary vascular access group recorded maximum number of VARS episodes; [femoral catheter (FC) group, (43.5%), followed by subclavian (SC) group, (28.2%)] and the lowest (8.8%) was seen in the AVF group. Vascular access salvage rate of 48/85 (56.4%) and mortality of 22/85 (25.9%) was observed in the present study. Antibiotic access salvage with Amikacin-Vancomycin combination has an advantage of preserving vascular access sites in at least, 50% of cases.


Optimization of photonic crystal structures.
We report on the numerical structural optimization of two-dimensional photonic crystal (PhC) power dividers by using two different classes of optimization algorithms, namely, a modified truncated Newton (TN) gradient search as deterministic local optimization scheme and an evolutionary optimization representing the probabilistic global search strategies. Because of the severe accuracy requirements during optimization, the proper PhC device has been simulated by using the multiple-multipole program that is contained in the MaX-1 software package. With both optimizer classes, we found reliable and promising solutions that provide vanishing power reflection and perfect power balance at any specified frequency within the photonic bandgap. This outcome is astonishing in light of the discrete nature inherent in the underlying PhC structure, especially when the optimizer is allowed to intervene only within a very small volume of the device. Even under such limiting constraints structural optimization is not only feasible but has proven to be highly successful.


Beta-endorphin in experimental canine spinal ischemia.
Plasma and cerebrospinal fluid beta-endorphin concentrations were radioimmunologically assayed in dogs subjected to spinal cord ischemia induced by infrarenal aortic ligature and in control sham-operated dogs. Plasma beta-endorphin levels rose significantly following surgery in control dogs but were unaffected by spinal ischemia. On the other hand, a significant increase in cerebrospinal fluid beta-endorphin concentration occurred after spinal ischemia, while surgical stress had no significant effect. Thus, the origins of plasma and cerebrospinal fluid beta-endorphin may be different, with the former secreted from the hypophysis and the latter from nervous tissue. Observed changes in cerebrospinal fluid beta-endorphin concentration could be related to the ischemic lesion of nervous tissue while the changes in plasma levels may reflect general stressing factors such as the surgery in our experiments.


Optimizing design efficiency of free recall events for FMRI.
Free recall is a fundamental paradigm for studying memory retrieval in the context of minimal cue support. Accordingly, free recall has been extensively studied using behavioral methods. However, the neural mechanisms that support free recall have not been fully investigated due to technical challenges associated with probing individual recall events with neuroimaging methods. Of particular concern is the extent to which the uncontrolled latencies associated with recall events can confer sufficient design efficiency to permit neural activation for individual conditions to be distinguished. The present study sought to rigorously assess the feasibility of testing individual free recall events with fMRI. We used both theoretically and empirically derived free recall latency distributions to generate simulated fMRI data sets and assessed design efficiency across a range of parameters that describe free recall performance and fMRI designs. In addition, two fMRI experiments empirically assessed whether differential neural activation in visual cortex at onsets determined by true free recall performance across different conditions can be resolved. Collectively, these results specify the design and performance parameters that can provide comparable efficiency between free recall designs and more traditional jittered event-related designs. These findings suggest that assessing BOLD response during free recall using fMRI is feasible, under certain conditions, and can serve as a powerful tool in understanding the neural bases of memory search and overt retrieval.


Microbiologic characterization and antimicrobial susceptibility of Clostridium tetani isolated from wounds of patients with clinically diagnosed tetanus.
Clostridium tetani is the etiologic agent of the muscle-spasming disease tetanus. Despite an effective vaccine, tetanus is an ongoing problem in some developing countries. Diagnosis by bacterial culture is not done because it is generally unnecessary and the entry of route of the bacteria can be inapparent. We attempted to isolate and evaluate C. tetani from the wounds of 84 patients with tetanus. We effectively isolated C. tetani from 45 patients. All strains tested positive by polymerase chain reaction for the gene encoding tetanus neurotoxin. Antimicrobial susceptibilities were determined by disc diffusion and E-test. All C. tetani isolates were susceptible to penicillin and metronidazole but resistant to co-trimoxazole. Despite treatment with high doses of penicillin, C. tetani was isolated after 16 days of intravenous penicillin in two cases. These data show that the intravenous route for penicillin may be inadequate for clearing the infection and emphasizes wound debridement in the treatment of tetanus.


Connective tissue mast cells exhibit time-dependent degranulation heterogeneity.
Previous studies have identified two ultrastructurally distinct forms of mast cell (MC) degranulation following activation. Immunoglobulin E (IgE)-mediated reactions are characterized by a very rapid swelling and fusion of MC granules and abrupt mediator release. In certain chronic disease states (e.g., bullous pemphigoid), there is "piecemeal" degranulation with a more-gradual mediator release effected by microvesicular transport of "pieces" of granules to the cell surface. It is unclear whether these two degranulation patterns are determined by the different natures of the stimuli, heterogeneity among responding MC granules, or temporal factors. To investigate these issues, we have carried out electron microscopic studies with skin biopsies obtained from ragweed-sensitive subjects 15 and 30 s and 1, 3, 5, and 10 min after intradermal ragweed injection. "Anaphylactic"-type granule changes began by 15 s after ragweed injection and were complete by 5 min; unaffected granules were juxtaposed with granules that were swollen and fused. The remaining granules subsequently underwent changes in appearance similar to those seen in piecemeal degranulation. However, microvesicular transport of granule components to the surface was not observed. These findings indicate that skin MC changes in sites of IgE-mediated reactions include not only the typical very rapid anaphylactic degranulation but also a slower onset of gradual alteration of other granules, frequently within the same MC. These different patterns could reflect MC granule heterogeneity with attendant different responses to IgE-mediated stimuli.


Hyperthermia in soft tissue sarcoma.
Patients with high-risk soft tissue sarcomas (STS)-FNCLCC grade 2-3, size >5 cm, deep to the fascia-are at risk for developing local recurrence and distant metastasis despite surgical tumor resection. Therefore, the management of high-risk STS requires a multidisciplinary approach. Besides surgery, radiotherapy, and chemotherapy, regional hyperthermia (RHT) has the potential to become the fourth standard treatment modality for the treatment of these patients. RHT means non-invasive selective heating of the tumor area to temperatures within the range of 40-43°C for 60 min by the use of an electromagnetic heating device. Thereby RHT is always applied in addition to radiotherapy or chemotherapy or both but is not effective as a single treatment. Beside direct cytotoxicity, RHT in combination with chemotherapy enhances the drug cytotoxicity mainly by increased chemical reaction and intratumoral drug accumulation. For the neoadjuvant setting, RHT in combination with a doxorubicin- and ifosfamide-based chemotherapy has been shown to dramatically improve the tumor response rate but also prevents from early disease progression as compared to chemotherapy alone. The addition of RHT to a multimodal treatment of high-risk STS consisting of surgery, radiotherapy, and chemotherapy either in the neoadjuvant setting but also after incomplete or marginal tumor resection has been shown to significantly improve local recurrence- and disease-free survival. Based on these results and in conjunction with the low RHT-related toxicity, RHT combined with preoperative or postoperative chemotherapy should be considered as an additional standard treatment option for the multidisciplinary treatment of locally advanced high-grade STS.


Evaluation of Tobacco Control Measures in the Organization for Economic Co-operation and Development Countries: A Comparative Study Using Data Envelopment Analysis.
This study aimed to measure the efficiency and productivity of tobacco control policies across 16 selected Organization for Economic Co-operation and Development (OECD) countries from 2008 to 2014. A panel-data study. Data envelopment analysis was used in this study. Taxation on tobacco products and pictorial warning labels were chosen as the inputs. Percentage of the population of daily smokers above 15 years old and the number of cigarettes used per smoker per day were output variables. Additionally, the Malmquist total factor productivity (TFP) was used to analyze the panel data and measure productivity change and technical efficiency changes over time. The highest technical efficiency score (1.05) was attributed to Norway, while the lowest (0.91) belonged to the UK. Technological change with a total mean of 1.06 implied that the technology and creativity have increased, while countries have been able to promote their creativity over the studied period. Norway with the TFP score of 1.15 was the most productive country, while the UK and Turkey with TFP scores of 0.95 and 0.98, respectively, were the least productive countries in terms of the implementation of the tobacco control policies. Most OECD countries have productively implemented tax and pictorial warning policies to reduce tobacco use. To achieve the optimum outcome of the tobacco control policies and overcome the challenges of smoking use, countries need to tackle the difficult underlying factors, i.e. tobacco industry opposition and lobbyists, smuggling, and low socioeconomic status.


High-grade glioma diffusive modeling using statistical tissue information and diffusion tensors extracted from atlases.
Glioma, especially glioblastoma, is a leading cause of brain cancer fatality involving highly invasive and neoplastic growth. Diffusive models of glioma growth use variations of the diffusion-reaction equation in order to simulate the invasive patterns of glioma cells by approximating the spatiotemporal change of glioma cell concentration. The most advanced diffusive models take into consideration the heterogeneous velocity of glioma in gray and white matter, by using two different discrete diffusion coefficients in these areas. Moreover, by using diffusion tensor imaging (DTI), they simulate the anisotropic migration of glioma cells, which is facilitated along white fibers, assuming diffusion tensors with different diffusion coefficients along each candidate direction of growth. Our study extends this concept by fully exploiting the proportions of white and gray matter extracted by normal brain atlases, rather than discretizing diffusion coefficients. Moreover, the proportions of white and gray matter, as well as the diffusion tensors, are extracted by the respective atlases; thus, no DTI processing is needed. Finally, we applied this novel glioma growth model on real data and the results indicate that prognostication rates can be improved.


Multiple sclerosis and environmental factors: the role of vitamin D, parasites, and Epstein-Barr virus infection.
Pathogenic mechanisms underlying multiple sclerosis development have yet to be clearly identified, but considerable evidence indicates that autoimmunity plays an important role in the etiology of the disease. It is generally accepted that autoimmune diseases like MS arise from complex interactions between genetic susceptibility and environmental factors. Although environmental factors unequivocally influencing MS development have yet to be established, accumulating evidence singles out several candidates, including sunlight-UV exposure or vitamin D deficiency, viral infections, hygiene, and cigarette smoking. Vitamin D deficiency has been associated with different autoimmune diseases. Several investigations indicate 125 (OH)2 vitamin D plays a critical role in shaping T-cell response and inducing T cells with immunosuppressive properties. Likewise, helminth infections represent another potential environmental factor exerting immunomodulatory properties. Both epidemiological and experimental data provide evidence to support autoimmune down-regulation secondary to parasite infections in patients with MS, through regulatory T- and B-cell action, with effects extending beyond simple response to an infectious agent. Finally, different epidemiological studies have demonstrated that Epstein-Barr virus infection confers added risk of developing MS. Proposed mechanisms responsible for this association include activation and expansion of self-reactive T and B cells, lower threshold for self-tolerance breakdown, and enhanced autoreactive B-cell survival, all to be discussed in this review. Understanding environmental factors influencing propensity to MS will lead to new and more effective approaches to prevent and treat the disease.


Get some respect - buy organic foods! When everyday consumer choices serve as prosocial status signaling.
Status considerations have recently been linked to prosocial behaviors. This research shows that even everyday consumer behaviors such as favoring organic foods serve as prosocial status signaling. Key ideas from the continuum model of consumer impression formation and the theories of costly signaling and symbolic consumption are synthetized to make sense of this phenomenon. Two web-surveys (Ns = 187, 259) and a field study (N = 336) following experimental designs are conducted. This approach allows the analysis of both the more and less conscious reactions of consumers. Study 1 shows that the image of consumers favoring organic product versions is marked by characteristics consistent with prosocial status signaling. Study 2 replicates these findings with another sample and a wider range of products and demonstrate that observers' conservative values influence the image formed of organic food users. Study 3 establishes that similar image effects also emerge through a less conscious formation process and that they extend to how organic food users are socially treated. This research advances the current understanding concerning the interlinkages between organic food usage, prosocial status signaling, consumer impressions and reputation management. Substantively, the studies provide novel compelling empirical evidence for the ability of non-luxurious everyday consumer behaviors to qualify as prosocial status signaling. Conceptually, the integration of evolutionary and sociocultural perspectives represents a major contribution. More specifically, this research yields new understanding as regards the role of individual variation in sensing and interpreting status symbols.


Assessment of Bone Health in Patients With Type 1 Gaucher Disease Using Impact Microindentation.
Gaucher disease (GD), one of the most common lysosomal disorders (a global population incidence of 1:50,000), is characterized by beta-glucocerebrosidase deficiency. Some studies have demonstrated bone infiltration in up to 80% of patients, even if asymptomatic. Bone disorder remains the main cause of morbidity in these patients, along with osteoporosis, avascular necrosis, and bone infarcts. Enzyme replacement therapy (ERT) has been shown to improve these symptoms. This cross-sectional study included patients with type 1 Gaucher disease (GD1) selected from the Catalan Study Group on GD. Clinical data were collected and a general laboratory workup was performed. Bone mineral density (BMD) was measured at the lumbar spine and hip using dual-energy X-ray absorptiometry (DXA). Patients with bone infarcts or any other focal lesion in the area of indentation visible on imaging were excluded. Bone Material Strength index (BMSi) was measured by bone impact microindentation using an Osteoprobe instrument. Analysis of covariance (ANCOVA) models were fitted to adjust for age, sex, weight, and height. Sixteen patients with GD1 and 29 age- and sex-matched controls were included. GD1 was associated with significantly lower BMSi (adjusted beta -9.30; 95% CI, -15.18 to -3.42; p = 0.004) and reduced lumbar BMD (adjusted beta -0.14; 95% CI, -0.22 to -0.06; p = 0.002) and total hip BMD (adjusted beta -0.09; 95% CI, -0.15 to -0.03; p = 0.006), compared to GD1-free controls. Chitotriosidase levels were negatively correlated with BMSi (linear R2 = 51.6%, p = 0.004). Bone tissue mechanical characteristics were deteriorated in patients with GD1. BMSi was correlated with chitotriosidase, the marker of GD activity. Bone disorder requires special consideration in this group of patients, and microindentation could be an appropriate tool for assessing and managing their bone health. © 2017 American Society for Bone and Mineral Research.


Ensuring the data-rich future of the social sciences.
Massive increases in the availability of informative social science data are making dramatic progress possible in analyzing, understanding, and addressing many major societal problems. Yet the same forces pose severe challenges to the scientific infrastructure supporting data sharing, data management, informatics, statistical methodology, and research ethics and policy, and these are collectively holding back progress. I address these changes and challenges and suggest what can be done.


Functional characterization and transcriptome analysis of embryonic stem cell-derived contractile smooth muscle cells.
Complete transcriptome profiling of contractile smooth muscle cells (SMCs) differentiated from embryonic stem cells is crucial for the characterization of smooth muscle gene expression signatures and will contribute to defining biological and physiological processes in these cells. We have generated a transgenic embryonic stem cell line expressing both the puromycin acetyl transferase and enhanced green fluorescent protein cassettes under the control of the Acta2 promoter. Applying a specific monolayer culture protocol using retinoic acid, a puromycin-resistant and enhanced green fluorescent protein-positive Acta2(+) SMC population of 95% purity was isolated. Acta2(+) SMCs were characterized by semiquantitative and quantitative RT-PCR profiling of SMC markers and by microarray expression profiling, as well as by immunostaining for SMC-specific cytoskeletal proteins. Patch-clamp electrophysiological characterization of these cells identified SMC-specific channels such as the ATP-sensitive potassium channel and the Ca(2+)-activated potassium channel. Culturing of Acta2(+) SMCs in serum-containing medium resulted in a significant number of hypertrophic and binucleated cells failing to complete cell division. Functional characterization of the cells has been proved by stimulation of the cells with vasoactive agents, such as angiotensin II and endothelin. We concluded that our embryonic stem cell-derived SMC population possesses the contractile and hypertrophic phenotype of SMCs incapable of proliferation. This is the first study describing the complete transcriptome of ES-derived SMCs allowing identification of specific biological and physiological processes in the contractile phenotype SMCs and will contribute to the understanding of these processes in early SMCs derived from embryonic stem cells.


Nanomaterials for the optical detection of fluoride.
Overexposure to fluoride ions (F-) causes serious diseases in human beings. Extensive efforts have been made to develop sensitive and selective approaches for F- detection and a variety of F- sensors have been constructed recently. The burgeoning nanotechnology has provided novel materials for F- analysis due to the extraordinary properties of nanomaterials. In this review, we present the recent advances in different nanomaterials-based approaches for the optical F- detection via colorimetric, fluorescent and chemiluminescent responses. The materials include gold nanomaterials, CeO2 nanoparticles, semiconductor quantum dots, carbon quantum dots, metal-organic frameworks, upconversion nanoparticles, micellar nanoparticles, polymer dots, SiO2 nanoparticles and graphene oxide. The recent trends and challenges in the optical detection of F- with various nanomaterials are also discussed.


Identifying genetic loci and spleen gene coexpression networks underlying immunophenotypes in BXD recombinant inbred mice.
The immune system plays a pivotal role in the susceptibility to and progression of a variety of diseases. Due to a strong genetic basis, heritable differences in immune function may contribute to differential disease susceptibility between individuals. Genetic reference populations, such as the BXD (C57BL/6J × DBA/2J) panel of recombinant inbred (RI) mouse strains, provide unique models through which to integrate baseline phenotypes in healthy individuals with heritable risk for disease because of the ability to combine data collected from these populations across both multiple studies and time. We performed basic immunophenotyping (e.g., percentage of circulating B and T lymphocytes and CD4(+) and CD8(+) T cell subpopulations) in peripheral blood of healthy mice from 41 BXD RI strains to define the immunophenotypic variation in this strain panel and to characterize the genetic architecture that underlies these traits. Significant QTL models that explained the majority (50-77%) of phenotypic variance were derived for each trait and for the T:B cell and CD4(+):CD8(+) ratios. Combining QTL mapping with spleen gene expression data uncovered two quantitative trait transcripts, Ptprk and Acp1, as candidates for heritable differences in the relative abundance of helper and cytotoxic T cells. These data will be valuable in extracting genetic correlates of the immune system in the BXD panel. In addition, they will be a useful resource for prospective, phenotype-driven model selection to test hypotheses about differential disease or environmental susceptibility between individuals with baseline differences in the composition of the immune system.


Determination of protein binding affinities within hydrogel-based molecularly imprinted polymers (HydroMIPs).
Hydrogel-based molecularly imprinted polymers (HydroMIPs) were prepared for several proteins (haemoglobin, myoglobin and catalase) using a family of acrylamide-based monomers. Protein affinity towards the HydroMIPs was investigated under equilibrium conditions and over a range of concentrations using specific binding with Hill slope saturation profiles. We report HydroMIP binding affinities, in terms of equilibrium dissociation constants (Kd) within the micro-molar range (25 ± 4 μM, 44 ± 3 μM, 17 ± 2 μM for haemoglobin, myoglobin and catalase respectively within a polyacrylamide-based MIP). The extent of non-specific binding or cross-selectivity for non-target proteins has also been assessed. It is concluded that both selectivity and affinity for both cognate and non-cognate proteins towards the MIPs were dependent on the concentration and the complementarity of their structures and size. This is tentatively attributed to the formation of protein complexes during both the polymerisation and rebinding stages at high protein concentrations. We have used atomic force spectroscopy to characterize molecular interactions in the MIP cavities using protein-modified AFM tips. Attractive and repulsive force curves were obtained for the MIP and NIP (non-imprinted polymer) surfaces (under protein loaded or unloaded states). Our force data suggest that we have produced selective cavities for the template protein in the MIPs and we have been able to quantify the extent of non-specific protein binding on, for example, a non-imprinted polymer (NIP) control surface.


Fast and quiet MRI using a swept radiofrequency.
A novel fast and quiet method of magnetic resonance imaging (MRI) is introduced which creates new opportunities for imaging in medicine and materials science. The method is called SWIFT, sweep imaging with Fourier transformation. In SWIFT, time-domain signals are acquired in a time-shared manner during a swept radiofrequency excitation of the nuclear spins. With negligible time between excitation and signal acquisition, new possibilities exist for imaging objects consisting of spins with extremely fast transverse relaxation rates, such as macromolecules, semi-solids, and quadrupolar nuclei. The field gradient used for spatial-encoding is not pulsed on and off, but rather is stepped in orientation in an incremental manner, which results in low acoustic noise. This unique acquisition method is expected to be relatively insensitive to sample motion, which is important for imaging live objects. Additionally, the frequency-swept excitation distributes the signal energy in time and thus dynamic range requirements for proper signal digitization are reduced compared with conventional MRI. For demonstration, images of a plastic object and cortical bone are shown.


Peer Victimization and DRD4 Genotype Influence Problem Behaviors in Young Children.
Decades of research supports the presence of significant genetic influences on children's internalizing (emotional), externalizing (acting out), and social difficulties, including victimization. Additionally, being victimized has been shown to relate to further behavioral problems. The current study assessed the nature of the gene-environment relationships between the DRD4 gene, peer victimization, and externalizing and internalizing difficulties in 6- to 10-year-old children. 174 children (56 % girls; 88.6 % Caucasian, 3.4 % African American, 8 % mixed race or Mayan) and their parents were administered victimization and problem behavior questionnaires, and DRD4 was genotyped for the children. An interaction between genes (DRD4) and environment (victimization) was significant and supported the differential susceptibility model for verbal victimization and child-reported externalizing behaviors. Children with the DRD4 7-repeat allele were differentially responsive to the verbal victimization environment, such that those experiencing little to no victimization reported significantly lower levels of externalizing behaviors, but if they experienced high amounts of victimization, they reported the highest levels of externalizing behaviors. Thus, consideration of how genes and environment affect children's experiences of victimization prior to adolescence is essential for understanding the trajectory of both externalizing and internalizing behaviors during adolescent development.


Experimental Studies on the Effect of Properties and Micro-Structure on the Creep of Concrete-Filled Steel Tubes.
To study different lateral restraints, different constituents of expansion agents, the influence of different steel ratios, and concrete creep properties, we carried out experiments with lateral restraint and without lateral restraint conditions separately on 12 specimens with the expansion agent content accounting for 4%, 8%, and 12% respectively. In addition, the creep tests were performed on specimens with different steel ratios of 0.0%, 3.8%, 6.6%, and 9.2%. The test results show that the lateral restraint improves the strength of the system (concrete-filled steel tubes) which resists further load after the concrete ultimate strength is surpassed and reduces the creep. The creep degree of the concrete-filled steel tube with lateral restraint is about 0.09⁻0.30 times smaller than that of the tube without lateral restraints. The creep degree of the concrete-filled steel tube increases as the steel ratio decreases. Creep tests with different amounts of expansion agent indicate that the creep degree of the concrete structure increases as expansion agent content decreases. To study the internal mechanism of the creep of concrete-filled steel tubes with different lateral restraints and different expansion agent concentrations, a microscopic pore structure test on the steel core concrete was conducted using the RapidAir457 pore structure instrument. Microscopic studies show that the air content and the length of the bubble chord of the laterally restrained core concrete are lower than those without lateral restraint core concrete. The amount of air content and the length of the bubble chord of core concrete specimens increase as the expansion agent content in the core concrete specimens decreases from 12% to 4%. Under the same external loading conditions, as steel ratio increases, the lateral restraint causes a further reduction of creep. The results of this study suggest that the creep of concrete can be reduced by selecting appropriate lateral restraint conditions and an optimal amount of expansion agent in the mix design of concrete for concrete-filled steel tubes.


Sensitivity of the Cogstate Test Battery for Detecting Prolonged Cognitive Alterations Stemming From Sport-Related Concussions.
To determine if the Cogstate test battery contains the requisite sensitivity to detect prolonged cognitive alterations. One hundred twenty collegiate athletes (71 with a history of concussion; 49 controls) completed the Cogstate test battery, to which we added a 2-back condition. In addition to the Cogstate clinical (transformed variables), we analyzed the raw data. The clinical variables failed to reveal any group differences. Further, although the raw data failed to reveal group differences for tasks measuring lower-level cognition, group differences were observed for accuracy on the 1- and 2-back tasks, which require multiple aspects of higher cognition. The overall classification accuracy was higher using the raw data than the clinical variables. The combined sensitivity of the 1- and 2-back task was moderate and specificity was high. These results suggest that using the raw scores over clinical variables increases the sensitivity of the test battery. Moreover, these results add another piece of evidence suggesting that concussive injuries are associated with subtle long-term alterations in aspects of higher cognition. Importantly, these deficits would have gone unobserved if we had relied solely on automated clinical variables. The current results further our scientific understanding of concussion and may be used to advance clinical practices.


Overshadowed prospect of programmed cell death protein-1 (PD-1) inhibitor as monotherapy for patients with advanced hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a prevalent and refractory cancer in the world and very few drugs are available for the disease treatment currently. Programmed cell death protein-1 (PD-1) monoclonal antibodies including nivolumab and pembrolizumab has received accelerated approval for treatment of advanced HCC based on phase 1/2 clinical trials. However, the recently disclosed results of phase 3 clinical trials showed that both nivolumab and pembrolizumab as monotherapy failed to meet the primary objectives, which might overshadow the prospect of PD-1 inhibitors as monotherapy in treatment of advanced and unresectable HCC. The feasibility of PD-1 inhibitors in combination with other therapies or in other HCC settings requires further verification in the future.


CCL2 upregulation triggers hypoxic preconditioning-induced protection from stroke.
A brief exposure to systemic hypoxia (i.e., hypoxic preconditioning; HPC) prior to transient middle cerebral artery occlusion (tMCAo) reduces infarct volume, blood-brain barrier disruption, and leukocyte migration. CCL2 (MCP-1), typically regarded as a leukocyte-derived pro-inflammatory chemokine, can also be directly upregulated by hypoxia-induced transcription. We hypothesized that such a hypoxia-induced upregulation of CCL2 is required for HPC-induced ischemic tolerance. Adult male SW/ND4, CCL2-null, and wild-type mice were used in these studies. Cortical CCL2/CCR2 message, protein, and cell-type specific immunoreactivity were determined following HPC (4 h, 8% O2) or room air control (21% O2) from 6 h through 2 weeks following HPC. Circulating leukocyte subsets were determined by multi-parameter flow cytometry in naïve mice and 12 h after HPC. CCL2-null and wild-type mice were exposed to HPC 2 days prior to tMCAo, with immunoneutralization of CCL2 during HPC achieved by a monoclonal CCL2 antibody. Cortical CCL2 mRNA and protein expression peaked at 12 h after HPC (both p < 0.01), predominantly in cortical neurons, and returned to baseline by 2 days. A delayed cerebral endothelial CCL2 message expression (p < 0.05) occurred 2 days after HPC. The levels of circulating monocytes (p < 0.0001), T lymphocytes (p < 0.0001), and granulocytes were decreased 12 h after HPC, and those of B lymphocytes were increased (p < 0.0001), but the magnitude of these respective changes did not differ between wild-type and CCL2-null mice. HPC did decrease the number of circulating CCR2+ monocytes (p < 0.0001) in a CCL2-dependent manner, but immunohistochemical analyses at this 12 h timepoint indicated that this leukocyte subpopulation did not move into the CNS. While HPC reduced infarct volumes by 27% (p < 0.01) in wild-type mice, CCL2-null mice subjected to tMCAo were not protected by HPC. Moreover, administration of a CCL2 immunoneutralizing antibody prior to HPC completely blocked (p < 0.0001 vs. HPC-treated mice) the development of ischemic tolerance. The early expression of CCL2 in neurons, the delayed expression of CCL2 in cerebral endothelial cells, and CCL2-mediated actions on circulating CCR2+ monocytes, appear to be required to establish ischemic tolerance to focal stroke in response to HPC, and thus represent a novel role for this chemokine in endogenous neurovascular protection.


PCR amplification of DNA containing non-standard base pairs by variants of reverse transcriptase from Human Immunodeficiency Virus-1.
As the next step towards generating a synthetic biology from artificial genetic information systems, we have examined variants of HIV reverse transcriptase (RT) for their ability to synthesize duplex DNA incorporating the non-standard base pair between 2,4-diaminopyrimidine (pyDAD), a pyrimidine presenting a hydrogen bond 'donor-acceptor-donor' pattern to the complementary base, and xanthine (puADA), a purine presenting a hydrogen bond 'acceptor-donor-acceptor' pattern. This base pair fits the Watson-Crick geometry, but is joined by a pattern of hydrogen bond donor and acceptor groups different from those joining the GC and AT pairs. A variant of HIV-RT where Tyr 188 is replaced by Leu, has emerged from experiments where HIV was challenged to grow in the presence of drugs targeted against the RT, such as L-697639, TIBO and nevirapine. These drugs bind at a site near, but not in, the active site. This variant accepts the pyDAD-puADA base pair significantly better than wild type HIV-RT, and we used this as a starting point. A second mutation, E478Q, was introduced into the Y188L variant, in the event that the residual nuclease activity observed is due to the RT, and not a contaminant. The doubly mutated RT incorporated the non-standard pair with sufficient fidelity that the variant could be used to amplify oligonucleotides containing pyDAD and puADA through several rounds of a polymerase chain reaction (PCR) without losing the non-standard base pair. This is the first time where DNA containing non-standard base pairs with alternative hydrogen bonding patterns has been amplified by a full PCR. This work also illustrates a research strategy that combines in clinico pre-evolution of proteins followed by rational design to obtain an enzyme that meets a particular technological specification.


Genome-wide patterns of genetic variation in worldwide Arabidopsis thaliana accessions from the RegMap panel.
Arabidopsis thaliana is native to Eurasia and is naturalized across the world. Its ability to be easily propagated and its high phenotypic variability make it an ideal model system for functional, ecological and evolutionary genetics. To date, analyses of the natural genetic variation of A. thaliana have involved small numbers of individual plants or genetic markers. Here we genotype 1,307 worldwide accessions, including several regional samples, using a 250K SNP chip. This allowed us to produce a high-resolution description of the global pattern of genetic variation. We applied three complementary selection tests and identified new targets of selection. Further, we characterized the pattern of historical recombination in A. thaliana and observed an enrichment of hotspots in its intergenic regions and repetitive DNA, which is consistent with the pattern that is observed for humans but which is strikingly different from that observed in other plant species. We have made the seeds we used to produce this Regional Mapping (RegMap) panel publicly available. This panel comprises one of the largest genomic mapping resources currently available for global natural isolates of a non-human species.


Influence of vitamin E and C supplementation on lipoprotein oxidation in patients with Alzheimer's disease.
Because increased oxidation is an important feature of Alzheimer's disease (AD) and low concentrations of antioxidant vitamins C and E have been observed in cerebrospinal fluid (CSF) of AD patients, supplementation with these antioxidants might delay the development of AD. Major targets for oxidation in brain are lipids and lipoproteins. We studied whether supplementation with antioxidative vitamins E and C can increase their concentrations not only in plasma but also in CSF, and as a consequence decrease the susceptibility of lipoproteins to in vitro oxidation. Two groups, each consisting of 10 patients with AD, were for 1 month supplemented daily with either a combination of 400 IU vitamin E and 1000 mg vitamin C, or 400 IU vitamin E alone. We found that supplementation with vitamin E and C significantly increased the concentrations of both vitamins in plasma and CSF. Importantly, the abnormally low concentrations of vitamin C were returned to normal level following treatment. As a consequence, susceptibility of CSF and plasma lipoproteins to in vitro oxidation was significantly decreased. In contrast, the supplementation with vitamin E alone significantly increased its CSF and plasma concentrations, but was unable to decrease the lipoprotein oxidizability. These findings document a superiority of a combined vitamin E + C supplementation over a vitamin E supplementation alone in AD and provide a biochemical basis for its use.


An exposome perspective: Early-life events and immune development in a changing world.
Advances in metagenomics, proteomics, metabolomics, and systems biology are providing a new emphasis in research; interdisciplinary work suggests that personalized medicine is on the horizon. These advances are illuminating sophisticated interactions between human-associated microbes and the immune system. The result is a transformed view of future prevention and treatment of chronic noncommunicable diseases, including allergy. Paradigm-shifting gains in scientific knowledge are occurring at a time of rapid global environmental change, urbanization, and biodiversity losses. Multifactorial and multigenerational implications of total environmental exposures, the exposome, require coordinated interdisciplinary efforts. It is clear that the genome alone cannot provide answers to urgent questions. Here we review the historical origins of exposome research and define a new concept, the metaexposome, which considers the bidirectional effect of the environment on human subjects and the human influence on all living systems and their genomes. The latter is essential for human health. We place the metaexposome in the context of early-life immune functioning and describe how various aspects of a changing environment, especially through microbiota exposures, can influence health and disease over the life course.


Diversity and association of psychrophilic bacteria in Antarctic sea ice.
The bacterial populations associated with sea ice sampled from Antarctic coastal areas were investigated by use of a phenotypic approach and a phylogenetic approach based on genes encoding 16S rRNA (16S rDNA). The diversity of bacteria associated with sea ice was also compared with the bacterial diversity of seawater underlying sea ice. Psychrophilic (optimal growth temperature, < or = 15 degrees C; no growth occurring at 20 degrees C) bacterial diversity was found to be significantly enriched in sea ice samples possessing platelet and bottom ice diatom assemblages, with 2 to 9 distinct (average, 5.6 +/- 1.8) psychrophilic taxa isolated per sample. Substantially fewer psychrophilic isolates were recovered from ice cores with a low or negligible population of ice diatoms or from under-ice seawater samples (less than one distinct taxon isolated per sample). In addition, psychrophilic taxa that were isolated from under-ice seawater samples were in general phylogenetically distinct from psychrophilic taxa isolated from sea ice cores. The taxonomic distributions of psychrotrophic bacterial isolates (optimal growth temperature, > 20 degrees C; growth can occur at approximately 4 degrees C) isolated from sea ice cores and under-ice seawater were quite similar. Overall, bacterial isolates from Antarctic sea ice were found to belong to four phylogenetic groups, the alpha and gamma subdivisions of the Proteobacteria, the gram-positive branch, and the Flexibacter-Bacteroides-Cytophaga phylum. Most of the sea ice strains examined appeared to be novel taxa based on phylogenetic comparisons, with 45% of the strains being psychrophilic. 16S rDNA sequence analysis revealed that psychrophilic strains belonged to the genera Colwellia, Shewanella, Marinobacter, Planococcus, and novel phylogenetic lineages adjacent to Colwellia and Alteromonas and within the Flexibacter-Bacteroides-Cytophaga phylum. Psychrotrophic strains were found to be members of the genera Pseudoalteromonas, Psychrobacter, Halomonas, Pseudomonas, Hyphomonas, Sphingomonas, Arthrobacter, Planococcus, and Halobacillus. From this survey, it is proposed that ice diatom assemblages provide niches conducive to the proliferation of a diverse array of psychrophilic bacterial species.


A RCT of three training and support strategies to encourage implementation of screening and brief alcohol intervention by general practitioners.
Providing doctors with new research findings or clinical guidelines is rarely sufficient to promote changes in clinical practice. An implementation strategy is required to provide clinicians with the skills and encouragement needed to alter established routines. To evaluate the effectiveness and cost-effectiveness of different training and support strategies in promoting implementation of screening and brief alcohol intervention (SBI) by general practitioners (GPs). Subjects were 128 GPs, one per practice, from the former Northern and Yorkshire Regional Health Authority, who agreed to use the 'Drink-Less' SBI programme in an earlier dissemination trial. GPs were stratified by previous marketing conditions and randomly allocated to three intensities of training and support: controls (n = 43) received the programme with written guidelines only, trained GPs (n = 43) received the programme plus practice-based training in programme usage, trained and supported GPs (n = 42) received the programme plus practice-based training and a support telephone call every two weeks. GPs were requested to use the programme for three months. Outcome measures included proportions of GPs implementing the programme and numbers of patients screened and intervened with. Seventy-three (57%) GPs implemented the programme and screened 11,007 patients for risk drinking. Trained and supported GPs were significantly more likely to implement the programme (71%) than controls (44%) or trained GPs (56%); they also screened, and intervened with, significantly more patients. Costs per patient screened were: trained and supported GPs, 1.05 Pounds; trained GPs, 1.08 Pounds; and controls, 1.47 Pounds. Costs per patient intervened with were: trained and supported GPs, 5.43 Pounds; trained GPs, 6.02 Pounds; and controls, 8.19 Pounds. Practice-based training plus support telephone calls was the most effective and cost-effective strategy to encourage implementation of SBI by GPs.


Endoscope-assisted inguinal hernia repair.
Since the advent of laparoscopic inguinal hernia repair, the procedure has invited numerous controversies, and although the procedure has some definitive advantages, no definitive indications for its use have been formulated. The objective of this study was to investigate a novel method for inguinal hernia repair (through a small 2 cm to 2.5 cm) single skin incision that combines the time-tested fundamentals of Lichtenstein's tension-free repair with the advantages of laparoscopic assistance. The study was conducted as a randomized, controlled trial over a 1-year period and included 50 patients. Only patients with simple reducible hernias without associated comorbid conditions were included. The patients were randomized into 2 groups of 25 patients each. One group underwent conventional tension-free meshplasty, while the other group underwent the repair through a single 2-cm to 2.5-cm skin incision with laparoscopic assistance. This repair was carried out with the help of an indigenously designed steel retractor, 10-mm laparoscope, and conventional instruments; the mesh was fixed with the help of endotacks. Univariate analysis of variance techniques using SPSS 7.5 software was used for data analysis. Two groups were compared for time taken for the procedure, size of skin incision, postoperative pain, complications, return to work, and cosmetic appearance. The results showed a significant decrease in postoperative pain and an earlier return to work, along with much improved cosmesis for the new procedure. Although the study was conducted with a limited number of patients and a very short follow-up, it is worth considering this method over laparoscopic and conventional techniques, especially in reducible hernias.


Key Concepts for Informed Health Choices: a framework for helping people learn how to assess treatment claims and make informed choices.
Many claims about the effects of treatments, though well intentioned, are wrong. Indeed, they are sometimes deliberately misleading to serve interests other than the well-being of patients and the public. People need to know how to spot unreliable treatment claims so that they can protect themselves and others from harm. The ability to assess the trustworthiness of treatment claims is often lacking. Acquiring this ability depends on being familiar with, and correctly applying, some key concepts, for example, that' association is not the same as causation.' The Informed Health Choices (IHC) Project has identified 36 such concepts and shown that people can be taught to use them in decision making. A randomised trial in Uganda, for example, showed that primary school children with poor reading skills could be taught to apply 12 of the IHC Key Concepts. The list of IHC Key Concepts has proven to be effective in providing a framework for developing and evaluating IHC resources to help children to think critically about treatment claims. The list also provides a framework for retrieving, coding and organising other teaching and learning materials for learners of any age. It should help teachers, researchers, clinicians, and patients to structure critical thinking about the trustworthiness of claims about treatment effects.


Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009-2018.
The mean cost of developing a new drug has been the subject of debate, with recent estimates ranging from $314 million to $2.8 billion. To estimate the research and development investment required to bring a new therapeutic agent to market, using publicly available data. Data were analyzed on new therapeutic agents approved by the US Food and Drug Administration (FDA) between 2009 and 2018 to estimate the research and development expenditure required to bring a new medicine to market. Data were accessed from the US Securities and Exchange Commission, Drugs@FDA database, and ClinicalTrials.gov, alongside published data on clinical trial success rates. Conduct of preclinical and clinical studies of new therapeutic agents. Median and mean research and development spending on new therapeutic agents approved by the FDA, capitalized at a real cost of capital rate (the required rate of return for an investor) of 10.5% per year, with bootstrapped CIs. All amounts were reported in 2018 US dollars. The FDA approved 355 new drugs and biologics over the study period. Research and development expenditures were available for 63 (18%) products, developed by 47 different companies. After accounting for the costs of failed trials, the median capitalized research and development investment to bring a new drug to market was estimated at $985.3 million (95% CI, $683.6 million-$1228.9 million), and the mean investment was estimated at $1335.9 million (95% CI, $1042.5 million-$1637.5 million) in the base case analysis. Median estimates by therapeutic area (for areas with ≥5 drugs) ranged from $765.9 million (95% CI, $323.0 million-$1473.5 million) for nervous system agents to $2771.6 million (95% CI, $2051.8 million-$5366.2 million) for antineoplastic and immunomodulating agents. Data were mainly accessible for smaller firms, orphan drugs, products in certain therapeutic areas, first-in-class drugs, therapeutic agents that received accelerated approval, and products approved between 2014 and 2018. Results varied in sensitivity analyses using different estimates of clinical trial success rates, preclinical expenditures, and cost of capital. This study provides an estimate of research and development costs for new therapeutic agents based on publicly available data. Differences from previous studies may reflect the spectrum of products analyzed, the restricted availability of data in the public domain, and differences in underlying assumptions in the cost calculations.


Tyrosinase exacerbates dopamine toxicity but is not genetically associated with Parkinson's disease.
Tyrosinase is a key enzyme in the synthesis of melanin in skin and hair and has also been proposed to contribute to the formation of neuromelanin (NM). The presence of NM, which is biochemically similar to melanin in peripheral tissues, identifies groups of neurons susceptible in Parkinson's disease (PD). Whether tyrosinase is beneficial or detrimental to neurons is unclear; whilst the enzyme activity of tyrosinase generates dopamine-quinones and other oxidizing compounds, NM may form a sink for such radical species. In the present study, we demonstrated that tyrosinase is expressed at low levels in the human brain. We found that mRNA, protein and enzyme activity are all present but at barely detectable levels. In cell culture systems, expression of tyrosinase increases neuronal susceptibility to oxidizing conditions, including dopamine itself. We related these in vitro observations to the human disease by assessing whether there was any genetic association between the gene encoding tyrosinase and idiopathic PD. We found neither genotypic or haplotypic association with three polymorphic markers of the gene. This argues against a strong genetic association between tyrosinase and PD, although the observed contribution to cellular toxicity suggests that a biochemical association is likely.


Cadaveric Study of the Articular Branches of the Shoulder Joint.
This cadaveric study investigated the anatomic relationships of the articular branches of the suprascapular (SN), axillary (AN), and lateral pectoral nerves (LPN), which are potential targets for shoulder analgesia. Sixteen embalmed cadavers and 1 unembalmed cadaver, including 33 shoulders total, were dissected. Following dissections, fluoroscopic images were taken to propose an anatomical landmark to be used in shoulder articular branch blockade. Thirty-three shoulders from 17 total cadavers were studied. In a series of 16 shoulders, 16 (100%) of 16 had an intact SN branch innervating the posterior head of the humerus and shoulder capsule. Suprascapular sensory branches coursed laterally from the spinoglenoid notch then toward the glenohumeral joint capsule posteriorly. Axillary nerve articular branches innervated the posterolateral head of the humerus and shoulder capsule in the same 16 (100%) of 16 shoulders. The AN gave branches ascending circumferentially from the quadrangular space to the posterolateral humerus, deep to the deltoid, and inserting at the inferior portion of the posterior joint capsule. In 4 previously dissected and 17 distinct shoulders, intact LPNs could be identified in 14 (67%) of 21 specimens. Of these, 12 (86%) of 14 had articular branches innervating the anterior shoulder joint, and 14 (100%) of 14 LPN articular branches were adjacent to acromial branches of the thoracoacromial blood vessels over the superior aspect of the coracoid process. Articular branches from the SN, AN, and LPN were identified. Articular branches of the SN and AN insert into the capsule overlying the glenohumeral joint posteriorly. Articular branches of the LPN exist and innervate a portion of the anterior shoulder joint.


Dual, hyperalgesic, and analgesic effects of the high-efficacy 5-hydroxytryptamine 1A (5-HT1A) agonist F 13640 [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl}piperidin-1-yl]methanone, fumaric acid salt]: relationship with 5-HT1A receptor occupancy and kinetic parameters.
The aim of the present study was to establish the relationship between the plasma and brain concentration-time profiles of F 13640 [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl}piperidin-1-yl]methanone, fumaric acid salt] after acute administration and both its hyper- and hypoanalgesic effects in rats. The maximal plasma concentration (C(max)) of F 13640 after i.p. administration of 0.63 mg/kg was obtained at 15 min and decreased to half its maximal value after about 1 h. The amount of F 13640 collected by means of in vivo microdialysis in hippocampal dialysates could be measured reliably after 0.63 and 2.5 mg/kg, reached its maximum at about 1 h, and fell to half of its maximal value at about 3 h. 5-Hydroxytryptamine 1A (5-HT(1A)) receptor occupancy was estimated by ex vivo binding in rat brain sections. F 13640 inhibited [(3)H]8-hydroxy-2-[di-n-propylamino] tetralin binding ex vivo in rat hippocampus, entorhinal cortex, and frontal cortex (ED(50), 0.34 mg/kg i.p.). Maximal inhibition was reached at approximately 30 min after 0.63 mg/kg F 13640 and fell to half of its value after about 4 to 8 h. After injection (15 min) in the paw pressure test, F 13640 (0.63 mg/kg i.p.) induced an initial hyperalgesia that was followed 4 h later by a paradoxical analgesia that lasted until 8 h. In contrast, in the formalin test, F 13640 inhibited pain behaviors until 4 h after drug administration. F 13640 also produced elements of the 5-HT syndrome that lasted up to 4 h after administration. These results demonstrate that F 13640 induces hyperalgesia and/or analgesia with a time course that parallels the occupancy of 5-HT(1A) receptors and the presence of the compound in blood and brain.


Potential in vivo UVC disinfection of catheter lumens: estimation of the doses received by the blood flow outside the catheter tip hole.
We have demonstrated that it is possible to launch UVC LED light into bacterial contaminated polymer tubes/catheters and disinfect the intraluminal space of these tubes. This can be achieved by UVC treatment of the catheters on a regular basis. Catheters are in the distal end equipped with an exit hole for administration of drugs, bloods or nutrients into the bloodstream. Even if the UVC light is strongly attenuated during its propagation through the catheter tube a fraction of the UVC launched into the catheter will escape through the exit hole and irradiate the blood. We demonstrate by calculations that very small effective doses are exposed to the blood (ca 10(-4) J m(-2)). This dosage level is very low compared with UVC doses reported from other therapeutic applications. The very short residence time of the blood constituents in the irradiated volume in front of the exit hole is the main reason why the UVC exposure to the blood in the catheter application is so low. The very low dose received by the blood through the catheter tip indicated that possible side effects are negligible and makes the UV disinfection technique feasible in a clinical setting.


DNA polymorphism of Pvu II site in the lipoprotein lipase gene in patients with non-insulin dependent diabetes mellitus.
We studied the effect of variation at the lipoprotein lipase (LPL) gene locus on the susceptibility of individuals with non-insulin dependent diabetes mellitus (NIDDM) in a population of 110 NIDDM patients and 91 controls. Our objective was to study the relationship between the LPL-Pvu II polymorphism and NIDDM and lipid metabolism. PCR-RFLP was used to determine the DNA polymorphism of the sixth intron of the LPL gene. The frequencies of the genotypes in case and control groups were 29.1 and 30.8% for P+/P+; 45.5 and 36.3% for P+/P-; 25.5 and 33% for P-/P- respectively. There was no significant difference in frequencies of genotypes between the two groups. Logistic regression analysis revealed that triacylglycerol (TAG) and apolipoprotein E levels were associated with NIDDM, whereas Pvu II genotypes were not found as independent risk factors for the disease. Overall this study demonstrates the role of the Pvu II polymorphism in the LPL gene in modulating plasma lipid/lipoprotein levels in patients with NIDDM.


Microcanonical coarse-graining of the kinetic Ising model.
We propose a scheme for coarse-graining the dynamics of the 2-D kinetic Ising model onto the microcanonical ensemble. At subcritical temperatures, 2-D and higher-dimensional Ising lattices possess two basins of attraction separated by a free energy barrier. Projecting onto the microcanonical ensemble has the advantage that the dependence of the crossing rate constant on environmental conditions can be obtained from a single Monte Carlo trajectory. Using various numerical methods, we computed the forward rate constants of coarse-grained representations of the Ising model and compared them with the true value obtained from brute force simulation. While coarse-graining preserves detailed balance, the computed rate constants for barrier heights between 5 kT and 9 kT were consistently 50% larger than the true value. Markovianity testing revealed loss of dynamical memory, which we propose accounts for coarse-graining error. Committor analysis did not support the alternative hypothesis that microcanonical projection is incompatible with an optimal reaction coordinate. The correct crossing rate constant was obtained by spectrally decomposing the diffusion coefficient near the free energy barrier and selecting the slowest (reactive) component. The spectral method also yielded the correct rate constant in the 3-D Ising lattice, where coarse-graining error was 6% and memory effects were diminished. We conclude that microcanonical coarse-graining supplemented by spectral analysis of short-term barrier fluctuations provides a comprehensive kinetic description of barrier crossing in a non-inertial continuous-time jump process.


Fluconazole resistance due to energy-dependent drug efflux in Candida glabrata.
We report on the mechanism of fluconazole resistance in Candida glabrata from a case of infection in which pre- and posttreatment isolates were available for comparison. The resistant, posttreatment isolate was cross-resistant to ketoconazole and itraconazole, in common with other azole-resistant yeasts. Resistance was due to reduced levels of accumulation of [3H]fluconazole rather than to changes at the level of ergosterol biosynthesis. Studies with metabolic or respiratory inhibitors showed that this phenomenon was a consequence of energy-dependent drug efflux, as opposed to a barrier to influx. Since energy-dependent efflux is a characteristic of multidrug resistance in bacteria, yeasts, and mammalian cells, we investigated the possibility that fluconazole resistance is mediated by a multidrug resistance-type mechanism. Benomyl, a substrate for the Candida albicans multidrug resistance protein, showed competition with fluconazole for efflux from resistance C. glabrata isolates, consistent with a common efflux mechanism for these compounds. By contrast, other standard substrates or inhibitors of multidrug resistance proteins had no effect on fluconazole efflux. In conclusion, we have identified energy-dependent efflux of fluconazole, possibly via a multidrug resistance-type transporter, as the mechanism of resistance to fluconazole in C. glabrata.


Germ cell survival in C. elegans and C. remanei is affected when the DEAD box RNA helicases VBH-1 or Cre-VBH-1 are silenced.
The Vasa family of proteins comprises several conserved DEAD box RNA helicases important for mRNA regulation whose exact function in the germline is still unknown. In Caenorhabditis elegans, there are six known members of the Vasa family, and all of them are associated with P granules. One of these proteins, VBH-1, is important for oogenesis, spermatogenesis, embryo development, and the oocyte/sperm switch in this nematode. We decided to extend our previous work in C. elegans to sibling species Caenorhabditis remanei to understand what is the function of the VBH-1 homolog in this gonochoristic species. We found that Cre-VBH-1 is present in the cytoplasm of germ cells and it remains associated with P granules throughout the life cycle of C. remanei. Several aspects between VBH-1 and Cre-VBH-1 function are conserved like their role during oogenesis, spermatogenesis, and embryonic development. However, Cre-vbh-1 silencing in C. remanei had a stronger effect on spermatogenesis and spermatid activation than in C. elegans. An unexpected finding was that silencing of vbh-1 in the C. elegans caused a decrease in germ cell apoptosis in the hermaphrodite gonad, while silencing of Cre-vbh-1 in C. remanei elicited germ cell apoptosis in the male gonad. These data suggest that VBH-1 might play a role in germ cell survival in both species albeit it appears to have an opposite role in each one.


Evidence for polyclonal T cell activation in murine models of systemic lupus erythematosus.
CD4+ T cells have been shown to be important in the development of disease in murine models of SLE. We compared the TCR V beta repertoires of young (healthy) and older (diseased) New Zealand hybrid mice as well as non-autoimmune strains to characterize changes in TCR usage associated with the development of disease. Despite large increases in the total number of splenic CD4+ T cells with age in diseased mice, we noted little skewing of the V beta repertoire. For example, diseased NZB.H-2bm12 mice failed to exhibit a significant change in the percentage of any V beta subset despite a fivefold increase in the number of CD4+ T cells. Strains without lupus-like disease, including NZB.H-2b mice, demonstrated no increase in CD4+ T cell numbers with age. Similar to NZB.H-2bm12 mice, (NZB x SWR)F, and (NZB x NZW)F1 mice showed disease-related increases in CD4+ T cell numbers, but no changes in V beta repertoire that could be linked to disease development. Differences in V beta usage between young autoimmune and non-autoimmune strains of mice matched for either MHC or background genes were consistent with genetic influences unrelated to disease. Overall, the heterogeneous repertoire of proliferating T cells provides evidence for polyclonal T cell expansion in murine models of lupus and suggests that activation either involves a multitude of conventional self-antigens or may be independent of the TCR. However, the requirement for specific class II MHC molecules suggests that this polyclonal T cell expansion is dependent on a much smaller and specific autoreactive response.


Psychogenic vocal cord dysfunction simulating bronchial asthma.
Upper airway obstruction can mimic bronchial asthma. A particular type results from psychogenic dysfunction of the vocal cord, and presents as bronchial asthma or organic upper airways obstruction. If not recognized, ineffective and potentially harmful therapy is given instead of focusing on the underlying psychopathology. We report three Saudi females with this condition, in whom polygamy and a large family system created associated social stress. Spirometry with a flow volume loop showed characteristic features, and in all three this test was the most important clinical tool that led to the correct diagnosis. Clinicians should perform spirometry and flow-volume loop tests routinely in patients presenting with asthmatic symptoms, and look for clues suggestive of this condition, including a psychosocial assessment.


Comparing Advance Care Planning in Young-Onset Dementia in the USA vs Belgium: Challenges Partly Related to Societal Context.
Advance care planning in young-onset dementia largely remains a blind spot within current literature. This study aimed to explore the engagement in and the conceptualization of advance care planning from the perspective of family caregivers of persons with young-onset dementia and to identify potential similarities and differences in this area between American and Belgian persons with young-onset dementia and their family caregivers. An exploratory qualitative study. We purposively sampled adult family caregivers of persons with young-onset dementia; our respondents were 13 American and 15 Belgian caregivers with varying familial relationships to the patient. We conducted 28 semi-structured interviews, using the same interview guide for American and Belgian respondents. Verbatim transcripts were analysed through the method of constant comparative analysis. Important similarities between American and Belgian respondents were restricted knowledge of advance care planning, limited communication about advance directives, and their recommendation for professionals to timely initiate advance care planning. Major differences were attention paid to those end-of-life decisions depicted in the legislature of their respective countries, American caregivers placed higher emphasis on financial planning than their Belgian peers, and, in the case of consulting professionals for advance directives, American caregivers turned to lawyers, whereas Belgian caregivers relied on physicians. Specific nuances and challenges in terms of advance care planning in young-onset dementia arise from a particular societal and legal context on the one hand, and from patients' and caregivers' younger age on the other. Professionals' awareness of and responsiveness to these specificities could facilitate the advance care planning process. Based on our interpretation of results, several recommendations for practice and policy are made.


Colorectal cancer screening with double-contrast barium enema: a national survey of diagnostic radiologists.
This article describes diagnostic radiologists' colorectal cancer screening activities and beliefs about screening effectiveness and future capacity for screening with double-contrast barium enema, and compares radiologists' opinions about colorectal cancer screening with those of primary care physicians. We surveyed a nationally representative sample of diagnostic radiologists. Of 381 eligible radiologists, 312 (82%) responded. Descriptive statistics and chi-square tests were used to assess radiologists' opinions about double-contrast barium enema volume and capacity and to compare radiologists' beliefs about colorectal cancer screening with those of primary care physicians. Logistic regression was used to identify characteristics of radiologists who receive referrals for or perform a higher volume of screening double-contrast barium enema and of those who expect the volume of double-contrast barium enemas to increase. Seventy-five percent of radiologists said that double-contrast barium enema is a "very effective" colorectal cancer screening procedure compared with 33% of primary care physicians. Although 86% of radiologists reported performing one or more screening double-contrast barium enema procedures during a typical month, only 27% indicated that they did so 11 or more times. Fifteen percent of radiologists said that their double-contrast barium enema volume had increased over the past 3 years, and 50% expect an increase over the next 3 years. Only 8% said that the capacity of facilities and personnel to meet the demand for double-contrast barium enemas in their geographic area of practice is inadequate. Geographic region and belief in double-contrast barium enema efficacy were predictors of double-contrast barium enema volume and referrals. Most diagnostic radiologists perform colorectal cancer screening with double-contrast barium enema, but procedure volumes are modest. Because primary care physicians view double-contrast barium enema less positively than do radiologists, radiologists' expectations for an increased volume of double-contrast barium enemas over the next few years may not be realized.


Systems-level understanding of ethanol-induced stresses and adaptation in E. coli.
Understanding ethanol-induced stresses and responses in biofuel-producing bacteria at systems level has significant implications in engineering more efficient biofuel producers. We present a computational study of transcriptomic and genomic data of both ethanol-stressed and ethanol-adapted E. coli cells with computationally predicated ethanol-binding proteins and experimentally identified ethanol tolerance genes. Our analysis suggests: (1) ethanol damages cell wall and membrane integrity, causing increased stresses, particularly reactive oxygen species, which damages DNA and reduces the O2 level; (2) decreased cross-membrane proton gradient from membrane damage, coupled with hypoxia, leads to reduced ATP production by aerobic respiration, driving cells to rely more on fatty acid oxidation, anaerobic respiration and fermentation for ATP production; (3) the reduced ATP generation results in substantially decreased synthesis of macromolecules; (4) ethanol can directly bind 213 proteins including transcription factors, altering their functions; (5) all these changes together induce multiple stress responses, reduced biosynthesis, cell viability and growth; and (6) ethanol-adapted E. coli cells restore the majority of these reduced activities through selection of specific genomic mutations and alteration of stress responses, ultimately restoring normal ATP production, macromolecule biosynthesis, and growth. These new insights into the energy and mass balance will inform design of more ethanol-tolerant strains.


Plasma nitric oxide level and its role in slow coronary flow phenomenon.
Previous studies have suggested that microvascular abnormalities and endothelial dysfunction cause slow coronary flow (SCF). The objective of this study was to assess the plasma nitric oxide (NO) level and determine its role in the pathogenesis of SCF phenomenon. Thirty-six patients with SCF (group 1) and otherwise patent coronary arteries and 34 subjects with normal coronary flow (group 2) were included in the study. Coronary flow was quantified according to the TIMI Frame Count (TFC) method. Brachial artery endothelium-dependent flow-mediated dilatation (FMD) and nitroglycerin (NTG)-induced endothelium-independent dilatation were studied in both groups. In addition, plasma NO levels were measured and their contribution to FMD was determined. The sex, age, body mass index, arterial blood pressure, and heart rate distributions were similar in both groups. TFC was significantly higher in group 1 compared to group 2 for each artery. The plasma NO level was lower in patients with SCF than in control subjects (18.4 +/- 4.4 versus 25.2 +/- 6.3 micromol/L P = 0.001). FMD was significantly smaller in group 1 than in group 2 (4.0 +/- 3.2% versus 10.6 +/- 5.8%, P = 0.0001). The percent NTG-induced dilatation was similar in the two groups (16.8 +/- 1.1% versus 17.1 +/- 1.1%, P = 0.42). In group 1, the plasma NO level was correlated with percent of FMD. Also, the plasma NO level was inversely correlated with TFC for each artery. Reduced NO bioactivity as well as impaired FMD support the presence of endothelial damage in the pathogenesis of SCF phenomenon.


T3NS: Three-Legged Tree Tensor Network States.
We present a new variational tree tensor network state (TTNS) ansatz, the three-legged tree tensor network state (T3NS). Physical tensors are interspersed with branching tensors. Physical tensors have one physical index and at most two virtual indices, as in the matrix product state (MPS) ansatz of the density matrix renormalization group (DMRG). Branching tensors have no physical index, but up to three virtual indices. In this way, advantages of DMRG, in particular a low computational cost and a simple implementation of symmetries, are combined with advantages of TTNS, namely incorporating more entanglement. Our code is capable of simulating quantum chemical Hamiltonians, and we present several proof-of-principle calculations on LiF, N2, and the bis(μ-oxo) and μ-η2:η2 peroxo isomers of [Cu2O2]2+.


Effect of different water conditions on dissolution of nanosilver.
This study evaluates the time-dependent dissolution of nanosilver (nAg) in common electrolytes and natural waters. nAg was synthesized via Tollens' method using sodium citrate as stabilizer; its morphology, UV-Vis spectrum, and particle size were characterized. The dissolved silver was monitored over time using filtration, centrifugation, and inductively coupled plasma atomic emission spectroscopy (ICP-AES). Our results indicated that nanoparticle aggregation, Cl(-) presence, and natural organic compounds could affect the dissolution behavior of nAg. The dissolution of nAg was highly dependent on Cl(-) concentration. Excessive Cl(-) enhanced nanoparticle dissolution, whereas natural organic compound inhibited the dissolution. The dissolution data fitted well with the first-order kinetic model, and the dissolution rate coefficients were calculated using the first-order equation. This study showed the dissolution of nAg under various water conditions. The obtained results may be helpful in predicting nAg behavior in relevant environmental aquatic systems.


The prevention of thymic lymphomas in transgenic mice by human O6-alkylguanine-DNA alkyltransferase.
Nitrosoureas form O6-alkylguanine-DNA adducts that are converted to G to A transitions, the mutation found in the activated ras oncogenes of nitrosourea-induced mouse lymphomas and rat mammary tumors. These adducts are removed by the DNA repair protein O6-alkylguanine-DNA alkyltransferase. Transgenic mice that express the human homolog of this protein in the thymus were found to be protected from developing thymic lymphomas after exposure to N-methyl-N-nitrosourea. Thus, transgenic expression of a single human DNA repair gene is sufficient to block chemical carcinogenesis. The transduction of DNA repair genes in vivo may unravel mechanisms of carcinogenesis and provide therapeutic protection from known carcinogens.


[The role of National Institute of Hygiene in historical perspective].
The article presents the role of the National Institute of Hygiene, during the 90 years of its presence, in the struggle for heath of the population. It underlines how the scope of action of the Institute was contiunuously adjusted in response to existing health treats and how the Institute contributed to detection of new risk factors. The main tasks of the Institute included prevention of disease and implementation of the most up-to-date developments in the country public health system.


Surveillance of sexually transmitted diseases in France: recent trends and incidence.
To present recent trends in sexually transmitted diseases (STDs) in France and to estimate the gonorrhoea incidence in 1990. Trends were analysed from data of three surveillance systems: (1) STD clinics: number of diagnoses, (2) a sentinel voluntary General Practitioner (GP) network: mean number of acute male urethritis/week/GP, characteristics of the notified urethritis (age, presence of discharge, sexual orientation), (3) a sentinel voluntary laboratory network: mean number of gonorrhoea isolates/month/laboratory, characteristics of patients with positive isolates (sex, age, site of sampling) and of strains (PPNG and TRNG rates). To estimate the gonorrhoea incidence in France in 1990, results of a study held among a national sample of laboratories were used, combined with data from surveillance systems and specific studies. Decreasing trends in gonorrhoea in STD clinics and in the laboratory network as well as in acute male urethritis in the GP network have been observed since implementation of the networks in 1985. The rate of PPNG strains has regularly increased in the laboratory network to reach 14% in 1991. Data suggest that the incidence in some acute non recurrent STDs could have increased among homo/bisexual men since 1988. Chlamydia trachomatis is now the most frequent diagnosis in STD clinics. Estimation of male gonorrhoea incidence rate in France in 1990 of 74/100,000 inhabitants (15-59 years) is consistent with figures observed in England and Wales, where the age distribution is very similar. On the other hand, the estimated female gonorrhoea incidence rate of 14/100,000, which concerns only microbiologically ascertained cases, is one third in France than that observed in England and Wales. The consistency of the decreasing trends in gonorrhoea and acute male urethritis observed from the different networks reduces the possibility of a bias due to any change in notification or in prescription. Trends in Chlamydia trachomatis will be better appraised in the near future with the recent implementation of new systems. The French STD surveillance appears quite satisfactory for male infections and has been able to show a marked decrease in the incidence of some STDs in the last years. Surveillance of female STDs is to be improved, in terms of monitored diagnoses and selected health care facilities. Differences between the female gonorrhoea incidence rate observed in England and Wales and the one computed for France could be attributed to differences in contact tracing policies between the two countries or to differences in sexual lifestyles.


Efficacy of afatinib or osimertinib plus cetuximab combination therapy for non-small-cell lung cancer with EGFR exon 20 insertion mutations.
Epidermal growth factor receptor (EGFR) mutation-positive lung cancer accounts for a significant subgroup of non-small cell lung cancers (NSCLC). Approximately 4-10% of EGFR mutations in NSCLC are EGFR exon 20 insertion mutations, which are reportedly associated with resistance to EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment. NSCLC patients carrying these mutations are rarely treated with EGFR-TKIs. The purpose of this study was to evaluate the efficacy of afatinib or osimertinib plus cetuximab combination therapy in experimental NSCLC models with EGFR exon 20 insertion mutations. The EGFR mutations examined in this study were A763_Y764insFQEA, Y764_V765insHH, A767_V769dupASV, and D770_N771insNPG. Ba/F3 cells constitutively expressing wild type or mutated EGFR were used to determine the efficacy of afatinib or osimertinib plus cetuximab combination therapy in vitro. To determine the efficacy of the combination therapy in vivo, female BALB/c-nu mice were injected subcutaneously with 1 million Ba/F3 cells carrying EGFR A767_V769dupASV or Y764_V765insHH. We observed a mild but significant (P < 0.05) additive effect of the combination therapy against several EGFR exon 20 insertion mutations in vitro. Regarding EGFR A767_V769dupASV and EGFR Y764_V765insHH, cetuximab and afatinib single treatment did not induce significant inhibition of tumor formation; however, afatinib plus cetuximab combination treatment induced significant (P < 0.05) tumor growth inhibition without significant body weight loss or skin rash. The combination therapy induced a more potent inhibitory effect against several EGFR exon 20 insertion mutations than either therapy alone. Cetuximab can potentially increase the efficacy of afatinib or osimertinib in NSCLC with EGFR exon 20 insertion mutations.


Comparison of 5-mg and 10-mg loading doses in initiation of warfarin therapy.
Loading doses of warfarin that are larger than those used for maintenance therapy are widely used in clinical practice, but they have never been prospectively evaluated. To compare the effect of 5- and 10-mg loading doses of warfarin on laboratory markers of warfarin's anticoagulant effect. Randomized clinical trial. Tertiary care teaching hospital. 49 patients seen over a 5-month period with a target international normalized ratio (INR) of 2.0 to 3.0. Patients were randomly assigned to receive an initial dose of 5 or 10 mg of warfarin. Subsequent doses of warfarin were administered on the basis of dosing nomograms. INRs and levels of factors II, VII, IX, and X and protein C were measured daily for 5 days. 11 of 25 patients in the 10-mg group (44% [95% CI, 34% to 54%]) and 2 of 24 patients in the 5-mg group (8% [CI, 3% to 14%]) had INRs greater than 2.0 at 36 hours (P = 0.005), at which time the factor VII levels were 27% (CI, 18% to 36%) in the 10-mg group and 54% (CI, 43% to 65%) in the 5-mg group (P < 0.001). In contrast, factor II levels were 74% (CI, 67% to 81%) in the 10-mg group and 82% (CI, 73% to 93%) in the 5-mg group (P > 0.2). At 60 hours, 9 of 25 patients in the 10-mg group (36% [CI, 17% to 54%]) and no patients in the 5-mg group had INRs greater than 3.0. At 84 hours, 15 of 24 patients in the 10-mg group (63% [CI, 43% to 81%]) and 19 of 24 patients in the 5-mg group (79% [CI, 62% to 95%]) had INRs between 2.0 and 3.0. Four patients in the 10-mg group and 1 patient in the 5-mg group received vitamin K for excessive prolongation of the INR. A 5-mg loading dose of warfarin produces less excess anticoagulation than does a 10-mg loading dose; the smaller dose also avoids the development of a potential hypercoagulable state caused by precipitous decreases in levels of protein C during the first 36 hours of warfarin therapy.


Quality and uptake of antenatal and postnatal care in Haiti.
Despite improvement, maternal mortality in Haiti remains high at 359/100,000 live births. Improving access to high quality antenatal and postnatal care has been shown to reduce maternal mortality and improve newborn outcomes. Little is known regarding the quality and uptake of antenatal and postnatal care among Haitian women. Exit interviews were conducted with all pregnant and postpartum women seeking care from large health facilities (n = 10) in the Nord and Nord-Est department and communes of St. Marc, Verrettes, and Petite Rivière in Haiti over the study period (March-April 2015; 3-4 days/facility). Standard questions related to demographics, previous pregnancies, current pregnancy, and services/satisfaction during the visit were asked. Total number of antenatal visits were abstracted from charts of recently delivered women (n = 1141). Provider knowledge assessments were completed by antenatal and postnatal care providers (n = 39). Frequencies were calculated for descriptive variables and multivariable logistic regression was used to explore predictors of receiving 5 out of 10 counseling messages among pregnant women. Among 894 pregnant women seeking antenatal care, most reported receiving standard clinical service components during their visit (97% were weighed, 80% had fetal heart tones checked), however fewer reported receiving recommended counseling messages (44% counselled on danger signs, 33% on postpartum family planning). Far fewer women were seeking postnatal care (n = 63) and similar service patterns were reported. Forty-three percent of pregnant women report receiving at least 5 out of 10 counseling messages. Pregnant women on a repeat visit and women with greater educational attainment had greater odds of reporting having received 5 out of 10 counseling messages (2nd visit: adjusted odds ratio [aOR] =1.70, 95% confidence interval [CI]: 1.09-2.66; 5+ visit: aOR = 5.44, 95% CI: 2.91-10.16; elementary school certificate: aOR = 2.06, 95% CI: 1.17-3.63; finished secondary school or more aOR = 1.97, 95% CI = 1.05-3.02). Chart reviews indicate 27% of women completed a single antenatal visit and 36% completed the recommended 4 visits. Antenatal and postnatal care uptake in Haiti is sub-optimal. Despite frequent reports of provision of standard service components, counseling messages are low. Consistent provision of standardized counseling messages with regular provider trainings is recommended to improve quality and uptake of care in Haiti.


Intraperitoneal chemotherapy: implications beyond ovarian cancer.
The National Cancer Institute (NCI) announced in January 2006 the use of intraperitoneal (IP) combined with IV chemotherapy postoperatively as the preferred treatment method for advanced ovarian cancer. The announcement stimulated the need for oncology nurses to become familiar with IP chemotherapy administration and patient management guidelines. IP administration allows a high concentration of chemotherapy to come into direct contact with tumors and surrounding tissues and organs. IP chemotherapy also is administered in clinical trials and some clinical settings for other histologies, such as low-grade gastrointestinal carcinoma and appendiceal carcinoma, which tend to spread locally before invading the bloodstream. Local-regional chemotherapy potentially is an ideal treatment for local spread of those peritoneal carcinomas. Overall side effects from regional treatment are less severe than with systemic treatment. Oncology nurses can help minimize and alleviate discomfort associated with IP chemotherapy administration. This article focuses on nursing management strategies for patients receiving IP chemotherapy for ovarian cancer and other peritoneal carcinomatosis.


Single-photon-counting detector for increased sensitivity in two-photon laser scanning microscopy.
We present the use and characterization of a photon-counting detector for increased sensitivity at low signal levels in fluorescence laser scanning microscopy (LSM). Conventional LSM photomultiplier tube detectors utilize analog current integration and thus suffer from excessive noise at low signal levels, introduced during current measurement. In this Letter we describe the implementation of a fast single-photon-counting (SPC) detector on a conventional two-photon laser scanning microscope and detail its use in imaging low fluorescence intensities. We show that for a low photon flux, the SPC detector is shot-noise limited and thus provides increased detection sensitivity compared with analog current integration.


The association between binge drinking and birth outcomes: results from the Born in Bradford cohort study.
Various human and animal studies suggest that peak alcohol exposure during a binge episode, rather than total alcohol exposure, may determine fetal development. Research about the impact of binge drinking on birth outcomes is sparse and inconclusive. Data from the Born in Bradford cohort study were used to explore the impact of binge drinking on birth outcomes. Interview-administered questionnaire data about the lifestyle and social characteristics of 10 851 pregnancies were linked to maternity and birth data. The impact of self-reported binge drinking (5 units: 40 g of pure alcohol) on two birth outcomes (small for gestational age (SGA) and preterm birth (<37 weeks)) was assessed using multivariate logistic regression models, while adjusting for confounders. The percentage of women classified as binge drinkers fell from 24.5% before pregnancy to 9% during the first trimester and 3.1% during the second trimester. There was a significant association between SGA birth and binge drinking (all categories combined; OR 1.68, 95% CI 1.15 to 2.47, p=0.01). No association was observed between moderate drinking and either birth outcome, or between binge drinking and preterm birth. Binge drinking during the second trimester of pregnancy was associated with an increased risk of SGA birth. No association was found between any level of alcohol consumption and premature birth. This work supports previous research showing no association between SGA and low-alcohol exposure but adds to evidence of a dose-response relationship with significant risks observed at binge drinking levels.


Serum Vitamin D Level as a Risk Factor for Female Genital Tuberculosis (FGTB).
Vitamin D is now known to be essential to Mycobacterium tuberculosis containment and killing through activation of 25-hydroxyvitamin-D receptors (VDRs) present on all immune cells or obtained from dietary food stuffs as either vitamin D3 or vegetable vitamin D2 (also known as ergocalciferol). To evaluate the association of serum vitamin D level between the Female Genital Tuberculosis (FGTB) cases and healthy controls. Total 120 cases and 120 controls enrolled for the study following inclusion and exclusion criteria. Detailed clinical history was taken from each subjects. Total of 3 ml of the blood was collected in EDTA vial from each subject (case and control). Quantification of serum vitamin D level was measured by active human vitamin D ELISA kit using an ELISA reader. Statistical analysis was done using Statistical Package for Social Science (SPSS) version 21.0. A p-value <0.05 was considered as significant. A total of 120 confirmed FGTB cases and 120 healthy control enrolled for study. Out of 120 women 97.5%, 10.0%, 3.3%, 3.3% were detected positive for M. tuberculosis respectively. Comparing the mean demographic value of age and BMI were (29.03±3.127, 28.03±3.00) and (22.92±3.33, 24.15±3.97) respectively with the p=0.012* and p=0.010* found to be significant among cases and controls. The mean serum vitamin D level was 14.96±8.81 in cases and 23.00±8.83 in controls with p-value<0.001. There was a significant positive association found in low serum vitamin D level among FGTB cases than controls. Vitamin D is important for normal immune cell function, as well as regression of FGTB disease. FGTB may be controlled by regulating the serum vitamin D level concentration. This study suggests that, vitamin D deficiency and BMI is strongly associated with the progression of active FGTB disease which alters the expression of antimicrobial peptide and lead to the persistence of TB infection. Therefore, serum vitamin D level may play an important role in treatment of FGTB.