Offering integrated medical equipment management in an application service provider model.
With the advancement of medical technology and thus the complexity of the equipment under their care, clinical engineering departments (CEDs) must continue to make use of computerized tools in the management of departmental activities. Authors of this paper designed, installed, and implemented an application service provider (ASP) model at the laboratory level to offer value added management tools in an online format to CEDs. The project, designed to investigate how to help meet demands across multiple healthcare organizations and provide a means of access for organizations that otherwise might not be able to take advantage of the benefits of those tools, has been well received. Ten hospitals have requested the service, and five of those are ready to proceed with the implementation of the ASP. With the proposed centralized system architecture, the model has shown promise in reducing network infrastructure labor and equipment costs, benchmarking of equipment performance indicators, and developing avenues for proper and timely problem reporting. The following is a detailed description of the design process from conception to implementation of the five main software modules and supporting system architecture.


The Clinical Anatomy and Imaging Laboratory: Vertical Integration in the Preclerkship Curriculum.
As medical schools implement integrated curricula, anatomy education especially has experienced increased pressure to make foundational content clinically relevant. We designed a novel type of integrative anatomy laboratory experience where students could use foundational anatomy concepts in concert with modern imaging/diagnostic techniques to enhance important clinical concepts. We selected a process called Lesson Study to develop the multidisciplinary Clinical Anatomy and Imaging Laboratory (CAIL) in the cardiovascular and gastrointestinal systems. We utilized soft-embalmed cadavers extensively for their highly realistic tissue appearance and texture, which allowed instructors and students to perform a wide array of procedures in case-based scenarios similar to practicing clinicians. We conducted field observations of participating students, focus-group discussions, and knowledge-based exams to examine efficacy of the CAIL. Approximately 150 first- and second-year students participated in each of the CAIL activities on an annual basis. Most focus-group participants felt the CAIL was a great learning experience. They commented on how the lab provided relevance to anatomy knowledge and helped integrate prior classroom learning more deeply. Instructors noted that students asked more advanced, clinically relevant questions than in a typical anatomy lab. Knowledge improved significantly after the CAIL, although it is unclear if this translates to summative exams. The CAIL creates a unique learning experience where students use prior foundational anatomy knowledge in conjunction with modern imaging and diagnostic techniques to reinforce important clinical concepts. We have continued to integrate CAIL experiences into more clinical systems in our medical school curriculum.


Estimating Human Cases of Avian Influenza A(H7N9) from Poultry Exposure.
In March 2013 an outbreak of avian influenza A(H7N9) was first recognized in China. To date there have been 130 cases in human, 47% of which are in men over the age of 55.The influenza strain is a novel subtype not seen before in humans; little is known about zoonotic transmission of the virus, but it is hypothesized that contact with poultry in live bird markets may be a source of exposure. The purpose of this study is to estimate the transmissibility of the virus from poultry to humans by estimating the amount of time shoppers, farmers, and live bird market retailers spend exposed to poultry each day. Results suggest that increased risk among older men is not due to greater exposure time at live bird markets.


Body composition in the rat: interactions of exercise, age, sex, and diet.
Changes in rat body composition (15 components) associated with changes in level of physical activity (cage restraint, ad libitum activity in living cages, and ad libitum wheel running), age at initiation of regimen (22 days-16 wk), sex, and diet (chow and 60% fat) are evaluated. Running regimen initiation at 7 wk of age or younger is associated with a decrease in the fat-free body mass (FFBM) in males and an increase in females. Initiation at 11 wk or older does not change FFBM. Both reduce body fatness in either sex. Age altered the mass of 11 components, diet altered the mass of 10 components, and activity altered the mass of 8 components, and there were 6 interactions between the experimental variables. The significance of interactions in general is discussed. Our data together with those of other investigators indicate that the responses to volitional wheel running and forced treadmill running are similar, but data from swimming rats may not be comparable in some cases.


Health Status and Transitions in Cohabiting Relationships of American Young Adults.
This study examines whether individual health predicts cohabitors' union transitions to marriage in American young adults. Associations between health and subsequent marital transitions are well documented, but less is known about how health influences transitions of cohabiting relationships. As cohabitation has become a common relationship experience, understanding how health may influence cohabitors' union transitions is an important component of how health shapes relationship exposures more broadly. Data were taken from Waves III and IV of the National Longitudinal Study of Adolescent to Adult Health (http://www.cpc.unc.edu/projects/addhealth), including the supplemental collection of relationship partners conducted during Wave III. Competing risk regressions for the transition of cohabiting unions to marriage were estimated in two samples: one of individuals and a smaller one of cohabiting couples with information from both partners. Healthier cohabiters are more likely to marry than are their less healthy counterparts, but only women's health is significantly associated with the transition to marriage. In the dyadic sample with information from both partners, the significant association between the female partner's health and the transition to marriage is robust to male partner characteristics, including health. Health is an important predictor of cohabitation transitions in early adulthood, but these transitions may only be sensitive to the female partner's health.


Low-affinity Nerve Growth Factor Receptor (CD271) Heterogeneous Expression in Adult and Fetal Mesenchymal Stromal Cells.
Human multipotent mesenchymal stromal cells (MSC) are isolated from a plethora of tissue sources for cell therapy purposes. In 2006, the International Society for Cellular Therapy (ISCT) published minimal guidelines to define MSC identity. Nevertheless, many independent studies demonstrated that cells meeting the ISCT criteria possessed heterogeneous phenotypes and functionalities, heavily influenced by culture conditions. In this study, human MSC derived from many adult (bone marrow and adipose tissue) or fetal (cord blood, Wharton's jelly, umbilical cord perivascular compartment and amniotic fluid) tissues were investigated. Their immunophenotype was analyzed to define consistent source-specific markers by extensive flow cytometry analysis and real-time qRT-PCR. CD271+ subpopulations were detected in adult MSC, whereas NG2 was significantly more expressed in fetal MSC but failed validation on independent samples coming from an external laboratory. The highest number of CD271+ adult MSC were detected soon after isolation in serum-based culture conditions. Furthermore, heterogeneous percentages of CD271 expression were found in platelet lysate-based or serum-free culture conditions. Finally, CD271+ adult MSC showed high clonogenic and osteogenic properties as compared to CD271- cells. To conclude, in this phenotype-function correlation study CD271+ subpopulation confers heterogeneity on adult MSC, confirming the need of more specific markers to address MSC properties.


Next day effects of a normal night's drinking on memory and psychomotor performance.
To investigate in social drinkers the effects of a 'normal' evening of drinking alcohol on cognitive performance. Aiming for ecological validity, the study required participants to consume their usual quantity of any type of alcoholic beverage in their chosen company (hangover situation). However, the timing of drinking was restricted to the period between 22:00 and 02:00 hours on the night before testing. Testing included memory and psychomotor performance tests; testing was also performed after an evening of abstinence (no hangover situation), following a counterbalanced design using repeated measures, with time of testing (09:00, 11:00 and 13:00 hours) and order of testing (hangover/no hangover; no hangover/hangover) as 'between participant' factors in the analysis. Forty-eight social drinkers (33 women, 15 men) aged between 18 and 43 years were tested, with a 1-week interval between test sessions. The morning after alcohol (mean consumption: 14.7 units for men; 10.4 units for women), free recall was impaired at 09:00 hours and delayed recognition and psychomotor performance were impaired throughout the morning, despite blood alcohol levels of zero or very near zero. Memory and psychomotor performance is impaired on the morning after heavy 'social' drinking.


Acupuncture Increases the Excitability of the Cortico-Spinal System in Patients with Chronic Disorders of Consciousness Following Traumatic Brain Injury.
To evaluate the immediate effect of acupuncture on cortico spinal tract (CST) activity in patients with chronic disorders of consciousness (DOC) after traumatic brain injury (TBI) by measuring motor-evoked potential (MEP) using transcranial magnetic stimulation (TMS). Changes in several variables in the acupuncture session were compared with those in the control session without acupuncture in the same patients. Chubu Medical Center for Prolonged Traumatic Brain Dysfunction, Gifu, Japan. Fourteen patients (mean age ± standard deviation, 39 ± 17 years; 12 men) with chronic DOC (5 in a vegetative state and 9 in a minimally conscious state) following severe TBI. Acupuncture treatment was performed at GV 26, Ex-HN 3, bilateral LI 4, and ST 36 for 10 minutes. Main outcome measure was MEP amplitude. MEP amplitude, measured by using TMS on the primary motor cortex, was recorded from the abductor pollicis brevis muscle. MEP recordings were performed before acupuncture (baseline), 10 minutes after needle insertion (phase 1), and 10 minutes after needle removal (phase 2). As a control, the same procedure without acupuncture was performed on another day with the order randomized. MEP amplitude and latency were calculated. Evoked F-wave measurements were also performed to calculate maximum M-wave amplitude (Mmax), M-wave latency, and F-wave latency in the same muscle. Central motor conduction time (CMCT) and MEP/Mmax ratio were also calculated from the MEP and F-wave measurement data. MEP amplitude and MEP/Mmax were increased significantly in the acupuncture session at phases 1 and 2 compared with the control session (p < 0.001, p < 0.001, p < 0.001, and p = 0.001, respectively). CMCTs were reduced at phases 1 and 2 in the acupuncture session compared with the control session, and the change at phase 1 was statistically significant (P = 0.002). Acupuncture treatment increased the CST activity of patients with chronic DOC after severe TBI.


Arthroscopic Shoulder Surgery in Female Professional Tennis Players: Ability and Timing to Return to Play.
To assess the outcome and time to return to previous level of competitive play after shoulder surgery in professional tennis players. Retrospective case series. Tertiary academic centre. The records of all female tennis players on the Women's Tennis Association (WTA) professional circuit between January 2008 and June 2010 were reviewed to identify players who underwent shoulder surgery on their dominant (serving) shoulder. Primary outcomes were the ability and time to return to professional play and if they were able to return to their previous level of function as determined by singles ranking. Preoperative and postoperative singles rankings were used to determine rate and completeness of return to preoperative function. During the study period, 8 professional women tennis players from the WTA tour underwent shoulder surgery on their dominant arm. Indications included rotator cuff debridement or repair, labral reconstruction for instability or superior labral anterior posterior lesion, and neurolysis of the suprascapular nerve. Seven players (88%) returned to professional play. The mean time to return to play was 7 months after surgery. However, only 25% (2 of 8) players achieved their preinjury singles rank or better by 18 months postoperatively. In total, 4 players returned to their preinjury singles ranking, with their peak singles ranking being attained at a mean of 2.4 years postoperatively. In professional female tennis players, a high return to play rate after arthroscopic shoulder surgery is associated with a prolonged and often incomplete return to previous level of performance. Thus, counseling the patient to this fact is important to manage expectations. Level IV-Case Series.


The DNA Repair Inhibitor DT01 as a Novel Therapeutic Strategy for Chemosensitization of Colorectal Liver Metastasis.
Metastatic liver disease from colorectal cancer is a significant clinical problem. This is mainly attributed to nonresectable metastases that frequently display low sensitivities to available chemotherapies and develop drug resistance partly via hyperactivation of some DNA repair functions. Combined therapies have shown some disease control; however, there is still a need for more efficient chemotherapies to achieve eradication of colorectal cancer liver metastasis. We investigated the tolerance and efficacy of a novel class of DNA repair inhibitors, Dbait, in association with conventional chemotherapy. Dbait mimics double-strand breaks and activates damage signaling, consequently inhibiting single- and double-stranded DNA repair enzyme recruitment. In vitro, Dbait treatment increases sensitivity of HT29 and HCT116 colorectal cancer cell lines. In vivo, the pharmacokinetics, biodistribution and the efficacy of the cholesterol-conjugated clinical form of Dbait, DT01, were assessed. The chemosensitizing abilities of DT01 were evaluated in association with oxaliplatin and 5-fluorouracil in intrahepatic HT29 xenografted mice used as a model for colorectal cancer liver metastasis. The high uptake of DT01 indicates that the liver is a specific target. We demonstrate significant antitumor efficacy in a liver metastasis model with DT01 treatment in combination with oxaliplatin and 5-fluorouracil (mean: 501 vs. 872 mm(2), P = 0.02) compared to chemotherapy alone. The decrease in tumor volume is further associated with significant histologic changes in necrosis, proliferation, angiogenesis and apoptosis. Repeated cycles of DT01 do not increase chemotherapy toxicity. Combining DT01 with conventional chemotherapy may prove to be a safe and effective therapeutic strategy in the treatment of metastatic liver cancer.


A single serving of caffeinated coffee impairs postprandial glucose metabolism in overweight men.
Previous studies regarding the acute effects of coffee on glycaemic control have used a single large dose of coffee, typically containing the caffeine equivalent of 2-4 servings of coffee. This study investigates whether the acute effects of coffee are dose-dependent, starting with a single serving. A total of ten healthy overweight males participated in a two-part randomised double-blind cross-over study. In the first part, they ingested 2, 4 or 8 g instant decaffeinated coffee (DC) dissolved in 400 ml water with caffeine added in proportion to the DC (total 100, 200 or 400 mg caffeine) or control (400 ml water) all with 50 g glucose. In the second part, they ingested the same amounts of DC (2, 4, 8 g) or control, but with a standard 100 mg caffeine added to each. Capillary blood samples were taken every 15 min for 2 h after each drink and glucose and insulin levels were measured. Repeated measures ANOVA on glucose results found an effect when caffeine was varied in line with DC (P=0·008). Post hoc analysis revealed that both 2 and 4 g DC with varied caffeine content increased the glycaemic response v. There was no effect of escalating doses of DC when caffeine remained constant at 100 mg. These results demonstrate that one standard serving of coffee (2 g) is sufficient to affect glucose metabolism. Furthermore, the amount of caffeine found in one serving (100 mg) is sufficient to mask any potential beneficial effects of increasing other components. No dose-dependent effect was found.


How does risk sharing between employers and a managed behavioral health organization affect mental health care?
To study the ways in which allocating the risk for behavioral health care expenses between employers and a managed behavioral health organization affects costs and the use of services. Claims from 87 plans that cover mental health and substance abuse services covering over one million member years in 1996/1997. Multi-part regression models for health care cost are used. Dependent variables are health care costs decomposed into access to any care, costs per user, any inpatient use, costs per outpatient user, and costs per inpatient user. The study compares full-risk plans, in which the managed care organization provides managed care services and acts as the insurer by assuming the risk for claims costs, with contracts in which the managed care organization only manages care (for a fixed administrative fee) and the employer retains the risk for claims. Full-risk plans are not statistically significantly different from non-risk plans in terms of any mental health specialty use or hospitalization rates, but costs per user are significantly lower, in particular for inpatients. Risk contracts do not affect initial access to mental health specialty care or hospitalization rates, but patients in risk contracts have lower costs, either because of lower intensity of care or because they are treated by less expensive providers.


Higher predation risk for insect prey at low latitudes and elevations.
Biotic interactions underlie ecosystem structure and function, but predicting interaction outcomes is difficult. We tested the hypothesis that biotic interaction strength increases toward the equator, using a global experiment with model caterpillars to measure predation risk. Across an 11,660-kilometer latitudinal gradient spanning six continents, we found increasing predation toward the equator, with a parallel pattern of increasing predation toward lower elevations. Patterns across both latitude and elevation were driven by arthropod predators, with no systematic trend in attack rates by birds or mammals. These matching gradients at global and regional scales suggest consistent drivers of biotic interaction strength, a finding that needs to be integrated into general theories of herbivory, community organization, and life-history evolution.


The putative RNA helicase HELZ promotes cell proliferation, translation initiation and ribosomal protein S6 phosphorylation.
The hypoxia-inducible transcription factor (HIF) is a key component of the cellular adaptation mechanisms to hypoxic conditions. HIFα subunits are degraded by prolyl-4-hydroxylase domain (PHD) enzyme-dependent prolyl-4-hydroxylation of LxxLAP motifs that confer oxygen-dependent proteolytic degradation. Interestingly, only three non-HIFα proteins contain two conserved LxxLAP motifs, including the putative RNA helicase with a zinc finger domain HELZ. However, HELZ proteolytic regulation was found to be oxygen-independent, supporting the notion that a LxxLAP sequence motif alone is not sufficient for oxygen-dependent protein destruction. Since biochemical pathways involving RNA often require RNA helicases to modulate RNA structure and activity, we used luciferase reporter gene constructs and metabolic labeling to demonstrate that HELZ overexpression activates global protein translation whereas RNA-interference mediated HELZ suppression had the opposite effect. Although HELZ interacted with the poly(A)-binding protein (PABP) via its PAM2 motif, PABP was dispensable for HELZ function in protein translation. Importantly, downregulation of HELZ reduced translational initiation, resulting in the disassembly of polysomes, in a reduction of cell proliferation and hypophosphorylation of ribosomal protein S6.


Data contradict common perceptions about a controversial provision of the US Endangered Species Act.
Separating myth and reality is essential for evaluating the effectiveness of laws. Section 7 of the US Endangered Species Act (Act) directs federal agencies to help conserve threatened and endangered species, including by consulting with the US Fish and Wildlife Service (FWS) or National Marine Fisheries Service on actions the agencies authorize, fund, or carry out. Consultations ensure that actions do not violate the Act's prohibitions on "jeopardizing" listed species or "destroying or adversely modifying" these species' critical habitat. Because these prohibitions are broad, many people consider section 7 the primary tool for protecting species under the Act, whereas others believe section 7 severely impedes economic development. This decades-old controversy is driven primarily by the lack of data on implementation: past analyses are either over 25 y old or taxonomically restricted. We analyze data on all 88,290 consultations recorded by FWS from January 2008 through April 2015. In contrast to conventional wisdom about section 7 implementation, no project was stopped or extensively altered as a result of FWS finding jeopardy or adverse modification during this period. We also show that median consultation duration is far lower than the maximum allowed by the Act, and several factors drive variation in consultation duration. The results discredit many of the claims about the onerous nature of section 7 but also raise questions as to how federal agencies could apply this tool more effectively to conserve species. We build on the results to identify ways to improve the effectiveness of consultations for imperiled species conservation and increase the efficiency of consultations.


Signaling through the phosphatidylinositol 3-kinase regulates mechanotaxis induced by local low magnetic forces in Entamoeba histolytica.
In micro-organisms, as well as in metazoan cells, cellular polarization and directed migration are finely regulated by external stimuli, including mechanical stresses. The mechanisms sustaining the transduction of such external stresses into intracellular biochemical signals remain mainly unknown. Using an external magnetic tip, we generated a magnetic field gradient that allows migration analysis of cells submitted to local low-intensity magnetic forces (50 pN). We applied our system to the amoeba Entamoeba histolytica. Indeed, motility and chemotaxis are key activities that allow this parasite to invade and destroy the human tissues during amoebiasis. The magnetic force was applied either inside the cytoplasm or externally at the rear pole of the amoeba. We observed that the application of an intracellular force did not affect cell polarization and migration, whereas the application of the force at the rear pole of the cell induced a persistent polarization and strongly directional motion, almost directly opposed to the magnetic force. This phenomenon was completely abolished when phosphatidylinositol 3-kinase activity was inhibited by wortmanin. This result demonstrated that the applied mechanical stimulus was transduced and amplified into an intracellular biochemical signal, a process that allows such low-intensity force to strongly modify the migration behavior of the cell.


Alpha-tocopherol and MRI outcomes in multiple sclerosis--association and prediction.
Alpha-tocopherol is the main vitamin E compound in humans, and has important antioxidative and immunomodulatory properties. The aim of this study was to study alpha-tocopherol concentrations and their relationship to disease activity in Norwegian multiple sclerosis (MS) patients. Prospective cohort study in 88 relapsing-remitting MS (RRMS) patients, originally included in a randomised placebo-controlled trial of omega-3 fatty acids (the OFAMS study), before and during treatment with interferon beta. The patients were followed for two years with repeated 12 magnetic resonance imaging (MRI) scans and nine serum measurements of alpha-tocopherol. During interferon beta (IFNB) treatment, each 10 µmol/L increase in alpha-tocopherol reduced the odds (CI 95%) for simultaneous new T2 lesions by 36.8 (0.5-59.8) %, p = 0.048, and for combined unique activity by 35.4 (1.6-57.7) %, p = 0.042, in a hierarchical regression model. These associations were not significant prior to IFNB treatment, and were not noticeably changed by gender, age, body mass index, HLA-DRB1*15, treatment group, compliance, or the concentrations of 25-hydroxyvitamin D, retinol, neutralising antibodies against IFNB, or the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid. The corresponding odds for having new T1 gadolinium enhancing lesions two months later was reduced by 65.4 (16.5-85.7) %, p = 0.019, and for new T2 lesions by 61.0 (12.4-82.6) %, p = 0.023. During treatment with IFNB, increasing serum concentrations of alpha-tocopherol were associated with reduced odds for simultaneous and subsequent MRI disease activity in RRMS patients.


Mutational analysis of the adenovirus 2 IVa2 initiator and downstream elements.
The initiator element of the adenovirus type 2 IVa2 promoter is sufficient to direct accurate initiation by RNA polymerase II. Analysis of the effects of substitution of specific base pairs on initiator activity in in vitro transcription systems indicated that specific sequences between positions -4 and +5 were essential for initiator activity. Mutations that impaired or eliminated initiator activity altered both base pairs that are conserved in sequence-related initiators and nonconserved sequences. Neither the downstream TA-rich sequence of the IVa2 promoter, nor the adenovirus 2 major late TATA element placed at the same downstream site could overcome the severe inhibitory effects of initiator mutations, indicating that the initiator is the primary determinant of the specificity and direction of IVa2 transcription. By contrast, when the ML TATA element was placed 31 nucleotides upstream of the IVa2 initiator, the precise specificity, but neither the efficiency nor direction of transcription, depended on the presence of a functional initiator. Activity of the IVa2 promoter was relatively insensitive to changes in the orientation or nature of the TA-rich sequence. Furthermore, only a promoter containing the ML TA-TAAAA sequence downstream of the IVa2 initiator was competent to direct both IVa2 transcription and transcription from the opposite strand. The implications of this functional difference for recognition of the downstream element are discussed.


Flupirtine blocks apoptosis in batten patient lymphoblasts and in human postmitotic CLN3- and CLN2-deficient neurons.
Multiple gene defects cause Batten disease. Accelerated apoptosis accounts for neurodegeneration in the late infantile and juvenile forms that are due to defects in the CLN3 and CLN2 genes. Extensive neuronal death is seen in CLN2- and CLN3-deficient human brain as well as in CLN6-deficient sheep brain and retina. When neurons in late infantile and juvenile brain survive, they manage to do so by upregulating the neuroprotective molecule Bcl-2. The CLN3 gene has antiapoptotic properties at the molecular level. We show that the CLN2 gene is neuroprotective: it enhances growth of NT2 cells and maintains survival of human postmitotic hNT neurons. Conversely, blocking CLN3 or CLN2 expression in hNT neurons with adenoviral antisense-CLN3 or antisense-CLN2-AAV2 constructs causes apoptosis. The drug flupirtine is a triaminopyridine derivative that acts as a nonopioid analgesic. Flupirtine upregulates Bcl-2, increases glutathione levels, activates an inwardly rectifying potassium channel, and delays loss of intermitochondrial membrane calcium retention capacity. We show that flupirtine aborts etoposide-induced apoptosis in CLN1-, CLN2-, CLN3-, and CLN6-deficient as well as normal lymphoblasts. Flupirtine also prevents the death of CLN3- and CLN2-deficient postmitotic hNT neurons at the mitochondrial level. We show that a mechanism of neuroprotection exerted by flupirtine involves complete functional antagonism of N-methyl-D-aspartate or N-methyl-D-aspartate-induced neuronal apoptosis. Flupirtine may be useful as a drug capable of halting the progression of neurodegenerative diseases caused by dysregulated apoptosis.


Loss-free and active optical negative-index metamaterials.
The recently emerged fields of metamaterials and transformation optics promise a family of exciting applications such as invisibility, optical imaging with deeply subwavelength resolution and nanophotonics with the potential for much faster information processing. The possibility of creating optical negative-index metamaterials (NIMs) using nanostructured metal-dielectric composites has triggered intense basic and applied research over the past several years. However, the performance of all NIM applications is significantly limited by the inherent and strong energy dissipation in metals, especially in the near-infrared and visible wavelength ranges. Generally the losses are orders of magnitude too large for the proposed applications, and the reduction of losses with optimized designs seems to be out of reach. One way of addressing this issue is to incorporate gain media into NIM designs. However, whether NIMs with low loss can be achieved has been the subject of theoretical debate. Here we experimentally demonstrate that the incorporation of gain material in the high-local-field areas of a metamaterial makes it possible to fabricate an extremely low-loss and active optical NIM. The original loss-limited negative refractive index and the figure of merit (FOM) of the device have been drastically improved with loss compensation in the visible wavelength range between 722 and 738 nm. In this range, the NIM becomes active such that the sum of the light intensities in transmission and reflection exceeds the intensity of the incident beam. At a wavelength of 737 nm, the negative refractive index improves from -0.66 to -1.017 and the FOM increases from 1 to 26. At 738 nm, the FOM is expected to become macroscopically large, of the order of 10(6). This study demonstrates the possibility of fabricating an optical negative-index metamaterial that is not limited by the inherent loss in its metal constituent.


Evaluation of exposure biomarkers in offshore workers exposed to low benzene and toluene concentrations.
Characterize ethylbenzene and xylene air concentrations, and explore the biological exposure markers (urinary t,t-muconic acid (t,t-MA) and unmetabolized toluene) among petroleum workers offshore. Offshore workers have increased health risks due to simultaneous exposures to several hydrocarbons present in crude oil. We discuss the pooled benzene exposure results from our previous and current studies and possible co-exposure interactions. BTEX air concentrations were measured during three consecutive 12-h work shifts among 10 tank workers, 15 process operators, and 18 controls. Biological samples were collected pre-shift on the first day of study and post-shift on the third day of the study. The geometric mean exposure over the three work shifts were 0.02 ppm benzene, 0.05 ppm toluene, 0.03 ppm ethylbenzene, and 0.06 ppm xylene. Benzene in air was significantly correlated with unmetabolized benzene in blood (r = 0.69, p < 0.001) and urine (r = 0.64, p < 0.001), but not with urinary t,t-MA (r = 0.27, p = 0.20). Toluene in air was highly correlated with the internal dose of toluene in both blood (r = 0.70, p < 0.001) and urine (r = 0.73, p < 0.001). Co-exposures were present; however, an interaction of metabolism was not likely at these low benzene and toluene exposures. Urinary benzene, but not t,t-MA, was a reliable biomarker for benzene at low exposure levels. Urinary toluene was a useful biomarker for toluene exposure. Xylene and ethylbenzene air levels were low. Dermal exposure assessment needs to be performed in future studies among these workers.


Prevalence of hearing loss and accuracy of self-report among factory workers.
Noise represents one of the most common occupational health hazards. A Healthy People 2020 objective aims to reduce hearing loss in the noise-exposed public. The purpose of this study was to describe and compare perceived and measured hearing, and to determine the prevalence of hearing loss among a group of factory workers. Data collected as part of an intervention study promoting hearing protector use among workers at an automotive factory in the Midwest were used. Plant employees (n=2691) provided information regarding their perceived hearing ability, work role, and other demographics. The relationships among audiograms, a single-item measure of perceived hearing ability, and demographic data were explored using chi-square, McNemar's test, Mann-Whitney U-test, sensitivity, and specificity. The prevalence of hearing loss among noise-exposed factory workers was 42% (where hearing loss was defined as >25 dB loss at the OSHA-recommended frequencies of 2, 3, and 4 kHz in either ear). However, 76% of workers reported their hearing ability as excellent or good. The difference in perceived hearing ability was significant at each tested frequency between those with and without measured hearing loss. Self-reported hearing ability was poorly related to results of audiometry. Although this group of workers was employed in a regulated environment and served by a hearing conservation program, hearing loss was highly prevalent. These findings, together with national prevalence estimates, support the need for evaluation of hearing conservation programs and increased attention to the national goal of reducing adult hearing loss.


Positional characterisation of false positives from computational prediction of human splice sites.
The performance of computational tools that can predict human splice sites are reviewed using a test set of EST-confirmed splice sites. The programs (namely HMMgene, NetGene2, HSPL, NNSPLICE, SpliceView and GeneID-3) differ from one another in the degree of discriminatory information used for prediction. The results indicate that, as expected, HMMgene and NetGene2 (which use global as well as local coding information and splice signals) followed by HSPL (which uses local coding information and splice signals) performed better than the other three programs (which use only splice signals). For the former three programs, one in every three false positive splice sites was predicted in the vicinity of true splice sites while only one in every 12 was expected to occur in such a region by chance. The persistence of this observation for programs (namely FEXH, GRAIL2, MZEF, GeneID-3, HMMgene and GENSCAN) that can predict all the potential exons (including optimal and sub-optimal) was assessed. In a high proportion (>50%) of the partially correct predicted exons, the incorrect exon ends were located in the vicinity of the real splice sites. Analysis of the distribution of proximal false positives indicated that the splice signals used by the algorithms are not strong enough to discriminate particularly those false predictions that occur within +/- 25 nt around the real sites. It is therefore suggested that specialised statistics that can discriminate real splice sites from proximal false positives be incorporated in gene prediction programs.


Differences in trabecular bone of leptin-deficient ob/ob mice in response to biomechanical loading.
It is known that bone mineral density (BMD) and the strength of bone is predicted by body mass. Fat mass is a significant predictor of bone mineral density which correlates with body weight. This suggests that body fat regulates bone metabolism first by means of hormonal factors and second that the effects of muscle and loading are signaling factors in mechanotransduction. Leptin, a peptide hormone produced predominantly by white fat cells, is one of these hormonal factors. The aim of this study was to investigate and measure by micro-CT the different effects of weight-bearing on trabecular bone formation in mice without the stimulation of leptin. Animals with an ad-libitum-diet (Group A) were found to increase body weight significantly at the age of six weeks in comparison with lean mice (Group B). From this point on, the difference increased constantly. At the age of twenty weeks the obese mice were almost twice as heavy as the lean mice. Significant statistical differences are shown between the two groups for body weight and bone mineral density. Examination of trabecular bone (BV/TV, trabecular number (Tb.N.), trabecular thickness (Tb.Th.)) revealed that the only statistically significant difference between the two groups was the Tb.N. for the proximal femur. High weight-bearing insignificantly improved all trabecular bone parameters in the obese mice. Compared with the control-diet Group B, the BV/TV and Tb.N. were slightly higher in the controlled-diet Group A, but not the Tb.Th.. However, correlation was found between Tb.N. and BMD on the one hand and body weight on the other hand. biomechanical loading led to decreased bone mineral density by a decrease in the number of trabeculae. Trabecular thickness was not increased by biomechanical loading in growing mice. Decreased body weight in leptin-deficient mice protects against bone loss. This finding is consistent with the principle of light-weight construction of bone. Differences in cortical and trabecular bone will be examined in later studies. It is not possible to conclude that these results also apply to human beings.


Imaging action potentials with calcium indicators.
The understanding of neuronal circuits has been, and will continue to be, greatly advanced by the simultaneous imaging of action potentials in neuronal ensembles. This protocol describes "bulk" loading of brain slices with acetoxymethyl (AM) ester calcium indicators in order to monitor action potential activity in large populations of neurons simultaneously. The imaging of calcium influx into neurons provides an indirect, but accurate, measure of action potential generation in individual neurons. Single-cell resolution, and thus the easy identification of every active cell, is the key advantage of the technique.


Impact of moderate functional mitral insufficiency in patients undergoing surgical revascularization.
Mild and moderate functional ischemic mitral insufficiency present at the time of surgical revascularization present clinical uncertainty. It is unclear whether the relatively poor outcomes in this cohort are dependent on valvular function or related to left ventricular dysfunction. The purpose of this study was to examine the early and late outcomes in patients with less-than-severe functional ischemic mitral insufficiency at the time of isolated coronary artery bypass grafting (CABG). From 1996 through 2004, 2242 consecutive patients undergoing isolated CABG were identified as having none to moderate mitral regurgitation (MR) and no valve leaflet pathology. All of the patients at this single institution routinely had an intraoperative transesophageal echocardiography, prospectively quantified MR, and ejection fraction (EF). The New York State Cardiac Surgery Reporting System infrastructure was used to prospectively collect in-hospital patient variables and outcomes. Social Security Death Benefit Index was used to determine long-term survival. Odds ratio and significance (P value) are presented for each determined risk factor. There were 841 patients (37.5%) with no MR, 1137 (50.7%) with mild MR, and 264 (11.8%) with moderate MR. The patients with moderate MR were more likely to be older, female, and have more renal disease, previous MI, congestive heart failure, previous cardiac surgery, and lower EFs. Hospital mortality was independently and significantly associated with renal disease, decreasing EF, increasing age, previous cardiac operation, and cerebral vascular disease. Multivariable analysis revealed decreased survival with increasing age, previous operation, congestive heart failure, diabetes, nonelective operation, decreasing EF, and the presence of moderate MR (expbeta = 1.49; P=0.007) and mild MR (expbeta = 1.34; P=0.033). Independent of ventricular function, mild and moderate functional mitral insufficiency are associated with significantly decreased survival in patients undergoing CABG. Whether correction of moderate functional MR at the time of CABG improves outcome still needs to be determined.


Chronic calorie restriction attenuates experimental autoimmune encephalomyelitis.
Calorie restriction (CR) prevents many age-associated diseases and prolongs the lifespan. CR induces multiple metabolic and physiologic modifications, including anti-inflammatory, antioxidant, and neuroprotective effects that may be beneficial in multiple sclerosis (MS). The present studies sought to determine whether CR or increased calorie intake alters the course of experimental autoimmune encephalomyelitis (EAE), the leading animal model for MS. SJL and C57BL/6 mice were subjected to 40% CR beginning at 5 weeks of age. After 5 weeks of CR, EAE was induced by immunizing with proteolipid protein in SJL mice and with myelin oligodendrocyte glycoprotein in C57BL/6 mice. Clinical, histologic, and immunologic features of EAE were compared with mice fed ad libitum and to SJL mice fed a high-fat, high-calorie diet. CR ameliorated clinical EAE in both mouse strains with less severe inflammation, demyelination, and axon injury. No suppression of immune function was observed. A high-calorie diet did not alter the EAE course. CR was associated with increased plasma levels of corticosterone and adiponectin and reduced concentrations of IL-6 and leptin. The CR-induced hormonal, metabolic, and cytokine changes observed in our studies suggest a combined anti-inflammatory and neuroprotective effect. CR with adequate nutrition and careful medical monitoring should be explored as a potential treatment for MS.


Physician Response to Contextualized Price-Comparison Claims in Prescription Drug Advertising.
Physician-targeted prescription drug advertisements sometimes include price comparisons between products that may misleadingly imply equivalence of efficacy and safety or misrepresent true savings, suggesting the potential utility of a context statement to explain what the claims do and do not mean. We manipulated the presence of a price claim and a context statement in a 1 × 3 (control condition, price-comparison-only, price-comparison-plus-context) between-subjects design. Physicians (N = 1,438), randomly assigned to condition, viewed the prescription drug ad and answered a brief survey. Primary outcome measures included recognition, perceived importance, and impact of the price-comparison claim, and recognition, understanding, and effectiveness of the context statement. The majority of physicians accurately recognized the price claim (76.0%) but far fewer accurately recognized the associated context statement (44.9%). The context statement did not affect evaluations of the price-comparison claim importance or accuracy and did not have the intended effects on perceptions of uncertainty about drug interchangeability. Physicians may be affected by price-comparison claims in thinking that the drug has risks that are relatively less severe. Price-comparison claims also affected intentions to look for information about the drug. Adding a realistic context statement to a physician-targeted prescription drug ad did not generate sufficient awareness of claim caveats to differentiate price-comparison response of those exposed to the context statement from those who were not.


Establishment of bone marrow-derived endothelial cell lines from ts-SV40 T-antigen gene transgenic rats.
Postneonatal neovascularization is thought to result exclusively from the proliferation, migration, and remodeling of fully differentiated endothelial cells (ECs). Recently, it has been reported that bone marrow contains cells which can differentiate into ECs and contribute to neoangiogenesis in adult species. In this study, we tried to establish conditionally immortalized endothelial cell lines (TR-BME) derived from rat bone marrow. Mononuclear cells were isolated and differentiated into ECs at 37 degrees C from the bone marrow of a transgenic rat harboring temperature-sensitive SV40 large T-antigen (ts T-Ag) gene. Then, the cells were transferred and incubated at 33 degrees C, a permissive temperature for ts T-Ag. Expression of vascular endothelial growth factor (VEGF) receptor (VEGFR)-1, 2, Tie-1, 2 and von Willebrand factor (VWF) were assayed by reverse transcriptase-mediated polymerase chain reaction (RT-PCR). We have established three cell lines incorporating 1,1'-dioctadecyl-3,3,3',3-tetramethylindo-carbocyanine perchlorate (DiI-Ac-LDL) with a spindle shape. One of these, clone 2, strongly expressed VEGFR-2, and weakly expressed VEGFR-1 and VWF. In contrast, clone 8 showed strong expression of Tie-1, 2, and VWF, and weak expression of VEGFR-1,2. All markers were expressed strongly in clone 3. These data confirm that the above three TR-BME cells are novel ECs derived from bone marrow progenitors.


Effects of dextromethorphan and oxycodone on treatment of neuropathic pain in mice.
Neuropathic pain is a very troublesome and difficult pain to treat. Although opioids are the best analgesics for cancer and surgical pain in clinic, only oxycodone among opioids shows better efficacy to alleviate neuropathic pain. However, many side effects associated with the use of oxycodone render the continued use of it in neuropathic pain treatment undesirable. Hence, we explored whether dextromethorphan (DM, a known N-methyl-D-aspartate receptor antagonist with neuroprotective properties) could potentiate the anti-allodynic effect of oxycodone and underlying mechanisms regarding to glial cells (astrocytes and microglia) activation and proinflammatory cytokines release in a spinal nerve injury (SNL) mice model. Oxycodone produced a dose-dependent anti-allodynic effect. Co-administration of DM at a dose of 10 mg/kg (i.p.) (DM10) which had no anti-allodynic effect by itself enhanced the acute oxycodone (1 mg/kg, s.c.) effect. When the chronic anti-allodynic effects were examined, co-administration of DM10 also significantly enhanced the oxycodone effect at 3 mg/kg. Furthermore, oxycodone decreased SNL-induced activation of glial cells (astrocytes and microglia) and plasma levels of proinflammatory cytokines (IL-6, IL-1β and TNF-α). Co-administration of DM10 potentiated these effects of oxycodone. The combined use of DM with oxycodone may have therapeutic potential for decreasing the effective dose of oxycodone on the treatment of neuropathic pain. Attenuation of the glial activation and proinflammatory cytokines in the spinal cord may be important mechanisms for these effects of DM.


Event-Triggered Fault Detection of Nonlinear Networked Systems.
This paper investigates the problem of fault detection for nonlinear discrete-time networked systems under an event-triggered scheme. A polynomial fuzzy fault detection filter is designed to generate a residual signal and detect faults in the system. A novel polynomial event-triggered scheme is proposed to determine the transmission of the signal. A fault detection filter is designed to guarantee that the residual system is asymptotically stable and satisfies the desired performance. Polynomial approximated membership functions obtained by Taylor series are employed for filtering analysis. Furthermore, sufficient conditions are represented in terms of sum of squares (SOSs) and can be solved by SOS tools in MATLAB environment. A numerical example is provided to demonstrate the effectiveness of the proposed results.


Intractable Otitis Media Presenting as Falsely Positive for Proteinase 3-ANCA: A Case Report.
Herein, we report a case of otitis media caused by methicillin-resistant Staphylococcus aureus (MRSA), presenting as falsely positive for proteinase 3 (PR3)-antineutrophil cytoplasmic antibodies (ANCA). A 47-year-old woman was referred to our hospital with a complaint of left otorrhea. An otorrhea culture yielded MRSA, and the patient was treated using tympanoplasty. Postoperative administration of teicoplanin lead to drug-induced neutropenia and was discontinued 4 days after the operation. One month after the operation, the patient's otorrhea recurred, and it was accompanied by hearing impairment. The otorrhea culture yielded MRSA again, while serum was positive for PR3-ANCA (6.8 U/mL). As MRSA was detected in the patient's otorrhea sample, she was treated with linezolid. Her symptoms then improved immediately. Although the PR3-ANCA positivity remained, the patient's otorrhea and hearing impairment had not recurred for 3 years when this report was submitted. Therefore, we conclude that this is a case of false PR3-ANCA positivity.


People and ideas in medical informatics - a half century review.
OBJECTIVE. Reviewing the onset and the rapid changes to make realistic predictions on the future of medical informatics. METHODS. Pointing to the contributions of the early pioneers, who had their roots in other disciplines and by illustrating that from the onset an interdisciplinary approach was characteristic for our field. RESULTS. Some of the reasons for the changes in medical informatics are that nobody was able to predict the advent of the personal computer in the 1970s, the world-wide web in 1991, and the public start of the Internet in 1992, but foremost that nobody expected that it was not primarily the hardware or the software, but human factors that would be crucial for successful applications of computers in health care. In the past sometimes unrealistic expectations were held, such as on the impact of medical decision-support systems, or on the overly optimistic contributions of electronic health records. Although the technology is widely available, some applications appear to be far more complex than expected. Health care processes can seldom be fully standardized. Humans enter at least in two very different roles in the loop of information processing: as subjects conducting care - the clinicians - and as subjects that are the objects of care - the patients. CONCLUSIONS. Medical informatics lacks a specific methodology; methods are borrowed from adjacent disciplines such as physics, mathematics and, of course, computer science. Human factors play a major role in applying computers in health care. Everyone pursuing a career in biomedical informatics needs to be very aware of this. It is to be expected that the quality of health care will increasingly be assessed by computer systems to fulfill the requirements of medical evidence.


Forest restoration, biodiversity and ecosystem functioning.
Globally, forests cover nearly one third of the land area and they contain over 80% of terrestrial biodiversity. Both the extent and quality of forest habitat continue to decrease and the associated loss of biodiversity jeopardizes forest ecosystem functioning and the ability of forests to provide ecosystem services. In the light of the increasing population pressure, it is of major importance not only to conserve, but also to restore forest ecosystems. Ecological restoration has recently started to adopt insights from the biodiversity-ecosystem functioning (BEF) perspective. Central is the focus on restoring the relation between biodiversity and ecosystem functioning. Here we provide an overview of important considerations related to forest restoration that can be inferred from this BEF-perspective. Restoring multiple forest functions requires multiple species. It is highly unlikely that species-poor plantations, which may be optimal for above-ground biomass production, will outperform species diverse assemblages for a combination of functions, including overall carbon storage and control over water and nutrient flows. Restoring stable forest functions also requires multiple species. In particular in the light of global climatic change scenarios, which predict more frequent extreme disturbances and climatic events, it is important to incorporate insights from the relation between biodiversity and stability of ecosystem functioning into forest restoration projects. Rather than focussing on species per se, focussing on functional diversity of tree species assemblages seems appropriate when selecting tree species for restoration. Finally, also plant genetic diversity and above - below-ground linkages should be considered during the restoration process, as these likely have prominent but until now poorly understood effects at the level of the ecosystem. The BEF-approach provides a useful framework to evaluate forest restoration in an ecosystem functioning context, but it also highlights that much remains to be understood, especially regarding the relation between forest functioning on the one side and genetic diversity and above-ground-below-ground species associations on the other. The strong emphasis of the BEF-approach on functional rather than taxonomic diversity may also be the beginning of a paradigm shift in restoration ecology, increasing the tolerance towards allochthonous species.


Vertical transmission of the human papillomavirus: a systematic quantitative review.
In order to better understand the exact mode and risk of vertical transmission in asymptomatic pregnant women, as well as the relationship between HPV transmission and mode of delivery, we have proposed this systematic quantitative review of prospective cohort studies. A comprehensive search was performed in the Cochrane Library, MEDLINE, LILACS, CANCERLIT, and EMBASE, as well as in the reference lists from the identified studies. Nine primary studies, which included 2,111 pregnant women and 2,113 newborns, met our selection criteria and were analyzed. A positive HPV test in the mother increased the risk of vertical HPV transmission (RR: 4.8; 95%CI: 2.2-10.4). We also observed a higher risk of HPV infection after vaginal delivery than after cesarean section (RR: 1.8; 95%CI: 1.3-2.4). The results of this meta-analysis showed the HPV DNA-positive rate only after birth, but an HPV DNA-positive neonatal sample does not necessarily indicate infection; it could merely indicate contamination (perinatal HPV contamination may have occurred). Infants born through vaginal delivery were at higher risk of exposure to HPV.


Teacher led school-based surveillance can allow accurate tracking of emerging infectious diseases - evidence from serial cross-sectional surveys of febrile respiratory illness during the H1N1 2009 influenza pandemic in Singapore.
Schools are important foci of influenza transmission and potential targets for surveillance and interventions. We compared several school-based influenza monitoring systems with clinic-based influenza-like illness (ILI) surveillance, and assessed the variation in illness rates between and within schools. During the initial wave of pandemic H1N1 (pdmH1N1) infections from June to Sept 2009 in Singapore, we collected data on nation-wide laboratory confirmed cases (Sch-LCC) and daily temperature monitoring (Sch-DTM), and teacher-led febrile respiratory illness reporting in 6 sentinel schools (Sch-FRI). Comparisons were made against age-stratified clinic-based influenza-like illness (ILI) data from 23 primary care clinics (GP-ILI) and proportions of ILI testing positive for pdmH1N1 (Lab-ILI) by computing the fraction of cumulative incidence occurring by epidemiological week 30 (when GP-ILI incidence peaked); and cumulative incidence rates between school-based indicators and sero-epidemiological pdmH1N1 incidence (estimated from changes in prevalence of A/California/7/2009 H1N1 hemagglutination inhibition titers ≥ 40 between pre-epidemic and post-epidemic sera). Variation in Sch-FRI rates in the 6 schools was also investigated through a Bayesian hierarchical model. By week 30, for primary and secondary school children respectively, 63% and 79% of incidence for Sch-LCC had occurred, compared with 50% and 52% for GP-ILI data, and 48% and 53% for Sch-FRI. There were 1,187 notified cases and 7,588 episodes in the Sch-LCC and Sch-DTM systems; given school enrollment of 485,723 children, this represented 0.24 cases and 1.6 episodes per 100 children respectively. Mean Sch-FRI rate was 28.8 per 100 children (95% CI: 27.7 to 29.9) in the 6 schools. We estimate from serology that 41.8% (95% CI: 30.2% to 55.9%) of primary and 43.2% (95% CI: 28.2% to 60.8%) of secondary school-aged children were infected. Sch-FRI rates were similar across the 6 schools (23 to 34 episodes per 100 children), but there was widespread variation by classrooms; in the hierarchical model, omitting age and school effects was inconsequential but neglecting classroom level effects led to highly significant reductions in goodness of fit. Epidemic curves from Sch-FRI were comparable to GP-ILI data, and Sch-FRI detected substantially more infections than Sch-LCC and Sch-DTM. Variability in classroom attack rates suggests localized class-room transmission.


INSL3 in the ruminant: a powerful indicator of gender- and genetic-specific feto-maternal dialogue.
The hormone Insulin-like peptide 3 (INSL3) is a major secretory product of the Leydig cells from both fetal and adult testes. Consequently, it is a major gender-specific circulating hormone in the male fetus, where it is responsible for the first phase of testicular descent, and in the adult male. In most female mammals, circulating levels are very low, corresponding to only a small production of INSL3 by the mature ovaries. Female ruminants are exceptional in exhibiting high INSL3 gene expression by the thecal cells of antral follicles and by the corpora lutea. We have developed a specific and sensitive immunoassay to measure ruminant INSL3 and show that, corresponding to the high ovarian gene expression, non-pregnant adult female sheep and cows have up to four times the levels observed in other female mammals. Significantly, this level declines during mid-pregnancy in cows carrying a female fetus, in which INSL3 is undetectable. However, in cows carrying a male fetus, circulating maternal INSL3 becomes elevated further, presumably due to the transplacental transfer of fetal INSL3 into the maternal circulation. Within male fetal blood, INSL3 is high in mid-pregnancy (day 153) corresponding to the first transabdominal phase of testicular descent, and shows a marked dependence on paternal genetics, with pure bred or hybrid male fetuses of Bos taurus (Angus) paternal genome having 30% higher INSL3 levels than those of Bos indicus (Brahman) paternity. Thus INSL3 provides the first example of a gender-specific fetal hormone with the potential to influence both placental and maternal physiology.


Experiences From Developing and Upgrading a Web-Based Surveillance System for Malaria Elimination in Cambodia.
Strengthening the surveillance component is key toward achieving country-wide malaria elimination in Cambodia. A Web-based upgraded malaria information system (MIS) was deemed to essentially act as the central component for surveillance strengthening. New functionality (eg, data visualization) and operational (eg, data quality) attributes of the system received particular attention. However, building from the lessons learned in previous systems' developments, other aspects unique to Cambodia were considered to be equally important; for instance, feasibility issues, particularly at the field level (eg, user acceptability at various health levels), and sustainability needs (eg, long-term system flexibility). The Cambodian process of identifying the essential changes and critical attributes for this new information system can provide a model for other countries at various stages of the disease control and elimination continuum. Sharing these experiences not only facilitates the establishment of "best practices" but also accelerates global and regional malaria elimination efforts. In this article, Cambodia's experience in developing and upgrading its MIS to remain responsive to country-specific needs demonstrates the necessity for considering functionality, operationalization, feasibility, and sustainability of an information system in the context of malaria elimination.


Self-titrating anticoagulant nanocomplexes that restore homeostatic regulation of the coagulation cascade.
Antithrombotic therapy is a critical portion of the treatment regime for a number of life-threatening conditions, including cardiovascular disease, stroke, and cancer; yet, proper clinical management of anticoagulation remains a challenge because existing agents increase the propensity for bleeding in patients. Here, we describe the development of a bioresponsive peptide-polysaccharide nanocomplex that utilizes a negative feedback mechanism to self-titrate the release of anticoagulant in response to varying levels of coagulation activity. This nanoscale self-titrating activatable therapeutic, or nanoSTAT, consists of a cationic thrombin-cleavable peptide and heparin, an anionic polysaccharide and widely used clinical anticoagulant. Under nonthrombotic conditions, nanoSTATs circulate inactively, neither releasing anticoagulant nor significantly prolonging bleeding time. However, in response to life-threatening pulmonary embolism, nanoSTATs locally release their drug payload and prevent thrombosis. This autonomous negative feedback regulator may improve antithrombotic therapy by increasing the therapeutic window and decreasing the bleeding risk of anticoagulants.


Epitomics: global profiling of immune response to disease using protein microarrays.
The immune system retains memory of current and past infections and can sense the presence of cancer by elaborating autoantibodies to tumor proteins. In the presence of an autoimmune disease, the immune system is an efficient, natural biosensor. Therefore we exploit the immune system through a high-throughput process to isolate disease-specific epitopes for diagnostic and therapeutic purposes. These cloned disease-specific antigens are robotically spotted onto protein microarrays and interrogated with serum from the subjects under analyses. These arrays deliver personalized profiles of antigenic exposures and therapeutic targets for personalized immunotherapy. The immune system is the ultimate biosensor, superior to anything a human could create and ready to be exploited for biotechnology and biomedicine.


'Nowadays you don't even see your neighbours': loneliness in the everyday lives of older Australians.
Loneliness is a pressing social issue for older people globally. Despite this, there is a paucity of studies on how older people themselves perceive loneliness and how service providers can support them. This study sought to address the gap using in-depth and semi-structured interviews with 60 older people and eight focus groups with aged care service providers in Australia in 2007. A purposive sampling strategy was employed to incorporate maximum participant variation. People 65 years and over were recruited from four large service providers in two Australian states. Our findings show that loneliness is influenced by private, relational and temporal dimensions and whether older people feel that they have, or are seen by others as having, a sense of connectedness with the wider community. Participants expressed the importance of maintaining social contact and having a sense of connection and belonging to the community. Our study highlights both the significance of gathering the views of older people to generate an understanding about loneliness and the need to recognise loneliness as a diverse and complex experience, bound to the context in which it is understood and perceived and not synonymous with social isolation. Such an understanding can be used to both evaluate and improve upon programmes that address loneliness and to help maintain an integration of older people in the community.


Erythropoietic cell cultures from chick embryos.
Erythropoietic cell cultures from very early chick blastoderms survive for several days They show four to seven doublings of the erythroid cells and the appropriate morphological changes from proerythroblasts to mature erythrocytes Cell cycle times are the same as in ovo for the first day of culture, but slow down thereafter The hemoglobins of both the primitive and the definitive red cell series are produced. 5-Bromodeoxyuridine added to the cultures inhibits differentiation and hemoglobin synthesis, though not cell division, but quite soon the cells cease being sensitive The effect of the drug can be reversed by the addition of thymidine.


Acute effects of force and vibration on finger blood flow.
To investigate the effects of contact force at the finger on acute changes in finger circulation during exposure to vibration. Each of 10 subjects attended 11 sessions in which they experienced five successive experimental 5-minute periods: (i) no force and no vibration; (ii) force and no vibration; (iii) force and vibration; (iv) force and no vibration; (v) no force and no vibration. During periods (ii) to (iv), the intermediate phalanx of the right middle finger applied one of two forces (2 N or 5 N) on a platform that vibrated during period (iii) at one of two frequencies: 31.5 Hz (at 4 or 16 ms(-2) r.m.s.) or 125 Hz (at 16 or 64 ms(-2) r.m.s.). Finger blood flow was measured in the exposed right middle finger, the unexposed right little finger, and the unexposed left middle fingers throughout the 25 minutes of each session. The application of force alone caused a reduction in finger blood flow in the exposed finger, but not other fingers. There were additional reductions in finger blood flow caused by vibration, with greater reductions at the higher vibration magnitudes at both frequencies but no difference between the two frequencies when using unweighted acceleration. The vibration caused a similar vasoconstriction in vibrated and non-vibrated fingers. Modest levels of force applied by a finger can have a large effect on the finger blood flow, possibly due to the constriction of local blood vessels. The acute vascular effects of vibration cause additional reductions in finger blood flow that are not limited to the finger experiencing force and vibration. In all fingers (exposed and not exposed to vibration), the greater the magnitude of vibration, the greater the reduction in finger blood flow. In all fingers (exposed and not exposed to vibration), when the vibration was frequency weighted according to current standards, 125 Hz vibration caused greater reductions in finger blood flow than 31.5 Hz vibration.


Risk factors for ganciclovir-induced thrombocytopenia and leukopenia.
Ganciclovir is a nucleoside guanosine analogue that exhibits therapeutic activity against human cytomegalovirus infection, and is primarily excreted via glomerular filtration and active tubular secretion. The adverse effects induced by ganciclovir therapy are generally of a hematological nature and include thrombocytopenia and leukopenia. Low marrow cellularity and elevated serum creatinine have been identified as risk factors for ganciclovir-induced neutropenia. However, the risk factors for thrombocytopenia have yet to be determined. Therefore, this study investigated patients administered ganciclovir to determine the risk factors for thrombocytopenia and leukopenia. Thrombocytopenia occurred in 41 of these patients (30.6%). Multivariate logistic regression analysis identified three independent risk factors for thrombocytopenia: cancer chemotherapy (odds ratio (OR)=3.1), creatinine clearance (<20 mL/min) (OR=12.8), and the ganciclovir dose (≥12 mg/kg/d) (OR=15.1). Leukopenia occurred in 36 patients (28.6%), and white blood cell count (<6000 cells/mm(3)) (OR=3.7) and the ganciclovir dose (≥12 mg/kg/d) (OR=7.8) were identified as risk factors. These results demonstrated that several factors influenced the occurrence of ganciclovir-induced thrombocytopenia and leukopenia, and suggest that special attention should be paid to patients receiving cancer chemotherapy with a low creatinine clearance (<20 mL/min) and high dose (≥12 mg/kg/d) in order to avoid ganciclovir-induced thrombocytopenia.


Super-resolution microscopy and studies of peroxisomes.
Fluorescence microscopy is an important tool for studying cellular structures such as organelles. Unfortunately, many details in the corresponding images are hidden due to the resolution limit of conventional lens-based far-field microscopy. An example is the study of peroxisomes, where important processes such as molecular organization during protein important can simply not be studied with conventional far-field microscopy methods. A remedy is super-resolution fluorescence microscopy, which is nowadays a well-established technique for the investigation of inner-cellular structures but has so far to a lesser extent been applied to the study of peroxisomes. To help advancing the latter, we here give an overview over the different super-resolution microscopy approaches and their potentials and challenges in cell-biological research, including labelling issues and a focus on studies on peroxisomes. Here, we also highlight experiments beyond simple imaging such as observations of diffusion dynamics of peroxisomal proteins.


Metabolites: messengers between the microbiota and the immune system.
The mammalian intestine harbors one of the largest microbial densities on Earth, necessitating the implementation of control mechanisms by which the host evaluates the state of microbial colonization and reacts to deviations from homeostasis. While microbial recognition by the innate immune system has been firmly established as an efficient means by which the host evaluates microbial presence, recent work has uncovered a central role for bacterial metabolites in the orchestration of the host immune response. In this review, we highlight examples of how microbiota-modulated metabolites control the development, differentiation, and activity of the immune system and classify them into functional categories that illustrate the spectrum of ways by which microbial metabolites influence host physiology. A comprehensive understanding of how microbiota-derived metabolites shape the human immune system is critical for the rational design of therapies for microbiota-driven diseases.


Complications and death at the start of the new academic year: is there a July phenomenon?
The "July Phenomenon" refers to the propensity for increased errors to occur with new housestaff, as they assume new responsibilities at the beginning of the academic year. The purpose of this study was to examine the impact of the new residents presenting in July at a high volume Level I Academic Trauma Center. The trauma registry at the Los Angeles County + University of Southern California Medical center was retrospectively reviewed to identify all injured patients admitted over a 5-year period ending in December 2006. All Morbidity and Mortality reports for the study period were reviewed to extract deaths and any complications classified as preventable or potentially preventable. Patients admitted in the first 2 months (July to August) of the academic year were compared with those treated at the end of the academic year (May to June). Baseline clinical and demographic characteristics were compared, and the rates of preventable and potentially preventable deaths and complications were determined for each of these groups. During the 5-year study period, 24,302 injured patients were admitted. Of those, 8,151 were admitted during the period from May to August with 4,030 (49.4%) at the beginning of the academic year (July to August) and 4,121 (50.6%) at the end of the academic year (May to June). Overall, the average age was 35.1 +/- 17.7 years, 77% were men with an Injury Severity Score of 8.4 +/- 9.7 and 24.2% penetrating injury rate. When examining mortality, after adjustment for differences between the two groups, there was no difference between patients admitted at the beginning or at the end of the academic year (adjusted odds ratio [95% confidence interval]: 1.1 [0.8, 1.5], p = 0.52). However, when compared with the patients treated for their injuries in May to June, those treated at the beginning of the academic year had a significantly higher rate of preventable and potentially preventable complications (adjusted odds ratio [95% confidence interval]: 1.9 [1.1, 3.2], p = 0.013). At an academic Level I trauma center, admission at the beginning of the academic year was associated with an increased risk of errors resulting in preventable and potentially preventable complications; however, these errors did not impact mortality. Specific errors associated with this increased rate of preventable complications warrant further investigation.


Comparison of phase-unwrapping algorithms by using gradient of first failure.
The comparison of phase-unwrapping algorithms has been an enigma because there has been no quantitative means of comparison. Noting that unwrapping routines are sensitive to noise and the local gradient of the phase array as well as fringe modulation, we have linked unwrapping performance to the gradient of first failure of the algorithm. When the gradient of first failure is plotted versus the signal-to-noise ratio, this can be used as an indicator of which algorithm to use in a given situation without the need for user intervention during the measurement and calculation. This study introduces three algorithms developed for their trade-offs in speed versus pixel noise (pointwise) sensitivity. The algorithms developed have been applied to live, noisy measurement data and have been proven to be robust.


Downregulation of Nuclear Protein H2B Induces Salicylic Acid Mediated Defense Against PVX Infection in Nicotiana benthamiana.
Histone H2B protein is not only structurally important for chromosomal DNA packaging but is also involved in the regulation of gene expression, including the immune response of plants against pathogens. In this study, we show that the potato virus X (PVX) infection resulted in the reduced expression of H2B at both the mRNA and protein level in Nicotiana benthamiana. Tobacco rattle virus (TRV)-based virus-induced gene silencing (VIGS) was then used to down-regulate the expression of H2B in N. benthamiana and tests showed that the titre of TRV was similar in these plants to that in control treated plants. When these H2B-silenced plants were inoculated with PVX, the virus spread more slowly through the plant and there was a lower titre of PVX compared to non-silenced plants. Abnormal leaf development and stem necrosis were observed in the H2B-silenced plants, which were alleviated in H2B-silenced NahG transgenic plants suggesting the involvement of salicylic acid (SA) in the production of these symptoms. Indeed, quantitative reverse transcription (qRT)-PCR and liquid chromatography tandem mass spectroscopy (LC-MS) results showed that endogenous SA is increased in H2B-silenced N. benthamiana. Thus, downregulation of H2B induced the accumulation of endogenous SA, which was correlated with stem necrosis and a decreased accumulation of PVX in N. benthamiana.


Conservative treatment for whiplash.
Many treatments are available for whiplash-patients, but to date, no evidence exists for their effectiveness. The objective of this systematic review was to assess the efficacy of conservative treatment in patients with whiplash-injuries (rated as Whiplash-Associated Disorders [WAD] I or II). A computerized literature search of Medline, Embase, Cinahl, Psychlit and the Cochrane Controlled Trial Register through June 1998 was carried out. We also screened reference lists of publications of identified randomized trials and relevant systematic reviews. Studies were selected for inclusion if they fit the following criteria: design was a (randomized) clinical trial (RCT); all patients had suffered a whiplash-injury; the type of intervention was a conservative one; pain, global perceived effect, or participation in daily activities was used as one of the outcome measures; and the publication was written in English, French, German or Dutch. The methodological quality of the studies was independently assessed by two reviewers using the Maastricht-Amsterdam list. Three quality scores were calculated using this criteria list: the Overall methodological Quality Score, the Internal Validity Score and the Delphi Quality Score. The conclusion of the review was based on articles that scored a quality score of at least 50 percent of the maximum available score on two out of three quality scores. Eleven studies met the inclusion criteria. A broad variety of conservative interventions were evaluated, and only one study was performed in chronic whiplash patients. Only three studies satisfied at least 50 percent on two out of three quality scores indicating poor overall methodological quality. A high rank correlation was observed among the three methods of quality. Because of the heterogeneity of patient selection, interventions and outcome measures, no statistical pooling was performed. This review indicates that active treatments show a beneficial effect on at least one of the primary outcome measures, preferably pain. It appears that "Rest makes rusty." In other words, rest and immobilization using collars are not recommended for the treatment of whiplash, while active interventions, such as advice to 'maintain usual activities' might be effective in whiplash-patients. Nevertheless, caution is needed when attempting to draw conclusions regarding the efficacy of conservative treatments in whiplash-patients, because of the paucity of high-quality studies. No conclusions can be drawn about the most effective therapy for chronic whiplash-patients because only one low quality trial was identified.


Functional properties and lineage relationship of CD8+ T cell subsets identified by expression of IL-7 receptor alpha and CD62L.
Three major subsets of Ag-experienced CD8+ T cells have been identified according to their expression of CD62L and CD127. These markers are associated with central memory T cells (CD62L+ CD127+), effector memory T cells (CD162L- CD127+), and effector T cells (CD62L- CD127-). In this study we characterized the development of these three populations during acute and chronic viral infections and after immunization with virus-like particles and determined their lineage relation and functional and protective properties. We found that the balance between the three subsets was critically regulated by the availability of Ag and time. After initial down-regulation of CD127, the responding CD8+ T cell population down-regulated CD62L and re-expressed CD127. Dependent on Ag availability, the cells then further differentiated into CD62L- CD127- effector cells or, in the absence of Ag, re-expressed CD62L to become central memory T cells. Although all three populations efficiently produced effector cytokines such as IFN-gamma, CD62L- CD127- effector cells exhibited the highest ex vivo lytic potential. In contrast, CD62L+ CD127+ central memory T cells most efficiently produced IL-2 and proliferated extensively in vitro and in vivo upon antigenic restimulation. Strikingly, only effector and effector memory, but not central memory, T cells were able to protect against peripheral infection with vaccinia virus, whereas central memory T cells were most potent at protecting against systemic infection with lymphocytic choriomeningitis virus, indicating that the antiviral protective capacities of specific CD8+ T cell subsets are closely related to the nature of the challenging pathogen.


Resolvin E1 protects the rat heart against reperfusion injury.
The purpose of the present study was to assess whether resolvin E1 (RvE1), an anti-inflammatory mediator derived from eicosapentaenoic acid, would limit myocardial infarct size in the rat. The H9c2 cell line was used to assess whether RvE1 has direct protective effects on cardiomyocytes. In in vivo experiments, Male Sprague-Dawley rats underwent 30 min of ischemia/4 h of reperfusion. Before reperfusion, rats received intravenous RvE1 (0, 0.03, 0.1, or 0.3mg/kg). In in vitro experiments, H9c2 cells were incubated with RvE1 (0, 1, 10, 100, or 1000 nM). Cells were subjected to 18 h of incubation under normoxic conditions, 16 h of hypoxia, or 16 h of hypoxia and 2 h of reoxygenation. In vivo, RvE1 dose dependently reduced infarct size (30.7 +/- 1.7% of the area at risk in the control group and 29.1 +/- 1.6%, 14.7 +/- 1.3%, and 9.0 +/- 0.6% in the 0.03, 0.1, and 0.3 mg/kg groups, respectively, P < 0.001). In vitro, RvE1 increased viability and decreased apoptosis in a dose-dependent fashion in cells exposed to hypoxia or hypoxia/reoxygenation. A maximal effect was achieved at a concentration of 100 nM. RvE1 augmented phosphoinositide 3-kinase activity, attenuated caspase-3 activity, and augmented calcium-dependent nitric oxide synthase activity in cells exposed to hypoxia or hypoxia/reoxygenation. RvE1 increased Akt, ERK1/2, and endothelial nitric oxide synthase phosphorylation and attenuated the levels of activated caspase-3 and phosphorylated p38 levels. AG-1478, an EGF receptor tyrosine kinase inhibitor, blocked the protective effect of RvE1 both in vivo and in vitro and attenuated the RvE1-induced increase in Akt and ERK1/2 phosphorylation. In conclusion, RvE1, an anti-inflammatory mediator derived from eicosapentaenoic acid, has a direct protective effect on cardiomyocytes against ischemia-reperfusion injury and limits infarct size when administered intravenously before reperfusion.


Longitudinal prevalence, oocyst shedding and molecular characterisation of Cryptosporidium species in sheep across four states in Australia.
The prevalence of Cryptosporidium in sheep in the eastern states of Australia has not been well described, therefore a study of the prevalence, oocyst concentration, species and subtypes of Cryptosporidium were assessed from lamb faecal samples at three sampling periods (weaning, post-weaning and pre-slaughter) from eight farms across South Australia, New South Wales, Victoria and Western Australia. A total of 3412 faecal samples were collected from approximately 1182 lambs across the four states and screened for the presence of Cryptosporidium using a quantitative PCR (qPCR) at the actin locus. Positives were typed at the 18S locus and at a second locus using C. parvum and C. hominis specific qPCR primers. The overall prevalence was 16.9% (95% CI: 15.6-18.1%) and of the 576 positives, 500 were successfully genotyped. In general, the prevalence of Cryptosporidium was higher in WA than the eastern states. Cryptosporidium prevalence peaked at 43.9% and 37.1% at Pingelly (WA2) and Arthur River (WA1), respectively during weaning and at Pingelly (WA2) during pre-slaughter (36.4%). The range of oocyst shedding at weaning overall across all states was 63-7.9×10(6) and the median was 3.2 × 10(4) oocysts g(-1). The following species were identified; C. xiaoi (69%-345/500), C. ubiquitum (17.6%-88/500), C. parvum (9.8%-49/500), C. scrofarum (0.8%-4/500), mixed C. parvum and C. xiaoi (2.4%-12/500), C. andersoni (0.2%-1/500) and sheep genotype 1 (0.2%-1/500). Subtyping of C. parvum and C. ubiquitum isolates identified IIa and IId subtype families within C. parvum (with IId as the dominant subtype) and XIIa within C. ubiquitum. This is the first published description of C. parvum subtypes detected in lambs in Australia.


A chimeric vesiculo/alphavirus is an effective alphavirus vaccine.
While a large number of mosquito-transmitted alphaviruses are known to cause serious human diseases, there are no licensed vaccines that protect against alphavirus infections. The alphavirus chikungunya virus (CHIKV) has caused multiple recent outbreaks of chikungunya fever. This virus has the potential to cause a worldwide epidemic and has generated strong interest in development of a prophylactic CHIKV vaccine. We report here on the development of a potent experimental vaccine for CHIKV based on a chimeric vesicular stomatitis virus (VSV) expressing the entire CHIKV envelope polyprotein (E3-E2-6K-E1) in place of the VSV glycoprotein (G). These VSVΔG-CHIKV chimeras incorporated functional CHIKV glycoproteins into the viral envelope in place of VSV G. The chimeric viruses were attenuated for growth in tissue culture but could be propagated to high titers without VSV G complementation. They also generated robust neutralizing antibody and cellular immune responses to CHIKV in mice after a single dose and protected mice against CHIKV infection. VSVΔG-alphavirus chimeras could have general applicability as alphavirus vaccines.


Preoperative sarcopenia status is associated with lymphovascular invasion in upper tract urothelial carcinoma patients treated with radical nephroureterectomy.
Sarcopenia is a novel concept representing skeletal muscle wasting and has been identified as a prognostic factor for several cancers. The aims of this study were to evaluate the prognostic significance of sarcopenia and the relationship between sarcopenia and poor pathological findings in upper tract urothelial carcinoma (UTUC) patients who underwent radical nephroureterectomy (RNU). We identified 123 UTUC patients who underwent RNU between 2003 and 2014. We assessed sarcopenia by measuring the area of skeletal muscle at the third lumber vertebra on preoperative computed tomography scans. Sarcopenia was classified based on a sex-specific consensus definition. We investigated whether sarcopenia predicts clinical outcomes, such as cancer death and poor pathological findings at RNU. A total of 50 (40.7%) patients had sarcopenia. In a multivariate Cox regression analysis, sarcopenia was not associated with cancer-specific survival (CSS), and lymphovascular invasion (LVI) (hazard ratio 5.88; p=0.002) was the only independent risk factor for CSS. A multivariate logistic regression analysis showed that sarcopenia independently correlated with the LVI status (odds ratio 2.36; p=0.025). LVI was positive in 27 of 50 (54%) and 25 of 73 (34%) patients with and without sarcopenia, respectively (p=0.029). Preoperative sarcopenia predicted the LVI status, which was a strong prognostic factor for UTUC patients after RNU.


Superficial radiotherapy for patients with basal cell carcinoma: recurrence rates, histologic subtypes, and expression of p53 and Bcl-2.
The histologic subtype of a basal cell carcinoma (BCC) may be an important factor for the success of a certain treatment modality. In the current article, the authors report recurrence rates among patients with BCC after superficial radiotherapy as well as Bcl-2 and p53 expression levels stratified by BCC subtype. The authors performed a retrospective study of 175 BCCs in 148 patients (64 female patients and 84 male patients; mean age, 69 years) who were treated with radiotherapy. According to their histologic patterns, BCCs were classified as nodular (n = 103), superficial (n = 25), and sclerosing (n = 47). In addition, six patients with metatypic BCC were reviewed. Bcl-2 and p53 protein expression was examined on a tissue microarray of 60 BCC samples (18 nodular tumors, 12 superficial tumors, and 30 sclerosing tumors). The estimated 5-year recurrence rate for all patients with BCC was 15.8%: 8.2% for patients with the nodular subtype, 26.1% for patients with the superficial subtype, and 27.7% for patients with the sclerosing subtype (Kaplan-Meier analysis: P = 0.055). The median follow-up was 48 months. The mean time to recurrence was 20 months, and 86.4% of all recurrences occurred within 3 years after treatment. No gender-specific differences were observed. In addition, one of six metatypic BCCs recurred. Nuclear p53 immunoreactivity and low Bcl-2 expression were significantly correlated with the sclerosing subtype. Overall, 61.5% of patients developed additional neoplasms during follow-up (76 developed additional BCCs, 15 developed squamous cell carcinomas, and 6 developed Bowen disease). The sclerosing subtype of BCC was a risk factor for recurrence after radiotherapy. In contrast, excellent results were achieved for patients with predominant nodular subtype. Nevertheless, radiotherapy may be the therapy of choice for patients with all BCC subtypes, depending on the individual patient's characteristics. Expression analyses confirmed that p53 and Bcl-2 levels may be used as indicators for the aggressiveness of a BCC subtype. Due to the high incidence of additional skin malignancies, patients with BCC need careful follow-up.


Peripheral vibration causes an adenosine-mediated postsynaptic inhibitory potential in dorsal horn neurons of the cat spinal cord.
We have previously reported a vibration-induced, adenosine-mediated inhibition of nociceptive dorsal horn neurons in the cat spinal cord. The present study was conducted to investigate the mechanisms of this inhibition. In vivo intracellular recording was obtained from dorsal horn neurons in the lower lumbar segments of the anaesthetized cat. Vibration (80-250 Hz for 2-3 s every 15-20 s) was applied to the glabrous skin of the toes of the hind foot using a feedback-controlled mechanical stimulator. In 32 of 43 neurons tested, vibration produced a pronounced hyperpolarization of the membrane potential. This hyperpolarization peaked at -10 mV and decayed throughout the period of the application of vibration. It was associated with a decrease in membrane resistance, had a reversal potential negative to the resting membrane potential and was Cl(-)-independent, suggesting that it was due to an increase in a K+ conductance, properties typical of the response to adenosine. This inhibitory postsynaptic potential was unaffected by intravenous administration of bicuculline, strychnine and naloxone but was blocked by iontophoretic administration of 8-sulphophenyltheophylline, a P1-purinergic receptor antagonist. These results confirm our previous finding that vibration-induced inhibition of nociceptive dorsal horn neurons is mediated via the release of an endogenous purine compound and further suggests that this inhibition involves a postsynaptic inhibitory mechanism.


Visual quality determines the direction of neural repetition effects.
One ubiquitous finding in functional magnetic resonance imaging studies is that repeated stimuli elicit lower responses than novel stimuli. In apparent contradiction, some studies have reported the exact opposite effect--greater responses to repeated than novel stimuli--in many of the same brain regions. Interestingly, these latter enhancement effects are typically obtained when stimuli have been degraded. To explore this observation, the present study examines the degree to which visual quality mediates repetition effects in a stimulus-selective ventral visual area. Subjects were presented with grayscale photographs of scenes that were either near or substantially above visual threshold, as determined by calibrating image contrast to behavioral performance. The presentation of 2 identical high-contrast scenes elicited lower blood oxygen level-dependent (BOLD) responses than the presentation of 2 different high-contrast scenes (repetition attenuation). Conversely, the presentation of 2 identical low-contrast scenes elicited greater BOLD responses than the presentation of 2 different low-contrast scenes (repetition enhancement). Neurophysiological studies suggest that repetition attenuation in ventral visual areas may reflect the reactivation of perceptual representations that have become sparse and selective as a result of prior experience, whereas repetition enhancement may reflect spared access to existing representations by severely degraded input.


Restriction of receptor movement alters cellular response: physical force sensing by EphA2.
Activation of the EphA2 receptor tyrosine kinase by ephrin-A1 ligands presented on apposed cell surfaces plays important roles in development and exhibits poorly understood functional alterations in cancer. We reconstituted this intermembrane signaling geometry between live EphA2-expressing human breast cancer cells and supported membranes displaying laterally mobile ephrin-A1. Receptor-ligand binding, clustering, and subsequent lateral transport within this junction were observed. EphA2 transport can be blocked by physical barriers nanofabricated onto the underlying substrate. This physical reorganization of EphA2 alters the cellular response to ephrin-A1, as observed by changes in cytoskeleton morphology and recruitment of a disintegrin and metalloprotease 10. Quantitative analysis of receptor-ligand spatial organization across a library of 26 mammary epithelial cell lines reveals characteristic differences that strongly correlate with invasion potential. These observations reveal a mechanism for spatio-mechanical regulation of EphA2 signaling pathways.


High-intensity and resistance training and elite young athletes.
Although in the past resistance and high-intensity exercise training among young children was the subject of numerous controversies, it is now well-documented that this training mode is a safe and effective means of developing maximal strength, maximal power output and athletic performance in youth, provided that exercises are performed with appropriate supervision and precautions. Muscular strength and power output values measured from vertical jump and Wingate anaerobic tests are higher in elite than in non-elite young athletes and normal children, and the specific training effects on maximal power output normalised for body size are clearly more distinct before puberty. At present, there is no scientific evidence to support the view that high-intensity and/or resistance training might hinder growth and maturation in young children. Pre-pubertal growth is not adversely affected by sport at a competitive level and anthropometric factors are of importance for choice of sport in children. However, coaches, teachers and parents should be aware that unsupervised high-intensity and resistance training programmes involving maximal loads or too frequently repeated resistance exercises increase the risk of injury. Resistance training alone is an effective additional means of developing athletic performance throughout planned youth sports training programmes. Strategies for enhancing the effectiveness and safety of youth resistance and high-intensity exercise training are discussed in this chapter.


Do end of treatment assessments predict outcome at follow-up in eating disorders?
To examine the predictive value of end of treatment (EOT) outcomes for longer term recovery status. We used signal detection analysis to identify the best predictors of recovery based on outcome at EOT using five different eating disorder samples from randomized clinical treatment trials. We utilized a transdiagnostic definition of recovery that included normalization of weight and eating related psychopathology. Achieving a body weight of 95.2% of expected body weight by EOT is the best predictor of recovery for adolescents with anorexia nervosa (AN). For adults with AN, the most efficient predictor of weight recovery (BMI > 19) was weight gain to greater than 85.8% of ideal body weight. In addition, for adults with AN, the most efficient predictor of psychological recovery was achievement of an eating disorder examination (EDE) weight concerns score below 1.8. The best predictor of recovery for adults with Bulimia Nervosa (BN) was a frequency of compensatory behaviors less than two times a month. For adolescents with BN, abstinence from purging and reduction in the EDE restraint score of more than 3.4 from baseline to EOT were good predictors of recovery. For adults with binge eating disorder, reduction of the Global EDE score to within the normal range (<1.58) was the best predictor of recovery. The relationship between EOT response and recovery remains understudied. Utilizing a transdiagnostic definition of recovery, no uniform predictors were identified across all eating disorder diagnostic groups.


In vitro characterization of the antiviral activity of fucoidan from Cladosiphon okamuranus against Newcastle Disease Virus.
Newcastle Disease Virus (NDV) causes a serious infectious disease in birds that results in severe losses in the worldwide poultry industry. Despite vaccination, NDV outbreaks have increased the necessity of alternative prevention and control measures. Several recent studies focused on antiviral compounds obtained from natural resources. Many extracts from marine organisms have been isolated and tested for pharmacological purposes, and their antiviral activity has been demonstrated in vitro and in vivo. Fucoidan is a sulfated polysaccharide present in the cell wall matrix of brown algae that has been demonstrated to inhibit certain enveloped viruses with low toxicity. This study evaluated the potential antiviral activity and the mechanism of action of fucoidan from Cladosiphon okamuranus against NDV in the Vero cell line. The cytotoxicity of fucoidan was determined by the MTT assay. To study its antiviral activity, fusion and plaque-forming unit (PFU) inhibition assays were conducted. The mechanism of action was determined by time of addition, fusion inhibition, and penetration assays. The NDV vaccine strain (La Sota) was used in the fusion inhibition assays. PFU and Western blot experiments were performed using a wild-type lentogenic NDV strain. Fucoidan exhibited antiviral activity against NDV La Sota, with an obtained IS50 >2000. In time of addition studies, we observed viral inhibition in the early stages of infection (0-60 min post-infection). The inhibition of viral penetration experiments with a wild-type NDV strain supported this result, as these experiments demonstrated a 48% decrease in viral infection as well as reduced HN protein expression. Ribavirin, which was used as an antiviral control, exhibited lower antiviral activity than fucoidan and high toxicity at active doses. In the fusion assays, the number of syncytia was significantly reduced (70% inhibition) when fucoidan was added before cleavage of the fusion protein, perhaps indicating a specific interaction between fucoidan and the F0 protein. The results of this study suggest that fucoidan from C. okamuranus represents a potential low-toxicity antiviral compound for the poultry industry, and our findings provide a better understanding of the mode of action of sulfated polysaccharides.