International collaboration: promises and challenges.
We currently face a myriad of grand global challenges in fields such as poverty, the environment, education, science, and medicine. However, our current means of dealing with such challenges has fallen short, and ingenious solutions are required to overcome the inherent resistance to progress toward ameliorating such difficulties. Here, we highlight the promises and challenges of international collaboration in achieving success toward these trials. We note prior successes in fields such as education, medicine, science, and environmental issues made to date, yet at the same time we do note deficiencies and shortcomings in these efforts. Hence, the notion of international collaboration should be strengthened and encouraged by governments, non-profit organizations, and others moving forward using creative means to bring talented teams together to tackle these challenges across the globe.


Noninvasive measures of vascular health are reliable in preschool-aged children.
Measures of vascular health are known to be important predictors of cardiovascular disease in adulthood. The reliability of commonly used measures of vascular health has been demonstrated in school-aged children, adolescents, and adults; however, their reliability in preschool-aged children remains to be determined. Twenty 2- to 6-year-old children participated in 2 identical testing sessions on different days. Following 10 min of supine rest, carotid artery blood pressures and common carotid artery images were assessed simultaneously for 10 heart cycles, using applanation tonometry and B-mode ultrasound, respectively, while electrocardiogram (ECG) and infrared measures of arterial pressure waves at the dorsalis pedis were recorded continuously. Brachial artery blood pressures were determined using an automated oscillometric device. Carotid artery diameters and intima-media thickness (IMT) were analyzed using a semiautomated detection software program. Carotid compliance, distensibility, and stiffness index were calculated from carotid diameters and carotid blood pressures. Whole-body pulse-wave velocity (PWV) was determined from the time delay between the R spike of the ECG and the foot of the dorsalis pedis arterial pressure wave. Reliability of all measures was assessed using the coefficient of variation (CV) and the intraclass correlation coefficient (ICC). The most reliable measures were carotid artery IMT and PWV with CVs of 2.6% and 3.5% and ICCs of 0.86 and 0.76, respectively. The lower reliability of carotid compliance and distensibility (ICC≤0.63) is likely attributable to the variability of blood pressure measurements. This study confirms that vascular measurements demonstrate substantial reliability in preschool-aged children as young as 2 years.


Trichothecene profiling and population genetic analysis of Gibberella zeae from barley in North Dakota and Minnesota.
Gibberella zeae, the principal cause of Fusarium head blight (FHB) of barley, contaminates grains with several mycotoxins, which creates a serious problem for the malting barley industry in the United States, China, and Europe. However, limited studies have been conducted on the trichothecene profiles and population genetic structure of G. zeae isolates collected from barley in the United States. Trichothecene biosynthesis gene (TRI)-based polymerase chain reaction (PCR) assays and 10 variable number tandem repeat (VNTR) markers were used to determine the genetic diversity and compare the trichothecene profiles of an older population (n = 115 isolates) of G. zeae collected in 1997 to 2000 with a newer population (n = 147 isolates) collected in 2008. Samples were from across the major barley-growing regions in North Dakota and Minnesota. The results of TRI-based PCR assays were further validated using a subset of 32 and 28 isolates of G. zeae by sequence analysis and gas chromatography, respectively. TRI-based PCR assays revealed that all the G. zeae isolates in both populations had markers for deoxynivalenol (DON), and the frequencies of isolates with a 3-acetyldeoxynivalenol (3-ADON) marker in the newer population were ≈11-fold higher than those among isolates in the older population. G. zeae populations from barley in the Midwest of the United States showed no spatial structure, and all the isolates were solidly in clade 7 of G. zeae, which is quite different from other barley-growing areas of world, where multiple species of G. zeae are commonly found in close proximity and display spatial structure. VNTR analysis showed high gene diversity (H = 0.82 to 0.83) and genotypic diversity but low linkage disequilibrium (LD = 0.02 to 0.07) in both populations. Low genetic differentiation (F(ST) = 0.013) and high gene flow (Nm = 36.84) was observed between the two populations and among subpopulations within the same population (Nm = 12.77 to 29.97), suggesting that temporal and spatial variations had little influence on population differentiation in the Upper Midwest. Similarly, low F(ST) (0.02) was observed between 3-ADON and 15-acetyldeoxynivalenol populations, indicating minor influence of the chemotype of G. zeae isolates on population subdivision, although there was a rapid increase in the frequencies of isolates with the 3-ADON marker in the Upper Midwest between the older collection made in 1997 to 2000 and the newer collection made in 2008. This study provides information to barley-breeding programs for their selection of isolates of G. zeae for evaluating barley genotypes for resistance to FHB and DON accumulation.


A novel voltammetric sensor for ascorbic acid based on molecularly imprinted poly(o-phenylenediamine-co-o-aminophenol).
A molecularly imprinted copolymer, poly(o-phenylenediamine-co-o-aminophenol) (PoPDoAP), was prepared as a new ascorbic acid (AA) sensor. The copolymer was synthesized by incorporation of AA as template molecules during the electrochemical copolymerization of o-phenylenediamine and o-aminophenol, and complementary sites were formed after the copolymer was electrochemically reduced in ammonium aqueous solution. The molecularly imprinted copolymer sensor exhibited a high sensitivity and selectivity toward AA. Differential pulse voltammograms (DPVs) showed a linear concentration range of AA from 0.1 to 10 mM, and the detection limit was calculated to be 36.4 μM. Compared to conventional polyaniline-based AA sensors, the analytical performance of the imprinted copolymer sensor was improved due to the broadened usable pH range of PoPDoAP (from pH 1.0 to pH 8.0). The sensor also exhibited a good reproducibility and stability. And it has been successfully applied in the determination of AA in real samples, including vitamin C tablet and orange juices, with satisfactory results.


Uncertainties in the current knowledge of some atmospheric trace gases associated with U.S. agriculture: a review.
Approximately 80 different crop species are grown in the United States in widely differing geographic areas, climatic and edaphic conditions, and management practices. Although the majority of cultivated acreage in the United States is planted with only about 10 primary crops, uncertainties associated with trace gas emissions arise from: (1) limited data availability, (2) inaccurate estimates because of large temporal and spatial variability in trace gas composition and magnitude of trace gas emissions from agricultural activities, (3) differing characteristics of pollutant emissions from highly dispersed animal feed-lots, and (4) limited understanding of the emissions of semi-volatile organic compounds (SVOCs) associated with agriculture. Although emission issues are of concern, so also is atmospheric deposition to cropping systems, including wet and dry nitrogen, minerals, and organic compounds. These can have feedback effects on trace gas emissions. Overall, the many gaps in our understanding of these aspects of agricultural systems deserve serious attention.


Cellulose Mesh with Charged Nanocellulose Coatings as a Promising Carrier of Skin and Stem Cells for Regenerative Applications.
Engineering artificial skin constructs is an ongoing challenge. An ideal material for hosting skin cells is still to be discovered. A promising candidate is low-cost cellulose, which is commonly fabricated in the form of a mesh and is applied as a wound dressing. Unfortunately, the structure and the topography of current cellulose meshes are not optimal for cell growth. To enhance the surface structure and the physicochemical properties of a commercially available mesh, we coated the mesh with wood-derived cellulose nanofibrils (CNFs). Three different types of mesh coatings are proposed in this study as a skin cell carrier: positively charged cationic cellulose nanofibrils (cCNFs), negatively charged anionic cellulose nanofibrils (aCNFs), and a combination of these two materials (c+aCNFs). These cell carriers were seeded with normal human dermal fibroblasts (NHDFs) or with human adipose-derived stem cells (ADSCs) to investigate cell adhesion, spreading, morphology, and proliferation. The negatively charged aCNF coating significantly improved the proliferation of both cell types. The positively charged cCNF coating significantly enhanced the adhesion of ADSCs only. The number of NHDFs was similar on the cCNF coatings and on the noncoated pristine cellulose mesh. However, the three-dimensional (3D) structure of the cCNF coating promoted cell survival. The c+aCNF construct proved to combine benefits from both types of CNFs, which means that the c+aCNF cell carrier is a promising candidate for further application in skin tissue engineering.


Impact of a modern firefighting protective uniform on the incidence and severity of burn injuries in New York City firefighters.
The New York City Fire Department (FDNY) is the largest fire department in the United States, with over 11,000 firefighters. In 1994, FDNY changed to a modern firefighting protective uniform. The major difference between traditional and modern uniforms is that modern uniforms include both protective over-coat and over-pant, whereas traditional uniforms include only the over-coat. Furthermore, modern uniforms are manufactured using improved thermal protective textiles that meet or exceed current National Fire Protection Association standards for structural firefighting. The purpose of this study was to determine the impact of the modern uniform on the incidence and severity of FDNY burn injuries. We also evaluated the incidence and severity of other non-burn injuries to determine whether there was serious adverse impact. The number of lower-extremity burns decreased by 85% when 2 years' experience while wearing the modern uniform was compared with 2 years while wearing the traditional uniform. Upper-extremity burns and head burns decreased by 65% and 40%, respectively. Severity indicators (days lost to medical leave, hospital admissions, and skin grafts) for lower- and upper-extremity burn injuries were all substantially reduced. This occurred without significant change in the incidence or severity of trunk burns, heat exhaustion, inhalation injuries (actually decreased), or cardiac events. The reduction in the incidence and severity of burn injuries, the major occupational injury affecting this workforce, has been so dramatic and without untoward effects that the introduction of the modern uniform must be characterized as a sentinel event in the history of firefighter health and safety.


A comparison between the minimal model and the glucose clamp in the assessment of insulin sensitivity across the spectrum of glucose tolerance. Insulin Resistance Atherosclerosis Study.
An insulin-modified frequently sampled intravenous glucose tolerance test (FSIGTT) with minimal model analysis was compared with the glucose clamp in 11 subjects with normal glucose tolerance (NGT), 20 with impaired glucose tolerance (IGT), and 24 with non-insulin-dependent diabetes mellitus (NIDDM). The insulin sensitivity index (SI) was calculated from FSIGTT using 22- and 12-sample protocols (SI(22) and SI(12), respectively). Insulin sensitivity from the clamp was expressed as SI(clamp) and SIP(clamp). Minimal model parameters were similar when calculated with SI(22) and SI(12). SI could not be distinguished from 0 in approximately 50% of diabetic patients with either protocol. SI(22) correlated significantly with SI(clamp) in the whole group (r = 0.62), and in the NGT (r = 0.53), IGT (r = 0.48), and NIDDM (r = 0.41) groups (P < 0.05 for each). SI(12) correlated significantly with SI(clamp) in the whole group (r = 0.55, P < 0.001) and in the NGT (r = 0.53, P = 0.046) and IGT (r = 0.58, P = 0.008) but not NIDDM (r = 0.30, P = 0.085) groups. When SI(22), SI(clamp), and SIP(clamp) were expressed in the same units, SI(22) was 66 +/- 5% (mean +/- SE) and 50 +/- 8% lower than SI(clamp) and SIP(clamp), respectively. Thus, minimal model analysis of the insulin-modified FSIGTT provides estimates of insulin sensitivity that correlate significantly with those from the glucose clamp. The correlation was weaker, however, in NIDDM. The insulin-modified FSIGTT can be used as a simple test for assessment of insulin sensitivity in population studies involving nondiabetic subjects. Additional studies are needed before using this test routinely in patients with NIDDM.


Arthroscopic management of shoulder osteoarthritis.
Osteoarthritis (OA) can cause severe pain and dysfunction of the shoulder. When conservative treatment fails and operative treatments such as shoulder arthroplasty and open glenohumeral resurfacing are not advisable, shoulder arthroscopy may be used to treat shoulder OA. Arthroscopic treatment of concomitant pathology in the shoulder including subacromial decompression, labral repair, capsular release, microfracture, and distal clavicle excision have been shown to yield good results when combined with glenohumeral debridement in the treatment of shoulder OA. Arthroscopic glenohumeral resurfacing has recently been described and has shown encouraging results. Arthroscopic treatment appears to have better results in shoulders with a lesser degree of osteoarthritis.


The Measurement of Subjective Value and Its Relation to Contingent Valuation and Environmental Public Goods.
Environmental public goods--including national parks, clean air/water, and ecosystem services--provide substantial benefits on a global scale. These goods have unique characteristics in that they are typically "nonmarket" goods, with values from both use and passive use that accrue to a large number of individuals both in current and future generations. In this study, we test the hypothesis that neural signals in areas correlated with subjective valuations for essentially all other previously studied categories of goods (ventromedial prefrontal cortex and ventral striatum) also correlate with environmental valuations. We use contingent valuation (CV) as our behavioral tool for measuring valuations of environmental public goods. CV is a standard stated preference approach that presents survey respondents with information on an issue and asks questions that help policymakers determine how much citizens are willing to pay for a public good or policy. We scanned human subjects while they viewed environmental proposals, along with three other classes of goods. The presentation of all four classes of goods yielded robust and similar patterns of temporally synchronized brain activation within attentional networks. The activations associated with the traditional classes of goods replicate previous correlations between neural activity in valuation areas and behavioral preferences. In contrast, CV-elicited values for environmental proposals did not correlate with brain activity at either the individual or population level. For a sub-population of participants, CV-elicited values were correlated with activity within the dorsomedial prefrontal cortex, a region associated with cognitive control and shifting decision strategies. The results show that neural activity associated with the subjective valuation of environmental proposals differs profoundly from the neural activity associated with previously examined goods and preference measures.


Adipose-derived stem cells differentiate to keratocytes in vitro.
Adipose-derived stem cells (ADSC) are an abundant population of adult stem cells with the potential to differentiate into several specialized tissue types, including neural and neural crest-derived cells. This study sought to determine if ADSC express keratocyte-specific phenotypic markers when cultured under conditions inducing differentiation of corneal stromal stem cells to keratocytes. Human subcutaneous adipose tissue was obtained by lipoaspiration. ADSC were isolated by collagenase digestion and differential centrifugation. Side population cells in ADSC were demonstrated using fluorescence-activated cell sorting after staining with Hoechst 33342. Differentiation to keratocyte phenotype was induced in fibrin gels or as pellet cultures with serum-free or reduced-serum media containing ascorbate. Keratocyte-specific gene expression was characterized using western blotting, quantitative RT-PCR, and immunostaining. ADSC contained a side population and exhibited differentiation to adipocytes and chondrocytes indicating adult stem-cell potential. Culture of ADSC in fibrin gels or as pellets in reduced-serum medium with ascorbate and insulin induced expression of keratocan, keratan sulfate, and aldehyde dehydrogenase 3 family, member A1 (ALDH3A1), products highly expressed by differentiated keratocytes. Expression of differentiation markers was quantitatively similar to corneal stromal stem cells and occurred in both serum-free and serum containing media. ADSC cultured under keratocyte-differentiation conditions express corneal-specific matrix components. Expression of these unique keratocyte products suggests that ADSC can adopt a keratocyte phenotype and therefore have potential for use in corneal cell therapy and tissue engineering.


[Pathophysiologic cardiovascular changes in stress and depression].
Fear, anger, and grief may precipitate myocardial ischemia and infarction. The prognosis of patients with inducible ischemia during mental stress is worse than in those without inducible ischemia. The sympathetic nervous system plays an important role in stress-associated changes in cardiovascular regulation and contributes to cardiovascular morbidity and mortality by inducing vasoconstriction and tachycardia, as well as arrhythmia. Hostility--previously termed type A personality--is often associated with sympathetic hyperreactivity to mental stress and carries an increased risk for atherosclerotic vascular disease. As endothelial dysfunction is an early manifestation of atherosclerosis, the impact of mental stress on endothelial function is also important. Acute mental stress induces prolonged endothelial dysfunction in healthy volunteers, which is prevented by selective endothelin A receptor antagonism. This represents an important link between mental stress and atherosclerotic vascular disease. In addition, patients with depression show hypercortisolemia, and changes in platelet function leading to a prothrombotic state. These findings help to explain the increased cardiovascular risk in patients with depression.


Anxiolytic, antidepressant, and antistress activities of the aqueous extract of Cinnamomum tamala Nees and Eberm in rats.
The current study was designed to explore anxiolytic, antidepressant, and antistress actions of Cinnamomum tamala (CT) leaves (aqueous extract) in rats. Behavioral procedures of anxiety, depression, and stress were assessed in rats. CT (100, 200, and 400 mg/kg) was given once a daily for 7 days via oral route and the efficacy was matched by those elicited by lorazepam (1 mg/kg, p.o.), imipramine (10 mg/kg, p.o.), and Withania somnifera (100 mg/kg, p.o.) for anxiolytic, antidepressant, and antistress studies, respectively. Standard drugs were given 1 time, 30 min preceding the behavioral trials. One-way analysis of variance followed by Newman-Keuls multiple comparison test was employed to analyze the results. P < 0.05 was considered statistically significant as compared to control. CT at 400 mg/kg produced an antianxiety effect equivalent to lorazepam, in the elevated plus maze, open field, and social interaction tests among selected doses of the CT. CT at 400 mg/kg also induced an antidepressant activity similar to imipramine, in the behavioral despair, learned helplessness test, and tail suspension among selected doses of the CT. Moreover, CT at 400 mg/kg produced a significant antistress effect comparable to W. somnifera in water immersion-restraint stress by decreasing ulcer index, adrenal gland weight, and by normalizing the plasma levels of corticosterone, glucose, cholesterol, and triglyceride levels when related to stress control. The study shows that among the different CT doses, CT at 400 mg/kg possesses significant anxiolytic, antidepressant, and anti-stress effects and has therapeutic beneficial for the management of psychological ailments.


Muscle mass to visceral fat ratio is an important predictor of the metabolic syndrome in college students.
This study aimed to evaluate the associations between the muscle mass to visceral fat (MVF) ratio and cardiometabolic risk factors in a large population of college students in Colombia and to propose cut-off points of this index for the metabolic syndrome (MetS). A total of 1464 young adults recruited from the FUPRECOL (Asociación de la Fuerza Prensil con Manifestaciones Tempranas de Riesgo Cardiovascular en Jóvenes y Adultos Colombianos) study were categorised into four groups based on their MVF ratio. Muscle mass and visceral fat level of the participants were measured using a bioelectrical impedance analysis. Cardiometabolic risk factors including lifestyle characteristics, anthropometry, blood pressure and biochemical parameters were assessed. The prevalence of moderate to severe obesity, hypertension and the MetS was higher in subjects in quartile (Q)1 (lower MVF ratio) (P <0·001). ANCOVA revealed that the subjects in Q1 had higher cardiometabolic disturbances, including altered anthropometry, blood pressure, muscle strength and biochemical parameters after adjusting for age and sex compared with young adults in higher MVF ratio quartiles (P <0·001). Muscular mass and physical activity levels were significantly lower in subjects with a lower MVF ratio (P <0·001). The receiver operating characteristic curve analyses indicated that in men the best MVF ratio cut-off point for detecting the MetS was 18·0 (AUC 0·83, sensitivity 78 % and specificity 77 %) and for women, the MVF ratio cut-off point was 13·7 (AUC 0·85, sensitivity 76 % and specificity 87 %). A lower MVF ratio is associated with a higher risk cardiometabolic profile in early adulthood, supporting that the MVF ratio could be used as a complementary screening tool that may help clinicians identify young adults at high cardiometabolic risk.


Double-Blind Sham-Controlled Crossover Trial of Repetitive Transcranial Magnetic Stimulation for Mal de Debarquement Syndrome.
To determine whether the chronic rocking dizziness that occurs in Mal de Debarquement Syndrome (MdDS) can be suppressed with repetitive transcranial magnetic stimulation (rTMS) beyond the treatment period. We performed a prospective randomized double-blind sham controlled crossover trial of 5-days of rTMS utilizing high frequency (10 Hz) stimulation over the left dorsolateral prefrontal cortex (DLPFC). Eight right-handed women (44.5 [SD 7.0] yr) with classical motion-triggered MdDS (mean duration 42.1 [SD 13.2] mo) participated. Group level mixed effects repeated measures analysis of variance (ANOVA) showed improvement in our primary outcome measure, the Dizziness Handicap Inventory (DHI) at Post TMS Weeks 1, 3, and 4 (p < 0.05) and a trend at Week 2 (p = 0.089) after Real rTMS. On the Hospital Anxiety and Depression Scale (HADS), improvements started at Post TMS Week 2 for the Anxiety subscore and Post TMS Week 3 for the Depression subscore after Real rTMS only (p < 0.05). There were no group level improvements on the MdDS Balance Rating Scale (MBRS) after Real rTMS though there were three participants who improved on an individual level. There were no significant group level changes after Sham stimulation on any measure. Our study provides evidence that the dizziness, mood and anxiety symptoms of MdDS can be improved with 10 Hz rTMS over left DLPFC beyond the treatment period in selected individuals. rTMS may be a useful adjunctive treatment for the management of chronic rocking dizziness in individuals with MdDS but treatment durations longer than 5 days or maintenance treatment are likely needed for sustained symptom suppression.


Recurrence of lupus nephritis after kidney transplantation.
The frequency and outcome of recurrent lupus nephritis (RLN) among recipients of a kidney allograft vary among single-center reports. From the United Network for Organ Sharing files, we estimated the period prevalence and predictors of RLN in recipients who received a transplant between 1987 and 2006 and assessed the effects of RLN on allograft failure and recipients' survival. Among 6850 recipients of a kidney allograft with systemic lupus erythematosus, 167 recipients had RLN, 1770 experienced rejection, and 4913 control subjects did not experience rejection. The period prevalence of RLN was 2.44%. Non-Hispanic black race, female gender, and age <33 years each independently increased the odds of RLN. Graft failure occurred in 156 (93%) of those with RLN, 1517 (86%) of those with rejection, and 923 (19%) of control subjects without rejection. Although recipients with RLN had a fourfold greater risk for graft failure compared with control subjects without rejection, only 7% of graft failure episodes were attributable to RLN compared and 43% to rejection. During follow-up, 867 (13%) recipients died: 27 (16%) in the RLN group, 313 (18%) in the rejection group, and 527 (11%) in the control group. In summary, severe RLN is uncommon in recipients of a kidney allograft, but black recipients, female recipient, and younger recipients are at increased risk. Although RLN significantly increases the risk for graft failure, it contributes far less than rejection to its overall incidence; therefore, these findings should not keep patients with lupus from seeking a kidney transplant.


Biomarker-based classification of bacterial and fungal whole-blood infections in a genome-wide expression study.
Sepsis is a clinical syndrome that can be caused by bacteria or fungi. Early knowledge on the nature of the causative agent is a prerequisite for targeted anti-microbial therapy. Besides currently used detection methods like blood culture and PCR-based assays, the analysis of the transcriptional response of the host to infecting organisms holds great promise. In this study, we aim to examine the transcriptional footprint of infections caused by the bacterial pathogens Staphylococcus aureus and Escherichia coli and the fungal pathogens Candida albicans and Aspergillus fumigatus in a human whole-blood model. Moreover, we use the expression information to build a random forest classifier to classify if a sample contains a bacterial, fungal, or mock-infection. After normalizing the transcription intensities using stably expressed reference genes, we filtered the gene set for biomarkers of bacterial or fungal blood infections. This selection is based on differential expression and an additional gene relevance measure. In this way, we identified 38 biomarker genes, including IL6, SOCS3, and IRG1 which were already associated to sepsis by other studies. Using these genes, we trained the classifier and assessed its performance. It yielded a 96% accuracy (sensitivities >93%, specificities >97%) for a 10-fold stratified cross-validation and a 92% accuracy (sensitivities and specificities >83%) for an additional test dataset comprising Cryptococcus neoformans infections. Furthermore, the classifier is robust to Gaussian noise, indicating correct class predictions on datasets of new species. In conclusion, this genome-wide approach demonstrates an effective feature selection process in combination with the construction of a well-performing classification model. Further analyses of genes with pathogen-dependent expression patterns can provide insights into the systemic host responses, which may lead to new anti-microbial therapeutic advances.


Mechanistic basis for overcoming platinum resistance using copper chelating agents.
Platinum-based antitumor agents are widely used in cancer chemotherapy. Drug resistance is a major obstacle to the successful use of these agents because once drug resistance develops, other effective treatment options are limited. Recently, we conducted a clinical trial using a copper-lowering agent to overcome platinum drug resistance in ovarian cancer patients and the preliminary results are encouraging. In supporting this clinical study, using three pairs of cisplatin (cDDP)-resistant cell lines and two ovarian cancer cell lines derived from patients who had failed in platinum-based chemotherapy, we showed that cDDP resistance associated with reduced expression of the high-affinity copper transporter (hCtr1), which is also a cDDP transporter, can be preferentially resensitized by copper-lowering agents because of enhanced hCtr1 expression, as compared with their drug-sensitive counterparts. Such a preferential induction of hCtr1 expression in cDDP-resistant variants by copper chelation can be explained by the mammalian copper homeostasis regulatory mechanism. Enhanced cell-killing efficacy by a copper-lowering agent was also observed in animal xenografts bearing cDDP-resistant cells. Finally, by analyzing a public gene expression dataset, we found that ovarian cancer patients with elevated levels of hCtr1 in their tumors, but not ATP7A and ATP7B, had more favorable outcomes after platinum drug treatment than those expressing low hCtr1 levels. This study reveals the mechanistic basis for using copper chelation to overcome cDDP resistance in clinical investigations.


High preoperative blood levels of HE4 predicts poor prognosis in patients with ovarian cancer.
The aim of this study was to assess the clinical value of preoperative blood levels of HE4 as a predictor of overall survival in patients with ovarian cancer and to validate previous data of HE4 and the ROMA algorithm including HE4 and CA125 in discriminating benign and malignant ovarian tumors. The preoperative plasma levels of HE4 and CA125 were analyzed with ELISA in 312 patients with adnexal lesions. Tumors were classified as benign (n= 206), borderline (i.e. low malignant potential tumors) (n= 25), and well (n= 14), moderately (n= 15), and poorly (n= 51) differentiated malignant. In univariate Cox regression analyses high levels (dichotomized at the median) of HE4, CA125, increased age (continuous variable), advanced-stage of disease 2-4, histological grade 3 and non-optimal tumor debulking at primary surgery were all significantly associated with shorter overall survival. A multivariate Cox regression model including pre-operative available covariates HE4 and CA125 both dichotomized at median in addition to age as continuous variable showed that high levels of HE4 was an independent prognostic marker for worse prognosis HR 2.02 (95% CI 1.1-3.8). In postmenopausal women the ROMA algorithm gave the highest AUC of 0.94 (95% CI, 0.90-0.97) which was higher than the separate markers HE4 AUC 0.91 (95% CI 0.86-0.95) and CA125 AUC 0.91(95% CI 0.87-0.96). High concentration of plasma HE4 is an independent preoperative marker of poor prognosis in patients with ovarian cancer. The algorithm ROMA discriminates in postmenopausal women between malignant and benign tumors with an AUC of 0.94.


"Hummingbird" floral traits interact synergistically to discourage visitation by bumble bee foragers.
Pollination syndromes are suites of floral traits presumed to reflect adaptations to attract and utilize a "primary" type of animal pollinator. However, syndrome traits may also function to deter "secondary" flower visitors that reduce plant fitness through their foraging activities. Here we use the hummingbird-pollinated plant species Mimulus cardinalis as a model to investigate the potential deterrent effects of classic bird syndrome traits on bumble bee foragers. To establish that M. cardinalis flowers elicit an avoidance response in bees, we assessed the choice behavior of individual foragers on a mixed experimental array of M. cardinalis and its bee-pollinated sister species M. lewisii. As expected, bees showed a strong preference against M. cardinalis flowers (only 22% of total bee visits were to M. cardinalis), but surprisingly also showed a high degree of individual specialization (95.2% of total plant transitions were between conspecifics). To determine M. cardinalis floral traits that discourage bee visitation, we then assessed foraging responses of individuals to M. cardinalis-like and M. lewisii-like floral models differing in color, orientation, reward, and combinations thereof. Across experiments, M. cardinalis-like trait combinations consistently produced a higher degree of flower avoidance behavior and individual specialization than expected based on bee responses to each trait in isolation. We then conducted a series of flower discrimination experiments to assess the ability of bees to utilize traits and trait combinations associated with each species. Relative to M. lewisii-like alternatives, M. cardinalis-like traits alone had a minimal effect on bee foraging proficiency but together increased the time bees spent searching for rewarding flowers from 1.49 to 2.65 s per visit. Collectively, our results show that M. cardinalis flowers impose foraging costs on bumble bees sufficient to discourage visitation and remarkably, generate such costs through synergistic color-orientation and color-reward trait interactions. Floral syndromes therefore represent complex adaptations to multiple pollinator groups, rather than simply the primary pollinator.


You have more capital than you think.
Senior executives typically delegate the responsibility for managing a firm's derivatives portfolio to in-house financial experts and the company's financial advisers. That's a strategic blunder, argues this Nobel laureate, because the inventiveness of modern financial markets makes it possible for companies to double or even triple their capacity to invest in their strategic assets and competencies. Risks fall into two categories: either a company adds value by assuming them on behalf of its shareholders or it does not. By hedging or insuring against non-value-adding risks with derivative securities and contracts, thereby removing them from what the author calls the risk balance sheet, managers can release equity capital for assuming more value-adding risk. This is not just a theoretical possibility. One innovation-the interest rate swap, introduced about 20 years ago-has already enabled the banking industry to dramatically increase its capacity for adding value to each dollar of invested equity capital. With the range of derivative instruments growing, there is no reason why other companies could not similarly remove strategic risks, potentially creating billions of dollars in shareholder value. The possibilities are especially important for private companies that have no access to public equity markets and therefore cannot easily increase their equity capital by issuing more shares. The author describes how derivative contracts of various kinds are already being employed strategically to mitigate or eliminate various risks. He also shows how companies can use the risk balance sheet to identify risks they should not bear directly and to determine how much equity capacity they can release for assuming more value-adding risk.


Palaeomagnetic analysis of the Sterkfontein palaeocave deposits: implications for the age of the hominin fossils and stone tool industries.
Palaeomagnetic analysis was conducted on speleothems from Members 1-5 at Sterkfontein Cave, South Africa. Palaeomagnetic analysis of siltstone and speleothem from the bulk of Member 4 indicate a reversed magnetic polarity that dates the deposits and its Australopithecus africanus fossils to between 2.58 and ~2.16 Ma. Further confirmation of this age comes in the form of two short normal polarity events correlated to the Rèunion (~2.16 Ma) and Huckleberry Ridge (~2.05 Ma) events in speleothem capping the bulk of Member 4 and coeval with deposition of the final phase of Member 4, including A. africanus fossil Sts 5. At ~2.16-2.05 Ma, Sts 5 is the youngest representative of A. africanus yet discovered. Palaeomagnetic analysis of the Silberberg Grotto deposits identifies a single short geomagnetic field event in flowstone overlying the StW 573 Australopithecus fossil, which is suggested to represent the Rèunion event at ~2.16 Ma. This further supports the uranium lead age estimates of 2.3-2.2 Ma for the StW 573 fossil. Based on a reversed polarity for the deposits below the skeleton it cannot be older than 2.58 Ma. If StW 573 is considered to be a second species of Australopithecus then this indicates that two species of Australopithecus are present at Sterkfontein between 2.6 and 2.0 Ma. All of the Member 5 deposits date to less than 1.8 Ma based on a comparison of palaeomagnetic, faunal, and electron spin resonance age estimates. The StW 53 fossil bearing infill (M5A) is intermediate in age between Member 4 and the rest of Member 5 (B-C) at around 1.78-1.49 Ma. The rest of Member 5 (B-C) containing Oldowan and Acheulian stone tools and Homo and Paranthropus fossils was deposited gradually between 1.40 and 1.07 Ma, much younger than previously suggested.


TRPV3 and TRPV4 ion channels are not major contributors to mouse heat sensation.
The discovery of heat-sensitive Transient Receptor Potential Vanilloid (TRPV) ion channels provided a potential molecular explanation for the perception of innocuous and noxious heat stimuli. TRPV1 has a significant role in acute heat nociception and inflammatory heat hyperalgesia. Yet, substantial innocuous and noxious heat sensitivity remains in TRPV1 knockout animals. Here we investigated the role of two related channels, TRPV3 and TRPV4, in these capacities. We studied TRPV3 knockout animals on both C57BL6 and 129S6 backgrounds, as well as animals deficient in both TRPV3 and TRPV4 on a C57BL6 background. Additionally, we assessed the contributions of TRPV3 and TRPV4 to acute heat nociception and inflammatory heat hyperalgesia during inhibition of TRPV1. TRPV3 knockout mice on the C57BL6 background exhibited no obvious alterations in thermal preference behavior. On the 129S6 background, absence of TRPV3 resulted in a more restrictive range of occupancy centered around cooler floor temperatures. TRPV3 knockout mice showed no deficits in acute heat nociception on either background. Mice deficient in both TRPV3 and TRPV4 on a C57BL6 background showed thermal preference behavior similar to wild-type controls on the thermal gradient, and little or no change in acute heat nociception or inflammatory heat hyperalgesia. Masking of TRPV1 by the TRPV1 antagonist JNJ-17203212 did not reveal differences between C57BL6 animals deficient in TRPV3 and TRPV4, compared to their wild-type counterparts. Our results support the notion that TRPV3 and TRPV4 likely make limited and strain-dependent contributions to innocuous warm temperature perception or noxious heat sensation, even when TRPV1 is masked. These findings imply the existence of other significant mechanisms for heat perception.


Function of lncRNAs and approaches to lncRNA-protein interactions.
Long non-coding RNAs (lncRNAs), which represent a new frontier in molecular biology, play important roles in regulating gene expression at epigenetic, transcriptional and post-transcriptional levels. More and more lncRNAs have been found to play important roles in normal cell physiological activities, and participate in the development of varieties of tumors and other diseases. Previously, we have only been able to determine the function of lncRNAs through multiple mechanisms, including genetic imprinting, chromatin remodeling, splicing regulation, mRNA decay, and translational regulation. Application of technological advances to research into the function of lncRNAs is extremely important. The major tools for exploring lncRNAs include microarrays, RNA sequencing (RNA-seq), Northern blotting, real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR), fluorescence in situ hybridization (FISH), RNA interference (RNAi), RNA-binding protein immunoprecipitation (RIP), chromatin isolation by RNA purification (ChIRP), crosslinking-immunopurification (CLIP), and bioinformatic prediction. In this review, we highlight the functions of lncRNAs, and advanced methods to research lncRNA-protein interactions.


Cellular distribution of p68, a new calcium-binding protein from lymphocytes.
A Ca2+-binding protein of mol. wt. 68 000 ( p68 ) is a major component of a Nonidet P-40 insoluble fraction of human and pig lymphocyte plasma membrane. An affinity-purified rabbit antibody has been produced against p68 and used to study its cellular distribution. The antibody stained fixed and permeabilised human B lymphoblastoid cells, peripheral blood lymphocytes and sections of human tonsil. Whole cells, however, were not stained, indicating that the protein was not represented at the cell surface. This assignment was consistent with the detection of p68 in immunoprecipitates from biosynthetically- but not surface-labelled cells. It is concluded that p68 is located on the cytoplasmic face of the plasma membrane. Subcellular fractionation experiments confirmed that p68 was largely membrane-bound in lymphocytes, although a small soluble fraction (approximately 10% of the total) was detected. Sub-fractionation of lymphocyte membranes revealed that p68 was associated not only with the plasma membrane but also with other endomembrane systems. As judged by immunoprecipitation, p68 was present in a variety of cultured cell lines of both lymphoid and non-lymphoid origin. p68 demonstrated a diffuse distribution in fixed and permeabilised fibroblasts which did not correspond to the distribution of either microfilaments or intermediate filaments. However, in detergent-extracted cells the protein was localised in a lamina-like network. A similar immunofluorescent staining pattern has recently been observed for spectrin-related proteins in the detergent-resistant cytoskeleton of fibroblasts. It is suggested that p68 is part of a sub-membranous cytoskeletal complex not only in lymphocytes but also in other cell types.


Changes in mRNA levels of the Myoc/Tigr gene in the rat eye after experimental elevation of intraocular pressure or optic nerve transection.
To isolate the rat Myoc/Tigr gene and investigate changes in its expression pattern in normal eyes and in eyes with either pressure-induced optic nerve damage or optic nerve transection. Expression pattern of the rat Myoc/Tigr gene was investigated by Northern blot hybridization. Optic nerve damage and death of ganglion cells in the retina were induced unilaterally, by injection of hypertonic saline solution, episcleral vein cauterization, or optic nerve transection. The levels of mRNA for Myoc/Tigr were compared between several tissues of the control and surgically altered eyes, by using semiquantitative RT-PCR, real-time PCR, and Northern blot analysis. The rat Myoc/Tigr gene is 10 kb long and contains three exons. Among the eye tissues analyzed, Myoc/Tigr mRNA was detected in the combined tissues of the eye angle, sclera, cornea, retina, and optic nerve head. With pressure-induced optic nerve degeneration, the level of Myoc/Tigr mRNA decreased in the retina and the combined tissues of the eye angle, but increased in the optic nerve head. After optic nerve transection, the level of Myoc/Tigr mRNA increased in the retina, but did not change in the combined tissues of the eye angle. The decreased level of Myoc/Tigr mRNA in the retina after induction of elevated intraocular pressure compared with that in the control retina cannot be explained by ganglion cell death alone. Differences in Myoc/Tigr mRNA levels in eye tissues after elevation of intraocular pressure or optic nerve transection may reflect the activation of different signaling pathways involved in regulation of this gene.


Determination of the methylation status of MGMT in different regions within glioblastoma multiforme.
Epigenetic silencing of the MGMT gene through promoter methylation correlates with improved survival in Glioblastoma Multiforme (GBM) patients receiving concurrent chemoradiotherapy. Although the clinical benefit is primarily seen in patients with methylated MGMT promoter, some unmethylated patients also respond to Temozolomide. One possible explanation may be intratumoral heterogeneity. This study was designed to assess the methylation status of the MGMT promoter in different areas of GBM and determine if methylation status varied depending on the fixation technique (paraffin-embedding versus fresh frozen) used to store tissue. Using intraoperative navigation, biopsies were obtained from three distinct regions: the enhancing outer area, the non-enhancing inner core, and an area immediately outside the enhancing region. Only patients with GBM were included for evaluation and analysis. Samples taken from each area were divided with half stored by flash freezing and the other half stored using paraffin fixation. Methylation Specific-PCR (MS-PCR) was used for analysis of MGMT promoter methylation. Thirteen patients were included. Ten were male with a median age of 62 years. In each patient, samples were taken from the enhancing rim and the necrotic centre. However, it was not considered safe or feasible to obtain samples from the area immediately adjacent to the enhancing tumor rim in one case. All patients were homogeneous for methylation status throughout their tumor and tissue taken adjacent to it when frozen tissue was used. However, four patients had discrepancies in the MGMT promoter status between the frozen and paraffin-embedded blocks and one patient was not homogeneous within the tumor when paraffin-embedded tissue was used. MGMT promoter methylation status was homogeneous in all GBM tumors. Our observation that methylation status varied depending if the DNA was extracted from paraffin-embedded versus frozen tissue is concerning. Although the reason for this is unclear, we postulate that the timing from resection to fixation or the process of fixation itself may potentially alter methylation status in paraffin-embedded tumors.


Optic Nerve Aplasia.
Optic nerve aplasia (ONA) is a rare ocular anomaly. We report ophthalmologic, systemic, and genetic findings in ONA. Patients were identified through an International Pediatric Ophthalmology listserv and from the practice of the senior author. Participating Listserv physicians completed a data collection sheet. Children of all ages were included. Neuroimaging findings were also recorded. Nine cases of ONA are reported. Patients' ages ranged from 10 days to 2 years (median 9 months). Seven cases were bilateral. All patients had absence of the optic nerve and retinal vessels in the affected eye or eyes. Ophthalmologic findings included glaucoma, microcornea, persistent pupillary membrane, iris coloboma, aniridia, retinal dysplasia, retinal atrophy, chorioretinal coloboma, and persistent fetal vasculature. Systemic findings included facial dysmorphism, cardiac, genitourinary, skeletal, and developmental defects. A BCOR mutation was found in one patient. One patient had rudimentary optic nerves and chiasm on imaging. ONA is a unilateral or bilateral condition that may be associated with anomalies of the anterior or posterior segment with or without systemic findings. Rudimentary optic nerve on neuroimaging in one case suggests that ONA is on the continuum of optic nerve hypoplasia.


Tests of integrin transmembrane domain homo-oligomerization during integrin ligand binding and signaling.
Integrin transmembrane (TM) and/or cytoplasmic domains play a critical role in integrin bidirectional signaling. Although it has been shown that TM and/or cytoplasmic α and β domains associate in the resting state and separation of these domains is required for both inside-out and outside-in signaling, the role of TM homomeric association remains elusive. Formation of TM homo-oligomers was observed in micelles and bacterial membranes previously, and it has been proposed that homomeric association is important for integrin activation and clustering. This study addresses whether integrin TM domains form homo-oligomers in mammalian cell membranes using cysteine scanning mutagenesis. Our results show that TM homomeric interaction does not occur before or after soluble ligand binding or during inside-out activation. In addition, even though the cysteine mutants and the heterodimeric disulfide-bounded mutant could form clusters after adhering to immobilized ligand, the integrin TM domains do not form homo-oligomers, suggesting that integrin TM homomeric association is not critical for integrin clustering or outside-in signaling. Therefore, integrin TM homo-oligomerization is not required for integrin activation, ligand binding, or signaling.


Prevalence of antibodies to West Nile fever, sandfly fever Sicilian, and sandfly fever Naples viruses in healthy adults in Israel.
The arbovirus infections West Nile fever (WNF) and sandfly fever (SFF) are both endemic in the Middle East. Despite the fact that the mosquito and sandfly vectors of these viruses are still found in Israel, SFF has not been reported since 1948, whereas outbreaks of WNF occur periodically. It is suspected that some of the cases of nonspecific febrile illnesses in Israel may in fact be either WNF or SFF. To determine the extent of past arbovirus infections in subgroups of Israeli soldiers. Sera from random samples of three groups of healthy soldiers aged 18-20 (n=273), 21-30 (n=497), and 40-55 years (n=285) were examined for IgG and IgM antibodies to West Nile virus (WNV), sandfly fever Sicilian virus (SFSV), and sandfly fever Naples virus (SFNV), using an ELISA method. The prevalence of antibodies increased with age for all three viruses examined, and ranged from 7.0%, 0, and 2.8%, for WNV, SFSV, AND SFNV, respectively, in soldiers aged 18-20 years, to 41.9%, 23.7%, and 30.8%, in those aged 40-55 years. The percentage of seropositives for IgG who were also IgM positive were 1.0%, 5.9%, and 3.4%, for WNV, SFSV, AND SFNV, respectively. 17.5% of the seropositives for WNV were also positive for SFSV, as compared with 5.7% among the WNV-seronegatives. Among the seropositives for WNV, 23.99% were positive for SFNV, compared with 9.1% of WNV seronegatives. 48.2% of seropositives for SFSV were positive for SFNV, as compared with 8.4% for SFSV-seronegatives. In the age agroup 40-55 years, there were significantly higher prevalence rates in those born in Israel compared with those born abroad. There is still significant exposure to WNV, SFSV, and SFNV in Israel. Arborviruses are probably responsible for many cases of non-specific febrile illness in this region.


U-shaped learning and frequency effects in a multi-layered perceptron: implications for child language acquisition.
A three-layer back-propagation network is used to implement a pattern association task in which four types of mapping are learned. These mappings, which are considered analogous to those which characterize the relationship between the stem and past tense forms of English verbs, include arbitrary mappings, identity mappings, vowel changes, and additions of a suffix. The degree of correspondence between parallel distributed processing (PDP) models which learn mappings of this sort (e.g., Rumelhart & McClelland, 1986, 1987) and children's acquisition of inflectional morphology has recently been at issue in discussions of the applicability of PDP models to the study of human cognition and language (Pinker & Mehler, 1989; Bever, in press). In this paper, we explore the capacity of a network to learn these types of mappings, focusing on three major issues. First, we compare the performance of a single-layered perceptron similar to the one used by Rumelhart and McClelland with a multi-layered perceptron. The results suggest that it is unlikely that a single-layered perceptron is capable of finding an adequate solution to the problem of mapping stems and past tense forms in input configurations that are sufficiently analogous to English. Second, we explore the input conditions which determine learning in these networks. Several factors that characterize linguistic input are investigated: (a) the nature of the mapping performed by the network (arbitrary, suffixation, identity, and vowel change); (b) the competition effects that arise when the task demands simultaneous learning of distinct mapping types; (c) the role of the type and token frequency of verb stems; and (d) the influence of phonological subregularities in the irregular verbs. Each of these factors is shown to have selective consequences on both successful and erroneous performance in the network. Third, we outline several types of systems which could result in U-shaped acquisition, and discuss the ways in which learning in multi-layered networks can be seen to capture several characteristics of U-shaped learning in children. In general, these models provide information about the role of input in determining the kinds of errors that a network will produce, including the conditions under which rule-like behavior and U-shaped learning will and will not emerge. The results from all simulations are discussed in light of behavioral data on children's acquisition of the past tense and the validity of drawing conclusions about the acquisition of language from models of this sort.


Modifying optical properties of reduced/graphene oxide with controlled ozone and thermal treatment in aqueous suspensions.
Graphene possesses a number of advantageous properties, however, does not exhibit optical emission, which limits its use in optoelectronics. Unlike graphene, its functional derivative, graphene oxide (GO) exhibits fluorescence emission throughout the visible. Here, we focus on controlled methods for tuning the optical properties of GO. We introduce ozone treatment of reduced graphene oxide (RGO) in order to controllably transform it from non-emissive graphene-like material into GO with a specific fluorescence emission response. Solution-based treatment of RGO for 5-45 min with ∼1.2 g l-1 ozone/oxygen gas mixture yields a drastic color change, bleaching of the absorption in the visible and the stepwise increase in fluorescence intensity and lifetime. This is attributed to the introduction of oxygen-containing functional groups to RGO graphitic platform as detected by the infrared spectroscopy. A reverse process: controllable quenching of this fluorescence is achieved by the thermal treatment of GO in aqueous suspension up to 90 °C. This methodology allows for the wide range alteration of GO optical properties starting from the dark-colored non-emissive RGO material up to nearly transparent highly ozone-oxidized GO showing substantial fluorescence emission. The size of the GO flakes is concomitantly altered by oxidation-induced scission. Semi-empirical PM3 theoretical calculations on HyperChem models are utilized to explore the origins of optical response from GO. Two models are considered, attributing the induced emission either to the localized states produced by oxygen-containing addends or the islands of graphitic carbon enclosed by such addends. Band gap values calculated from the models are in the agreement with experimentally observed transition peak maxima. The controllable variation of GO optical properties in aqueous suspension by ozone and thermal treatments shown in this work provides a route to tune its optical response for particular optoelectronics or biomedical applications.


Systematic review of whole body vibration exercises in the treatment of cerebral palsy: Brief report.
Whole body vibration (WBV) is increasingly being used to improve balance and motor function and reduce the secondary complications associated with cerebral palsy (CP). The purpose of this study was to systematically appraise published research regarding the effects of static and/or dynamic exercise performed on a vibrating platform on gait, strength, spasticity and bone mineral density (BMD) within this population. Systematic searches of six electronic databases identified five studies that met our inclusion criteria (2 at Level II and 3 at Level III-2). Studies were analysed to determine: (a) participant characteristics; (b) optimal exercise and WBV treatment protocol; (c) effect on gait, strength, spasticity and BMD; and (d) the outcome measures used to evaluate effect. As data was not homogenous a meta-analysis was not possible. Several design limitations were identified and intervention protocols are poorly described. The effects on strength, gait, spasticity and BMD in persons with CP remain inconclusive with weak evidence that WBV may improve selected muscle strength and gait parameters and that prolonged exposure may improve BMD; there is currently no evidence that WBV can reduce spasticity. The evidence for exercise performed on a vibrating platform on mobility, strength, spasticity and BMD in CP remains scant and further larger scale investigations with controlled parameters to better understand the effects of WBV exercises in this population is recommended.


Alien species pathways to the Galapagos Islands, Ecuador.
Alien species, one of the biggest threats to natural ecosystems worldwide, are of particular concern for oceanic archipelagos such as Galápagos. To enable more effective management of alien species, we reviewed, collated and analysed all available records of alien species for Galápagos. We also assembled a comprehensive dataset on pathways to and among the Galápagos Islands, including tourist and resident numbers, tourist vessels, their itineraries and visitation sites, aircraft capacity and occupancy, air and sea cargo and biosecurity interceptions. So far, 1,579 alien terrestrial and marine species have been introduced to Galápagos by humans. Of these, 1,476 have become established. Almost half of these were intentional introductions, mostly of plants. Most unintentional introductions arrived on plants and plant associated material, followed by transport vehicles, and commodities (in particular fruit and vegetables). The number, frequency and geographic origin of pathways for the arrival and dispersal of alien species to and within Galápagos have increased over time, tracking closely the increase in human population (residents and tourists) on the islands. Intentional introductions of alien species should decline as biosecurity is strengthened but there is a danger that unintentional introductions will increase further as tourism on Galápagos expands. This unique world heritage site will only retain its biodiversity values if the pathways for invasion are managed effectively.


Renal Angiotensin receptor type 1 and 2 upregulation in intrauterine growth restriction of newborn piglets.
Epidemiological and experimental studies suggest that intrauterine growth restriction (IUGR) is associated with abnormalities in kidney development which is thought to be linked with alterations causing adult cardiovascular diseases. The renin-angiotensin system (RAS) plays an important role in the development of renal vascular and tubular structures, and is known to be altered by experimentally induced IUGR. These experimental models of IGUR have been criticized because they may have a more severe impact on intrauterine development than that which is normally encountered in humans. Therefore, we asked whether naturally occurring small-for-gestational-age newborn piglets exhibit features of altered RAS activity. We investigated the regional renal expression of angiotensin II type 1 (AT1) and AT2 receptors in normal-weight and IUGR piglets. The AT1 receptor mRNA expression was markedly enhanced in IUGR piglets, in the renal cortex by 64% and in the renal medulla by 52% (p < 0.05, compared with normal littermates). In contrast, mRNA expression for the AT2 receptor was similar in both the normal-weight and IUGR piglets. A significantly higher AT1 receptor protein expression was found in the IUGR piglets (p < 0.05) in the glomeruli, in the proximal and distal tubules, as well as in the collecting ducts by immunohistochemistry. Furthermore, AT2 receptor protein expression was significantly higher in the IUGR piglets (p < 0.05) in the subcapsular nephrogenic zone and in the distal tubules and collecting ducts. Thus, IUGR is accompanied by an upregulation of angiotensin II receptor expression in the kidneys of newborn piglets. This may indicate an alteration of the RAS in newborns suffering from naturally occurring IUGR.


A case of successful kidney transplantation after an extremely long-term maintenance haemodialysis of 38 years.
We describe herein a case of kidney transplantation after extremely long-term haemodialysis. A 66-year-old male received a kidney transplant from a deceased donor after maintenance haemodialysis for 38 years and 2 months. In spite of long-term haemodialysis, he showed minimal calcification of the iliac vessels, and transplantation was carried out successfully. Other than some difficulties in vesical rehabilitation, his postoperative course was favourable and he was finally discharged from the hospital on the 84th postoperative day. On a review of the literature, this case might represent the longest period of haemodialysis ever prior to kidney transplantation in the world.


Early life stress and inherited variation in monkey hippocampal volumes.
Opportunities for research on the causes and consequences of stress-related hippocampal atrophy are limited in human psychiatric disorders. Therefore, this longitudinal study investigated early life stress and inherited variation in monkey hippocampal volumes. Paternal half-siblings raised apart from one another by different mothers in the absence of fathers were randomized to 1 of 3 postnatal conditions that disrupted diverse aspects of early maternal care (n = 13 monkeys per condition). These conditions were previously shown to produce differences in social behavior, emotional reactivity, and neuroendocrine stress physiology. Hippocampal volumes were subsequently determined in adulthood by high-resolution magnetic resonance imaging. Adult hippocampal volumes did not differ with respect to the stressful postnatal conditions. Based on paternal half-sibling effects, the estimated proportion of genetic variance, ie, heritability, was 54% for hippocampal size. Paternal half-siblings with small adult hippocampal volumes responded to the removal of all mothers after weaning with initially larger relative increases in cortisol levels. Plasma cortisol levels 3 and 7 days later, and measures of cortisol-negative feedback in adulthood were not, however, correlated with hippocampal size. In humans with mood and anxiety disorders, small hippocampal volumes have been taken as evidence that excessive stress levels of cortisol induce hippocampal volume loss. Results from this study of monkeys suggest that small hippocampi also reflect an inherited characteristic of the brain. Genetically informed clinical studies should assess whether inherited variation in hippocampal morphology contributes to excessive stress levels of cortisol through diminished neuroendocrine regulation.


WAC loss-of-function mutations cause a recognisable syndrome characterised by dysmorphic features, developmental delay and hypotonia and recapitulate 10p11.23 microdeletion syndrome.
Rare de novo mutations have been implicated as a significant cause of idiopathic intellectual disability. Large deletions encompassing 10p11.23 have been implicated in developmental delay, behavioural abnormalities and dysmorphic features, but the genotype-phenotype correlation was not delineated. Mutations in WAC have been recently reported in large screening cohorts of patients with intellectual disability or autism, but no full phenotypic characterisation was described. Clinical and molecular characterisation of six patients with loss-of-function WAC mutations identified by whole exome sequencing was performed. Clinical data were obtained by retrospective chart review, parental interviews, direct patient interaction and formal neuropsychological evaluation. Five heterozygous de novo WAC mutations were identified in six patients. Three of the mutations were nonsense, and two were frameshift; all are predicted to cause loss of function either through nonsense-mediated mRNA decay or protein truncation. Clinical findings included developmental delay (6/6), hypotonia (6/6), behavioural problems (5/6), eye abnormalities (5/6), constipation (5/6), feeding difficulties (4/6), seizures (2/6) and sleep problems (2/6). All patients exhibited common dysmorphic features, including broad/prominent forehead, synophrys and/or bushy eyebrows, depressed nasal bridge and bulbous nasal tip. Posteriorly rotated ears, hirsutism, deep-set eyes, thin upper lip, inverted nipples, hearing loss and branchial cleft anomalies were also noted. Our case series show that loss-of-function mutations in WAC cause a recognisable genetic syndrome characterised by a neurocognitive phenotype and facial dysmorphism. Our data highly suggest that WAC haploinsufficiency is responsible for most of the phenotypic features associated with deletions encompassing 10p11.23.


A homozygous donor splice-site mutation in the meiotic gene MSH4 causes primary ovarian insufficiency.
Premature ovarian insufficiency (POI) is a frequent pathology that affects women under 40 years of age, characterized by an early cessation of menses and high FSH levels. Despite recent progresses in molecular diagnosis, the etiology of POI remains idiopathic in most cases. Whole-exome sequencing of members of a Colombian family affected by POI allowed us to identify a novel homozygous donor splice-site mutation in the meiotic gene MSH4 (MutS Homolog 4). The variant followed a strict mendelian segregation within the family and was absent in a cohort of 135 women over 50 years of age without history of infertility, from the same geographical region as the affected family. Exon trapping experiments showed that the splice-site mutation induced skipping of exon 17. At the protein level, the mutation p.Ile743_Lys785del is predicted to lead to the ablation of the highly conserved Walker B motif of the ATP-binding domain, thus inactivating MSH4. Our study describes the first MSH4 mutation associated with POI and increases the number of meiotic/DNA repair genes formally implicated as being responsible for this condition.


Indicators of regime shifts in ecological systems: what do we need to know and when do we need to know it?
Because novel ecological conditions can cause severe and long-lasting environmental damage with large economic costs, ecologists must identify possible environmental regime shifts and pro-actively guide ecosystem management. As an illustrative example, we applied six potential indicators of impending regime shifts to S. R. Carpenter and W. A. Brock's model of lake eutrophication and analyzed whether or not they afforded adequate advance warning to enable preventative interventions. Our initial analyses suggest that an indicator based on the high-frequency signal in the spectral density of the time-series provides the best advance warning of a regime shift, even when only incomplete information about underlying system drivers and processes is available. In light of this result, we explored two key factors associated with using indicators to prevent regime shifts. The first key factor is the amount of inertia in the system; i.e., how fast the system will react to a change in management, given that a manager can actually control relevant system drivers. If rapid, intensive management is possible, our analyses suggest that an indicator must provide at least 20 years advance warning to reduce the probability of a regime shift to < 5%. As time to intervention is increased or intensity of intervention is decreased, the necessary amount of advance warning required to avoid a regime shift increases exponentially. The second key factor concerns the amount and type of variability intrinsic to the system, and the impact of this variability on the power of an indicator. Indicators are considered powerful if they detect an impending regime shift with adequate lead time for effective management intervention, but not so far in advance that interventions are too costly or unnecessary. Intrinsic "noise" in the system obscures the "signal" provided by all indicators, and therefore, the power of the indicators declines rapidly with increasing within- and between-year variability in measurable variables or parameters. Our results highlight the key role of human decisions in managing ecosystems and the importance of pro-active application of the precautionary principle to avoid regime shifts.


Heterodyne detection of multiply scattered monochromatic light with a multipixel detector.
A new technique is presented for measuring the spectral broadening of light that has been multiply scattered from scatterers in motion. In our method the scattered light is detected by a heterodyne receiver that uses a CCD as a multipixel detector. We obtain the frequency spectrum of the scattered light by sweeping the heterodyne local oscillator frequency. Our detection scheme combines a high optical etendue (product of the surface by the detection solid angle) with an optimal detection of the scattered photons (shot noise). Using this technique, we measure, in vivo, the frequency spectrum of the light scattered through the breast of a female volunteer.


Differential effects of P-glycoprotein inhibitors on NIH3T3 cells transfected with wild-type (G185) or mutant (V185) multidrug transporters.
Multidrug resistance (MDR) may be associated with the expression of the MDR1 gene which encodes the 170-kDa cell surface P-glycoprotein (PGP) acting as an energy-dependent multidrug efflux pump. This pump can be inhibited by a variety of drugs including cyclosporin A, quinidine, and verapamil. Substrate specificity of the MDR1 gene product can be altered by a point mutation at amino acid residue 185 in which valine is substituted for glycine, but the effect of this mutation on inhibition of PGP is unknown. Multidrug-resistant NIH3T3 cells transfected with the MDR1 retroviral vector pHaMDR-1/A (G185) or pHaMDR1/A (V185) expressing comparable levels of PGP were compared for patterns of drug resistance and inhibition of drug resistance by MDR reversing agents. The NIH-MDR-G185 transfectants were somewhat preferentially resistant to daunorubicin, taxol, and vinblastine. The mutant (V185) conferred increased resistance to colchicine. This MDR phenotype in both NIH-MDR-G185- and NIH-MDR-V185-transfected NIH3T3 cells was overcome by the addition of cyclosporin A, quinidine, or verapamil. Verapamil was the most potent of the three agents affecting wild-type PGP. However, specific inhibitors showed different potency with wild-type or mutant transporters, depending on the cytotoxic drug whose resistance was being reversed. For example, cyclosporin A at a concentration of 1 microgram/ml, was a powerful reverser of taxol and colchicine resistance for the mutant drug transporter, but was much less effective for the wild-type transporter. In contrast, verapamil reversed resistance to vinblastine more efficiently for the wild-type transporter than for the mutant transporter. These results suggest that the sensitivity of a multidrug transporter to a reversing agent will depend on the reversing agent, the cytotoxic drug, and the presence or absence of mutations which alter substrate specificity.


Old age mortality and macroeconomic cycles.
As mortality is more and more concentrated at old age, it becomes critical to identify the determinants of old age mortality. It has counter-intuitively been found that mortality rates at all ages are higher during short-term increases in economic growth. Work-stress is found to be a contributing factor to this association, but cannot explain the association for the older, retired population. Historical figures of gross domestic product (Angus Maddison) were compared with mortality rates (Human Mortality Database) of middle aged (40-44 years) and older people (70-74 years) in 19 developed countries for the period 1950-2008. Regressions were performed on the de-trended data, accounting for autocorrelation and aggregated using random effects models. Most countries show pro-cyclical associations between the economy and mortality, especially with regard to male mortality rates. On average, for every 1% increase in gross domestic product, mortality increases with 0.36% for 70-year-old to 74-year-old men (p<0.001) and 0.38% for 40-year-old to 44-year-old men (p<0.001). The effect for women is 0.18% for 70-year-olds to 74-year-olds (p=0.012) and 0.15% for 40-year-olds to 44-year-olds (p=0.118). In developed countries, mortality rates increase during upward cycles in the economy, and decrease during downward cycles. This effect is similar for the older and middle-aged population. Traditional explanations as work-stress and traffic accidents cannot explain our findings. Lower levels of social support and informal care by the working population during good economic times can play an important role, but this remains to be formally investigated.


Paracetamol self-poisoning. Characteristics, prevention and harm reduction.
Paracetamol is now the most common drug used for self-poisoning in the UK and is associated with potentially fatal liver damage. Patients admitted to hospital because of paracetamol overdoses were studied in order to determine their characteristics and factors which might have deterred them from taking paracetamol or reduced the dangers of the overdose. Eighty patients were studied in hospital using a structured interview schedule, measures of depression and suicidal intent, information collected through the Oxford Monitoring System for Attempted Suicide, and the results of liver function tests. Acute liver dysfunction (25 patients) was associated with consumption of more than 25 tablets (odds ration 4.46, 95% CI 1.31 to 17.41, P = 0.014). The proportionate use of tablets from blister packs (60%) and loose preparations (46%; 5 patients using both types) reflected their general availability. More of those who took tablets from a loose preparation consumed 25 or more tablets (69%) than those who used a blister-pack preparation (40%; odds ratio = 3.0, 95% CI 1.12 to 9.95, P = 0.028). Only 20 patients thought that any type of warning label would have deterred them from taking a paracetamol overdose. Establishing a maximum number of tablets (e.g. 25) that can be available in individual preparations is likely to reduce the dangers of paracetamol self-poisoning. The potential effects of other measures are uncertain.


A novel flexible endovascular stent for use in small and tortuous vessels.
We assessed in vivo the mode of delivery, short-term patency and cellular response to a prototype endovascular stent. The stent is designed for delivery through a modified microcatheter and is retrievable with detachment from a delivery wire effected by electrolysis. We successfully deployed 12 stents in a range of sizes from 3-4 mm in straight and angled arteries of pigs. At control angiography 3 and 6 weeks later, nine arteries were patent, two occluded and one narrowed; patency was not related to vessel or stent size. The device shows promise as a stent for intracranial arteries since it can be delivered through microcatheters small enough for intracranial navigation and provides the operator with greater control than currently available self- or balloon-expanded stents.


Mitochondrial membrane remodelling regulated by a conserved rhomboid protease.
Rhomboid proteins are intramembrane serine proteases that activate epidermal growth factor receptor (EGFR) signalling in Drosophila. Rhomboids are conserved throughout evolution, and even in eukaryotes their existence in species with no EGFRs implies that they must have additional roles. Here we report that Saccharomyces cerevisiae has two rhomboids, which we have named Rbd1p and Rbd2p. RBD1 deletion results in a respiratory defect; consistent with this, Rbd1p is localized in the inner mitochondrial membrane and mutant cells have disrupted mitochondria. We have identified two substrates of Rbd1p: cytochrome c peroxidase (Ccp1p); and a dynamin-like GTPase (Mgm1p), which is involved in mitochondrial membrane fusion. Rbd1p mutants are indistinguishable from Mgm1p mutants, indicating that Mgm1p is a key substrate of Rbd1p and explaining the rbd1Delta mitochondrial phenotype. Our data indicate that mitochondrial membrane remodelling is regulated by cleavage of Mgm1p and show that intramembrane proteolysis by rhomboids controls cellular processes other than signalling. In addition, mitochondrial rhomboids are conserved throughout eukaryotes and the mammalian homologue, PARL, rescues the yeast mutant, suggesting that these proteins represent a functionally conserved subclass of rhomboid proteases.


Early steroid therapy for respiratory failure.
We performed a randomized double-blind trial to determine the usefulness of early methylprednisolone therapy for patients with pulmonary failure. We selected 81 acutely ill, mechanically ventilated patients at high risk for adult respiratory distress syndrome (ARDS). Thirty-nine patients received methylprednisolone, 30 mg/kg, every six hours for 48 hours; 42 patients received mannitol placebo. All patients were given a positive end-expiratory pressure of 5 cm H2O, monitored with pulmonary artery catheters, and treated for their primary disease processes. Twenty-five steroid-treated patients (64%) and 14 placebo-treated patients (33%) developed ARDS. Early infectious complications occurred in 30 steroid-treated patients (77%) and 18 placebo-treated patients (43%). There were no significant differences in factors predisposing to ARDS, ventilatory requirements, or days of intensive care. These results do not support the use of methylprednisolone for ARDS. Steroids failed to improve pulmonary function and were associated with an increased infection rate. Intensive pulmonary and general supportive care remain the preferred therapy for ARDS.


Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy.
Studies of psychiatric disorders have traditionally focused on emotional symptoms such as depression, anxiety and hallucinations. However, poorly controlled cognitive deficits are equally prominent and severely compromise quality of life, including social and professional integration. Consequently, intensive efforts are being made to characterize the cellular and cerebral circuits underpinning cognitive function, define the nature and causes of cognitive impairment in psychiatric disorders and identify more effective treatments. Successful development will depend on rigorous validation in animal models as well as in patients, including measures of real-world cognitive functioning. This article critically discusses these issues, highlighting the challenges and opportunities for improving cognition in individuals suffering from psychiatric disorders.


[Seroprevalence of HTLV-1/2 in blood donors from Misiones Province].
Human T-cell Lymphotropic viruses type 1 (HTLV-1), the first human oncoretrovirus to be discovered, is the etiologic agent of Adult T-cell Leukemia (ATL) and HTLV-1 Associated Mielopathy or Tropical Spastic Paraparesis (HAM/TSP). It is endemic worldwide, including the North of Argentina where both associated diseases have also been detected. No etiologic role has been described for HTLV-2, although it has been associated with HAM/TSP-like neurologic syndromes. Both retroviruses are endemic in native populations of The Americas, Africa and at-risk populations. They are transmitted through sex contact, parenterally and from mother to child. The aim of this study was to estimate the seroprevalence of HTLV-1/2 in a blood donor population from Misiones province. A total of 6912 accepted blood donations in 2008 were analyzed. HTLV-1/2 screening was performed with ELISA and particle agglutination, and reactive samples were confirmed by Western Blot. From the total, 5 samples resulted seropositive with a final prevalence of 0.00072. Out of the 5 positive samples, one was an HTLV, three HTLV-1 and one HTLV-2. These blood donors were residents of Posadas, Eldorado and Oberá, with no risk antecedents. This study demonstrates the presence of HTLV-1/2 in a population of Misiones with a prevalence rate similar to those reported among blood donors from non-endemic areas.


Alterations in venous endothelial cell and smooth muscle cell relaxation induced by high glucose concentrations can be prevented by aminoguanidine.
High glucose concentrations lead to the formation of advanced glycosylation end-products (AGE). Increased glucose concentrations are found during the systemic inflammatory response syndrome and during coronary artery bypass surgery. This study examines the pharmacological effect of AGE on venous endothelial-dependent and -independent relaxation and seeks to determine if aminoguanidine, a known AGE inhibitor, can prevent changes induced by the presence of high glucose concentrations. Standard isometric tension studies on rings from endothelialized and deendothelialized rabbit external jugular veins were performed after incubation for 6 hr in 5.5 mM glucose (control) or 44 mM glucose. The effects of preincubation with either indomethacin (10 microM) to inhibit cyclo-oxygenase activity or aminoguanidine (10 microM) to inhibit protein glycosylation were also studied. In the presence of 44 mM glucose, there was a significant reduction in acetylcholine (endothelial cell based)- and forskolin-induced (smooth muscle cell based) relaxation without associated alterations in serotonin-, calcium ionophore-, and sodium nitroprusside-mediated relaxations. The alterations in acetylcholine-mediated relaxation were inhibited by the addition of indomethacin; co-incubation with aminoguanidine prevented the decrease in acetylcholine-mediated and forskolin-mediated responses. This study shows that in vitro elevated glucose concentrations lead to a reduction in both endothelial cell and smooth muscle cell relaxation, which may be due to AGE-mediated generation of endothelial cell cyclo-oxygenase products and AGE-induced changes in cAMP-mediated relaxation. Therefore, AGE production in the vessel wall cells produces alterations in receptor-dependent and receptor-independent cyclo-oxygenase production and these changes result in altered endothelial- and nonendothelial-mediated relaxation. Alterations in the endothelial and smooth muscle cell responses can be inhibited by aminoguanidine, suggesting that means to reduce or prevent glycosylation are beneficial in ameliorating the acute changes induced by short-term exposure to elevated glucose concentrations.


Single cell genomics indicates horizontal gene transfer and viral infections in a deep subsurface Firmicutes population.
A major fraction of Earth's prokaryotic biomass dwells in the deep subsurface, where cellular abundances per volume of sample are lower, metabolism is slower, and generation times are longer than those in surface terrestrial and marine environments. How these conditions impact biotic interactions and evolutionary processes is largely unknown. Here we employed single cell genomics to analyze cell-to-cell genome content variability and signatures of horizontal gene transfer (HGT) and viral infections in five cells of Candidatus Desulforudis audaxviator, which were collected from a 3 km-deep fracture water in the 2.9 Ga-old Witwatersrand Basin of South Africa. Between 0 and 32% of genes recovered from single cells were not present in the original, metagenomic assembly of Desulforudis, which was obtained from a neighboring subsurface fracture. We found a transposable prophage, a retron, multiple clustered regularly interspaced short palindromic repeats (CRISPRs) and restriction-modification systems, and an unusually high frequency of transposases in the analyzed single cell genomes. This indicates that recombination, HGT and viral infections are prevalent evolutionary events in the studied population of microorganisms inhabiting a highly stable deep subsurface environment.


Random phase plate for wavefront sensing via phase retrieval and a volume speckle field.
A random phase plate is prepared by illuminating a photoresist plate with a fully developed speckle field and using the developed phase plate (DPP) as a diffuser. Wavefront sensing is implemented using phase retrieval based on the recording of speckle intensity patterns at various distances from the DPP and the wave propagation equation. The effects of the roughness height of the DPP on the phase retrieval are investigated. From simulations a roughness height of lambda/10 results in a speckle field that yields good phase reconstruction for the spherical test wavefront incident on the DPP. From the experiments different portions of the DPP that received varying exposures are examined. A section of the phase plate with a characteristic roughness height facilitated the generation of a speckle field that is optimum for the phase retrieval algorithm. Thus a random phase plate with varying roughness height allows optimized measurements of wavefronts with different curvatures. Analytical expressions describing the second-order intensity statistics (fourth-order field statistics) for a field traversing a specific diffuser are presented. This DPP will not give rise to a fully developed speckle field, but knowing the statistics of the depth of the DPP will facilitate a rigorous treatment of the problem.


Changes in shoulder pain and disability after thrust manipulation in subjects presenting with second and third rib syndrome.
The purpose of this preliminary study was to investigate changes in shoulder pain, disability, and perceived level of recovery after 2 sessions of upper thoracic and upper rib high-velocity low-amplitude (HVLA) thrust manipulation in patients with shoulder pain secondary to second and third rib syndrome. This exploratory study evaluated 10 consecutive individuals with shoulder pain, with or without brachial pain, and a negative Neer impingement test, who completed the Shoulder Pain and Disability Index (SPADI), the numeric pain rating scale (NPRS), and the global rating of change. Patients received 2 sessions of HVLA thrust manipulation targeting the upper thoracic spine bilaterally and the second and third ribs on the symptomatic side. Outcome measures were completed after the first treatment session, at 48 hours, 1 month, and 3 months. Patients showed a significant decrease in SPADI (F = 59.997; P = .001) and significant decrease in resting shoulder NPRS (F = 63.439; P = .001). For both NPRS and SPADI, there were significant differences between the pretreatment scores and each of the postintervention scores through 3-month follow-up (P < .05). Large within-group effect sizes (Cohen's d ≥ 0.8) were found between preintervention data and all postintervention assessments in both outcomes. Mean global rating of change scores (+6.8 at 3 months) indicated "a very great deal better" outcome at long-term follow-up. This group of patients with shoulder pain secondary to second and third rib syndrome who received upper thoracic and upper rib HVLA thrust manipulations showed significant reductions in pain and disability and improvement in perceived level of recovery.


Cancer and breast cancer awareness interventions in an intellectual disability context: A review of the literature.
Women with an intellectual disability (ID) have a similar risk of developing breast cancer as women in the general population yet present with later stage breast cancers, which have poorer outcomes. To identify whether there is a need to develop a breast cancer awareness intervention for women with an ID. Interventions aimed at increasing cancer awareness and breast cancer awareness for people with an ID were identified and critically appraised. Five interventions to increase cancer awareness or breast cancer awareness in people with an ID were identified. The review highlighted the paucity of theoretically underpinned breast cancer awareness interventions specifically aimed at women with an ID. Facilitating breast cancer awareness for women with an ID could potentially lead to earlier presentation of potential symptoms of breast cancer, earlier treatment, better prognosis and ultimately, improved survival. This article establishes that there is a need for an intervention underpinned by theory to increase breast cancer awareness in women with an ID.


Improving the diagnosis of severe malaria in African children using platelet counts and plasma PfHRP2 concentrations.
Severe malaria caused by Plasmodium falciparum is difficult to diagnose accurately in children in high-transmission settings. Using data from 2649 pediatric and adult patients enrolled in four studies of severe illness in three countries (Bangladesh, Kenya, and Uganda), we fitted Bayesian latent class models using two diagnostic markers: the platelet count and the plasma concentration of P. falciparum histidine-rich protein 2 (PfHRP2). In severely ill patients with clinical features consistent with severe malaria, the combination of a platelet count of ≤150,000/μl and a plasma PfHRP2 concentration of ≥1000 ng/ml had an estimated sensitivity of 74% and specificity of 93% in identifying severe falciparum malaria. Compared with misdiagnosed children, pediatric patients with true severe malaria had higher parasite densities, lower hematocrits, lower rates of invasive bacterial disease, and a lower prevalence of both sickle cell trait and sickle cell anemia. We estimate that one-third of the children enrolled into clinical studies of severe malaria in high-transmission settings in Africa had another cause of their severe illness.


Increasing the clinical efficacy of NK and antibody-mediated cancer immunotherapy: potential predictors of successful clinical outcome based on observations in high-risk neuroblastoma.
Disease recurrence is frequent in high-risk neuroblastoma (NBL) patients even after multi-modality aggressive treatment [a combination of chemotherapy, surgical resection, local radiation therapy, autologous stem cell transplantation, and cis-retinoic acid (CRA)]. Recent clinical studies have explored the use of monoclonal antibodies (mAbs) that bind to disialoganglioside (GD(2)), highly expressed in NBL, as a means to enable immune effector cells to destroy NBL cells via antibody-dependent cell-mediated cytotoxicity (ADCC). Preclinical data indicate that ADCC can be more effective when appropriate effector cells are activated by cytokines. Clinical studies have pursued this by administering anti-GD(2) mAb in combination with ADCC-enhancing cytokines (IL2 and GM-CSF), a regimen that has demonstrated improved cancer-free survival. More recently, early clinical studies have used a fusion protein that consists of the anti-GD(2) mAb directly linked to IL2, and anti-tumor responses were seen in the Phase II setting. Analyses of genes that code for receptors that influence ADCC activity and natural killer (NK) cell function [Fc receptor (FcR), killer immunoglublin-like receptor (KIR), and KIR-ligand (KIR-L)] suggest patients with anti-tumor activity are more likely to have certain genotype profiles. Further analyses will need to be conducted to determine whether these genotypes can be used as predictive markers for favorable therapeutic outcome. In this review, we discuss factors that affect response to mAb-based tumor therapies such as hu14.18-IL2. Many of our observations have been made in the context of NBL; however, we will also include some observations made with mAbs targeting other tumor types that are consistent with results in NBL. Therefore, we hypothesize that the NBL observations discussed here may also be relevant to mAb therapy for other cancers, in which ADCC is known to play a role.


Topological features without a lattice in Rashba spin-orbit coupled atoms.
Topological order can be found in a wide range of physical systems, from crystalline solids, photonic meta-materials and even atmospheric waves to optomechanic, acoustic and atomic systems. Topological systems are a robust foundation for creating quantized channels for transporting electrical current, light, and atmospheric disturbances. These topological effects are quantified in terms of integer-valued 'invariants', such as the Chern number, applicable to the quantum Hall effect, or the [Formula: see text] invariant suitable for topological insulators. Here, we report the engineering of Rashba spin-orbit coupling for a cold atomic gas giving non-trivial topology, without the underlying crystalline structure that conventionally yields integer Chern numbers. We validated our procedure by spectroscopically measuring both branches of the Rashba dispersion relation which touch at a single Dirac point. We then measured the quantum geometry underlying the dispersion relation using matter-wave interferometry to implement a form of quantum state tomography, giving a Berry's phase with magnitude π. This implies that opening a gap at the Dirac point would give two dispersions (bands) each with half-integer Chern number, potentially implying new forms of topological transport.


Effect of Crystallization Firing on Marginal Gap of CAD/CAM Fabricated Lithium Disilicate Crowns.
To evaluate the marginal gaps of CAD/CAM (CEREC 3) produced crowns made from leucite-reinforced glass-ceramic (IPS Empress CAD) blocks (LG), and lithium-disilicate (IPS e.max CAD) blocks before (LD-B), and after (LD-A) crystallization firing. A human molar tooth (#19) was mounted with adjacent teeth on a typodont and prepared for a full-coverage ceramic crown. The typodont was assembled in the mannequin head to simulate clinical conditions. After tooth preparation 15 individual optical impressions were taken by the same operator using titanium dioxide powder and a CEREC 3 camera per manufacturer's instructions. One operator designed and machined the crowns in leucite-reinforced glass-ceramic blocks (n = 5) and lithium-disilicate blocks (n = 10) using the CEREC 3 system. The crowns were rigidly seated on the prepared tooth, and marginal gaps (μm) were measured with an optical microscope (500×) at 12 points, 3 on each of the M, B, D, and L surfaces of the leucite-reinforced glass-ceramic crowns and the lithium-disilicate crowns before and after crystallization firing. Results were analyzed by two-way ANOVA followed by a Tukey's post hoc multiple comparison test (α = 0.05). The overall mean marginal gaps (μm) for the crowns evaluated were: LG = 49.2 ± 5.5, LD-B = 42.9 ± 12.2, and LD-A = 57.2 ± 16.0. The marginal gaps for LG and LD-B were not significantly different, but both were significantly less than for LD-A. The type of ceramic material did not affect the marginal gap of CAD/CAM crowns. The crystallization firing process required for lithium-disilicate crowns resulted in a significant increase in marginal gap size, likely due to shrinkage of the ceramic during the crystallization process. The marginal gap of CAD/CAM-fabricated lithium disilicate crowns increases following crystallization firing. The marginal gap still remains within clinically acceptable parameters.


Monocytes as a diagnostic marker of cardiovascular diseases.
Inflammation is an important pathogenic factor of cardiovascular diseases. Inflammatory processes induce the organism systemic changes that are sensed by the cells of innate immune system. These systemic changes include increased concentrations of soluble factors capable of activating monocytes in the blood circulation therefore monocytes represent highly attractive cell population for diagnostic use. To date various parameters of circulating monocytes were associated with cardiovascular diseases. These comprise monocyte count, increased adhesive properties, alteration of lipid metabolism, phagocytosis and endocytosis of LDL. Search for markers, better suitable for clinical use led to identification of monocyte population heterogeneity. One of the best studied markers for identification of monocyte subpopulation is CD16. Although there is no consensus regarding the origin and composition of various monocyte subpopulations, association of increased size of CD16+ monocyte population with atherosclerosis is well established. Further surface markers of monocytes found to be associated with cardiovascular diseases are CD18, CD11b, CXCR1, CD36 and STAB1. Functional studies performed on primary human monocytes support the importance of these molecules for the pathogenesis of cardiovascular diseases. Continuous research on monocyte biology leads to identification of perspective markers that show significant potential of clinical use. These include analysis of monocyte response to a challenge and level of mitochondrial DNA heteroplasmy. Further research involving genomic, proteomic and cell biology techniques supplemented with systems biology approaches for data analysis and computer simulations are required for defining molecular and functional parameters of monocytes to be used as a diagnostic tool or therapeutic target.


Crystal structure of the Aequorea victoria green fluorescent protein.
The green fluorescent protein (GFP) from the Pacific Northwest jellyfish Aequorea victoria has generated intense interest as a marker for gene expression and localization of gene products. The chromophore, resulting from the spontaneous cyclization and oxidation of the sequence -Ser65 (or Thr65)-Tyr66-Gly67-, requires the native protein fold for both formation and fluorescence emission. The structure of Thr65 GFP has been determined at 1.9 angstrom resolution. The protein fold consists of an 11-stranded beta barrel with a coaxial helix, with the chromophore forming from the central helix. Directed mutagenesis of one residue adjacent to the chromophore, Thr203, to Tyr or His results in significantly red-shifted excitation and emission maxima.