Neonicotinoid-Coated Zea mays Seeds Indirectly Affect Honeybee Performance and Pathogen Susceptibility in Field Trials.
Thirty-two honeybee (Apis mellifera) colonies were studied in order to detect and measure potential in vivo effects of neonicotinoid pesticides used in cornfields (Zea mays spp) on honeybee health. Honeybee colonies were randomly split on four different agricultural cornfield areas located near Quebec City, Canada. Two locations contained cornfields treated with a seed-coated systemic neonicotinoid insecticide while the two others were organic cornfields used as control treatments. Hives were extensively monitored for their performance and health traits over a period of two years. Honeybee viruses (brood queen cell virus BQCV, deformed wing virus DWV, and Israeli acute paralysis virus IAPV) and the brain specific expression of a biomarker of host physiological stress, the Acetylcholinesterase gene AChE, were investigated using RT-qPCR. Liquid chromatography-mass spectrometry (LC-MS) was performed to detect pesticide residues in adult bees, honey, pollen, and corn flowers collected from the studied hives in each location. In addition, general hive conditions were assessed by monitoring colony weight and brood development. Neonicotinoids were only identified in corn flowers at low concentrations. However, honeybee colonies located in neonicotinoid treated cornfields expressed significantly higher pathogen infection than those located in untreated cornfields. AChE levels showed elevated levels among honeybees that collected corn pollen from treated fields. Positive correlations were recorded between pathogens and the treated locations. Our data suggests that neonicotinoids indirectly weaken honeybee health by inducing physiological stress and increasing pathogen loads.


Management of multiple myeloma and related-disorders: guidelines from the Italian Society of Hematology (SIE), Italian Society of Experimental Hematology (SIES) and Italian Group for Bone Marrow Transplantation (GITMO).
Perceiving the need for rigorous recommendations to facilitate decisions concerning the management of patients with multiple myeloma (MM), the Italian Society of Hematology (SIE) and the two affiliate societies (SIES and GITMO) commissioned a project to develop guidelines for the therapy of MM using evidence-based knowledge and consensus formation techniques. After a comprehensive systematic review of 1,450 papers, an Expert Panel formulated and graded sixty recommendations according to the supporting evidence. Evidence gaps were filled with twenty-two consensus-based statements. High grade recommendations (grade A) are reported below. Treatment should be immediately initiated in MM patients with related organ damage: those patients aged below 65 years who do not have severe co-morbidities should receive autologous stem cell transplantation, while patients not candidates for autologous stem cell transplantation should receive oral melphalan and prednisone. Interferon-a should not be associated with conventional chemotherapy, but it can be offered with or without steroids as a maintenance therapy to patients who have reached a plateau phase. High-dose dexamethasone-containing regimens or high-dose dexamethasone alone are recommended as a first-line therapy when cytoreduction is urgently required (i.e., MM with spinal cord compression or with rapidly progressive renal failure). MM patients with moderate-to-severe anemia should receive erythropoietin, while patients with bone disease or osteopenia should receive long-term bisphophonates. Recommendations for the management of the clinical manifestations caused by the monoclonal protein (i.e. hyperviscosity, cast nephropathy, AL amyloidosis) and of solitary bone and extramedullary plasmacytoma were also elaborated. A substantial proportion of clinical care for MM can be guided by evidence-based treatment recommendations.


On the influence of diphosphine ligands on the chemical order in small RuPt nanoparticles: combined structural and surface reactivity studies.
Diphenylphosphinobutane (dppb) stabilized bimetallic RuPt nanoparticles were prepared by co-decomposition of [Ru(COD)(COT)] [(1,5-cyclooctadiene)(1,3,5-cyclooctatriene)ruthenium] and [Pt(CH(3))(2)(COD)] [dimethyl(1,5-cyclooctadiene) platinum(II)] organometallic precursors under mild conditions (room temperature, 3 bar of dihydrogen) and in the presence of dppb. The determination of the nanoparticles' chemical composition was made possible thanks to a combination of several characterization techniques (HREM, STEM-HAADF, WAXS, EXAFS, IR, NMR) associated with surface reactivity studies based on simple catalytic reactions. The obtained nanoparticles display a ruthenium rich core and a disordered shell containing both ruthenium and platinum. The results were compared with those obtained on nanoparticles of similar size and composition but not containing ligands. The complexity observed in the present structure of these nanoparticles arises from the high chemical affinity of the diphosphine ligand used as a stabilizer for both metals.


Effect of short-term versus long-term grassland management and seasonal variation in organic and conventional dairy farming on the composition of bulk tank milk.
Bulk tank milk from 28 dairy farms was sampled every second month for 2 yr to assess the effects of grassland management, production system and season on milk fatty acid (FA) composition, concentrations of fat-soluble vitamins, Se, and milk sensory quality. Grassland management varied in terms of time since establishment. Short-term grassland management (SG) was defined as establishment or reseeding every fourth year or more often, and long-term grassland management (LG) was defined as less frequent establishment or reseeding. Fourteen organic (ORG) dairy farms with either short-term or long-term grassland management were paired with 14 conventional (CON) farms with respect to grassland management. Within ORG farms, SG farms differed from LG farms in herbage botanical composition, but not in concentrate FA concentrations, dry matter intake, or milk yield. Within CON farms, herbage composition, concentrate FA concentrations, dry matter intake, and milk yield showed no or insignificant variations. The ORG farms differed from CON farms in herbage botanical composition, concentrate FA concentrations, concentrate intake, and milk yield. Compared with ORG-LG farms, ORG-SG farms produced milk fat with higher proportions of C10:0 and C12:0 associated with higher herbage proportions of legumes (Fabaceae) and lower proportions of other dicotyledon families. Compared with milk from CON farms, milk fat from ORG farms had higher proportions of most saturated FA and all n-3 FA, but lower proportions of C18:0 and C18:1 cis-9 associated with higher forage proportion and differences in concentrations of FA in concentrates. Compared with the outdoor-feeding periods, the indoor feeding periods yielded milk fat with higher proportions of most short-chain and medium-chain FA and lower proportions of most C18-FA associated with grazing and higher forage proportions. Milk concentrations of α-tocopherol and β-carotene were lower during the grazing periods. Inclusion of fishmeal in organic concentrates may explain higher Se concentrations in organically produced milk. Milk sensory quality was not affected in this study. In conclusion, grassland management had minor effects on milk composition, and differences between ORG farms and CON farms may be explained by differences in concentrate intake and concentrate FA concentrations. Milk produced on ORG farms versus CON farms and milk produced during the outdoor versus indoor feeding periods had potential health benefits due to FA composition. In contrast, the higher milk-fat proportions of saturated FA in milk from ORG farms may be perceived as negative for human health.


Adenosine Triphosphate-Sensitive Potassium Channel Kir Subunits Implicated in Cardioprotection by Diazoxide.
ATP-sensitive potassium (K(ATP)) channel openers provide cardioprotection in multiple models. Ion flux at an unidentified mitochondrial K(ATP) channel has been proposed as the mechanism. The renal outer medullary kidney potassium channel subunit, potassium inward rectifying (Kir)1.1, has been implicated as a mitochondrial channel pore-forming subunit. We hypothesized that subunit Kir1.1 is involved in cardioprotection (maintenance of volume homeostasis and contractility) of the K(ATP) channel opener diazoxide (DZX) during stress (exposure to hyperkalemic cardioplegia [CPG]) at the myocyte and mitochondrial levels. Kir subunit inhibitor Tertiapin Q (TPN-Q) was utilized to evaluate response to stress. Mouse ventricular mitochondrial volume was measured in the following groups: isolation buffer; 200 μmol/L of ATP; 100 μmol/L of DZX+200 μmol/L of ATP; or 100 μmol/L of DZX+200 μmol/L of ATP+TPN-Q (500 or 100 nmol/L). Myocytes were exposed to Tyrode's solution (5 minutes), test solution (Tyrode's, cardioplegia [CPG], CPG+DZX, CPG+DZX+TPN-Q, Tyrode's+TPN-Q, or CPG+TPN-Q), N=12 for all (10 minutes); followed by Tyrode's (5 minutes). Volumes were compared. TPN-Q, with or without DZX, did not alter mitochondrial or myocyte volume. Stress (CPG) resulted in myocyte swelling and reduced contractility that was prevented by DZX. TPN-Q prevented the cardioprotection afforded by DZX (volume homeostasis and maintenance of contractility). TPN-Q inhibited myocyte cardioprotection provided by DZX during stress; however, it did not alter mitochondrial volume. Because TPN-Q inhibits Kir1.1, Kir3.1, and Kir3.4, these data support that any of these Kir subunits could be involved in the cardioprotection afforded by diazoxide. However, these data suggest that mitochondrial swelling by diazoxide does not involve Kir1.1, 3.1, or 3.4.


Leveraging social networks for understanding the evolution of epidemics.
To understand how infectious agents disseminate throughout a population it is essential to capture the social model in a realistic manner. This paper presents a novel approach to modeling the propagation of the influenza virus throughout a realistic interconnection network based on actual individual interactions which we extract from online social networks. The advantage is that these networks can be extracted from existing sources which faithfully record interactions between people in their natural environment. We additionally allow modeling the characteristics of each individual as well as customizing his daily interaction patterns by making them time-dependent. Our purpose is to understand how the infection spreads depending on the structure of the contact network and the individuals who introduce the infection in the population. This would help public health authorities to respond more efficiently to epidemics. We implement a scalable, fully distributed simulator and validate the epidemic model by comparing the simulation results against the data in the 2004-2005 New York State Department of Health Report (NYSDOH), with similar temporal distribution results for the number of infected individuals. We analyze the impact of different types of connection models on the virus propagation. Lastly, we analyze and compare the effects of adopting several different vaccination policies, some of them based on individual characteristics -such as age- while others targeting the super-connectors in the social model. This paper presents an approach to modeling the propagation of the influenza virus via a realistic social model based on actual individual interactions extracted from online social networks. We implemented a scalable, fully distributed simulator and we analyzed both the dissemination of the infection and the effect of different vaccination policies on the progress of the epidemics. The epidemic values predicted by our simulator match real data from NYSDOH. Our results show that our simulator can be a useful tool in understanding the differences in the evolution of an epidemic within populations with different characteristics and can provide guidance with regard to which, and how many, individuals should be vaccinated to slow down the virus propagation and reduce the number of infections.


Increased glioma growth in mice depleted of macrophages.
Macrophages can promote the growth of some tumors, such as those of the breast and lung, but it is unknown whether this is true for all tumors, including those of the nervous system. On the contrary, we have previously shown that macrophages can slow the progression of malignant gliomas through a tumor necrosis factor-dependent mechanism. Here, we provide evidence suggesting that this antitumor effect could be mediated by T lymphocytes, as their number was drastically reduced in tumor necrosis factor-deficient mice and inversely correlated with glioma volume. However, this correlation was only observed in allogeneic recipients, prompting a reevaluation of the role of macrophages in a nonimmunogenic context. Using syngeneic mice expressing the herpes simplex virus thymidine kinase under the control of the CD11b promoter, we show that macrophages can exert an antitumor effect without the help of T lymphocytes. Macrophage depletion achieved by ganciclovir treatment resulted in a 33% increase in glioma volume. The antitumor effect of macrophages was not likely due to a tumoricidal activity because phagocytosis or apoptosis of glioma cells, transduced ex vivo with a lentiviral vector expressing green fluorescent protein, was rarely observed. Their antitumor effect was also not due to a destructive action on the tumor vasculature because macrophage depletion resulted in a modest reduction in vascular density. Therefore, this study suggests that macrophages can attenuate glioma growth by an unconventional mechanism. This study also validates a new transgenic model to explore the role of macrophages in cancer.


Asking semi-literate adolescents about sexual behaviour: the validity of assisted self-completion questionnaire (ASCQ) data in rural Tanzania.
To develop and test a sexual behaviour survey method for semi-literate populations, combining the privacy of a self-completion questionnaire (SCQ) with the clarity of a face-to-face questionnaire (FFQ). In 1998, 6079 Tanzanian primary school students (mean age 15.1 years) were surveyed using an innovative assisted self-completion questionnaire (ASCQ). The format of the questionnaire was simple, all responses were closed, and conceptually complex questions such as those involving ranking or multiple answers were avoided. The ASCQ was administered to groups of 20 by a research assistant who read questions and answers aloud in two languages so pupils could tick or write responses independently. A total of 4958 of respondents from the 1998 ASCQ Cohort also participated in a 1998 FFQ interview and, in 2000, 4424 again completed an ASCQ. In the 1998 ASCQ survey, 55.0% of males and 21.1% of females reported they had had vaginal intercourse, of whom 71.5% and 66.0%, respectively reported their first sexual relationship lasted for a week or less, and 49.5% and 59.6%, respectively reported they had had sex in the last 4 weeks. After adjustment for age, reported sex was associated with alcohol use in both males (OR = 1.57) and females (OR = 1.69), earning money for males (OR = 1.32) and not living with a mother for females (OR = 0.77). The vast majority of respondents did not appear to have difficulty completing the ASCQ, but 7.4% of 1998 respondents and 2.9% of 2000 respondents selected all first or all last answers in a section for which this was inconsistent. This bias was associated with female, less educated and more geographically remote respondents. Of those respondents who reported sex in the 1998 ASCQ survey, 32.1% reported fewer total partners in the 2000 ASCQ survey, 25.2% reported having had sex fewer times than originally reported, and 61.9% of those who reported having used a condom in 1998 reported never having used one in 2000. While the proportions reporting sex were very similar in the 1998 ASCQ and FFQ surveys, 37.9% of males and 59.2% of females reporting sex only did so on one of the two questionnaires. Higher proportions of respondents reported sensitive information in the ASCQ than the FFQ, although in some cases this may have related to answer order bias. The results suggest that an ASCQ may be useful in assessing sexual behaviour in African adolescents, particularly for older, male and/or educated respondents. However, triangulation with data from other surveys raises questions about the validity of self-reported sexual behaviour in general.


Neuroprotective role of chrysin in attenuating loss of dopaminergic neurons and improving motor, learning and memory functions in rats.
Selective degeneration of dopaminergic neurons is the pathological hallmark of Parkinson disease (PD). Enhanced oxidative stress, lipid peroxidation and susceptibility of dopaminergic neurons to apoptotic cellular death are the leading pathogenetic mechanisms. Chrysin is an active flavonoid. Its neuroprotective effects have been reported. This study examined the neuroprotective effects of chrysin in ameliorating the dopaminergic neuronal degeneration and motor behavioral changes in rotenone model of PD. Thirty Sprague-Dawley rats were assigned into three groups: Control, rotenone-treated, and rotenone+chrysin treated groups. Rotenone was given at a dose of 3 mg/kg daily intraperitoneally, and chrysin was given at a dose of 50 mg/kg daily intraperitoneally for 4 weeks. Using five neurobehavioral assessment tests, evaluation was done weekly to record the motor behavioral changes. After 4 weeks, animals were sacrificed, brains were removed, and section from striatum and substantia nigra were stained using hematoxylin and eosin and cresyl violet stains. Immunohistochemical sections were also prepared using anti-tyrosine hydroxylase (TH) antibody. Rotenone-induced Parkinson like changes were evident from deteriorating motor behavior. These animals showed extensive loss of dopaminergic neurons, decreased immunoreactivity against anti-TH antibodies and number of TH positive dopaminergic neurons in the nigrostriatal region. Chrysin treated animals showed a significant reduction in motor behavioral changes, degeneration and loss of nigrostriatal dopaminergic neurons and increased immunoreactivity to anti-TH antibody. This study concludes that chrysin confers neuroprotection in rat model of PD. It attenuates the degeneration of the nigrostriatal dopaminergic neurons and motor behavioral abnormalities.


Changes in the expression of splicing factor transcripts and variations in alternative splicing are associated with lifespan in mice and humans.
Dysregulation of splicing factor expression and altered alternative splicing are associated with aging in humans and other species, and also with replicative senescence in cultured cells. Here, we assess whether expression changes of key splicing regulator genes and consequent effects on alternative splicing are also associated with strain longevity in old and young mice, across 6 different mouse strains with varying lifespan (A/J, NOD.B10Sn-H2(b) /J, PWD.Phj, 129S1/SvlmJ, C57BL/6J and WSB/EiJ). Splicing factor expression and changes to alternative splicing were associated with strain lifespan in spleen and to a lesser extent in muscle. These changes mainly involved hnRNP splicing inhibitor transcripts with most changes more marked in spleens of young animals from long-lived strains. Changes in spleen isoform expression were suggestive of reduced cellular senescence and retained cellular proliferative capacity in long-lived strains. Changes in muscle isoform expression were consistent with reduced pro-inflammatory signalling in longer-lived strains. Two splicing regulators, HNRNPA1 and HNRNPA2B1, were also associated with parental longevity in humans, in the InCHIANTI aging study. Splicing factors may represent a driver, mediator or early marker of lifespan in mouse, as expression differences were present in the young animals of long-lived strains. Changes to alternative splicing patterns of key senescence genes in spleen and key remodelling genes in muscle suggest that correct regulation of alternative splicing may enhance lifespan in mice. Expression of some splicing factors in humans was also associated with parental longevity, suggesting that splicing regulation may also influence lifespan in humans.


Contrasting disease and nondisease protein aggregation by molecular simulation.
[Figurre: see text]. Protein aggregation can be defined as the sacrifice of stabilizing intrachain contacts of the functional state that are replaced with interchain contacts to form non-functional states. The resulting aggregate morphologies range from amorphous structures without long-range order typical of nondisease proteins involved in inclusion bodies to highly structured fibril assemblies typical of amyloid disease proteins. In this Account, we describe the development and application of computational models for the investigation of nondisease and disease protein aggregation as illustrated for the proteins L and G and the Alzheimer's Abeta systems. In each case, we validate the models against relevant experimental observables and then expand on the experimental window to better elucidate the link between molecular properties and aggregation outcomes. Our studies show that each class of protein exhibits distinct aggregation mechanisms that are dependent on protein sequence, protein concentration, and solution conditions. Nondisease proteins can have native structural elements in the denatured state ensemble or rapidly form early folding intermediates, which offers avenues of protection against aggregation even at relatively high concentrations. The possibility that early folding intermediates may be evolutionarily selected for their protective role against unwanted aggregation could be a useful strategy for reengineering sequences to slow aggregation and increase folding yield in industrial protein production. The observed oligomeric aggregates that we see for nondisease proteins L and G may represent the nuclei for larger aggregates, not just for large amorphous inclusion bodies, but potentially as the seeds of ordered fibrillar aggregates, since most nondisease proteins can form amyloid fibrils under conditions that destabilize the native state. By contrast, amyloidogenic protein sequences such as Abeta 1-40,42 and the familial Alzheimer's disease (FAD) mutants favor aggregation into ordered fibrils once the free-energy barrier for forming a critical nucleus is crossed. However, the structural characteristics and oligomer size of the soluble nucleation species have yet to be determined experimentally for any disease peptide sequence, and the molecular mechanism of polymerization that eventually delineates a mature fibril is unknown. This is in part due to the limited experimental access to very low peptide concentrations that are required to characterize these early aggregation events, providing an opportunity for theoretical studies to bridge the gap between the monomer and fibril end points and to develop testable hypotheses. Our model shows that Abeta 1-40 requires as few as 6-10 monomer chains (depending on sequence) to begin manifesting the cross-beta order that is a signature of formation of amyloid filaments or fibrils assessed in dye-binding kinetic assays. The richness of the oligomeric structures and viable filament and fibril polymorphs that we observe may offer structural clues to disease virulence variations that are seen for the WT and hereditary mutants.


Initial excited-state relaxation of the bilin chromophores of phytochromes: a computational study.
The geometric relaxation following light absorption of the biliverdin, phycocyanobilin and phytochromobilin tetrapyrrole chromophores of bacterial, cyanobacterial and plant phytochromes has been investigated using density functional theory methods. Considering stereoisomers relevant for both red-absorbing Pr and far-red-absorbing Pfr forms of the photoreceptor, it is found that the initial excited-state evolution is dominated by torsional motion at the C10-C11 bond. This holds true for all three chromophores and irrespective of which configuration the chromophores adopt. This finding suggests that the photochromic cycling of phytochromes between their Pr and Pfr forms, which is known to be governed by Z/E photoisomerizations at the C15-C16 bond, relies on interactions between the chromophore and the protein to prevent photoisomerizations at C10-C11. Further, it is found that the uneven distribution of positive charge between the pyrrole rings is a major factor for the photochemical reactivity of the C10-C11 bond.


Type 1 diabetes outcomes: Does distance to clinic matter?
To access care, pediatric type 1 diabetes (T1D) patients living in British Columbia (BC), Canada, travel to the sole tertiary pediatric hospital (BC Children's Hospital; BCCH), or they receive community care from pediatric endocrinologists and/or pediatricians. We sought to determine whether hemoglobin A1C (HbA1C ) and patient-reported outcomes were associated with (1) distance to clinic and (2) tertiary vs community care. Patients were recruited from T1D clinics across BC. Clinical chart review and patient surveys were completed, including the Diabetes Treatment Satisfaction Questionnaire (DTSQ). Clinic type was categorized as tertiary (BCCH) or community, and the travel time to BCCH was categorized as <1 hour, 1 to 2 hours, or >2 hours. There were 189 participants. Age and duration of T1D were similar across groups. Mean number of visits/year for BCCH groups were 2.23, 2.24, and 2.05 for the <1-hour, 1- to 2-hour, and >2-hour groups, respectively, vs 3.26 for the community group. Adjusted mean difference in HbA1C was +0.65% (95% confidence interval [CI]: 0.15, 1.15) and +0.52% (95% CI: 0.02, 1.02) for the BCCH >2-hour group compared to the BCCH <1-hour group and community groups, respectively. Child DTSQ scores were significantly lower in the BCCH >2-hour group compared to the BCCH <1-hour and community groups. Children traveling >2 hours to T1D clinic at BCCH had significantly higher HbA1C values and lower satisfaction with care vs those traveling <1 hour to BCCH and those receiving community care. Access to care closer to home may benefit glycemic control in children with T1D and improve treatment satisfaction. Future research should determine whether these findings can be replicated in other regions.


Structure and activity analyses of Escherichia coli K-12 NagD provide insight into the evolution of biochemical function in the haloalkanoic acid dehalogenase superfamily.
The HAD superfamily is a large superfamily of proteins which share a conserved core domain that provides those active site residues responsible for the chemistry common to all family members. The superfamily is further divided into the four subfamilies I, IIA, IIB, and III, based on the topology and insertion site of a cap domain that provides substrate specificity. This structural and functional division implies that members of a given HAD structural subclass may target substrates that have similar structural characteristics. To understand the structure/function relationships in all of the subfamilies, a type IIA subfamily member, NagD from Escherichia coli K-12, was selected (type I, IIB, and III members have been more extensively studied). The structure of the NagD protein was solved to 1.80 A with R(work) = 19.8% and R(free) = 21.8%. Substrate screening and kinetic analysis showed NagD to have high specificity for nucleotide monophosphates with k(cat)/K(m) = 3.12 x 10(4) and 1.28 x 10(4) microM(-)(1) s(-)(1) for UMP and GMP, respectively. This specificity is consistent with the presence of analogues of NagD that exist as fusion proteins with a nucleotide pyrophosphatase from the Nudix family. Docking of the nucleoside substrate in the active site brings it in contact with conserved residues from the cap domain that can act as a substrate specificity loop (NagD residues 144-149) in the type IIA subfamily. NagD and other subfamily IIA and IIB members show the common trait that substrate specificity and catalytic efficiencies (k(cat)/K(m)) are low (1 x 10(4) M(-)(1) s(-)(1)) and the boundaries defining physiological substrates are somewhat overlapping. The ability to catabolize other related secondary metabolites indicates that there is regulation at the genetic level.


A comparison of visual analogue and numerical rating scale formats for the Lung Cancer Symptom Scale (LCSS): does format affect patient ratings of symptoms and quality of life?
The Lung Cancer Symptom Scale (LCSS), a site-specific health-related quality of life measure for patients with lung cancer, was originally developed using a Visual Analogue Scale (VAS) format. However, the VAS format is not readily compatible with data management and software programs using scanning. The primary aim of this study was to evaluate the convergence of ratings obtained with a Numerical Rating Scale (NRS), with an 11-pt response category format, to those obtained with a VAS format. The intent was to determine the degree of agreement between two formats to generalize the existing psychometric properties for the original measure to the new presentation. This methodological study evaluated the feasibility, reliability, and validity of a NRS format for the LCSS. The study was conducted at two cancer centers in New York City. PATIENTS/PROCEDURES: Sixty-eight patients with non-small cell lung cancer (NSCLC) completed both versions of the LCSS along with demographic and feasibility questions on a single occasion. The VAS form was administered first, followed by the NRS form to prevent bias. The intraclass correlation coefficient (ICC), Lin's concordance correlation coefficient (CCC), and Bland-Altman plots were used to evaluate agreement and to characterize bias. Cronbach's alpha for the NRS format total score was 0.89 for the 68 patients with NSCLC. Agreement was excellent, with both the ICC and CCC > or = 0.90 for the two summary scores (total score and average symptom burden index) for the LCSS. Only five of the nine individual items showed this level of strict agreement. An agreement criterion of > or = 0.80 (representing excellent) was observed for seven of the nine individual items (all but appetite loss and hemoptysis). Mean differences tended to be slightly lower for the VAS format compared to the NRS format (more so for the appetite and hemoptysis items), with evidence of scale shift for the same two items. The summary measures showed good concordance as measured by the ICC and CCC, but did display mean differences (VAS - NRS) of -2.7 and -3.1, respectively. Overall, the NRS format for the LCSS suitable for scanning has good feasibility, reliability (internal consistency), and convergent validity. The complete set of concordance evaluation measures supports the reproducibility of VAS scores by NRS scores, particularly for the two summary scores.


Phase I and pharmacokinetic study of sunitinib in pediatric patients with refractory solid tumors: a children's oncology group study.
Sunitinib is an oral multitargeted receptor tyrosine kinase inhibitor. The purpose of this study was to determine the recommended phase 2 dose, pharmacokinetics, pharmacodynamic effects, and preliminary antitumor activity of sunitinib in a pediatric population. Patients who were 2 to 21 years of age with refractory solid tumors were eligible if they had measurable or evaluable disease and met baseline organ function requirements. Patients received sunitinib once daily for 28 days followed by a 14-day break between each cycle. Dose levels of 15 and 20 mg/m(2)/d were evaluated, with dose escalation based on a 3 + 3 design. Sunitinib pharmacokinetics and biomarkers of angiogenesis were also evaluated during the first cycle. Twenty-three patients were treated (median age 13.9 years; range, 3.9-20.6 years). The most common toxicities were neutropenia, thrombocytopenia, elevated liver transaminases, gastrointestinal symptoms, and fatigue. Two patients developed dose-limiting reductions in cardiac ejection fraction prompting a protocol amendment to exclude patients with previous exposure to anthracyclines or cardiac radiation. In patients without these cardiac risk factors, the maximum tolerated dose (MTD) was 15 mg/m(2)/d. Steady-state plasma concentrations were reached by day 7. No objective responses were observed. Four patients with sarcoma and glioma had stable disease for 2 to 9 cycles. Cardiac toxicity precluded determination of a recommended dose for pediatric patients with previous anthracycline or cardiac radiation exposure. The MTD of sunitinib for patients without risk factors for cardiac toxicity is 15 mg/m(2)/d for 28 days followed by a 14-day break.


EnzyMiner: automatic identification of protein level mutations and their impact on target enzymes from PubMed abstracts.
A better understanding of the mechanisms of an enzyme's functionality and stability, as well as knowledge and impact of mutations is crucial for researchers working with enzymes. Though, several of the enzymes' databases are currently available, scientific literature still remains at large for up-to-date source of learning the effects of a mutation on an enzyme. However, going through vast amounts of scientific documents to extract the information on desired mutation has always been a time consuming process. In this paper, therefore, we describe an unique method, termed as EnzyMiner, which automatically identifies the PubMed abstracts that contain information on the impact of a protein level mutation on the stability and/or the activity of a given enzyme. We present an automated system which identifies the abstracts that contain an amino-acid-level mutation and then classifies them according to the mutation's effect on the enzyme. In the case of mutation identification, MuGeX, an automated mutation-gene extraction system has an accuracy of 93.1% with a 91.5 F-measure. For impact analysis, document classification is performed to identify the abstracts that contain a change in enzyme's stability or activity resulting from the mutation. The system was trained on lipases and tested on amylases with an accuracy of 85%. EnzyMiner identifies the abstracts that contain a protein mutation for a given enzyme and checks whether the abstract is related to a disease with the help of information extraction and machine learning techniques. For disease related abstracts, the mutation list and direct links to the abstracts are retrieved from the system and displayed on the Web. For those abstracts that are related to non-diseases, in addition to having the mutation list, the abstracts are also categorized into two groups. These two groups determine whether the mutation has an effect on the enzyme's stability or functionality followed by displaying these on the web.


Interactions between nutrition and reproduction in the management of the mature male ruminant.
In mature male sheep and goats, changes in feed intake seem to have little effect on gonadal endocrine function but induce profound changes on sperm production. These outcomes are due to changes in size of the seminiferous tubules and in spermatogenic efficiency. Except with severe underfeeding, there are only minor changes in the endocrine function of the testis (testosterone production) unless season-long treatments are imposed. For cattle, nutrition clearly affects testicular development and the production of spermatozoa in young bulls, as it does in other species but, after the period of rapid growth has ended, there appears to be little or no response to nutrition. We are developing a clear picture of the metabolic signals, neuroendocrine processes and hormonal control systems that are involved, particularly for the mature male sheep. The energetic components of the diet, rather than protein, seem to be responsible, so we have envisaged a model of the relationship between energy balance and reproduction that has 4 'dimensions': genotype, structure (organs), communication (chemical and neural signals, nutrient sensing) and time (dynamics, metabolic memory, programming). We have linked these perspectives to 'resource allocation theory' and incorporated them into strategies for 'clean, green and ethical animal production'. In contrast to the clear outcomes with respect to spermatogenesis, the effects of nutrition on sexual behaviour are more difficult to define, perhaps because the behaviour is affected by a complex mix of physiological factors and because of flawed methods for quantifying male behaviour. For example, sexual behaviour is compromised by severe feed restriction, but male sexual behaviour requires intensive motor activity so a decline in libido could be caused by general weakness rather than specific nutritional limitations. The interaction between sexual activity and feeding behaviour also complicates the issue under field conditions. At the other end of the scale, overweight males can show reduced sexual success because they have difficulty courting and mounting. For this reason, exercise can enhance the fertilising capacity of rams. This will be important in extensive mating systems where males need to assemble and guard a harem and then mate many times for several weeks. For artificial insemination centres, there seems to be very few data on the nutritional management of males, but problems with overfed animals appear to be a risk. Future research should concentrate on the intra-testicular systems mediating the effects of nutrition on the production of spermatozoa.


A comparison of online versus on-site training in health research methodology: a randomized study.
Distance learning may be useful for building health research capacity. However, evidence that it can improve knowledge and skills in health research, particularly in resource-poor settings, is limited. We compared the impact and acceptability of teaching two distinct content areas, Biostatistics and Research Ethics, through either on-line distance learning format or traditional on-site training, in a randomized study in India. Our objective was to determine whether on-line courses in Biostatistics and Research Ethics could achieve similar improvements in knowledge, as traditional on-site, classroom-based courses. Volunteer Indian scientists were randomly assigned to one of two arms. Students in Arm 1 attended a 3.5-day on-site course in Biostatistics and completed a 3.5-week on-line course in Research Ethics. Students in Arm 2 attended a 3.5-week on-line course in Biostatistics and 3.5-day on-site course in Research Ethics. For the two course formats, learning objectives, course contents and knowledge tests were identical. Improvement in knowledge immediately and 3-months after course completion, compared to baseline. Baseline characteristics were similar in both arms (n = 29 each). Median knowledge score for Biostatistics increased from a baseline of 49% to 64% (p < 0.001) 3 months after the on-site course, and from 48% to 63% (p = 0.009) after the on-line course. For the on-site Research Ethics course, median score increased from 69% to 83% (p = 0.005), and for the on-line Research Ethics course from 62% to 80% (p < 0.001). Three months after the course, median gains in knowledge scores remained similar for the on-site and on-line platforms for both Biostatistics (16% vs. 12%; p = 0.59) and Research Ethics (17% vs. 13%; p = 0.14). On-line and on-site training formats led to marked and similar improvements of knowledge in Biostatistics and Research Ethics. This, combined with logistical and cost advantages of on-line training, may make on-line courses particularly useful for expanding health research capacity in resource-limited settings.


SERS in salt wells.
We report herein a simple, inexpensive fabrication methodology of salt microwells, and define the utility of the latter as nanoparticle containers for highly sensitive surface-enhanced Raman scattering (SERS) studies. AFM characterization of Ag and Au loaded salt microwells reveal the ability to contain favorable nanostructures such as nanoparticle dimers, which can significantly enhance the Raman intensity of molecules. By performing diffraction-limited confocal Raman microscopy on salt microwells, we show high sensitivity and fidelity in the detection of dyes, peptides, and proteins, as a proof of our concept. The SERS limit of detection (accumulation time of 1 s) for rhodamine B and TAT contained in salt mircowells is 10 pM and 1 nM, respectively. The Raman characterization measurements of salt microwells with three different laser lines (532 nm, 632.81 nm, 785 nm) reveal low background intensity and high signal-to-noise ratio upon nanoparticle loading, which makes them suitable for enhanced Raman detection. SERS mapping of these sub-femtoliter containers show spatial confinement of the relevant analyte to a few microns, which make them potential candidates for microscale bioreactors.


Conceptual framework for behavioral and social science in HIV vaccine clinical research.
HIV vaccine clinical research occurs within a context where biomedical science and social issues are interlinked. Previous HIV vaccine research has considered behavioral and social issues, but often treated them as independent of clinical research processes. Systematic attention to the intersection of behavioral and social issues within a defined clinical research framework is needed to address gaps, such as those related to participation in trials, completion of trials, and the overall research experience. Rigorous attention to these issues at project inception can inform trial design and conduct by matching research approaches to the context in which trials are to be conducted. Conducting behavioral and social sciences research concurrent with vaccine clinical research is important because it can help identify potential barriers to trial implementation, as well as ultimate acceptance and dissemination of trial results. We therefore propose a conceptual framework for behavioral and social science in HIV vaccine clinical research and use examples from the behavioral and social science literature to demonstrate how the model can facilitate identification of significant areas meriting additional exploration. Standardized use of the conceptual framework could improve HIV vaccine clinical research efficiency and relevance.


Evolution and revolution: gauging the impact of technological and technical innovation on Olympic performance.
A number of studies have pointed to a plateauing of athletic performance, with the suggestion that further improvements will need to be driven by revolutions in technology or technique. In the present study, we examine post-war men's Olympic performance in jumping events (pole vault, long jump, high jump, triple jump) to determine whether performance has indeed plateaued and to present techniques, derived from models of human growth, for assessing the impact of technological and technical innovation over time (logistic and double logistic models of growth). Significantly, two of the events involve well-documented changes in technology (pole material in pole vault) or technique (the Fosbury Flop in high jump), while the other two do not. We find that in all four cases, performance appears to have plateaued and that no further "general" improvement should be expected. In the case of high jump, the double logistic model provides a convenient method for modelling and quantifying a performance intervention (in this case the Fosbury Flop). However, some shortcomings are revealed for pole vault, where evolutionary post-war improvements and innovation (fibre glass poles) were concurrent, preventing their separate identification in the model. In all four events, it is argued that further general growth in performance will indeed need to rely predominantly on technological or technical innovation.


Gemcitabine and vinorelbine in recurrent advanced non-small cell lung cancer: sequence does matter.
Gemcitabine and vinorelbine have demonstrated clinical efficacy both as single agents and in combination in patients with metastatic non-small cell lung cancer (NSCLC). This phase II trial evaluated biweekly gemcitabine and vinorelbine in NSCLC patients who have had one prior chemotherapeutic regimen and have had disease progression. Gemcitabine (1,200 mg/m(2) IV over 30 min) was followed by vinorelbine (30 mg/m(2) IV over 6-10 min) on days 1 and 15 of each 28 day cycle. Chemotherapy was given for six cycles unless disease progression or unacceptable toxicity was seen. From 11/1998 to 10/2000, 15 of 20 patients enrolled (6 males, 9 females) were evaluable for response and survival. Two patients had grade 4 neutropenia, and one patient had grade 4 thrombocytopenia. The only non-hematologic grade 3 toxicities were fatigue, phlebitis, and arthralgias. No objective responses were observed, but 11 patients had stable disease for a mean of 6 months. The median survival time was 9.4 months (95% CI = 4.2, 14.8), with a median time to progression of 4.2 months (95% CI = 1.9, 5.6). The 1 year survival was 47%. While this schedule of gemcitabine and vinorelbine was well tolerated, it was felt to be inactive. In vitro and pharmacokinetic studies published after the completion of our trial, suggest gemcitabine followed by vinorelbine may have antagonistic effects leading to lower dose delivery of both drugs. Our study was the only study of gemcitabine and vinorelbine in second-line NSCLC in the literature without an objective response. Our study was the only second-line study that administered gemcitabine prior to vinorelbine. First-line studies in the literature that administered vinorelbine prior to gemcitabine had, on average, a 1.7 month higher median survival (10.0 vs. 8.3 mos; P value <0.001). Because of the lack of response, further studies using this drug sequence, dose, and schedule for gemcitabine and vinorelbine are not recommended.


Optimal prophylactic vaccination in segregated populations: When can we improve on the equalising strategy?
One of the fundamental problems in public health is how to allocate a limited set of resources to have the greatest benefit on the health of the population. This often leads to difficult value judgements about budget allocations. However, one scenario that is directly amenable to mathematical analysis is the optimal allocation of a finite stockpile of vaccine when the population is partitioned into many relatively small cliques, often conceptualised as households. For the case of SIR (susceptible-infectious-recovered) dynamics, analysis and numerics have supported the conjecture that an equalising strategy (which leaves equal numbers of susceptible individuals in each household) is optimal under certain conditions. However, there exists evidence that some of these conditions may be invalid or unsuitable in many situations. Here we consider how well the equalising strategy performs in a range of other scenarios that deviate from the idealised household model. We find that in general the equalising strategy often performs optimally, even far from the idealised case. However, when considering large subpopulation sizes, frequency-dependent transmission and intermediate levels of vaccination, optimality is often achieved through more heterogeneous vaccination strategies.


Signs of mood and anxiety disorders in chimpanzees.
In humans, traumatic experiences are sometimes followed by psychiatric disorders. In chimpanzees, studies have demonstrated an association between traumatic events and the emergence of behavioral disturbances resembling posttraumatic stress disorder (PTSD) and depression. We addressed the following central question: Do chimpanzees develop posttraumatic symptoms, in the form of abnormal behaviors, which cluster into syndromes similar to those described in human mood and anxiety disorders? In phase 1 of this study, we accessed case reports of chimpanzees who had been reportedly subjected to traumatic events, such as maternal separation, social isolation, experimentation, or similar experiences. We applied and tested DSM-IV criteria for PTSD and major depression to published case reports of 20 chimpanzees identified through PrimateLit. Additionally, using the DSM-IV criteria and ethograms as guides, we developed behaviorally anchored alternative criteria that were applied to the case reports. A small number of chimpanzees in the case studies met DSM-IV criteria for PTSD and depression. Measures of inter-rater reliability, including Fleiss' kappa and percentage agreement, were higher with use of the alternative criteria for PTSD and depression. In phase 2, the alternative criteria were applied to chimpanzees living in wild sites in Africa (n = 196) and chimpanzees living in sanctuaries with prior histories of experimentation, orphanage, illegal seizure, or violent human conflict (n = 168). In phase 2, 58% of chimpanzees living in sanctuaries met the set of alternative criteria for depression, compared with 3% of chimpanzees in the wild (p = 0.04), and 44% of chimpanzees in sanctuaries met the set of alternative criteria for PTSD, compared with 0.5% of chimpanzees in the wild (p = 0.04). Chimpanzees display behavioral clusters similar to PTSD and depression in their key diagnostic criteria, underscoring the importance of ethical considerations regarding the use of chimpanzees in experimentation and other captive settings.


ADAM17 mediates MMP9 expression in lung epithelial cells.
The purposes were to study the role of lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α/nuclear factor-κB (NF-κB) signaling in matrix metalloproteinase 9 (MMP9) expression in A549 cells and to investigate the effects of lentivirus-mediated RNAi targeting of the disintegrin and metalloproteinase 17 (ADAM17) gene on LPS-induced MMP9 expression. MMP9 expression induced by LPS in A549 cells was significantly increased in a dose- and time-dependent manner (p<0.05). Pyrrolidine dithiocarbamate (PDTC) and a TNFR1 blocking peptide (TNFR1BP) significantly inhibited LPS-induced MMP9 expression in A549 cells (p<0.05). TNFR1BP significantly inhibited LPS-induced TNF-α production (p<0.05). Both PDTC and TNFR1BP significantly inhibited the phosphorylation of IκBα and expression of phosphorylation p65 protein in response to LPS (p<0.05), and the level of IκBα in the cytoplasm was significantly increased (p<0.05). Lentivirus mediated RNA interference (RNAi) significantly inhibited ADAM17 expression in A549 cells. Lentivirus-mediated RNAi targeting of ADAM17 significantly inhibited TNF-α production in the supernatants (p<0.05), whereas the level of TNF-α in the cells was increased (p<0.05). Lentiviral ADAM17 RNAi inhibited MMP9 expression, IκBα phosphorylation and the expression of phosphorylation p65 protein in response to LPS (p<0.05). PDTC significantly inhibited the expression of MMP9 and the phosphorylation of IκBα, as well as the expression of phosphorylation p65 protein in response to TNF-α (p<0.05). Lentiviral RNAi targeting of ADAM17 down-regulates LPS-induced MMP9 expression in lung epithelial cells via inhibition of TNF-α/NF-κB signaling.


Strategic design to create HER2-targeting proteins with target-binding peptides immobilized on a fibronectin type III domain scaffold.
Tumor-binding peptides such as human epidermal growth factor receptor 2 (HER2)-binding peptides are attractive therapeutic and diagnostic options for cancer. However, the HER2-binding peptides (HBPs) developed thus far are susceptible to proteolysis and lose their affinity to HER2 in vivo. In this report, a method to create a HER2-binding fluctuation-regulated affinity protein (HBP-FLAP) consisting of a fibronectin type III domain (FN3) scaffold with a structurally immobilized HBP is presented. HBPs were selected by phage-library screening and grafted onto FN3 to create FN3-HBPs, and the HBP-FLAP with the highest affinity (HBP sequence: YCAHNM) was identified after affinity maturation of the grafted HBP. HBP-FLAP containing the YCAHNM peptide showed increased proteolysis-resistance, binding to HER2 with a dissociation constant (K D) of 58 nM in ELISA and 287 nM in biolayer interferometry and specifically detects HER2-expressing cancer cells. In addition, HBP-FLAP clearly delineated HER2-expressing tumors with a half-life of 6 h after intravenous injection into tumor-bearing mice. FN3-based FLAP is an excellent platform for developing target-binding small proteins for clinical applications.


Characteristics of HIV-infected adolescents enrolled in a disclosure intervention trial in western Kenya.
Knowledge of one's own HIV status is essential for long-term disease management, but there are few data on how disclosure of HIV status to infected children and adolescents in sub-Saharan Africa is associated with clinical and psychosocial health outcomes. We conducted a detailed baseline assessment of the disclosure status, medication adherence, HIV stigma, depression, emotional and behavioral difficulties, and quality of life among a cohort of Kenyan children enrolled in an intervention study to promote disclosure of HIV status. Among 285 caregiver-child dyads enrolled in the study, children's mean age was 12.3 years. Caregivers were more likely to report that the child knew his/her diagnosis (41%) compared to self-reported disclosure by children (31%). Caregivers of disclosed children reported significantly more positive views about disclosure compared to caregivers of non-disclosed children, who expressed fears of disclosure related to the child being too young to understand (75%), potential psychological trauma for the child (64%), and stigma and discrimination if the child told others (56%). Overall, the vast majority of children scored within normal ranges on screenings for behavioral and emotional difficulties, depression, and quality of life, and did not differ by whether or not the child knew his/her HIV status. A number of factors were associated with a child's knowledge of his/her HIV diagnosis in multivariate regression, including older age (OR 1.8, 95% CI 1.5-2.1), better WHO disease stage (OR 2.5, 95% CI 1.4-4.4), and fewer reported caregiver-level adherence barriers (OR 1.9, 95% CI 1.1-3.4). While a minority of children in this cohort knew their HIV status and caregivers reported significant barriers to disclosure including fears about negative emotional impacts, we found that disclosure was not associated with worse psychosocial outcomes.


The natural history of disease expression in CD4 and CD8 gene-deleted New Zealand black (NZB) mice.
CD4 and CD8 gene-deleted New Zealand black (NZB) mice and, as controls, B6.CD4 -/-, B6.CD8 -/-, NZB, and B6 wild-type (wt) mice were studied for phenotypic and immunologic parameters to determine the contribution of CD4 and CD8 cell lineages in NZB mice. These studies suggest surprisingly that a number of abnormalities are not due to either CD4+ or CD8+ cell lineages but rather are most likely due to non-CD4+ and -CD8+ cell lineages and/or background genes. Such abnormalities include altered thymic architecture, decreased staining of MITS 33+ medullary thymocytes, and an increased frequency of splenic IgM secretory cells. In contrast, deletion of either CD4+ or CD8+ cells appears to differentially influence immunologic function. Deletion of CD8+ cells did not influence titers of spontaneously occurring anti-erythrocyte or anti-DNA autoantibodies. interestingly, 50% of NZB.CD4 -/- mice contained levels of anti-erythrocyte IgG and anti-ssDNA IgM autoantibodies; even without detectable CD4+ cells. Such deletion of CD4+ cells, while leading to marked decreases in the prototype cytokines that characterize Th1 and Th2 subsets in B6 mice, led to a marked increase in IFN-gamma and a moderate increase in IL-4 mRNA levels in NZB.CD4 -/- mice. These data suggest that whereas non-CD4+ and -CD8+ cell lineages and NZB background genes have a marked influence in the development of autoimmune abnormalities, CD4+ cells appear to play a major role in influencing the cytokine environment, whereas CD8+ cells appear to play a minor role.


TIME management by medicinal larvae.
Wound bed preparation (WBP) is an integral part of the care programme for chronic wounds. The acronym TIME is used in the context of WBP and describes four barriers to healing in chronic wounds; namely, dead Tissue, Infection and inflammation, Moisture imbalance and a non-migrating Edge. Larval debridement therapy (LDT) stems from observations that larvae of the blowfly Lucilia sericata clean wounds of debris. Subsequent clinical studies have proven debriding efficacy, which is likely to occur as a result of enzymatically active alimentary products released by the insect. The antimicrobial, anti-inflammatory and wound healing activities of LDT have also been investigated, predominantly in a pre-clinical context. This review summarises the findings of investigations into the molecular mechanisms of LDT and places these in context with the clinical concept of WBP and TIME. It is clear from these findings that biotherapy with L. sericata conforms with TIME, through the enzymatic removal of dead tissue and its associated biofilm, coupled with the secretion of defined antimicrobial peptides. This biotherapeutic impact on the wound serves to reduce inflammation, with an associated capacity for an indirect effect on moisture imbalance. Furthermore, larval serine proteinases have the capacity to alter fibroblast behaviour in a manner conducive to the formation of granulation tissue.


Activation of replication origins in phi29-related phages requires the recognition of initiation proteins to specific nucleoprotein complexes.
Protein p6 of Bacillus subtilis phage phi29 activates the initiation of viral DNA replication by forming a multimeric nucleoprotein complex at the origins of replication, located at both ends of the linear genome. This activation requires a precise positioning of the protein p6 array with respect to the initiation site. To investigate this activation mechanism, we have purified the phi29 protein p6 counterparts from the related phages Nf and GA-1 and analyzed the formation of complexes with DNA. In the homologous protein p6-DNA complexes the phi29 and Nf protein arrays showed an identical positioning, different than that of the GA-1 protein array. In contrast, in the heterologous complexes the protein showed a different arrangement except in the case of the Nf protein-phi29 DNA complex. We have also purified the proteins involved in the initiation of replication (terminal protein and DNA polymerase) from phages Nf and GA-1 and measured the ability of the different p6 proteins to activate homologous and heterologous replication origins. The results obtained indicate that the activation requires not only the formation of a specific nucleoprotein complex but also its specific recognition by the proteins involved in the initiation of DNA replication.


Improving stopping construction to minimize leakage.
The proper sealing of stoppings is an important step in reducing leakage from the intake to the return airways. Leakage and the subsequent loss of ventilation resulting from improperly sealed stoppings can lead to unhealthy and unsafe working conditions. The research presented in this paper investigates the total leakage of a stopping, including air leakage through the stopping, at the stopping perimeter, and through the coalbed. The study also examines sealing considerations for stoppings that are constructed under roof control screen, the effects that wooden wedges had on inhibiting efficient application of polyurethane foam sealant, and airflow leakage through the surrounding coal. The work involved building a stopping in a dead end room of the NIOSH Safety Research Coal Mine and then pressurising the room using compressed air. Stopping leakage was evaluated by measuring air pressure loss in the enclosed room due to the air leakage. Part of the research utilises a diluted soap solution that was applied to the stopping and the surrounding coal to detect air leakage signified by bubble formations. The results show that stopping leakage can be minimised with proper sealing.


Lymphoma of the nasal cavity and paranasal sinuses: A case series.
Lymphomas of the sinonasal tract are a rare and heterogeneous subset of solid sinonasal neoplasms. To characterize, in this case series, presenting symptoms, treatment modalities, and outcomes for patients with sinonasal lymphoma within a single institution. Retrospective patient data were collected from an academic, oncologic center and entered into a repository designed to capture outcomes for sinonasal malignancies. Patient demographics, presenting symptoms, imaging findings, treatment modalities, and health status were retrospectively extrapolated and evaluated by using Kaplan-Meier estimations for survival probability. Patients with sinonasal lymphoma with a mean follow-up of 50 months were identified (n = 18). Histologic diagnosis included the following: diffuse large B-cell lymphoma (n = 9), natural killer/T-cell lymphoma (n = 5), follicular lymphoma (n = 1), T-cell lymphoma (n = 1), and lymphoma-not otherwise specified (n = 2). The most frequent presenting symptoms were nasal obstruction (78%), facial pain (72%), facial swelling (50%), and nasal discharge (44%). Treatment before lymphoma diagnosis included antibiotics (83%), oral steroids (22%), decongestants (22%), and topical steroids (11%). Treatment regimens after diagnosis included both chemotherapy (94%) and chemoradiotherapy (56%). Survival rates by lymphoma subtype were 56% for B-cell lymphoma and 40% for natural killer/T-cell lymphoma. Overall, 2- and 5-year survival rates were 67% and 50%, respectively. The combination of chemotherapy and radiation resulted in significantly higher survival rates (p ≤ 0.001) than chemotherapy alone. Sinonasal lymphomas are characterized by meager survival rates, which differ by histopathologic subtype. The diagnosis of sinonasal lymphoma is challenging because symptoms frequently parallel those of chronic rhinosinusitis. Increased awareness of these rare malignancies may improve detection and more timely treatment. Clinical trial registration NCT01332136.


Induction of Hair Keratins Expression by an Annurca Apple-Based Nutraceutical Formulation in Human Follicular Cells.
Hair disorders may considerably impact the social and psychological well-being of an individual. Recent advances in the understanding the biology of hair have encouraged the research and development of novel and safer natural hair growth agents. In this context, we have previously demonstrated-at both preclinical and clinical level-that an Annurca apple-based dietary supplement (AMS), acting as a nutraceutical, is endowed with an intense hair-inductive activity (trichogenicity), at once increasing hair tropism and keratin content. Herein, in the framework of preclinical investigations, new experiments in primary human models of follicular keratinocytes and dermal papilla cells have been performed to give an insight around AMS biological effects on specific hair keratins expression. As well as confirming the biocompatibility and the antioxidant proprieties of our nutraceutical formulation, we have proven an engagement of trichokeratins production underlying its biological effects on human follicular cells. Annurca apples are particularly rich in oligomeric procyanidins, natural polyphenols belonging to the broader class of bioflavonoids believed to exert many beneficial health effects. To our knowledge, none of the current available remedies for hair loss has hitherto shown to stimulate the production of hair keratins so clearly.


Evidence for apoptotic cell death in Huntington disease and excitotoxic animal models.
Huntington disease (HD) is an inherited neurodegenerative disorder characterized by selective death of striatal medium spiny neurons. Intrastriatal injections of glutamate receptor agonists (excitotoxins) recapitulate some neuropathological features of this disorder. Although this model suggests that excitotoxic injury may be involved in HD, the exact mechanisms of cell death in HD and its models are unknown. The present study was designed to test the hypothesis that HD can develop via the activation of an apoptotic mechanism of cell death and to examine whether excitotoxic striatal lesions with quinolinic acid in rats represent accurate models of HD. To characterize cell death, we employed DNA electrophoresis, electron microscopy (EM), and the terminal transferase-mediated (TdT) deoxyuridine triphosphate (d-UTP)-biotin nick end labeling (TUNEL) method for the in situ detection of DNA strand breaks. In the neostriatum of individuals with HD, patterns of distribution of TUNEL-positive neurons and glia were reminiscent of those seen in apoptotic cell death during normal development of the nervous system; in the same areas, nonrandom DNA fragmentation was detected occasionally. Following excitotoxic injury of the rat striatum, internucleosomal DNA fragmentation (evidence of apoptosis) was seen at early time intervals and random DNA fragmentation (evidence of necrosis) at later time points. In addition, EM detected necrotic profiles of medium spiny neurons in the lesioned rats. In concert, these results suggest that apoptosis occurs in both HD and excitotoxic animal models and that apoptotic and necrotic mechanisms of neuronal death may occur simultaneously within individual dying cells in the excitotoxically injured brain. However, the distribution of dying neurons in the neostriatum, the degree of glial degeneration, and the involvement of striatofugal pathways are very different between HD and excitotoxically damaged striatum. The present study suggests that multiple methods should be employed for a proper characterization of neuronal cell death in vivo.


Current treatments of isolated articular cartilage lesions of the knee achieve similar outcomes.
Many surgical techniques, including microfracture, periosteal and perichondral grafts, chondrocyte transplantation, and osteochondral grafts, have been studied in an attempt to restore damaged articular cartilage. However, there is no consensus regarding the best method to repair isolated articular cartilage defects of the knee. We compared postoperative functional outcomes, followup MRI appearance, and arthroscopic examination after microfracture (MF), osteochondral autograft transplantation (OAT), or autologous chondrocyte implantation (ACI). We prospectively investigated 30 knees with MF, 22 with OAT, and 18 with ACI. Minimum followup was 3 years (mean, 5 years; range, 3-10 years). We included only patients with isolated cartilage defects and without other knee injuries. The three procedures were compared in terms of function using the Lysholm knee evaluation scale, Tegner activity scale, and Hospital for Special Surgery (HSS) score; modified Outerbridge cartilage grades using MRI; and International Cartilage Repair Society (ICRS) repair grade using arthroscopy. All three procedures showed improvement in functional scores. There were no differences in functional scores and postoperative MRI grades among the groups. Arthroscopy at 1 year showed excellent or good results in 80% after MF, 82% after OAT, and 80% after ACI. Our study did not show a clear benefit of either ACI or OAT over MF. Owing to a lack of superiority of any one treatment, we believe MF is a reasonable option as a first-line therapy given its ease and affordability relative to ACI or OAT. Level II, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.


Metabolomics approach based on NMR spectroscopy and multivariate data analysis to explore the interaction between the leafminer Tuta absoluta and tomato (Solanum lycopersicum).
Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae) is one of the most devastating and harmful pests of tomato (Solanum lycopersicum) crops causing up to 80-100% yield losses. A large arsenal of plant metabolites is induced by the leafminer feeding including defence compounds that could differ among varieties. To compare the metabolomic changes of different genotypes of tomato (tolerant "T", susceptible "S" and "F1" hybrid obtained between T and S) after exposition to T. absoluta. Nuclear magnetic resonance (NMR) spectroscopy followed by multivariate data analysis were performed to analyse the metabolic profiles of control and infested samples on three different tomato genotypes. Signals related to GABA (γ-aminobutyric acid) were relatively much higher in all infested samples compared to the non-infested plants used as control. Infested T genotype samples were the most abundant in organic acids, including fatty acids and acyl sugars, chlorogenic acid, neo-chlorogenic acid and feruloyl quinic acid, indicating a clear link between the exposure to leafminer. Results also showed an increase of trigonelline in all tomato varieties after exposition to T. absoluta. Metabolomics approach based on NMR spectroscopy followed by multivariate data analysis allowed for a detailed metabolite profile of plant defences, providing fundamental information for breeding programmes in plant crops.


Identification of a Master Regulator of Differentiation in Toxoplasma.
Toxoplasma gondii chronically infects a quarter of the world's population, and its recrudescence can cause life-threatening disease in immunocompromised individuals and recurrent ocular lesions in the immunocompetent. Acute-stage tachyzoites differentiate into chronic-stage bradyzoites, which form intracellular cysts resistant to immune clearance and existing therapies. The molecular basis of this differentiation is unknown, despite being efficiently triggered by stresses in culture. Through Cas9-mediated screening and single-cell profiling, we identify a Myb-like transcription factor (BFD1) necessary for differentiation in cell culture and in mice. BFD1 accumulates during stress and its synthetic expression is sufficient to drive differentiation. Consistent with its function as a transcription factor, BFD1 binds the promoters of many stage-specific genes and represents a counterpoint to the ApiAP2 factors that dominate our current view of parasite gene regulation. BFD1 provides a genetic switch to study and control Toxoplasma differentiation and will inform prevention and treatment of chronic infections.


Anti-shock actions of a new converting enzyme inhibitor, enalaprilic acid, in hemorrhagic shock in cats.
A new angiotensin converting enzyme inhibitor, enalaprilic acid (MK-422), was given in a bolus of 0.5 mg/kg i.v., followed by an infusion of 0.25 mg/kg/hr to determine its effects in hemorrhagic shock. MK-422 produced no significant hemodynamic effects in sham shock controls, yet it effectively blocked the pressor effect of exogenously administered angiotensin I throughout the 260-min experimental period and reduced angiotensin converting enzyme activity by 90% as determined by radiochemical assay. In vitro studies on cat papillary muscles and pancreatic homogenates revealed no direct inotropic or antiproteolytic effect of enalaprilic acid. Nevertheless, converting enzyme inhibitor treatment maintained postreinfusion mean arterial blood pressure at a significantly higher value (P less than .01) than that of untreated hemorrhaged animals (66 +/- 5 vs. 27 +/- 10 mm Hg, respectively). Superior mesenteric artery flow for hemorrhaged cats was significantly higher (P less than .05) in the treated group both during the end of the oligemic period (6.1 +/- 0.4 vs. 3.8 +/- 0.8 ml/kg/min) and during the postreinfusion period (6.5 +/- 0.7 vs. 1.9 +/- 1.0 ml/kg/min). Moreover, enalaprilic acid blunted the marked rise in plasma cathepsin D (P less than .01) and myocardial depressant factor activities (P less than .01), and plasma amino-nitrogen concentrations (P less than .05) observed in the untreated hemorrhaged cats. These results indicate that enalaprilic acid improved the hemodynamic and metabolic status of cats in hemorrhagic shock.


Dietary protein intake and bone mass in women.
Population-based strategies to combat osteoporosis are urgently needed. The role of nutrition in such strategies has been particularly contentious. We examined the relationship among six key nutrients that are thought to affect bone metabolism and bone mineral density in the axial and appendicular skeleton using data from a population-based study in the northern United States. Data on the dietary intake of calcium, phosphorus, vitamin D, protein, fat, and total energy were obtained from a 7-day dietary record. Bone density measurements were made by dual photon absorptiometry in the lumbar spine and proximal femur, and by single photon absorptiometry in the distal and midradius. Among the 72 premenopausal women studied, there was a statistically significant positive association between protein intake and bone mineral in the distal radius and proximal femur, which was not altered by adjustment for age, weight, and physical activity. Among 218 postmenopausal women, no such relationship was found between protein intake and bone mineral, and the only significant findings in this group were negative associations between fat consumption and bone density in the lumbar spine and radius. Our results suggest that dietary protein intake may be a determinant of the peak bone mass attained by premenopausal white women. The relevance of this finding for the design of population strategies to maximize skeletal growth requires further investigation.


A highway for war and peace: the secretory pathway in plant-microbe interactions.
Secretion of proteins and other molecules is the primary means by which a cell interacts with its surroundings. The overall organization of the secretory system is remarkably conserved among eukaryotes, and many of the components have been investigated in detail in animal models. Plant cells, because of their sessile lifestyle, are uniquely reliant on the secretory pathway to respond to changes in their environments, either abiotic, such as the absence of nutrients, or biotic, such as the presence of predators or pathogens. In particular, most plant pathogens are extracellular, which demands a robust and efficient host secretory system directed at the site of attack. Here, we present a summary of recent advances in our understanding of the molecular details of the secretory pathway during plant-microbe interactions. Secretion is required not only for the delivery of antimicrobial molecules, but also for the biogenesis of cell surface sensors to detect microbes. The deposition of extracellular material is important in the defense against classical bacterial pathogens as well as in the so-called 'non-host' resistance. Finally, boosting the protein secretion capacity is vital for avoiding infection as well as for achieving symbiosis, even though in the latter case, the microbes are engulfed in intracellular compartments. The emerging evidence indicates that secretion provides an essential interface between plant hosts and their associated microbial partners.


Genetics of type 2 diabetes.
After several years of uncertain progress, the stage is now set for a transformation in understanding the genetic landscape of type 2 diabetes. Advances in genome informatics, genotyping technology, and statistical methodology, allied to availability of large-scale clinical material, are having a salutary effect on susceptibility gene discovery. The advent of genuinely genome-wide association scans and the prospects for combining genetics with high-throughput genomics are additional sources of optimism for the future.


Genetics of resistance to race TTKSK of Puccinia graminis f. sp. tritici in Triticum monococcum.
Race TTKSK (or Ug99) of Puccinia graminis f. sp. tritici possesses virulence to several stem rust resistance genes commonly present in wheat cultivars grown worldwide. New variants detected in the race TTKSK lineage further broadened the virulence spectrum. The identification of sources of genetic resistance to race TTKSK and its relatives is necessary to enable the development and deployment of resistant varieties. Accessions of Triticum monococcum, an A-genome diploid wild and cultivated wheat, have previously been characterized as resistant to stem rust. Three resistance genes were identified and introgressed into hexaploid wheat: Sr21, Sr22, and Sr35. The objective of this study was to determine the genetic control and allelic relationships of resistance to race TTKSK in T. monococcum accessions identified through evaluations at the seedling stage. Generation F(2) progeny of 8 crosses between resistant and susceptible accessions and 13 crosses between resistant accessions of T. monococcum were evaluated with race TTKSK and often with North American races, including races QFCSC, TTTTF, and MCCFC. For a selected population segregating for three genes conferring resistance to race TTKSK, F(2:3) progeny were evaluated with races TTKSK, QFCSC, and TTTTF. In that population, we detected two genes conferring resistance to race TTKSK that are different from Sr21, Sr22, and Sr35. One of the new genes was effective to all races tested. The identification of these genes will facilitate the development of varieties with new resistance to race TTKSK.


3D nanopillar optical antenna photodetectors.
We demonstrate 3D surface plasmon photoresponse in nanopillar arrays resulting in enhanced responsivity due to both Localized Surface Plasmon Resonances (LSPRs) and Surface Plasmon Polariton Bloch Waves (SPP-BWs). The LSPRs are excited due to a partial gold shell coating the nanopillar which acts as a 3D Nanopillar Optical Antenna (NOA) in focusing light into the nanopillar. Angular photoresponse measurements show that SPP-BWs can be spectrally coincident with LSPRs to result in a x2 enhancement in responsivity at 1180 nm. Full-wave Finite Difference Time Domain (FDTD) simulations substantiate both the spatial and spectral coupling of the SPP-BW / LSPR for enhanced absorption and the nature of the LSPR. Geometrical control of the 3D NOA and the self-aligned metal hole lattice allows the hybridization of both localized and propagating surface plasmon modes for enhanced absorption. Hybridized plasmonic modes opens up new avenues in optical antenna design in nanoscale photodetectors.


Single-Molecule Fluorescence Microscopy Reveals Local Diffusion Coefficients in the Pore Network of an Individual Catalyst Particle.
We used single-molecule fluorescence microscopy to study self-diffusion of a feedstock-like probe molecule with nanometer accuracy in the macropores of a micrometer-sized, real-life fluid catalytic cracking (FCC) particle. Movies of single fluorescent molecules allowed their movement through the pore network to be reconstructed. The observed tracks were classified into three different states by machine learning and all found to be distributed homogeneously over the particle. Most probe molecules (88%) were immobile, with the molecule most likely being physisorbed or trapped; the remainder was either mobile (8%), with the molecule moving inside the macropores, or showed hybrid behavior (4%). Mobile tracks had an average diffusion coefficient of D = 8 × 10-14 ± 1 × 10-13 m2 s-1, with the standard deviation thought to be related to the large range of pore sizes found in FCC particles. The developed methodology can be used to evaluate, quantify and map heterogeneities in diffusional properties within complex hierarchically porous materials.


Stable isotopes confirm a coastal diet for critically endangered Mediterranean monk seals.
Understanding the ecology and behaviour of endangered species is essential for developing effective management and conservation strategies. We used stable isotope analysis to investigate the foraging behaviour of critically endangered Mediterranean monk seals (Monachus monachus) in Greece. We measured carbon and nitrogen isotope ratios (expressed as δ(13)C and δ(15)N values, respectively) derived from the hair of deceased adult and juvenile seals and the muscle of their known prey to quantify their diets. We tested the hypothesis that monk seals primarily foraged for prey that occupy coastal habitats in Greece. We compared isotope values from seal hair to their coastal and pelagic prey (after correcting all prey for isotopic discrimination) and used these isotopic data and a stable isotope mixing model to estimate the proportion of coastal and pelagic resources consumed by seals. As predicted, we found that seals had similar δ(13)C values as many coastal prey species and higher δ(13)C values than pelagic species; these results, in conjunction with mean dietary estimates (coastal=61 % vs. pelagic=39 %), suggest that seals have a diverse diet comprising prey from multiple trophic levels that primarily occupy the coast. Marine resource managers should consider using the results from this study to inform the future management of coastal habitats in Greece to protect Mediterranean monk seals.


A high-resolution gridded dataset to assess electrification in sub-Saharan Africa.
Spatially explicit data on electricity access and use are essential for effective policy-making and infrastructure planning in low-income, data-scarce regions. We present and validate a 1-km resolution electricity access dataset covering sub-Saharan Africa built on gridded nighttime light, population, and land cover data. Using light radiance probability distributions, we define electricity consumption tiers for urban and rural areas and estimate the by-tier split of consumers living in electrified areas. The approach provides new insight into the spatial distribution and temporal evolution of electricity access, and a measure of its quality beyond binary access. We find our estimates to be broadly consistent with recently published province- and national-level statistics. Moreover, we demonstrate consistency between the estimated electricity access quality indicators and survey-based consumption levels defined in accordance with the World Bank Multi-Tier Framework. The dataset is readily reproduced and updated using an open-access scientific computing framework. The data and approach can be applied for improving the assessment of least-cost electrification options, and examining links between electricity access and other sustainable development objectives.


James Watson's most inconvenient truth: race realism and the moralistic fallacy.
Recent editorials in this journal have defended the right of eminent biologist James Watson to raise the unpopular hypothesis that people of sub-Saharan African descent score lower, on average, than people of European or East Asian descent on tests of general intelligence. As those editorials imply, the scientific evidence is substantial in showing a genetic contribution to these differences. The unjustified ill treatment meted out to Watson therefore requires setting the record straight about the current state of the evidence on intelligence, race, and genetics. In this paper, we summarize our own previous reviews based on 10 categories of evidence: The worldwide distribution of test scores; the g factor of mental ability; heritability differences; brain size differences; trans-racial adoption studies; racial admixture studies; regression-to-the-mean effects; related life-history traits; human origins research; and the poverty of predictions from culture-only explanations. The preponderance of evidence demonstrates that in intelligence, brain size, and other life-history variables, East Asians average a higher IQ and larger brain than Europeans who average a higher IQ and larger brain than Africans. Further, these group differences are 50-80% heritable. These are facts, not opinions and science must be governed by data. There is no place for the "moralistic fallacy" that reality must conform to our social, political, or ethical desires.


A proinflammatory diet is associated with systemic inflammation and reduced kidney function in elderly adults.
Diet can affect kidney health through its effects on inflammation. We tested whether the Adapted Dietary Inflammatory Index (ADII) is associated with kidney function and whether effects of diet on chronic low-grade inflammation explain this association. This was an observational analysis in 1942 elderly community-dwelling participants aged 70-71 y from 2 independent cohorts: the Uppsala Longitudinal Study of Adult Men (n = 1097 men) and the Prospective Investigation of Vasculature in Uppsala Seniors (n = 845 men and women). The ADII was calculated from 7-d food records, combining putatively proinflammatory and anti-inflammatory effects of nutrients, vitamins, and trace elements. The ADII was validated against serum C-reactive protein (CRP) concentrations. The estimated glomerular filtration rate (eGFR) was assessed from serum cystatin C (cys) and creatinine (crea). Associations between the ADII and eGFR were investigated, and CRP was considered to be a mediator. In adjusted analysis, a 1-SD higher ADII was associated with higher CRP (β: 6%; 95% CI: 1%, 10%; P = 0.01) and lower eGFR [Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)cys: -2.1%; 95% CI: -3.2%, -1.1%; CKD-EPIcys+crea: -1.8%; 95% CI: -2.7%, -0.9%; both P < 0.001]. CRP was also inversely associated with eGFR. Mediation analyses showed that of the total effect of the ADII on kidney function, 15% and 17% (for CKD-EPIcys+crea and CKD-EPIcys equations, respectively) were explained/mediated by serum CRP. Findings were similar when each cohort was analyzed separately. A proinflammatory diet was associated with systemic inflammation as well as with reduced kidney function in a combined analysis of 2 community-based cohorts of elderly individuals. Our results also suggest systemic inflammation to be one potential pathway through which this dietary pattern is linked to kidney function.


High-speed digital-image correlation method.
Provided that the software and hardware equipment in a digital-image correlation method is unchanged, the only major factor affecting integer-pixel correlation computation precision and the integer-pixel processing time is the size of the computing window. The bigger the size of the computing window is, the more reliable the computation result is. However, a bigger computing window means longer processing time. For reduction of the integer-pixel processing time without affecting the reliability of the result, a two-step correlation computation method (which uses a small window and a big window in the correlation computation) is proposed. The experiment results confirm the validity of the new method, and the total processing time of this method can be approximately reduced to a twentieth of that of the traditional method.


Oncostatin M induces IL-33 expression in liver endothelial cells in mice and expands ST2+CD4+ lymphocytes.
Interleukin (IL)-33 is crucially involved in liver pathology and drives hepatoprotective functions. However, the regulation of IL-33 by cytokines of the IL-6 family, including oncostatin M (OSM) and IL-6, is not well studied. The aim of the present study was to determine whether OSM mediates regulation of IL-33 expression in liver cells. Intramuscular administration in mice of an adenovirus encoding OSM (AdOSM) leads to increase in expression of OSM in muscles, liver, and serum of AdOSM-infected mice compared with control mice. The increase of circulating OSM markedly regulated mRNA of genes associated with blood vessel biology, chemotaxis, cellular death, induction of cell adhesion molecules, and the alarmin cytokine IL-33 in liver. Steady-state IL-33 mRNA was upregulated by OSM at an early phase (8 h) following AdOSM infection. At the protein level, the expression of IL-33 was significantly induced in liver endothelial cells [liver sinusoidal endothelial cells (LSEC) and vascular endothelial cells] with a peak at 8 days post-AdOSM infection in mice. In addition, we found OSM-stimulated human microvascular endothelial HMEC-1 cells and human LSEC/TRP3 cells showed a significant increase in expression of IL-33 mRNA in a dose-dependent manner in cell culture. The OSM-mediated overexpression of IL-33 was associated with the activation/enrichment of CD4(+)ST2(+) cells in liver of AdOSM-infected mice compared with adenovirus encoding green fluorescent protein-treated control mice. In summary, these data suggest that the cytokine OSM regulates the IL-33 expression in liver endothelial cells in vivo and in HMEC-1/TRP3 cells in vitro and may specifically expand the target CD4(+)ST2(+) cells in liver.


Incidence, aetiology and outcomes of obstetric-related acute kidney injury in Malawi: a prospective observational study.
Obstetric-related acute kidney injury (AKI) is thought to be a key contributor to the overall burden of AKI in low resource settings, causing significant and preventable morbidity and mortality. However, epidemiological data to corroborate these hypotheses is sparse. This prospective observational study aims to determine the incidence, aetiology and maternal-fetal outcomes of obstetric-related AKI in Malawi. Women greater than 20 weeks gestation or less than 6 weeks postpartum admitted to obstetric wards at a tertiary hospital in Blantyre, Malawi, and at high-risk of AKI were recruited between 21st September and 11th December 2015. All participants had serum creatinine tested at enrolment; those with creatinine above normal range (> 82 μmol/L) underwent serial measurement, investigations to determine cause of kidney injury, and were managed by obstetric and nephrology teams. AKI was diagnosed and staged by Kidney Disease Improving Global Outcomes (KDIGO) criteria. Primary outcomes were the incidence proportion and aetiology of AKI. Secondary outcomes were in-hospital maternal mortality, need for dialysis, renal recovery and length of stay; in-hospital perinatal mortality, gestational age at delivery, birthweight and Apgar score. 354 patients were identified at risk of AKI from the approximate 2300 deliveries that occurred during the study period. Three hundred twenty-two were enrolled and 26 (8.1%) had AKI (median age 27 years; HIV 3.9%). The most common primary causes of AKI were preeclampsia/eclampsia (n = 19, 73.1%), antepartum haemorrhage (n = 3, 11.5%), and sepsis (n = 3, 11.5%). There was an association between preeclampsia spectrum and AKI (12.2% AKI incidence in preeclampsia spectrum vs. 4.3% in other patients, p = 0.015). No women with AKI died or required dialysis and complete renal recovery occurred in 22 (84.6%) cases. The perinatal mortality rate across all high-risk admissions was 13.8%. AKI did not impact on maternal or fetal outcomes. The incidence of AKI in high-risk obstetric admissions in Malawi is 8.1% and preeclampsia was the commonest cause. With tertiary nephrology and obstetric care the majority of AKI resolved with no effect on maternal-fetal outcomes. Maternal-fetal outcomes in Sub-Saharan Africa may be improved with earlier detection of hypertensive disease in pregnancy.


Endocrinology of growth.
Growth is a remarkably complex biological phenomenon, requiring the coordinated production of multiple hormones and growth factors. Human growth is characterized by several distinct features, including: (1) rapid growth in late gestation; (2) growth deceleration immediately following birth; (3) a prolonged childhood and a mid-childhood growth spurt; (4) a pubertal growth spurt; (5) relatively late attainment of adult height, and (6) minimal sexual dimorphism of adult stature. Secular changes in the height of humans probably reflect nutritional and environmental factors, rather than major genomic changes. While multiple hormones impact growth, the growth hormone (GH)-insulin-like growth factor (IGF) axis plays a central role in both intrauterine and postnatal growth. GH, after being secreted by the pituitary, binds to a transmembrane receptor and activates a postreceptor signaling cascade, ultimately leading to phosphorylation of signal transducer and activator of transcription (STAT) 5b. STAT5b transcriptionally regulates the genes for IGF-I and for key IGF-binding proteins. IGF-I, in turn, binds to the type 1 IGF receptor, resulting in chondrocyte proliferation and statural growth. IGF-deficient states may be divided into secondary forms, reflecting defects in GH production, and primary forms. Molecular defects of the GH-IGF axis have been identified in humans, with phenotypes that correspond to the specific genetic lesions. Therapy with GH or IGF-I can now be matched to specific defects in the GH-IGF axis.


Imaging evidence for endothelin ETA/ETB receptor heterodimers in isolated rat mesenteric resistance arteries.
In engineered cells, endothelin ETA and ETB receptors can heterodimerize. We tested whether this can also be observed in native tissue. Rat mesenteric resistance arteries (rMRA) were maintained in organ culture for 24h to upregulate ETB-mediated contractions in addition to their normal ETA-mediated responses. They were then exposed to 100 nM linear ET-1 (ETB-agonist) labeled with Oregon Green 488 (OG488/L.-ET-1) and/or to 16nM intact ET-1 (ETA/ETB-agonist) labeled with the rhodamine dye TAMRA (TAMRA/ET-1). Two photon laser scanning microscopy (TPLSM) was used for the visualization of their binding in the tissue. Fluorescence Lifetime Imaging Microscopy (FLIM) was employed for measurements of the OG488/L.-ET-1 lifetime in the absence and presence of TAMRA/ET-1. After incubation with the labeled ligands, medial smooth muscle cells (SMCs) were efficiently stained and became visible under TPLSM. TAMRA/ET-1 bound to all SMCs whereas OG488/L.-ET-1 stained only groups of SMCs. Interaction of the two receptor subtypes in SMC was investigated in double staining experiments. Fluorescence lifetime of OG488/L.-ET-1 was reduced in the presence of TAMRA/ET-1, which indicates the occurrence of Fluorescence Resonant Energy Transfer (FRET) and suggests close proximity of the two receptor subtypes within the arterial wall. The methodology that is introduced by these new observations may be useful to assess ET-receptor heterodimerization in biopsies from relevant experimental animal models and human patients.


The clinical perspectives of CDX2 expression in colorectal cancer: a qualitative systematic review.
Homeobox genes are often deregulated in cancer. They can have both oncogenic and tumor-suppressing potential. The Caudal-related homeobox transcription factor 2 (CDX2) is an intestine-specific transcription factor. It is implicated in differentiation, proliferation, cell-adhesion, and migration. CDX2 has been proposed as a tumor suppressor in colorectal cancer but its role is still controversial. This systematic review were undertaken in order to clarify CDX2s role in colorectal cancer. A literature search was performed in the MEDLINE database from 1966 to February 2014. Only studies in which all or a part of the experimental design were performed on human colorectal cancer tissue were included. Thus, studies solely performed in cell-lines or animal models were excluded. Fifty-two articles of relevance were identified. CDX2 expression was rarely lost in colorectal cancers, however the expression pattern may often be heterogeneous within the tumor and can be selectively down regulated at the invasive front and in tumor buddings. Loss of CDX2 expression is probably correlated to tumor grade, stage, right-sided tumor location, MMR-deficiency, CIMP, and BRAF mutations. The CDX2 gene is rarely mutated but the locus harboring the gene is often amplified and may suggest CDX2 as a linage-survival oncogene. CDX2 might be implicated in cell proliferation and migration through cross-talk with the Wnt-signaling pathway, tumor-stroma proteins, and inflammatory cytokines. A clear role for CDX2 expression in colorectal cancer remains to be elucidated, and it might differ in relation to the underlying molecular pathways leading to the cancer formation.


Artificial intelligence-based morphological fingerprinting of megakaryocytes: a new tool for assessing disease in MPN patients.
Accurate diagnosis and classification of myeloproliferative neoplasms (MPNs) requires integration of clinical, morphological, and genetic findings. Despite major advances in our understanding of the molecular and genetic basis of MPNs, the morphological assessment of bone marrow trephines (BMT) is critical in differentiating MPN subtypes and their reactive mimics. However, morphological assessment is heavily constrained by a reliance on subjective, qualitative, and poorly reproducible criteria. To improve the morphological assessment of MPNs, we have developed a machine learning approach for the automated identification, quantitative analysis, and abstract representation of megakaryocyte features using reactive/nonneoplastic BMT samples (n = 43) and those from patients with established diagnoses of essential thrombocythemia (n = 45), polycythemia vera (n = 18), or myelofibrosis (n = 25). We describe the application of an automated workflow for the identification and delineation of relevant histological features from routinely prepared BMTs. Subsequent analysis enabled the tissue diagnosis of MPN with a high predictive accuracy (area under the curve = 0.95) and revealed clear evidence of the potential to discriminate between important MPN subtypes. Our method of visually representing abstracted megakaryocyte features in the context of analyzed patient cohorts facilitates the interpretation and monitoring of samples in a manner that is beyond conventional approaches. The automated BMT phenotyping approach described here has significant potential as an adjunct to standard genetic and molecular testing in established or suspected MPN patients, either as part of the routine diagnostic pathway or in the assessment of disease progression/response to treatment.