Novel nanoparticles with Cr3+ substituted ferrite for self-regulating temperature hyperthermia.
For hyperthermia to be used under clinical conditions for cancer therapeutics the temperature regulation needs to be precise and accurately controllable. In the case of the metal nanoparticles used for such activities, a high coercivity is a prerequisite in order to couple more energy in a single heating cycle for efficient and faster differential heating. The chemically stable Co-Zn ferrite nanoparticles have typically not been used in such self-regulating hyperthermia temperature applications to date due to their low Curie temperature usually accompanied by a poor coercivity. The latter physical property limitation under clinically applied magnetic field conditions (frequency: 100 kHz, intensity: 200 Oe) restricts the transfer of a reasonable heat energy, and thus limits the hyperthermia efficiency. Here, we report a novel Cr3+ substituted Co-Zn ferrite (Zn0.54Co0.46Cr0.6Fe1.4O4), whose Curie temperature and coercivity values are 45.7 °C and 174 Oe, respectively. Under clinically acceptable magnetic field conditions, the temperature of these nanoparticle suspensions can be self-regulated to 44.0 °C and, most importantly with a specific absorption rate (SAR) of 774 W kg-1, which is two-fold higher than the SAR standard for magnetic nanoparticles used in hyperthermia (300 W kg-1). The evaluation of the in vitro cytotoxicity of the nanoparticles reports a low toxicity, which points to a novel set of magnetic nanoparticles for use in self-regulating hyperthermia.


Texture Feature Variability in Ultrasound Video of the Atherosclerotic Carotid Plaque.
The objective of this paper was to investigate texture feature variability in ultrasound video of the carotid artery during the cardiac cycle in an attempt to define new discriminatory biomarkers of the vulnerable plaque. More specifically, in this paper, 120 longitudinal ultrasound videos, acquired from 40 normal (N) subjects from the common carotid artery and 40 asymptomatic (A) and 40 symptomatic (S) subjects from the proximal internal carotid artery were investigated. The videos were intensity normalized and despeckled, and the intima-media complex (IMC) (from the N subjects) and the atherosclerotic carotid plaques (from the A and S subjects) were segmented from each video, in order to extract the M-mode image, and the texture features associated with cardiac states of systole and diastole. The main results of this paper can be summarized as follows: 1) texture features varied significantly throughout the cardiac cycle with significant differences identified between the cardiac systolic and cardiac diastolic states; 2) gray scale median was significantly higher at cardiac systole versus diastole for the N, A, and S groups investigated; 3) plaque texture features extracted during the cardiac cycle at the systolic and diastolic states were statistically significantly different between A and S subjects (and can thus be used to discriminate between A and S subjects successfully). The combination of systolic and diastolic features yields better performance than those alone. It is anticipated that the proposed system may aid the physician in clinical practice in classifying between N, A, and S subjects using texture features extracted from ultrasound videos of IMC and carotid artery plaque. However, further evaluation has to be carried out with more videos and additional features.


A symbiotic view of the origin of life at hydrothermal impact crater-lakes.
Submarine hydrothermal vents are generally considered as the likely habitats for the origin and evolution of early life on Earth. The theory suffers from the 'concentration problem' of cosmic and terrestrial biomolecules because of the vastness of the Eoarchean global ocean. An attractive alternative site would be highly sequestered, small, hydrothermal crater-lakes that might have cradled life on early Earth. A new symbiotic model for the origin of life at hydrothermal crater-lakes is proposed here. Meteoritic impacts on the Eoarchean crust at the tail end of the Heavy Bombardment period might have played important roles in the origin of life. Impacts and collisions that created hydrothermal crater lakes on the Eoarchean crust inadvertently became the perfect crucibles for prebiotic chemistry with building blocks of life, which ultimately led to the first organisms by prebiotic synthesis. In this scenario, life arose through four hierarchical stages of increasing molecular complexity in multiple niches of crater basins. In the cosmic stage (≥4.6 Ga), the building blocks of life had their beginnings in the interstellar space during the explosion of a nearby star. Both comets and carbonaceous chondrites delivered building blocks of life and ice to early Earth, which were accumulated in hydrothermal impact crater-lakes. In the geologic stage (∼4 Ga), crater basins contained an assortment of cosmic and terrestrial organic compounds, powered by hydrothermal, solar, tidal, and chemical energies, which drove the prebiotic synthesis. At the water surface, self-assembled primitive lipid membranes floated as a thick oil slick. Archean Greenstone belts in Greenland, Australia, and South Africa possibly represent the relics of these Archean craters, where the oldest fossils of thermophilic life (∼3.5 Ga) have been detected. In the chemical stage, monomers such as nucleotides and amino acids were selected from random assemblies of the prebiotic soup; they were polymerized at pores of mineral surfaces with the coevolution of RNA and protein molecules to form the 'RNA/protein world'. Lipid membranes randomly encapsulated these RNA and protein molecules to initiate a molecular symbiosis in a 'RNA/protein/lipid world' that led to hierarchical emergence of several cell components: plasma membranes, ribosomes, coding RNA and proteins, DNA, and finally protocells with a primitive genetic code. In the biological stage, the emergence of the first cells capable of reproduction, heredity, variation, and Darwinian evolution is the key breakthrough in the origin of life. RNA virus and prions may represent the evolutionary relics of the RNA/protein world that survived as parasites for billions of years. Although the proposed endosymbiotic model is speculative it has intrinsic heuristic value. Future experiments on encapsulated RNA virus and prions have the potential to create a synthetic cell that may confirm a coherent narrative of this hierarchical evolutionary sequence.


Inhibition of indium-111 platelet accretion onto venous thrombi in dogs by prostacyclin.
The known platelet anti-aggregant effects of prostacyclin (epoprostenol) suggest that it may have therapeutic potential in conditions in which the platelet plays a pathophysiological role. The growth of venous thrombi is one such condition. We have attempted to determine, in a canine model of fresh venous thrombosis, whether prostacyclin infusion inhibits platelet accretion in vivo and how this in vivo event related to hemodynamic and in vitro platelet anti-aggregant effects. Gamma camera imaging over thrombi for accretion of indium-111-labeled platelets disclosed that prostacyclin, at an infusion rate of 50 ng/kg per min, inhibited platelet accretion in vivo and resulted in a 95 +/- 4% decrease in in vitro adenosine diphosphate-induced platelet aggregation, and a decrease in mean arterial pressure to 86 +/- 4% of pre-infusion values. Step-wise decrements of prostacyclin infusion demonstrated that platelet accretion occurred in vivo at infusion rates of approximately 10-20 ng/kg per min and correlated with an in vitro adenosine diphosphate-induced aggregation of 54 +/- 13% of control values. Thus, prostacyclin, in a dose that causes only a mild decrease in systemic pressure, can completely inhibit platelet uptake onto fresh venous thrombi in the dog, and this inhibition correlates closely with in vitro adenosine diphosphate-induced platelet aggregation. The potential therapeutic implications of these findings are discussed.


Cases of intestinal intussusception in young fowls.
In a flock of 1017 pullets aged 7 weeks feeding was reduced from 2 to 0.5 bags a day due to feed scarcity. The pullets became weak and some died 5 days later. Necropsy showed duodenal coccidiosis, often an empty gastro-intestinal tract and intussusception of the ileum near the ileocaecal junction. The tips of the caecae and/or their mesentery were often telescoped into the ileum. Affected areas were inflamed, necrotic and often gangrenous and sloughing. On another farm with 328 pullets of 12-weeks-old intussusception of the ileum near the ileocaecal junction was again observed when feeding was reduced from two bags in 3 days to 1 in 5 days. The caecae and/or their mesentery were also involved. Examinations for coccidiosis gave negative results. These observations indicate that starvation may cause intestinal intussusception in fowls.


Incorporation of carbon from photosynthetic products into 2-carboxyarabinitol-1-phosphate and 2-carboxyarabinitol.
The synthesis of 2-carboxy-D-arabinitol-1-phosphate (CA1P), the naturally occurring inhibitor of ribulose-1,5-bisphosphate carboxylase/oxygenase, was studied in leaves of the French bean Phaseolus vulgaris, L. Leaves were supplied with air containing 14CO2 in the light then the plants were transferred to normal air in the light or in the dark. Leaf samples were frozen in liquid nitrogen, ground to a powder and extracted with acid. Lipids, pigments and cations were removed from the extract and CA1P and 2-carboxy-D-arabinitol (CA) recovered by anion exchange chromatography. The CA1P was further purified by its specific binding to purified ribulose-1,5-bisphosphate carboxylase/oxygenase. CA and CA1P were identified by chromatographic properties and n.m.r. spectra. When plants were kept for 15 h in darkness after exposure to 14CO2, up to 2.2% and 5.5% of the radioactivity in the extracts was present in CA1P and CA, respectively. The most radioactivity appeared in these compounds when photosynthesis from 14CO2 took place at low photosynthetic photon flux density (PPFD). Under such conditions, radioactivity was detected in CA1P after only 10 min. During subsequent exposure to normal air (12CO2) at low PPFD the amount of radioactivity in CA1P remained almost constant for 6 h; in darkness the rate of incorporation of radioactivity into CA1P reached a maximum after 2 h and the radioactivity was still increasing 6 h later. At low PPFD, the amount of CA1P in the leaves reached a maximum after 2 h. In darkness, the amount of CA1P began to increase rapidly after a lag of almost 1 h, well ahead of the increase in radioactivity in CA1P.


Bupropion sustained release versus paroxetine for the treatment of depression in the elderly.
Depression is a serious and widespread emotional disorder among the elderly. This study compared the efficacy and safety of bupropion sustained release (SR) with the selective serotonin reuptake inhibitor paroxetine in the treatment of major depression in elderly outpatients. Elderly (> or = 60 years) outpatients with major depressive disorder (DSM-IV criteria) were evaluated in this 6-week multicenter, randomized, double-blind study comparing bupropion SR, 100-300 mg/day, and paroxetine, 10-40 mg/day. Efficacy was assessed by changes in scores on the Hamilton Rating Scales for Depression (HAM-D) and Anxiety (HAM-A) and the Clinical Global Impressions-Severity of Illness and -Improvement scales. Safety was assessed by monitoring adverse events, vital signs, and body weight. A total of 100 patients ranging in age from 60 to 88 years were randomly assigned to treatment with bupropion SR (N = 48) or paroxetine (N = 52). Measurements of efficacy were similar between the 2 treatment groups, with both groups showing improved scores on all depression rating scales. Headache, insomnia, dry mouth, agitation, dizziness, and nausea occurred in > 10% of patients in both groups; somnolence, diarrhea, constipation, and anorexia occurred in > 10% of patients in the paroxetine group. No statistically significant differences between groups in vital signs or weight were found. Both bupropion SR and paroxetine were safe and effective for the treatment of depression in the elderly. Because of its favorable side effect profile, bupropion SR may provide a safe and effective nonserotonergic treatment alternative that is well suited as an antidepressant for the elderly.


Fructose 1-phosphate is the one and only physiological effector of the Cra (FruR) regulator of Pseudomonas putida.
Fructose-1-phosphate (F1P) is the preferred effector of the catabolite repressor/activator (Cra) protein of the soil bacterium Pseudomonas putida but its ability to bind other metabolic intermediates in vivo is unclear. The Cra protein of this microorganism (Cra(PP)) was submitted to mobility shift assays with target DNA sequences (the PfruB promoter) and candidate effectors fructose-1,6-bisphosphate (FBP), glucose 6-phosphate (G6P), and fructose-6-phosphate (F6P). 1 mM F1P was sufficient to release most of the Cra protein from its operators but more than 10 mM of FBP or G6P was required to free the same complex. However, isothermal titration microcalorimetry failed to expose any specific interaction between Cra(PP) and FBP or G6P. To solve this paradox, transcriptional activity of a PfruB-lacZ fusion was measured in wild-type and ΔfruB cells growing on substrates that change the intracellular concentrations of F1P and FBP. The data indicated that PfruB activity was stimulated by fructose but not by glucose or succinate. This suggested that Cra(PP) represses expression in vivo of the cognate fruBKA operon in a fashion dependent just on F1P, ruling out any other physiological effector. Molecular docking and dynamic simulations of the Cra-agonist interaction indicated that both metabolites can bind the repressor, but the breach in the relative affinity of Cra(PP) for F1P vs FBP is three orders of magnitude larger than the equivalent distance in the Escherichia coli protein. This assigns the Cra protein of P. putida the sole role of transducing the presence of fructose in the medium into a variety of direct and indirect physiological responses.


Saxagliptin add-on therapy to insulin with or without metformin for type 2 diabetes mellitus: 52-week safety and efficacy.
Achievement of glycemic control is an important objective in the management of type 2 diabetes mellitus (T2DM). The objective of this study was to evaluate the safety and efficacy of the dipeptidyl peptidase-4 inhibitor saxagliptin versus placebo as add-on therapy in patients with T2DM inadequately controlled with insulin alone or insulin plus metformin. This was a long-term (28-week) extension of a short-term (24-week), randomized, double-blind, parallel-group trial of saxagliptin 5 mg once daily versus placebo as add-on therapy to open-label insulin or insulin plus metformin therapy totaling 52 weeks of treatment. In contrast with the goal of maintaining a stable insulin dosage during the short-term phase, during the extension phase the insulin dosage was flexible and adjusted as deemed appropriate by the investigator. The study was conducted in a clinical practice setting, including family practice and hospital sites. Patients with T2DM aged 18-78 years with glycated hemoglobin (HbA1c) 7.5-11 % on a stable insulin regimen (30-150 U/day with or without metformin) for ≥8 weeks at screening were included in the study. Patients were stratified by metformin use and randomly assigned 2:1 to oral saxagliptin 5 mg (n = 304) or placebo (n = 151) once daily. All patients who completed the initial 24 weeks of treatment were eligible to participate in the 28-week extension, regardless of whether they had required rescue treatment. The main outcome measure was change in HbA1c from baseline to week 52. In general, the outcomes achieved at week 24 were sustained to week 52. Adjusted mean change from baseline HbA1c at week 52 was greater with saxagliptin (-0.75 %) versus placebo (-0.38 %); the adjusted between-group difference was -0.37 % (95 % CI -0.55 to -0.19); between-group differences were similar in patients treated with metformin (-0.37 % [95 % CI -0.59 to -0.15]) and without metformin (-0.37 % [95 % CI -0.69 to -0.04]). At week 52, a greater proportion of patients receiving saxagliptin achieved HbA1c <7 % than those receiving placebo (21.3 vs. 8.7 %; between-group difference 12.6 % [95 % CI 6.1-19.1]). The increase from baseline in mean total daily insulin dose at week 52 was numerically smaller with saxagliptin (5.67 vs 6.67 U with placebo; difference, -1.01 U [95 % CI -3.24 to 1.22]). During the 52-week study period, the proportion of patients reporting ≥1 adverse event (AE) was 66.4 % with saxagliptin and 71.5 % with placebo, the majority being mild or moderate in intensity. The most common AEs (≥5 % with saxagliptin or placebo) were urinary tract infection, nasopharyngitis, upper respiratory tract infection, headache, influenza, and pain in extremity; the incidence of each AE was similar between treatment groups. In the saxagliptin and placebo groups, the incidence of reported hypoglycemia was 22.7 and 26.5 %, respectively; the incidence of confirmed hypoglycemia (fingerstick glucose ≤50 mg/dL [≤2.77 mmol/L] with characteristic symptoms) was 7.6 and 6.6 %, respectively. Adjusted mean change from baseline body weight was +0.8 kg with saxagliptin and +0.5 kg with placebo. Saxagliptin 5 mg once daily as add-on to insulin, with or without concomitant metformin, produced a durable improvement in glycemic control and was well tolerated over 52 weeks of treatment.


The cGMP synthesis and PKG1 expression in murine lymphoid organs.
Numerous reports indicate that cyclic 3',5' guanosine monophosphate (cGMP) is involved in the regulation of immune processes. However, the mechanisms responsible for the synthesis of this nucleotide and its signaling pathways in immune cells are still not well recognized. The aim of our studies was to establish: 1) which form of guanylyl cyclase (GC) synthesizes cGMP in murine lymphoid organs and 2) whether the same organs express the isoforms PKG1alpha and/or PKG1beta of protein kinase G, known as possible target for synthesized cGMP. Cells isolated from thymus, lymph nodes, and spleen were treated with activators (SNP, ANP, CNP, STa) of soluble or particulate cyclases. Sodium nitroprusside (SNP) elevated intracellular cGMP 2-fold in thymic and lymph node cells and about 10-fold in spleen cells. Atrial natriuretic peptide (ANP) caused modest but statistically significant increases of cGMP in cells of all three organs. Additionally, spleen cells elevated their cGMP content about 2-fold in response to C-type natriuretic protein (CNP). In cellular homogenates of the all analyzed organs, the antibody anti-PKG1beta stained the 78 kDa band corresponding to the molecular mass of PKG1. Only homogenates of spleen cells were stained by the antibody recognizing PKG1alpha. Our results indicate that in the investigated organs cGMP may be synthesized mainly by soluble GC in response to nitric oxide. The modest increase of cGMP upon stimulation by ANP suggests that in all these organs either exists only a small subpopulation of cells that express particulate cyclase GC-A or GC-A is expressed at very low level. In spleen cells, however, cyclase GC-B appears to be the more active enzyme. Elevated cGMP concentration may in turn activate PKG1beta in thymus, lymph node, and spleen cells and also PKG1alpha in spleen cells.


Physical activity and exercise in patients with pediatric rheumatic disease: A systematic search and review.
Childhood rheumatic diseases are a group of diseases that can affect many organs and systems, resulting in pain, joint stiffness, muscle atrophy and weakness. Physical inactivity has been reported in many childhood rheumatic diseases. There are many studies in the literature comparing the effectiveness of exercise programs in children with juvenile idiopathic arthritis. Exercise and physical activity are considered major parts of the treatment of children with rheumatic disease. The aim of this review is to systematically present studies on physical activity and exercise programs in children with rheumatism from the last 5 years. An internet-based search of three databases-PubMed, PEDro and Medline- was conducted to find relevant studies. Two reviewers individually identified studies on the basis of their title, abstract or full text-as necessary-to determine their eligibility. Differences of opinion between the two examiners were resolved by discussion. Scientific studies of children with different rheumatic diagnoses have shown that physical activity and exercise have a significant effect on reducing the symptoms of the disease. However, the duration, frequency, method and evaluation of the exercises are still being discussed in the literature.


Can a novel clinical risk score improve pneumonia prediction in acute stroke care? A UK multicenter cohort study.
Pneumonia frequently complicates stroke and has a major impact on outcome. We derived and internally validated a simple clinical risk score for predicting stroke-associated pneumonia (SAP), and compared the performance with an existing score (A(2)DS(2)). We extracted data for patients with ischemic stroke or intracerebral hemorrhage from the Sentinel Stroke National Audit Programme multicenter UK registry. The data were randomly allocated into derivation (n=11 551) and validation (n=11 648) samples. A multivariable logistic regression model was fitted to the derivation data to predict SAP in the first 7 days of admission. The characteristics of the score were evaluated using receiver operating characteristics (discrimination) and by plotting predicted versus observed SAP frequency in deciles of risk (calibration). Prevalence of SAP was 6.7% overall. The final 22-point score (ISAN: prestroke Independence [modified Rankin scale], Sex, Age, National Institutes of Health Stroke Scale) exhibited good discrimination in the ischemic stroke derivation (C-statistic 0.79; 95% CI 0.77 to 0.81) and validation (C-statistic 0.78; 95% CI 0.76 to 0.80) samples. It was well calibrated in ischemic stroke and was further classified into meaningful risk groups (low 0 to 5, medium 6 to 10, high 11 to 14, and very high ≥15) associated with SAP frequencies of 1.6%, 4.9%, 12.6%, and 26.4%, respectively, in the validation sample. Discrimination for both scores was similar, although they performed less well in the intracerebral hemorrhage patients with an apparent ceiling effect. The ISAN score is a simple tool for predicting SAP in clinical practice. External validation is required in ischemic and hemorrhagic stroke cohorts.


Eye-movement patterns are associated with communicative competence in autistic spectrum disorders.
Investigations using eye-tracking have reported reduced fixations to salient social cues such as eyes when participants with autism spectrum disorders (ASD) view social scenes. However, these studies have not distinguished different cognitive phenotypes. The eye-movements of 28 teenagers with ASD and 18 typically developing peers were recorded as they watched videos of peers interacting in familiar situations. Within ASD, we contrasted the viewing patterns of those with and without language impairments. The proportion of time spent viewing eyes, mouths and other scene details was calculated, as was latency of first fixation to eyes. Finally, the association between viewing patterns and social-communicative competence was measured. Individuals with ASD and age-appropriate language abilities spent significantly less time viewing eyes and were slower to fixate the eyes than typically developing peers. In contrast, there were no differences in viewing patterns between those with language impairments and typically developing peers. Eye-movement patterns were not associated with social outcomes for either language phenotype. However, increased fixations to the mouth were associated with greater communicative competence across the autistic spectrum. Attention to both eyes and mouths is important for language development and communicative competence. Differences in fixation time to eyes may not be sufficient to disrupt social competence in daily interactions. A multiple cognitive deficit model of ASD, incorporating different language phenotypes, is advocated.


Neutralising properties of peptides derived from CXCR4 extracellular loops towards CXCL12 binding and HIV-1 infection.
The chemokine receptor CXCR4 interacts with a single endogenous chemokine, CXCL12, and regulates a wide variety of physiological and pathological processes including inflammation and metastasis development. CXCR4 also binds the HIV-1 envelope glycoprotein, gp120, resulting in viral entry into host cells. Therefore, CXCR4 and its ligands represent valuable drug targets. In this study, we investigated the inhibitory properties of synthetic peptides derived from CXCR4 extracellular loops (ECL1-X4, ECL2-X4 and ECL3-X4) towards HIV-1 infection and CXCL12-mediated receptor activation. Among these peptides, ECL1-X4 displayed anti-HIV-1 activity against X4, R5/X4 and R5 viruses (IC50=24 to 76μM) in cell viability assay without impairing physiological CXCR4-CXCL12 signalling. In contrast, ECL2-X4 only inhibited X4 and R5/X4 strains, interfering with HIV-entry into cells. At the same time, ECL2-X4 strongly and specifically interacted with CXCL12, blocking its binding to CXCR4 and its second receptor, CXCR7 (IC50=20 and 100μM). Further analysis using mutated and truncated peptides showed that ECL2 of CXCR4 forms multiple contacts with the gp120 protein and the N-terminus of CXCL12. Chemokine neutralisation was mainly driven by four aspartates and the C-terminal residues of ECL2-X4. These results demonstrate that ECL2 represents an important structural determinant in CXCR4 activation. We identified the putative site for the binding of CXCL12 N-terminus and provided new structural elements to explain the recognition of gp120 and dimeric CXCR4 ligands.


The expression of G-protein-gated inwardly rectifying K+ channels GIRK1 and GIRK2 mRNAs in the supraoptic nucleus of the rat and possible role involved.
The expression of G-protein-gated inwardly rectifying K channels subunits GIRK1 and GIRK2 mRNAs in the supraoptic nucleus (SON) was investigated in the rat by in situ hybridization with non-radioactive dig-labeled cRNA probes. Double-labeled methods were used to study the co-localization of GIRK1 and 2 and oxytocin (OT) and vasopressin (AVP) in the SON. The present study revealed wide and intense expression of GIRK1 and GIRK2 mRNAs with high overlapping in the SON, indicating the heterologous channel of GIRK1/GIRK2 was a major functional channel in the SON. Given that 100% of OT-positive and 95% of (AVP)-positive neurons in the SON expressed GIRK1/GIRK2 mRNAs, it is possible that GIRK1/GIRK2 channel, activated through G-protein coupled receptors, may be involved in the inhibitory regulation of the release of OT and AVP from the SON.


Mechanistic studies on the degradation and protein release characteristics of poly(lactic-co-glycolic-co-hydroxymethylglycolic acid) nanospheres.
The purpose of this study was to gain mechanistic insights into the effect of different formulation parameters on the degradation and release behavior of protein-loaded nanoparticulate carrier systems based on an aliphatic polyester with pendant hydroxyl groups, poly(lactic-co-glycolic-hydroxymethyl glycolic acid) (pLGHMGA). Bovine serum albumin (BSA) was used as a model protein. BSA-loaded pLGHMGA nanospheres of 400-700 nm were prepared using a solvent evaporation method using pLGHMGA of different molecular weights and different compositions. Also, the concentration of pLGHMGA in the organic phase was varied. The nanospheres showed a continuous mass loss accompanied by continuous decrease in number average molecular weight, which indicates that the degradation of the nanospheres is by bulk degradation with a rapid release of water-soluble low molecular weight fragments. On the basis of NMR analysis, it is concluded that intramolecular transesterification precedes extensive hydrolysis of the polymer and degradation of the nanospheres. BSA-loaded freeze-dried nanospheres showed a significant burst release of 40-50% of the BSA loading. In contrast, nonfreeze-dried samples showed a small burst of around 10-20%, indicating that freeze-drying induced pore formation. Nonlyophilized nanospheres prepared from pLGHMGA with 64/18/18 lactic/glycolic/hydroxymethylglycolic acid (L/G/HMG) ratio showed a relatively fast release of BSA for the next 30 days. Nanospheres prepared from a more hydrophobic pLGHMGA (74/13/13, L/G/HMG) showed a two-phase release. Circular dichroism analysis showed that the secondary structure of the released protein was preserved. This study shows a correlation between release behavior and particle erosion rate, which can be modulated by the copolymer composition.


The biology and preliminary host range of Megacopta cribraria (Heteroptera: Plataspidae) and its impact on kudzu growth.
The bean plataspid, Megacopta cribraria (F.), recently was discovered in the United States feeding on kudzu, Pueraria montana Lour. (Merr.) variety lobata (Willd.), an economically important invasive vine. We studied its biology on kudzu and its impact on kudzu growth. We also tested its ability to use other common forest legumes for oviposition and development. Flight intercept traps operated from 17 May 2010 to 31 May 2011 in a kudzu field near Athens, GA showed three peaks of adult flight activity suggesting there are two generations per year on kudzu. Vine samples examined for eggs from April 2010 to April 2011 and June to October 2011 showed two periods of oviposition activity in 2010, which coincided with the peaks in adult activity. In 2011, the second period of oviposition began on or before 24 June and then egg abundance declined gradually thereafter until late August when we recovered <2 eggs/0.5 m of vine. Samples of the five nymphal instars and adults on vines did not show similar trends in abundance. Adults did not lay eggs on the various legume species tested in 2010 in a no-choice test possibly because the cages were too small. In the 2011 field host range experiments conducted in a kudzu field by using 12 legume species, M. cribraria preferentially oviposited on kudzu over soybean, Glycine max Merrill., but they still laid 320 eggs per plant on soybean. Lespedeza hirta (L.) Hornem. and Lespedeza cuneata (Dum. Cours.) G. Don had 122.2 and 108.4 eggs per plant, respectively. Kudzu and soybean were the only species M. cribraria completed development on. Plots protected from M. cribraria feeding by biweekly insecticide applications had 32.8% more kudzu biomass than unprotected plots. Our results show that M. cribraria has a significant impact on kudzu growth and could help suppress this pest weed.


Identifying progressive gene network perturbation from single-cell RNA-seq data.
Identifying the gene regulatory networks that control development or disease is one of the most important problems in biology. Here, we introduce a computational approach, called PIPER (ProgressIve network PERturbation), to identify the perturbed genes that drive differences in the gene regulatory network across different points in a biological progression. PIPER employs algorithms tailor-made for single cell RNA sequencing (scRNA-seq) data to jointly identify gene networks for multiple progressive conditions. It then performs differential network analysis along the identified gene networks to identify master regulators. We demonstrate that PIPER outperforms state-of-the-art alternative methods on simulated data and is able to predict known key regulators of differentiation on real scRNA-Seq datasets.


Steady state visual evoked potentials in reading aloud: Effects of lexicality, frequency and orthographic familiarity.
The present study explored the possibility to use Steady-State Visual Evoked Potentials (SSVEPs) as a tool to investigate the core mechanisms in visual word recognition. In particular, we investigated three benchmark effects of reading aloud: lexicality (words vs. pseudowords), frequency (high-frequency vs. low-frequency words), and orthographic familiarity ('familiar' versus 'unfamiliar' pseudowords). We found that words and pseudowords elicited robust SSVEPs. Words showed larger SSVEPs than pseudowords and high-frequency words showed larger SSVEPs than low-frequency words. SSVEPs were not sensitive to orthographic familiarity. We further localized the neural generators of the SSVEP effects. The lexicality effect was located in areas associated with early level of visual processing, i.e. in the right occipital lobe and in the right precuneus. Pseudowords produced more activation than words in left sensorimotor areas, rolandic operculum, insula, supramarginal gyrus and in the right temporal gyrus. These areas are devoted to speech processing and/or spelling-to-sound conversion. The frequency effect involved the left temporal pole and orbitofrontal cortex, areas previously implicated in semantic processing and stimulus-response associations respectively, and the right postcentral and parietal inferior gyri, possibly indicating the involvement of the right attentional network.


Repeated divergent selection on pigmentation genes in a rapid finch radiation.
Instances of recent and rapid speciation are suitable for associating phenotypes with their causal genotypes, especially if gene flow homogenizes areas of the genome that are not under divergent selection. We study a rapid radiation of nine sympatric bird species known as capuchino seedeaters, which are differentiated in sexually selected characters of male plumage and song. We sequenced the genomes of a phenotypically diverse set of species to search for differentiated genomic regions. Capuchinos show differences in a small proportion of their genomes, yet selection has acted independently on the same targets in different members of this radiation. Many divergent regions contain genes involved in the melanogenesis pathway, with the strongest signal originating from putative regulatory regions. Selection has acted on these same genomic regions in different lineages, likely shaping the evolution of cis-regulatory elements, which control how more conserved genes are expressed and thereby generate diversity in classically sexually selected traits.


Pharmacogenetic profiling for cetuximab plus irinotecan therapy in patients with refractory advanced colorectal cancer.
Regulation of epidermal growth factor receptor (EGFR) signaling pathways may play a relevant role in determining the activity of cetuximab therapy in patients with metastatic colorectal cancer (MCRC). We investigated possible associations between genetic variants and clinical outcomes of MCRC patients treated with cetuximab-irinotecan salvage therapy. Patients who underwent cetuximab-irinotecan salvage therapy after disease progression during or after first-line bolus/infusional fluorouracil, leucovorin, and oxaliplatin chemotherapy and a second-line irinotecan-based regimen were considered eligible for analysis of polymorphisms with putative influence on cetuximab-related pathways. Epidermal growth factor (EGF) 61A>G, EGF receptor (EGFR) 216G>T, EGFR 497G>A, EGFR intron-1 (CA)(n) dinucleotide short (S)/long (L) variant, cyclin-D1 870A>G, immunoglobulin-G fragment-C receptors RIIIa 158G>T, and RIIa 131G>A were studied for a possible association with overall survival (OS) as the primary end point. Additional analyses were addressed at possible associations among polymorphisms and EGFR expression, toxicity, and response. In 110 assessable patients, significant association with favorable OS was observed for EGFR intron-1 S/S and EGF 61 G/G genotypes. In the multivariate model, EGFR intron-1 S/S and EGF 61 G/G genotypes showed a hazard ratio of 0.41 (95% CI, 0.21 to 0.78; P = .006) and 0.44 (95% CI, 0.23 to 0.84; P = .01), respectively. EGFR intron-1 S/S carriers showed more frequent G2-G3 skin toxicity (chi(2) test = 12.7; P = .001) and treatment response (chi(2) test = 9.45; P = .008) than EGFR intron-1 L/L carriers. Although additional studies are required for confirmation, our findings could optimize the use of cetuximab in MCRC patients.


Anoxygenic photosynthesis modulated Proterozoic oxygen and sustained Earth's middle age.
Molecular oxygen (O(2)) began to accumulate in the atmosphere and surface ocean ca. 2,400 million years ago (Ma), but the persistent oxygenation of water masses throughout the oceans developed much later, perhaps beginning as recently as 580-550 Ma. For much of the intervening interval, moderately oxic surface waters lay above an oxygen minimum zone (OMZ) that tended toward euxinia (anoxic and sulfidic). Here we illustrate how contributions to primary production by anoxygenic photoautotrophs (including physiologically versatile cyanobacteria) influenced biogeochemical cycling during Earth's middle age, helping to perpetuate our planet's intermediate redox state by tempering O(2) production. Specifically, the ability to generate organic matter (OM) using sulfide as an electron donor enabled a positive biogeochemical feedback that sustained euxinia in the OMZ. On a geologic time scale, pyrite precipitation and burial governed a second feedback that moderated sulfide availability and water column oxygenation. Thus, we argue that the proportional contribution of anoxygenic photosynthesis to overall primary production would have influenced oceanic redox and the Proterozoic O(2) budget. Later Neoproterozoic collapse of widespread euxinia and a concomitant return to ferruginous (anoxic and Fe(2+) rich) subsurface waters set in motion Earth's transition from its prokaryote-dominated middle age, removing a physiological barrier to eukaryotic diversification (sulfide) and establishing, for the first time in Earth's history, complete dominance of oxygenic photosynthesis in the oceans. This paved the way for the further oxygenation of the oceans and atmosphere and, ultimately, the evolution of complex multicellular organisms.


A comparative study of telephone versus onsite completion of the WOMAC 3.0 osteoarthritis index.
Outcome assessment in clinical trials using the Western Ontario and McMaster University (WOMAC 3.0) Osteoarthritis Index is traditionally achieved through self-administration of the Index. However, in other areas of clinical measurement, telephone administration has been shown to be a reliable method of acquiring data that are both accurate and complete. To address this issue in knee osteoarthritis (OA), we conducted a comparative study of telephone administration by interviewer of WOMAC LK3.0 versus onsite self-completion at the hospital. Fifty consenting patients with knee OA were randomized to complete the WOMAC LK3.0 Index by telephone interview one day, followed by onsite completion the following day, or vice versa. Neither patients nor interviewers had access to any prior scores. The mean age of the 50 patients was 66.3 years (range 44-82); 34 (68%) were female and 16 (32%) male. There was excellent agreement between the mean office and telephone scores, with mean differences for the WOMAC LK3.0 pain, stiffness, and function subscale scores and total score of 0.09, 0.12, 0.78, and 0.98, respectively. These differences were well within the respective protocol defined equivalence criteria of +/- 1.7, +/- 0.9, +/- 6.4, and +/- 9.1, and represented differences from office scores of 0.9, 2.6, 2.4, and 2.2%, respectively. The use of telephone interviews for the WOMAC LK3.0 Index is a valid method of obtaining OA outcome measurements. These observations have important implications for designing data acquisition strategies for future OA clinical trials and for longterm observational studies.


A neonatal mouse model characterizes transmissibility of SARS-CoV-2 variants and reveals a role for ORF8.
Small animal models have been a challenge for the study of SARS-CoV-2 transmission, with most investigators using golden hamsters or ferrets. Mice have the advantages of low cost, wide availability, less regulatory and husbandry challenges, and the existence of a versatile reagent and genetic toolbox. However, adult mice do not robustly transmit SARS-CoV-2. Here we establish a model based on neonatal mice that allows for transmission of clinical SARS-CoV-2 isolates. We characterize tropism, respiratory tract replication and transmission of ancestral WA-1 compared to variants Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Omicron BA.1 and Omicron BQ.1.1. We identify inter-variant differences in timing and magnitude of infectious particle shedding from index mice, both of which shape transmission to contact mice. Furthermore, we characterize two recombinant SARS-CoV-2 lacking either the ORF6 or ORF8 host antagonists. The removal of ORF8 shifts viral replication towards the lower respiratory tract, resulting in significantly delayed and reduced transmission in our model. Our results demonstrate the potential of our neonatal mouse model to characterize viral and host determinants of SARS-CoV-2 transmission, while revealing a role for an accessory protein in this context.


New perspectives in hypertension research. Potentials of vascular biology.
The vessel wall was once considered to be a passive conduit responding to the circulating endocrine system. However, the emergence of molecular and vascular biology in hypertension research has redefined our understanding of the role of the vasculature as a vital organ in the pathogenesis of hypertension. It is now recognized that the vasculature can regulate its own tone by a variety of previously unknown autocrine and/or paracrine vasoactive systems. Recent evidence indicates that the process of vascular remodeling in hypertension appears to be mediated by locally generated factors within the vessel wall. This review examines the implications of this new paradigm in hypertension, focusing on five topics that have developed through the emergence of molecular vascular biology: the discovery and characterization of novel biologically active molecules synthesized by the vessel wall, the molecular mechanisms and consequences of vascular remodeling, the developmental biology of the blood vessel and the relation to pathobiology, the use of in vivo gene transfer to test hypotheses in vivo, and novel treatment strategies based on gene therapy of the vessel wall.


Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets.
We purified poly(A)+ mRNA from the spleen and lymph nodes at designated times after infection with Leishmania major in genetically susceptible BALB/c and resistant C57BL/6 mice. The steady-state levels of IL-2, IFN-gamma, IL-4, and IL-1 beta mRNA were determined using Northern hybridizations. IL-2 mRNA levels in the infected organs of BALB/c and C57BL/6 mice were comparable after infection, but IFN-gamma and IL-4 mRNA levels were reciprocally expressed. Levels of IFN-gamma mRNA in C57BL/6 draining nodes and spleen were significantly greater than in BALB/c mice except at 4 and 6 wk of infection, when splenic IFN-gamma mRNA levels were transiently comparable. In contrast, IL-4 mRNA was apparent only in BALB/c and not in C57BL/6 nodes and spleen. Tissue levels of IL-1 beta mRNA were 10-20-fold greater in BALB/c mice. BALB/c mice were pretreated with GK1.5 mAb, a manipulation that promotes healing of subsequent infection by transiently depleting L3T4+ cells. At 8 wk of infection, by which time lymphoid organs were repopulated with L3T4+ cells, GK1.5-pretreated BALB/c mice produced IFN-gamma, but not IL-4 message. Serum levels of IgE were markedly elevated in infected BALB/c, but not in infected C57BL/6 or GK1.5-pretreated BALB/c mice, consistent with in vivo biologic activity of IL-4 in nonhealing mice. Treatment of infected BALB/c mice with neutralizing anti-IL-4 antibody abolished the elevation of serum IgE and significantly attenuated the progression of disease as assessed by size and ulceration of the lesion, and by reduction in the number of tissue parasites. Both protective and deleterious responses to Leishmania infection have previously been shown to be L3T4+ cell dependent. Our findings are consistent with the differential expansion of protective, IFN-gamma-producing Th1 cells in healing mice, and the expansion of deleterious, IL-4-producing Th2 cells in nonhealing mice. The inverse relationship of IFN-gamma and IL-4 gene expression during leishmaniasis may underlie the divergence of cellular and humoral immunity that occurs during chronic infection with Leishmania and possibly other intracellular parasites.


British Army recruits with low serum vitamin D take longer to recover from stress fractures.
Recruits undergoing military training experience a particularly high incidence of stress fractures. The role of combined calcium and vitamin D (25-OHD) deficiency and subsequent supplementation has been well described in the literature, but the role of 25-OHD deficiency alone is less well understood, particularly its influence on recovery once a stress fracture has been incurred. Retrospective data of recruits who had incurred stress fractures were collected (n=37). Independent-samples t-tests were conducted in Microsoft Excel to investigate the association between serum-25 OHD and the time taken to recover. Significant differences (p<0.05) were found in the mean time taken to recover from stress fractures when participants were grouped according to serum 25-OHD level. Sufficient levels of serum 25-OHD (>50 nmol/L) at the time of injury resulted in shorter recovery times than all other groups. The study demonstrated an association between serum 25-OHD level and the time taken to recover from a stress fracture. The sample population of this study was too small to contribute to the discussion about whether a minimum serum 25-OHD status should be met before entering British Army training, but a larger prospective study should be able to provide the data required for a cost benefit analysis to be conducted and a decision made.


Focusing of spatially inhomogeneous partially coherent, partially polarized electromagnetic fields.
We report a general framework capable of describing the focusing of electromagnetic waves with spatially varying coherence and polarization properties in optical systems of arbitrary numerical aperture and Fresnel number. We also investigate the reduction of the dimensionality of the requisite integrals by use of a coherent mode expansion. We find that coherent mode expansions treating each component of the electric field vector individually are unsuitable for describing focusing systems because of the inter-component mixing that can occur in high numerical aperture systems. In addition, we show that the assumption of harmonic angular dependence allows the azimuthal integration to be performed analytically, providing further simplification of the analysis. We also find that the effective degree of spectral coherence of an electromagnetic beam is unchanged upon focusing. Finally, as an illustration of the developed framework, we calculate the transverse and axial focal distributions for a partially coherent source formed by incoherent superposition of radially and azimuthally polarized Laguerre-Gauss modes.


Unemployment and stillbirth risk among foreign-born and Spanish pregnant women in Spain, 2007-2010: a multilevel analysis study.
We describe stillbirth and unemployment rates by autonomous region in Spain and analyse whether women who gave birth in regions with high unemployment rates were more likely to have a stillborn. We designed a multilevel population-based observational study of births from 2007 to 2010. We defined stillbirth as the outcome, individual maternal socioeconomic and pregnancy-related characteristics as covariates, and maternal autonomous region of residence as the contextual covariate. We used mixed-logistic regression models to account for differences across regions. In total, 1,920,235 singleton births and 5,560 stillbirths were included in the study. Women residing in autonomous regions with the highest rates of unemployment had a two-times-greater chance of delivering a stillborn (adjusted OR 2.60; 95 % CI 2.08-3.21). The region where women resided explained 14 % of the total individual differences in the risk of delivering a stillborn. The odds of stillbirth were 1.82 (95 % CI 1.62-2.05) times higher for African-born women than for Spanish-born women and 1.90 (95 % CI 1.68-2.15) times higher for women with low educational attainment than for women with higher education. In conclusion, regional disparities in stillbirth rates in Spain in the period 2007-2010 were mainly associated with mothers who had low levels of education, were African-born, and lived in regions with higher unemployment.


NOTCH1 signaling promotes human T-cell acute lymphoblastic leukemia initiating cell regeneration in supportive niches.
Leukemia initiating cells (LIC) contribute to therapeutic resistance through acquisition of mutations in signaling pathways, such as NOTCH1, that promote self-renewal and survival within supportive niches. Activating mutations in NOTCH1 occur commonly in T cell acute lymphoblastic leukemia (T-ALL) and have been implicated in therapeutic resistance. However, the cell type and context specific consequences of NOTCH1 activation, its role in human LIC regeneration, and sensitivity to NOTCH1 inhibition in hematopoietic microenvironments had not been elucidated. We established humanized bioluminescent T-ALL LIC mouse models transplanted with pediatric T-ALL samples that were sequenced for NOTCH1 and other common T-ALL mutations. In this study, CD34(+) cells from NOTCH1(Mutated) T-ALL samples had higher leukemic engraftment and serial transplantation capacity than NOTCH1(Wild-type) CD34(+) cells in hematopoietic niches, suggesting that self-renewing LIC were enriched within the NOTCH1(Mutated) CD34(+) fraction. Humanized NOTCH1 monoclonal antibody treatment reduced LIC survival and self-renewal in NOTCH1(Mutated) T-ALL LIC-engrafted mice and resulted in depletion of CD34(+)CD2(+)CD7(+) cells that harbor serial transplantation capacity. These results reveal a functional hierarchy within the LIC population based on NOTCH1 activation, which renders LIC susceptible to targeted NOTCH1 inhibition and highlights the utility of NOTCH1 antibody targeting as a key component of malignant stem cell eradication strategies.


Structural and functional studies of FKHR-PAX3, a reciprocal fusion gene of the t(2;13) chromosomal translocation in alveolar rhabdomyosarcoma.
Alveolar rhabdomyosarcoma (ARMS) is an aggressive pediatric cancer of skeletal muscle. More than 70% of ARMS tumors carry balanced t(2;13) chromosomal translocation that leads to the production of two novel fusion genes, PAX3-FKHR and FKHR-PAX3. While the PAX3-FKHR gene has been intensely studied, the reciprocal FKHR-PAX3 gene has rarely been described. We report here the cloning and functional characterization of the FKHR-PAX3 gene as the first step towards a better understanding of its potential impact on ARMS biology. From RH30 ARMS cells, we detected and isolated three versions of FKHR-PAX3 cDNAs whose C-terminal sequences corresponded to PAX3c, PAX3d, and PAX3e isoforms. Unlike the nuclear-specific localization of PAX3-FKHR, the reciprocal FKHR-PAX3 proteins stayed predominantly in the cytoplasm. FKHR-PAX3 potently inhibited myogenesis in both non-transformed myoblast cells and ARMS cells. We showed that FKHR-PAX3 was not a classic oncogene but could act as a facilitator in oncogenic pathways by stabilizing PAX3-FKHR expression, enhancing cell proliferation, clonogenicity, anchorage-independent growth, and matrix adhesion in vitro, and accelerating the onset of tumor formation in xenograft mouse model in vivo. In addition to these pro-oncogenic behaviors, FKHR-PAX3 also negatively affected cell migration and invasion in vitro and lung metastasis in vivo. Taken together, these functional characteristics suggested that FKHR-PAX3 might have a critical role in the early stage of ARMS development.


Health-Related Behaviors by Urban-Rural County Classification - United States, 2013.
Persons living in rural areas are recognized as a health disparity population because the prevalence of disease and rate of premature death are higher than for the overall population of the United States. Surveillance data about health-related behaviors are rarely reported by urban-rural status, which makes comparisons difficult among persons living in metropolitan and nonmetropolitan counties. 2013. The Behavioral Risk Factor Surveillance System (BRFSS) is an ongoing, state-based, random-digit-dialed landline- and cellular-telephone survey of noninstitutionalized adults aged ≥18 years residing in the United States. BRFSS collects data on health-risk behaviors, chronic diseases and conditions, access to health care, and use of preventive health services related to the leading causes of death and disability. BRFSS data were analyzed for 398,208 adults aged ≥18 years to estimate the prevalence of five self-reported health-related behaviors (sufficient sleep, current nonsmoking, nondrinking or moderate drinking, maintaining normal body weight, and meeting aerobic leisure time physical activity recommendations) by urban-rural status. For this report, rural is defined as the noncore counties described in the 2013 National Center for Health Statistics Urban-Rural Classification Scheme for Counties. Approximately one third of U.S. adults practice at least four of these five behaviors. Compared with adults living in the four types of metropolitan counties (large central metropolitan, large fringe metropolitan, medium metropolitan, and small metropolitan), adults living in the two types of nonmetropolitan counties (micropolitan and noncore) did not differ in the prevalence of sufficient sleep; had higher prevalence of nondrinking or moderate drinking; and had lower prevalence of current nonsmoking, maintaining normal body weight, and meeting aerobic leisure time physical activity recommendations. The overall age-adjusted prevalence of reporting at least four of the five health-related behaviors was 30.4%. The prevalence among the estimated 13.3 million adults living in noncore counties was lower (27.0%) than among those in micropolitan counties (28.8%), small metropolitan counties (29.5%), medium metropolitan counties (30.5%), large fringe metropolitan counties (30.2%), and large metropolitan centers (31.7%). This is the first report of the prevalence of these five health-related behaviors for the six urban-rural categories. Nonmetropolitan counties have lower prevalence of three and clustering of at least four health-related behaviors that are associated with the leading chronic disease causes of death. Prevalence of sufficient sleep was consistently low and did not differ by urban-rural status. Chronic disease prevention efforts focus on improving the communities, schools, worksites, and health systems in which persons live, learn, work, and play. Evidence-based strategies to improve health-related behaviors in the population of the United States can be used to reach the Healthy People 2020 objectives for these five self-reported health-related behaviors (sufficient sleep, current nonsmoking, nondrinking or moderate drinking, maintaining normal body weight, and meeting aerobic leisure time physical activity recommendations). These findings suggest an ongoing need to increase public awareness and public education, particularly in rural counties where prevalence of these health-related behaviors is lowest.


Projecting the demographic impact of AIDS and the number of people in need of treatment: updates to the Spectrum projection package.
In the Joint United Nations Programme on HIV/AIDS (UNAIDS) approach to HIV and AIDS estimates, estimates of adult prevalence produced by the Estimation and Projection Package (EPP) or the Workbook are transferred to Spectrum to estimate the consequences of the HIV/AIDS epidemic, including the number of people living with HIV by age and sex, new infections, AIDS deaths, AIDS orphans, treatment needs, and the impact of treatment on survival. The UNAIDS Reference Group on Estimates, Models and Projections recommends updates to the methodology and assumptions based on the latest research findings and international policy and programme guidelines. The latest update to Spectrum has been used in the 2005 round of global estimates. Several new features have been added to Spectrum in the past two years. New patterns of the age distribution of prevalence over time are based on the latest survey data. A more detailed treatment of mother to child transmission of HIV is now based on information about current breastfeeding practices, treatment options offered to prevent mother to child transmission (PMTCT), infant feeding options, and the percentage or number of pregnant women accessing PMTCT services. A new section on child survival includes the effects of cotrimoxazole and ART on child survival. Projections can now be calibrated with national survey data. A new set of outputs is provided for all adults over the age of 15 in addition to the traditional 15-49 age group. New outputs are now available to show plausibility bounds and regional estimates for key indicators. The latest update to the Spectrum program is intended to incorporate the latest research findings and provide new outputs needed by national and international planners.


Polycystic kidney disease in children: a genetic and epidemiological study of 82 Finnish patients.
Information of 82 children in Finland, treated during the years 1974 to 1983 for polycystic kidney disease, was collected retrospectively. The occurrence was of the order of 1:8000 births. Fifty-one of the children had early lethal disease and 31 survived for over 28 days. These children came from 69 families. They were divided by family studies into three groups: autosomal dominant polycystic kidney disease (DPKD) in 11 families, autosomal recessive polycystic kidney disease (RPKD) in 14 families, and sporadic cases in 44 families. In three of the DPKD families there were two or more sibs with DPKD which manifested neonatally. The majority of the grandparents of the children with RPKD and sporadic polycystic kidney disease were born in the same sparsely populated areas in northern, central, and eastern Finland, which suggests that most of the sporadic cases are also actually RPKD. The purpose of this study was to find patients with polycystic kidney disease manifesting in childhood and to categorise them using genetic criteria. The observed series of cases genetically classified as DPKD and RPKD will serve as a basis for the further aim of defining clinical criteria for the differential diagnosis of these two entities.


A binary ant colony optimization classifier for molecular activities.
Chemical fingerprints encode the presence or absence of molecular features and are available in many large databases. Using a variation of the Ant Colony Optimization (ACO) paradigm, we describe a binary classifier based on feature selection from fingerprints. We discuss the algorithm and possible cross-validation procedures. As a real-world example, we use our algorithm to analyze a Plasmodium falciparum inhibition assay and contrast its performance with other machine learning paradigms in use today (decision tree induction, random forests, support vector machines, artificial neural networks). Our algorithm matches established paradigms in predictive power, yet supplies the medicinal chemist and basic researcher with easily interpretable results. Furthermore, models generated with our paradigm are easy to implement and can complement virtual screenings by additionally exploiting the precalculated fingerprint information.


Monozygotic twins discordant for neurofibromatosis 1.
We present monozygotic twins discordant for the autosomal dominant disorder neurofibromatosis type 1 (NF1). The affected twin was diagnosed with NF1 at age 12, based upon accepted clinical criteria for the disorder. Both twins were re-examined at ages 35 and 57, at which times the unaffected twin continued to show no clinical manifestations of NF1. Short tandem repeat marker (STR) genotyping at 10 loci on chromosome 17 and 10 additional loci dispersed across the genome revealed identical genotypes for the twins, confirming their monozygosity. The affected twin has three children, two of whom also have NF1, while the unaffected twin has two children, both unaffected. Using lymphoblastoid, fibroblast, and buccal cell samples collected from both twins and from other family members in three generations, we discovered a pathogenic nonsense mutation in exon 40 of the NF1 gene. This mutation was found in all cell samples from the affected twin and her affected daughter, and in lymphoblastoid and buccal cells but not fibroblasts from the unaffected twin. We also found a novel non-synonymous change in exon 16 of the NF1 gene that was transmitted from the unaffected mother to both twins and co-segregated with the pathogenic mutation in the ensuing generation. All cells from the twins were heterozygous for this apparent exon 16 polymorphism and for single nucleotide polymorphisms (SNPs) within 2.5 kb flanking the site of the exon 40 nonsense mutation. This suggests that the NF1 gene of the unaffected twin differed in the respective lymphoblastoid cells and fibroblasts only at the mutation site itself, making post-zygotic mutation leading to mosaicism the most likely mechanism of phenotypic discordance. Although the unaffected twin is a mosaic, the distribution of the mutant allele among different cells and tissues appears to be insufficient to cause overt clinical manifestations of NF1.


Identification of secreted and surface proteins from Enterococcus faecalis.
Secreted and surface proteins of bacteria are key molecules that interface the cell with the environment. Some of them, corresponding to virulence factors, have already been described for Enterococcus faecalis, the predominant species involved in enterococcal nosocomial infections. In a global proteomic approach, the identification of the most abundant secreted and surface-associated proteins of E. faecalis JH2-2 strain was carried out. These proteins were separated by gel electrophoresis or directly subjected to in vivo trypsinolysis and then analyzed by liquid chromatography - electrospray ion trap tandem mass spectrometry. Putative functions were assigned by homology to the translated genomic database of E. faecalis. A total of 44 proteins were identified, eight secreted proteins from the supernatant culture and 38 cell surface proteins from two-dimensional gel electrophoresis and in vivo trypsinolysis among which two are common to the two groups. Their sequences analysis revealed that 35 of the 44 proteins harbour characteristic features (signal peptide or transmembrane domains) consistent with an extracellular localization. This study may be considered as an important step to encourage proteomic-based investigations of E. faecalis cell surface associated proteins that could lead to the discovery of virulence factors and to the development of new therapeutic tools.


Rasch validation of the Prosthetic Mobility Questionnaire: A new outcome measure for assessing mobility in people with lower limb amputation.
To create a new outcome measure of mobility in people with lower limb amputation, based on a pool of 14 items assessing prosthetic mobility, comprising the 12-item Prosthesis Evaluation Questionnaire (Mobility Section) plus 2 new items. Cross-sectional study. A total of 100 subjects (median age 58 years; 46 males; median body mass index 23.8) who had recently undergone lower limb amputation. Each patient completed the 14-item questionnaire twice: (i) at admission to the rehabilitation unit for prosthetic rehabilitation training; (ii) at 6-month follow-up after discharge. After Rasch analysis, 2 items were deleted (one due to misfit, the other because showing large (> 0.30) positive correlation of residuals with two other items (local dependence). The remaining items fitted the Rasch model (internal construct validity), giving a new 12-item scale with a 5-level response format, the Prosthetic Mobility Questionnaire (PMQ), which demonstrated unidimensionality, lack of differential item functioning, and good reliability indices (person-separation reliability = 0.87; Cronbach's alpha 0.88). Although further studies are needed to increase confidence in clinical use of the PMQ, this new questionnaire appears to be a promising, psychometrically-sound patient-reported outcome measure for assessment of mobility in subjects with lower limb amputation who use a prosthesis.


The error-prone DNA polymerase ι provides quantitative resistance to lung tumorigenesis and mutagenesis in mice.
Opposite undamaged nucleotide T, DNA polymerase ι (Polι) preferentially incorporates G rather than A, violating the Watson-Crick rule. Although the actual biological role of Polι remains enigmatic, we have identified its coding gene as a candidate for pulmonary adenoma resistance 2 (Par2), a mouse quantitative trait locus modulating chemically induced lung tumor susceptibility. Notably, the most tumor-sensitive Par2 allele possessed by the 129X1/SvJ mouse is associated with a loss-of-function mutation in Polι. To determine whether the nonfunctional Polι is responsible for the 129X1/SvJ-specific Par2 phenotype, we knocked out Polι in a C57BL/6J mouse carrying a less tumor-sensitive Par2 allele. Disruption of the C57BL/6J Polι conferred 129X1/SvJ-like sensitivity on the C57BL/6J Par2 locus and increased the in vivo mutation frequency in the lung, providing definitive proof that Polι causes the Par2 effect and inhibits tumorigenesis and mutagenesis, despite its extreme replication infidelity.


Rab11-FIP1 phosphorylation by MARK2 regulates polarity in MDCK cells.
MARK2/Par1b/EMK1, a serine/threonine kinase, is required for correct apical/basolateral membrane polarization in epithelial cells. However, the specific substrates mediating MARK2 action are less well understood. We have now found that MARK2 phosphorylates Rab11-FIP1B/C at serine 234 in a consensus site similar to that previously identified in Rab11-FIP2. In MDCK cells undergoing repolarization after a calcium switch, antibodies specific for pS234-Rab11-FIP1 or pS227-Rab11-FIP2 demonstrate that the spatial and temporal activation of Rab11-FIP1 phosphorylation is distinct from that for Rab11-FIP2. Phosphorylation of Rab11-FIP1 persists through calcium switch and remains high after polarity has been reestablished whereas FIP2 phosphorylation is highest early in reestablishment of polarity but significantly reduced once polarity has been re-established. MARK2 colocalized with FIP1B/C/D and p(S234)-FIP1 in vivo. Overexpression of GFP-Rab11-FIP1C wildtype or non-phosphorylatable GFP-Rab11-FIP1C(S234A) induced two significant phenotypes following calcium switch. Overexpression of FIP1C wildtype and FIP1C(S234A) caused a psuedo-stratification of cells in early time points following calcium switch. At later time points most prominently observed in cells expressing FIP1C(S234A) a significant lateral lumen phenotype was observed, where F-actin-rich lateral lumens appeared demarcated by a ring of ZO1 and also containing ezrin, syntaxin 3 and podocalyxin. In contrast, p120 and E-Cadherin were excluded from the new apical surface at the lateral lumens and now localized to the new lateral surface oriented toward the media. GFP-FIP1C(S234A) localized to membranes deep to the lateral lumens, and immunostaining demonstrated the reorientation of the centrosome and the Golgi apparatus toward the lateral lumen. These results suggest that both Rab11-FIP1B/C and Rab11-FIP2 serve as critical substrates mediating aspects of MARK2 regulation of epithelial polarity.


The wild sweetpotato (Ipomoea trifida) genome provides insights into storage root development.
Sweetpotato (Ipomoea batatas (L.) Lam.) is the seventh most important crop in the world and is mainly cultivated for its underground storage root (SR). The genetic studies of this species have been hindered by a lack of high-quality reference sequence due to its complex genome structure. Diploid Ipomoea trifida is the closest relative and putative progenitor of sweetpotato, which is considered a model species for sweetpotato, including genetic, cytological, and physiological analyses. Here, we generated the chromosome-scale genome sequence of SR-forming diploid I. trifida var. Y22 with high heterozygosity (2.20%). Although the chromosome-based synteny analysis revealed that the I. trifida shared conserved karyotype with Ipomoea nil after the separation, I. trifida had a much smaller genome than I. nil due to more efficient eliminations of LTR-retrotransposons and lack of species-specific amplification bursts of LTR-RTs. A comparison with four non-SR-forming species showed that the evolution of the beta-amylase gene family may be related to SR formation. We further investigated the relationship of the key gene BMY11 (with identity 47.12% to beta-amylase 1) with this important agronomic trait by both gene expression profiling and quantitative trait locus (QTL) mapping. And combining SR morphology and structure, gene expression profiling and qPCR results, we deduced that the products of the activity of BMY11 in splitting starch granules and be recycled to synthesize larger granules, contributing to starch accumulation and SR swelling. Moreover, we found the expression pattern of BMY11, sporamin proteins and the key genes involved in carbohydrate metabolism and stele lignification were similar to that of sweetpotato during the SR development. We constructed the high-quality genome reference of the highly heterozygous I. trifida through a combined approach and this genome enables a better resolution of the genomics feature and genome evolutions of this species. Sweetpotato SR development genes can be identified in I. trifida and these genes perform similar functions and patterns, showed that the diploid I. trifida var. Y22 with typical SR could be considered an ideal model for the studies of sweetpotato SR development.


Independent practice association physician groups in California.
We surveyed independent practice association (IPA) physician groups in California about their approaches to staffing, physician payment, and governance. Most IPAs desired more primary care physicians but not more specialists. Capitation was the major mode of remuneration for primary care physicians in 77 percent of IPAs, and for specialists in 30 percent of IPAs. Most IPAs also used financial incentives related to use of referral or ancillary services. Boards of directors were dominated by physicians, but governance tended to be centralized rather than highly democratic. We found that IPAs mirror many of the broader trends in physician staffing and physician payment that exist in managed care organizations.


Paradoxical elevation of high-molecular weight adiponectin in acquired extreme insulin resistance due to insulin receptor antibodies.
Total plasma adiponectin and high-molecular weight (HMW) polymeric adiponectin are strongly positively correlated with insulin sensitivity. However, we have recently reported paradoxical hyperadiponectinemia in patients with severe insulin resistance due to genetically defective insulin receptors. This implies either that the insulin receptor has a critical physiological role in controlling adiponectin production and/or clearance or that constitutive insulin receptor dysfunction influences adiponectin levels through developmental effects. The aim of the current study was to distinguish between these possibilities using a human model of reversible antibody-mediated insulin receptor dysfunction and to refine the previous observations by determining adiponectin complex distribution. Cross-sectional and longitudinal determination of fasting plasma adiponectin and adiponectin complex distribution was undertaken in patients with extreme insulin resistance due to insulin receptor mutations, anti-insulin receptor antibodies (type B insulin resistance), or an undefined cause. Despite extreme insulin resistance, patients with type B insulin resistance (all women; mean age 42 years [range 12-54]) had dramatically elevated total plasma adiponectin compared with the general population (mean 43.0 mg/l [range 31.3-54.2] vs. 8.9 mg/l [1.5-28.5 for BMI <25 kg/m(2)]), which was accounted for largely by HMW polymers. Hyperadiponectinemia resolved in parallel with reduction of insulin receptor antibodies and clinical resolution of insulin resistance. Although the well-established inverse relationship between plasma insulin and adiponectin levels may, in part, reflect positive effects of adiponectin on insulin sensitivity, these data suggest that the magnitude of the effect of insulin action on adiponectin levels may have been underestimated.


B7-1 but not B7-2 efficiently costimulates CD8+ T lymphocytes in the P815 tumor system in vitro.
We recently have developed a method to generate primary P815-specific CTL in vitro from normal syngeneic splenocytes by employing transfection of B7-1 combined with exogenous IL-12 and IL-6. Surprisingly, when the homologous costimulator molecule B7-2 was substituted for B7-1 in this system, no specific CTL activity was obtained. Similarly, B7-1- but not B7-2-transfected P815 cells generated alloantigen-specific CTL activity from C57BL/6, accessory cell- and CD4(+)-depleted splenocytes, and costimulated proliferation of CD8+ lymphocytes in the presence of low doses of anti-CD3 mAb. In all systems, combined expression of both B7-1 and B7-2 costimulated as effectively as B7-1 alone, arguing against delivery of a dominant negative signal by B7-2. Proliferation of allogeneic, CD4(+)-depleted splenocytes in response to P815 cells, which relies on costimulation by normal accessory cells, was inhibited by anti-B7-1 but not anti-B7-2 mAbs. Finally, indirect evidence suggested a higher avidity of B7-1+ cells than B7-2+ cells for CTLA4. Thus, at least in the context of primary stimulation by irradiated P815 transfectants, B7-1 appears to be superior to B7-2 at costimulation of CD8+ T lymphocytes.


The transcription factor SP4 is reduced in postmortem cerebellum of bipolar disorder subjects: control by depolarization and lithium.
Regulation of gene expression is important for the development and function of the nervous system. However, the transcriptional programs altered in psychiatric diseases are not completely characterized. Human gene association studies and analysis of mutant mice suggest that the transcription factor specificity protein 4 (SP4) may be implicated in the pathophysiology of psychiatric diseases. We hypothesized that SP4 levels may be altered in the brain of bipolar disorder (BD) subjects and regulated by neuronal activity and drug treatment. We analyzed messenger RNA (mRNA) and protein levels of SP4 and SP1 in the postmortem prefrontal cortex and cerebellum of BD subjects (n = 10) and controls (n = 10). We also examined regulation of SP4 mRNA and protein levels by neuronal activity and lithium in rat cerebellar granule neurons. We report a reduction of SP4 and SP1 proteins, but not mRNA levels, in the cerebellum of BD subjects. SP4 protein and mRNA levels were also reduced in the prefrontal cortex. Moreover, we found in rat cerebellar granule neurons that under non-depolarizing conditions SP4, but not SP1, was polyubiquitinated and degraded by the proteasome while lithium stabilized SP4 protein. Our study provides the first evidence of altered SP4 protein in the cerebellum and prefrontal cortex in BD subjects supporting a possible role of transcription factor SP4 in the pathogenesis of the disease. In addition, our finding that SP4 stability is regulated by depolarization and lithium provides a pathway through which neuronal activity and lithium could control gene expression suggesting that normalization of SP4 levels could contribute to treatment of affective disorders.


JMJD1C Exhibits Multiple Functions in Epigenetic Regulation during Spermatogenesis.
Jmjd1C is one of the Jmjd1 family genes that encode putative demethylases against histone H3K9 and non-histone proteins and has been proven to play an indispensable role in mouse spermatogenesis. Here, we analyzed a newly-bred transgenic mouse strain carrying a Jmjd1C loss-of-function allele in which a β-geo cassette was integrated into the intron of the Jmjd1C locus. Jmjd1C gene-trap homozygous testes exhibited malformations in postmeiotic processes and a deficiency in the long-term maintenance of undifferentiated spermatogonia. Some groups of spermatids in the homozygous testis showed abnormal organization and incomplete elongation from the first wave of spermatogenesis onwards. Moreover, histone H4K16 acetylation, which is required for the onset of chromatin remodeling, appeared to be remarkably decreased. These effects may not have been a result of the drastic decrease in gene expression related to the events but instead may have been due to the lack of interaction between JMJD1C and its partner proteins, such as MDC1 and HSP90. Additionally, significant decreases in Oct4 expression and NANOG- and OCT4-expressing spermatogonia were found in the Jmjd1C homozygous mature testis, suggesting that JMJD1C may participate in the maintenance of spermatogonial stem cell self-renewal by up-regulating Oct4 expression. These results indicate that JMJD1C has multiple functions during spermatogenesis through interactions with different partners during the spermatogenic stages.


Knowledge and use of sterile water injections amongst midwives in the United Kingdom: A cross-sectional study.
The use of sterile water injections (SWI) for the relief of pain in labour is popular amongst midwives in countries such as Sweden and Australia. Anecdotal reports suggest the procedure is used less commonly in the United Kingdom (UK) and that a number of barriers to introducing the practice may exist. The objective of this study was to explore the awareness and use of SWI amongst midwives in the UK. A cross-sectional study using an internet-based questionnaire. Midwives with Nursing and Midwifery Council Registration and currently practicing. The questionnaire was distributed via the Royal College of Midwives Facebook page and Twitter account. Invitations to participate were also sent to Heads of Midwifery to distribute to staff. Three hundred and ninety-eight midwives completed the survey. Eighty-two percent of midwives did not use SWI in practice although 69% would consider learning the procedure. There was considerable variation in techniques amongst midwives that did provide SWI. The lack of available practice guidelines and the advice from the National Institute for Health and Care Excellence to not use SWI were cited as the main barriers. SWI use is uncommon in the UK although midwives are interested in incorporating the procedure into practice. National guidance on SWI and the lack of information and training is restricting the use of the procedure in practice, despite SWI being widely used in other countries and being effective in the treatment of pain in labour.


Blood pressure after stroke. A one-year follow-up study.
Blood pressure changes in the year after acute stroke have been poorly documented. We therefore studied blood pressure for 1 year after discharge from the hospital in 226 consecutive patients (mean age, 73 years) surviving an acute stroke. Marked increases (p < 0.001) in mean systolic and mean diastolic blood pressures were seen in two thirds (69%) of the patients 1 month after discharge, and blood pressure remained stable at this level during the remainder of the follow-up year. Similar blood pressure changes were seen irrespective of sex, final stroke diagnosis, or whether the patient had a history of hypertension before the stroke. Patients with a history of hypertension had significantly higher blood pressures (p < 0.001) throughout the follow-up year than previously normotensive patients. One month after discharge blood pressure was found to have decreased in 31% of the patients; these were older and had a higher mortality during the follow-up year than patients with blood pressure increases. About 20% of all patients suffered from orthostatism (defined as a decrease in systolic blood pressure of > or = 20 mm Hg when rising from the supine position to standing). We conclude that antihypertensive treatment should not be reduced before discharge from the hospital and that blood pressure should be checked about 1 month after discharge. We suggest that standing blood pressure also be measured to make an appropriate treatment decision.


Association of UV radiation with Parkinson disease incidence: A nationwide French ecologic study.
Vitamin D is thought to contribute to brain health, but it is unclear whether low vitamin D levels are associated with increased incidence of Parkinson's disease (PD). Using ultraviolet B (UV-B) as a surrogate for vitamin D levels, we conducted a nationwide ecologic study in France in order to examine the association of UV-B with PD incidence. We used French national drug claims databases to identify PD cases using a validated algorithm. UV-B data from the solar radiation database were derived from satellite images. We estimated PD incidence (2010-2012) at the canton level (small administrative French unit) and used multilevel Poisson regression to examine its association with UV-B (2005 annual average), after adjustment for age, sex, deprivation index, density of neurologists, smoking, proportion of agricultural land, and vitamin D supplementation. Analyses are based on 69,010 incident PD patients. The association between UV-B and PD incidence was quadratic (P<0.001) and modified by age (P<0.001). Below 70y, incidence was higher in the bottom quintile (relative risk, RRQ1:45-49y=1.18, 95% CI=1.08-1.29) compared with the middle UV-B quintile, and lower in the top quintile (RRQ5:45-49y=0.85 [0.77-0.94]). An opposite pattern was observed in older subjects (RRQ1:85-89y=0.92 [0.89-0.96]; RRQ5:85-89y=1.06 [1.02-1.11]). Analysis based on continuous UV-B yielded similar conclusions. In this nationwide study, there was an age-dependent quadratic association between UV-B and PD incidence. This study suggests that reasonable UV-B exposure is associated with lower PD risk in younger persons and that future studies should examine dose-response relations and take age into account.


On the Stability of BOLD fMRI Correlations.
Measurement of correlations between brain regions (functional connectivity) using blood oxygen level dependent (BOLD) fMRI has proven to be a powerful tool for studying the functional organization of the brain. Recently, dynamic functional connectivity has emerged as a major topic in the resting-state BOLD fMRI literature. Here, using simulations and multiple sets of empirical observations, we confirm that imposed task states can alter the correlation structure of BOLD activity. However, we find that observations of "dynamic" BOLD correlations during the resting state are largely explained by sampling variability. Beyond sampling variability, the largest part of observed "dynamics" during rest is attributable to head motion. An additional component of dynamic variability during rest is attributable to fluctuating sleep state. Thus, aside from the preceding explanatory factors, a single correlation structure-as opposed to a sequence of distinct correlation structures-may adequately describe the resting state as measured by BOLD fMRI. These results suggest that resting-state BOLD correlations do not primarily reflect moment-to-moment changes in cognitive content. Rather, resting-state BOLD correlations may predominantly reflect processes concerned with the maintenance of the long-term stability of the brain's functional organization.


Comparative effects of thyroxine and/or retinoic acid treatment in vivo on growth hormone synthesis and release by pituitaries from thyroidectomized rats.
Thyroid hormones and retinoic acid (RA) coregulate growth hormone (GH) synthesis and release from cultured pituitary tumor cells by interacting with nuclear receptors that activate GH gene transcription. Whether these two compounds share overlapping GH regulatory activities in vivo is unclear. Therefore we compared the effects of in vivo replacement therapy with thyroxine (T4) and/or retinoic acid (RA) on GH synthesis and release in pituitaries from hypothyroid rats. Three weeks after thyroidectomy, male rats (100-150 grams, body weight) received 7 days of intraperitoneal T4 (20 ug/kg/day) and/or RA (500 ug/kg/day) or vehicle. Isolated pituitary fragments were incubated for 3 h with [14C]leucine followed by 2 h with [3H]leucine and 3 nM rat growth hormone-releasing hormone (GHRH). Basal synthesis, GHRH-induced release of stored [14C]GH, and GHRH-stimulated release of newly synthesized [3H]GH were assessed by specific immunopercipitation of media and tissue homogenates. T4 increased the synthesis of GH in the absence and presence of GHRH. T4, but not RA, increased the absolute amount of stored and newly synthesized GH released by GHRH. Neither T4 nor RA altered the percent of stored GH released by GHRH, however, both independently or additively decreased the percent of newly synthesized GH released by GHRH. In summary, treatment of hypothyroidism with T4 increased GH synthesis and absolute release. Interestingly the fractional release of GH was unchanged or decreased by T4 treatment. RA treatment had no effect on GH synthesis or absolute release, but like T4 it decreased the fractional release of newly synthesized GH. Thus T4 and RA did not share similar regulatory effects on GH synthesis and stored GH release but did have similar effects on the fractional release of newly synthesized GH in pituitaries from thyroidectomized male rats.


Ion beam induced surface pattern formation and stable travelling wave solutions.
The formation of ripple structures on ion bombarded semiconductor surfaces is examined theoretically. Previous models are discussed and a new nonlinear model is formulated, based on the infinitesimal local atomic relocation induced by elastic nuclear collisions in the early stages of collision cascades and an associated density change in the near surface region. Within this framework ripple structures are shown to form without the necessity to invoke surface diffusion or large sputtering as important mechanisms. The model can also be extended to the case where sputtering is important, and it is shown that in this case certain 'magic' angles can occur at which the ripple patterns are most clearly defined. The results are in very good agreement with experimental observations.


The chromosome translocation (11;14)(p13;q11) associated with T-cell acute lymphocytic leukemia: an 11p13 breakpoint cluster region.
The translocation (11;14)(p13;q11) was observed in karyotypes of leukemic cells from a 3-year-old boy with T-cell acute lymphocytic leukemia (T-ALL). Since this translocation is a recurrent marker of T-ALL, we undertook to investigate its mode of formation and role in leukemogenesis. The cytogenetic breakpoint on chromosome 14 occurs in 14q11, the same band wherein lies the T-cell receptor alpha/delta chain gene; and Southern hybridization analysis of peripheral blood and bone marrow DNA uncovered a tumor-specific rearrangement in the D delta-J delta region of this locus. DNA encompassing the rearrangement was isolated by molecular cloning, and further analysis revealed it to be the t(11;14)(p13;q11) junction. Nucleotide sequence determination of the junction indicates that the 14q11 breakpoint occurs immediately adjacent to the D delta 2 gene segment. Hence, the translocation arose as an aberrant rearrangement between the downstream recombination signal of D delta 2 and a pseudo recombination signal adjacent to the chromosome 11 breakpoint. Finally, comparison of the breakpoint in band 11p13 with those of other translocations (11;14)(p13;q11) identified a breakpoint cluster region of approximately 1.2 kilobase-pairs (kb), alterations of which may promote the development of T-ALL.


Anaplastic Pleomorphic Xanthoastrocytoma in a Case of Neurofibromatosis Type 1: A Case Report.
Pleomorphic Xanthoastrocytoma (PXA) is a rare brain tumour comprising only <1% of primary brain tumours which is seen in children and young adults. Only 9-20% of the PXA shows anaplastic features and this has a bad prognosis. PXA is a WHO grade II tumour while anaplastic PXA is a WHO grade III tumour. Neurofibromatosis type 1(NF1), which is an autosomal dominant condition, predisposes to tumours of the central nervous system; most of which are pilocytic astrocytomas. Association of PXA with NF1 is very rare and only a very few cases have been reported. Here, we present a case of 42-year-old male, a known case of NF1, with multiple neurofibromas, who presented with right sided hemiparesis, seizures and vomiting. The histopathology and immunohistochemistry features were suggestive of anaplastic PXA.


Lanthanoid-free perovskite oxide catalyst for dehydrogenation of ethylbenzene working with redox mechanism.
For the development of highly active and robust catalysts for dehydrogenation of ethylbenzene (EBDH) to produce styrene; an important monomer for polystyrene production, perovskite-type oxides were applied to the reaction. Controlling the mobility of lattice oxygen by changing the structure of Ba1 - x SrxFe y Mn1 - y O3 - δ (0 ≤ x ≤ 1, 0.2 ≤ y ≤ 0.8), perovskite catalyst showed higher activity and stability on EBDH. The optimized Ba/Sr and Fe/Mn molar ratios were 0.4/0.6 and 0.6/0.4, respectively. Comparison of the dehydrogenation activity of Ba0.4Sr0.6Fe0.6Mn0.4O3 - δ catalyst with that of an industrial potassium promoted iron (Fe-K) catalyst revealed that the Ba0.4Sr0.6Fe0.6Mn0.4O3 - δ catalyst showed higher initial activity than the industrial Fe-K oxide catalyst. Additionally, the Ba0.4Sr0.6Fe0.6Mn0.4O3 - δ catalyst showed high activity and stability under severe conditions, even at temperatures as low as 783 K, or at the low steam/EB ratio of 2, while, the Fe-K catalyst showed low activity in such conditions. Comparing reduction profiles of the Ba0.4Sr0.6Fe0.6Mn0.4O3 - δ and the Fe-K catalysts in a H2O/H2 atmosphere, reduction was suppressed by the presence of H2O over the Ba0.4Sr0.6Fe0.6Mn0.4O3 - δ catalyst while the Fe-K catalyst was reduced. In other words, Ba0.4Sr0.6Fe0.6Mn0.4O3 - δ catalyst had higher potential for activating the steam than the Fe-K catalyst. The lattice oxygen in perovskite-structure was consumed by H2, subsequently the consumed lattice oxygen was regenerated by H2O. So the catalytic performance of Ba0.4Sr0.6Fe0.6Mn0.4O3 - δ was superior to that of Fe-K catalyst thanks to the high redox property of the Ba0.4Sr0.6Fe0.6Mn0.4O3 - δ perovskite oxide.


Coronary artery embolism in a patient with Fontan palliation: a rare complication.
Coronary artery embolism is extremely rare in children with Fontan palliation. We report a 10-year-old boy with hypoplastic left heart syndrome post-Fontan procedure who presented with acute onset chest pain and ST-segment changes on electrocardiogram. Cardiac catheterisation revealed coronary artery emboli requiring stent placement. Our case highlights the importance of evaluating chest pain in a systematic manner in Fontan patients as acute coronary artery embolism can be a part of the spectrum of well-known thromboembolic complications.


Pre-saccadic shifts of visual attention.
The locations of visual objects to which we attend are initially mapped in a retinotopic frame of reference. Because each saccade results in a shift of images on the retina, however, the retinotopic mapping of spatial attention must be updated around the time of each eye movement. Mathôt and Theeuwes [1] recently demonstrated that a visual cue draws attention not only to the cue's current retinotopic location, but also to a location shifted in the direction of the saccade, the "future-field". Here we asked whether retinotopic and future-field locations have special status, or whether cue-related attention benefits exist between these locations. We measured responses to targets that appeared either at the retinotopic or future-field location of a brief, non-predictive visual cue, or at various intermediate locations between them. Attentional cues facilitated performance at both the retinotopic and future-field locations for cued relative to uncued targets, as expected. Critically, this cueing effect also occurred at intermediate locations. Our results, and those reported previously [1], imply a systematic bias of attention in the direction of the saccade, independent of any predictive remapping of attention that compensates for retinal displacements of objects across saccades [2].


Role of lipoprotein-X in the pathogenesis of cholestatic hypercholesterolemia. Uptake of lipoprotein-X and its effect on 3-hydroxy-3-methylglutaryl coenzyme A reductase and chylomicron remnant removal in human fibroblasts, lymphocytes, and in the rat.
Cholestasis is accompanied by the appearance of lipoprotein-X (LP-X) in plasma. This lipoprotein has a high content of unesterified cholesterol and phospholipids and appears to be ineffective in suppressing the enhanced hepatic cholesterogenesis of cholestasis. Its role as a possible causative factor for cholestatic hypercholesterolemia was investigated. When 125I-LP-X was injected into rats, it disappeared rapidly from the circulation. Calculated on the basis of gram wet weight, spleen took up more LP-X than liver. Prior ligation of the bile duct reduced the uptake in spleen. Experiments with isolated perfused rat liver showed that nonparenchymal cells (NPC) took up over eightfold more 125I-LP-X than hepatic parenchymal cells (PC). Incubation of PC, NPC, human lymphocyte suspensions, or fibroblast cultures with LP-X showed that NPC bound more LP-X than PC or fibroblasts. Lymphocytes took up 20-fold more LP-X than PC and the activity of 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase was depressed by LP-X. Lymphocytes isolated from cholestatic patients showed low activity of this enzyme. The activity was increased by LP-X in isolated perfused livers, but suppressed in isolated microsomes. LP-X competitively inhibited the uptake of chylomicron remnants in isolated perfused livers and hepatocytes. In contrast, degradation of LDL by perfused livers, which were isolated from ethinyl estradiol-treated rats or human fibroblast cultures, remained unchanged in the presence of LP-X. The results indicate that cholesterol transported by LP-X is mainly taken up by the cells of the reticuloendothelial system. It increases the activity of hepatic HMG-CoA reductase and suppresses remnant uptake, thus emphasizing a major role of LP-X in cholestatic hypercholesterolemia.


Effect of Organic Diet Intervention on Pesticide Exposures in Young Children Living in Low-Income Urban and Agricultural Communities.
Recent organic diet intervention studies suggest that diet is a significant source of pesticide exposure in young children. These studies have focused on children living in suburban communities. We aimed to determine whether consuming an organic diet reduced urinary pesticide metabolite concentrations in 40 Mexican-American children, 3-6 years of age, living in California urban and agricultural communities. In 2006, we collected urine samples over 16 consecutive days from children who consumed conventionally grown food for 4 days, organic food for 7 days, and then conventionally grown food for 5 days. We measured 23 metabolites, reflecting potential exposure to organophosphorous (OP), pyrethroid, and other pesticides used in homes and agriculture. We used linear mixed-effects models to evaluate the effects of diet on urinary metabolite concentrations. For six metabolites with detection frequencies > 50%, adjusted geometric mean concentrations during the organic phase were generally lower for all children, and were significant for total dialkylphosphates (DAPs) and dimethyl DAPs (DMs; metabolites of OP insecticides) and 2,4-D (2,4-dichlorophenoxyacetic acid, a herbicide), with reductions of 40%, 49%, and 25%, respectively (p < 0.01). Chemical-specific metabolite concentrations for several OP pesticides, pyrethroids, and herbicides were either infrequently detected and/or not significantly affected by diet. Concentrations for most of the frequently detected metabolites were generally higher in Salinas compared with Oakland children, with DMs and metolachlor at or near significance (p = 0.06 and 0.03, respectively). An organic diet was significantly associated with reduced urinary concentrations of nonspecific dimethyl OP insecticide metabolites and the herbicide 2,4-D in children. Additional research is needed to clarify the relative importance of dietary and non-dietary sources of pesticide exposures to young children.


Effect of asynchronous nitrogen and energy supply on growth of ruminal bacteria in batch culture.
The effects of an asynchronous supply of fixed amounts of N and carbohydrate on bacterial growth were measured in two batch culture experiments. In Exp. 1, aqueous glucose and urea solutions were added at hourly intervals to culture flasks containing strained ruminal liquor and phosphate/bicarbonate buffer. The ratio of urea N to glucose was either constant (Synchrony, 26 mg of N/g of glucose) or increased exponentially over time (Asynchrony, .013 to 48,900 mg of N/g of glucose). After 12 h, identical quantities of glucose and urea had been added in both treatments. Bacterial population size (estimated from optical density) was greater (P less than .001) from 5 to 8 h of incubation for Synchrony than for Asynchrony, but after 12 h there was no difference (P greater than .1) between treatments. In Exp. 2, large (1 to 1.5 mm) and small (less than .5 mm) corn particles were used as slowly and rapidly degraded energy sources, with soybean meal (1 to 1.5 mm) and a papaic digest of soybean meal as sources of slowly and rapidly degraded N. At incubation times, when the ratio between total starch and N degraded was equal between treatments, bacterial population size was unaffected by the relative rate of N and OM supply. In both experiments, bacterial growth recovered quickly from transient restriction caused by deficits of N.