Circadian rhythms, sleep, and metabolism.
The discovery of the genetic basis for circadian rhythms has expanded our knowledge of the temporal organization of behavior and physiology. The observations that the circadian gene network is present in most living organisms from eubacteria to humans, that most cells and tissues express autonomous clocks, and that disruption of clock genes results in metabolic dysregulation have revealed interactions between metabolism and circadian rhythms at neural, molecular, and cellular levels. A major challenge remains in understanding the interplay between brain and peripheral clocks and in determining how these interactions promote energy homeostasis across the sleep-wake cycle. In this Review, we evaluate how investigation of molecular timing may create new opportunities to understand and develop therapies for obesity and diabetes.


Dissociating the Impact of Movement Time and Energy Costs on Decision-Making and Action Initiation in Humans.
Recent theories and data suggest that adapted behavior involves economic computations during which multiple trade-offs between reward value, accuracy requirement, energy expenditure, and elapsing time are solved so as to obtain rewards as soon as possible while spending the least possible amount of energy. However, the relative impact of movement energy and duration costs on perceptual decision-making and movement initiation is poorly understood. Here, we tested 31 healthy subjects on a perceptual decision-making task in which they executed reaching movements to report probabilistic choices. In distinct blocks of trials, the reaching duration ("Time" condition) and energy ("Effort" condition) costs were independently varied compared to a "Reference" block, while decision difficulty was maintained similar at the block level. Participants also performed a simple delayed-reaching (DR) task aimed at estimating movement initiation duration in each motor condition. Results in that DR task show that long duration movements extended reaction times (RTs) in most subjects, whereas energy-consuming movements led to mixed effects on RTs. In the decision task, about half of the subjects decreased their decision durations (DDs) in the Time condition, while the impact of energy on DDs were again mixed across subjects. Decision accuracy was overall similar across motor conditions. These results indicate that movement duration and, to a lesser extent, energy expenditure, idiosyncratically affect perceptual decision-making and action initiation. We propose that subjects who shortened their choices in the time-consuming condition of the decision task did so to limit a drop of reward rate.


Effect of environmental parameters on the inactivation of the waterborne pathogen Campylobacter in a Mediterranean river.
Campylobacter is a major waterborne pathogen that can be found in rivers of the Mediterranean area. Characteristics of these rivers change throughout the seasons due to variations in environmental parameters. As these variations may affect water survival of Campylobacter, we analyzed it in the Llobregat River using three approaches whose complexity increase progressively: (i) river water microcosms in the laboratory subjected to varying temperatures; (ii) in situ experiments carried out in the river, in which bacteria were exposed to varying levels of environmental parameters; and (iii) monitoring of thermotolerant Campylobacter in the river over two years. Campylobacter was quantified using the most probable number (MPN) method. The results showed that an increase in water temperature accelerates Campylobacter inactivation, measured as the loss of culturability. In situ experiments revealed that inactivation rates were also affected by sunlight, but not by pH, oxygen concentration or water conductivity. These observations are supported by the seasonality detected in Llobregat River. Campylobacter inactivation was fastest in spring and summer, when temperature and solar radiation were at their highest. The results highlight the importance of considering the inactivation rates in natural conditions to improve the monitoring of this pathogen and thus evaluate properly the health risk associated to water.


Quality of life in patients with recurrent ovarian cancer treated with niraparib versus placebo (ENGOT-OV16/NOVA): results from a double-blind, phase 3, randomised controlled trial.
Quality of life (QOL) has become an important complementary endpoint in cancer clinical studies alongside more traditional assessments (eg, tumour response, progression-free survival, overall survival). Niraparib maintenance treatment has been shown to significantly improve progression-free survival in patients with recurrent ovarian cancer. We aimed to assess whether the benefits of extending progression-free survival are offset by treatment-associated toxic effects that affect QOL. The ENGOT-OV16/NOVA trial was a multicentre, double-blind, phase 3, randomised controlled trial done in 107 study sites in the USA, Canada, Europe, and Israel. Patients with recurrent ovarian cancer who were in response to their last platinum-based chemotherapy were randomly assigned (2:1) to receive either niraparib (300 mg once daily) as a maintenance treatment or placebo. Randomisation was stratified based on time to progression after the penultimate platinum-based regimen, previous use of bevacizumab, and best response (complete or partial) to the last platinum-based regimen with permuted-block randomisation (six in each block) using an interactive web response system. The trial enrolled two independent cohorts on the basis of germline BRCA (gBRCA) mutation status (determined by BRACAnalysis Testing, Myriad Genetics, Salt Lake City, UT, USA). The primary endpoint of the trial was progression-free survival, and has already been reported. In this study, we assessed patient-reported outcomes (PROs) in the intention-to-treat population using the Functional Assessment of Cancer Therapy-Ovarian Symptoms Index (FOSI) and European QOL five-dimension five-level questionnaire (EQ-5D-5L). We collected PROs from trial entry every 8 weeks for the first 14 cycles and every 12 weeks thereafter. If a patient discontinued, we collected PROs at discontinuation and during a postprogression visit 8 weeks (plus or minus 2 weeks) later. We assessed the effect of haematological toxic effects on QOL with disutility analyses of the most common grade 3-4 adverse events (thrombocytopenia, anaemia, and neutropenia) using a mixed model with histology, region, previous treatment, age, planned treatment, and baseline score as covariates. This study is registered with ClinicalTrials.gov, number NCT01847274. Between Aug 28, 2013, and June 1, 2015, 553 patients were enrolled and randomly assigned to receive niraparib (n=138 in the gBRCAmut cohort, n=234 in the non-gBRCAmut cohort) or placebo (n=65 in the gBRCAmut cohort, n=116 in the non-gBRCAmut cohort). The mean FOSI score at baseline was similar between the two groups (range between 25·0-25·6 in the two groups). Overall QOL scores remained stable during the treatment and preprogression period in the niraparib group; no significant differences were observed between the niraparib and placebo group, and preprogression EQ-5D-5L scores were similar between the two groups in both cohorts (0·838 [0·0097] in the niraparib group vs 0·834 [0·0173] in the placebo group in the gBRCAmut cohort; and 0·833 [0·0077] in the niraparib group vs 0·815 [0·0122] in the placebo group in the non-gBRCAmut cohort). The most common adverse events reported at screening (baseline) were lack of energy (425 [79%]; 97 [18%] reporting severe lack of energy), pain (236 [44%]), and nausea (118 [22%]). All symptoms, except nausea, either remained stable or improved over time in the niraparib group. The most common grade 3 or 4 toxicities observed in the niraparib group were haematological in nature: thrombocytopenia (124 [34%] of 367 patients), anaemia (93 [25%]), and neutropenia (72 [20%]); disutility analyses showed no significant QOL impairment associated with these toxic effects. These PRO data suggest that women who receive niraparib as maintenance treatment for recurrent ovarian cancer after responding to platinum treatment are able to maintain QOL during their treatment when compared with placebo. TESARO.


Interest in politics modulates neural activity in the amygdala and ventral striatum.
Studies on political participation have found that a person's interest in politics contributes to the likelihood that he or she will be involved in the political process. Here, we looked at whether or not interest in politics affects patterns of brain activity when individuals think about political matters. Using functional magnetic resonance imaging (fMRI), we scanned individuals (either interested or uninterested in politics based on a self-report questionnaire) while they were expressing their agreement or disagreement with political opinions. After scanning, participants were asked to rate each political opinion presented in the scanner for emotional valence and emotional intensity. Behavioral results showed that those political opinions participants agreed with were perceived as more emotionally intense and more positive by individuals interested in politics relative to individuals uninterested in politics. In addition, individuals interested in politics showed greater activation in the amygdala and the ventral striatum (ventral putamen) relative to individuals uninterested in politics when reading political opinions in accordance with their own views. This study shows that having an interest in politics elicits activations in emotion- and reward-related brain areas even when simply agreeing with written political opinions.


Mutants in dolichol synthesis: conversion of polyprenol to dolichol appears to be a rate-limiting step in dolichol synthesis.
Chinese hamster ovary (CHO) cells of the Lec9 recessive complementation group display a distinctive profile of resistance to a variety of toxic lectins. In addition, they accumulate cis-alpha-unsaturated polyprenol and use mainly polyprenol rather than dolichol to synthesize the glycosylated lipids used in asparagine-linked glycosylation of proteins. The primary defect in these cells is thought to result from a deficiency in polyprenol reductase activity. Three new mutants were isolated and determined to have qualitatively, although not quantitatively, similar lectin resistance profiles to Lec9 cells. Two of these mutants (AbrR and RicR) also contained polyprenol rather than dolichol. The lectin resistance profile of an independent mutant which accumulates polyprenol, F2A8, was also found to be qualitatively similar to the Lec9 pattern. The relationship among these mutants was analysed in more detail by construction of cell-cell hybrids. Lectin resistance profiles of the hybrids demonstrated that AbrR, RicR and F2A8 fell into the Lec9 complementation group. Analysis of prenols in the hybrids also showed that F2A8 was a member of the Lec9 group. Surprisingly, a significant fraction of the prenols found in Lec9 x Parent hybrids was polyprenol (up to 30% of the neutral fraction), whereas the prenols found in Parent x Parent hybrids were nearly exclusively dolichol (97% of the neutral lipid fraction). Therefore, reduction of polyprenol to dolichol appears to be a rate-limiting step in the synthesis of dolichol since hybrids with differing numbers of wild-type alleles can be biochemically distinguished.


Interleukin 12 primes macrophages for nitric oxide production in vivo and restores depressed nitric oxide production by macrophages from tumor-bearing mice: implications for the antitumor activity of interleukin 12 and/or interleukin 2.
Interleukin-12 (IL-12) is a recently described immunoregulatory cytokine with potent therapeutic activity in various preclinical models of infectious or malignant disease. As part of our ongoing evaluation of potential mechanisms accounting for the potent antitumor activity of IL-12, we have investigated the influence of IL-12 administration on total serum nitrate/nitrite (NO(x)(-)) levels and the production of nitric oxide (NO) by peritoneal macrophages from normal and tumor-bearing mice. We report here that IL-12 administration to either normal or tumor-bearing mice for periods of time ranging from 7-19 days induced progressive increases in serum NO(x)(-) levels and primed peritoneal macrophages for NO production on subsequent exposure to lipopolysaccharide or IL-2 ex vivo. Treatment of resident peritoneal macrophages or the macrophage cell line ANA-1 with IL-12 alone or IL-12 in combination with various other stimuli failed to induce NO production, suggesting that the effects of IL-12 occurred via an indirect mechanism. Furthermore, we have shown that not only was the production of NO by macrophages from untreated long-term, tumor- bearing mice suppressed compared with control mice treated with vehicle or IL-12, but also that IL-12 administration overcame this suppression and delayed tumor growth. Lastly, we have shown that administration of weekly pulses of IL-2 in combination with IL-12 additively enhanced the priming of macrophages for NO production ex vivo and delayed tumor growth far more effectively than either agent alone. These observations and reports in the literature regarding the potential influence of NO on development of the immune response and on the regulation of tumor growth and vascularization suggest that NO may play a significant role in the antitumor activity of IL-12 and IL-2.


Cloning and expression of the VHDL receptor from fat body of the corn ear worm, Helicoverpa zea.
In Noctuids, storage proteins are taken up into fat body by receptor-mediated endocytosis. These include arylphorin and a second, structurally unrelated very high-density lipoprotein (VHDL). Previously, we have isolated a single storage protein receptor from the corn earworm, Helicoverpa zea, which binds both VHDL and arylphorin. The receptor protein is a basic, N-terminally blocked, approximately 80 kDa protein that is associated with fat body membranes. Microsequencing of proteolytic fragments of the isolated receptor protein revealed internal sequences that were used to clone the complete cDNA of the VHDL receptor by 3' and 5' RACE techniques. The receptor protein, when expressed in vitro via a suitable insect expression vector, reacted with antibodies against the native VHDL receptor and bound strongly to its ligand VHDL, thus confirming that the cloned cDNA represents indeed the previously purified VHDL receptor. The receptor protein and a second, similar protein also found associated with the fat body membrane show considerable homology to putative basic juvenile hormone suppressible proteins cloned previously from other Noctuid species. Sequence analysis revealed that the receptor is likely a peripheral membrane protein that may mediate the selective uptake of VHDL.


Oysters and eelgrass: potential partners in a high pCO2 ocean.
Climate change is affecting the health and physiology of marine organisms and altering species interactions. Ocean acidification (OA) threatens calcifying organisms such as the Pacific oyster, Crassostrea gigas. In contrast, seagrasses, such as the eelgrass Zostera marina, can benefit from the increase in available carbon for photosynthesis found at a lower seawater pH. Seagrasses can remove dissolved inorganic carbon from OA environments, creating local daytime pH refugia. Pacific oysters may improve the health of eelgrass by filtering out pathogens such as Labyrinthula zosterae (LZ), which causes eelgrass wasting disease (EWD). We examined how co-culture of eelgrass ramets and juvenile oysters affected the health and growth of eelgrass and the mass of oysters under different pCO2 exposures. In Phase I, each species was cultured alone or in co-culture at 12°C across ambient, medium, and high pCO2 conditions, (656, 1,158 and 1,606 μatm pCO2 , respectively). Under high pCO2 , eelgrass grew faster and had less severe EWD (contracted in the field prior to the experiment). Co-culture with oysters also reduced the severity of EWD. While the presence of eelgrass decreased daytime pCO2 , this reduction was not substantial enough to ameliorate the negative impact of high pCO2 on oyster mass. In Phase II, eelgrass alone or oysters and eelgrass in co-culture were held at 15°C under ambient and high pCO2 conditions, (488 and 2,013 μatm pCO2 , respectively). Half of the replicates were challenged with cultured LZ. Concentrations of defensive compounds in eelgrass (total phenolics and tannins), were altered by LZ exposure and pCO2 treatments. Greater pathogen loads and increased EWD severity were detected in LZ exposed eelgrass ramets; EWD severity was reduced at high relative to low pCO2 . Oyster presence did not influence pathogen load or EWD severity; high LZ concentrations in experimental treatments may have masked the effect of this treatment. Collectively, these results indicate that, when exposed to natural concentrations of LZ under high pCO2 conditions, eelgrass can benefit from co-culture with oysters. Further experimentation is necessary to quantify how oysters may benefit from co-culture with eelgrass, examine these interactions in the field and quantify context-dependency.


Promotion of human T lymphocyte activation and proliferation by fatty acids in low density and high density lipoproteins.
Mitogen-induced lymphocyte DNA synthesis measured by [3H]thymidine incorporation and lymphocyte proliferation assessed by counting the number of cells were reduced by greater than 95% when cells were cultured at low density in the absence of serum. Supplementation with either transferrin or lipoprotein alone only partially restored lymphocyte responses. Addition of both transferrin and lipoproteins of each major subclass permitted mitogen-induced lymphocyte DNA synthesis and proliferation equal to that observed in serum-containing medium. The degree of enhancement was dependent on the concentration of the lipoprotein added and could not be explained by the nonspecific addition of protein to the defined medium. The mechanisms of growth promotion by various lipoprotein fractions did not appear to be explained by provision of cholesterol to the cells. Neither cholesterol nor cholesteryl ester from endogenous sources or supplied exogenously was able to enhance mitogen-induced lymphocyte responses. In contrast, fatty acids, phospholipid, and triglyceride alone supported lymphocyte responses. Furthermore, lipoproteins retained the capacity to enhance lymphocyte responses following extraction of neutral lipid. Both low density lipoprotein and high density lipoprotein, subclass 3, increased the number of cells initially activated by mitogenic stimulation and supported the subsequent continued growth of the activated cells. Low density lipoprotein was more efficient than high density lipoprotein, subclass 3, in this latter regard. These results indicate that lipoproteins can promote maximal growth of mitogen-activated lymphocytes in transferrin-containing medium by providing growth factors other than cholesterol necessary for initial activation and required for continued lymphocyte proliferation.


Altered physiology of rainbow trout in response to modified energy intake combined with pulp and paper effluent exposure.
Two experiments using rainbow trout (Oncorhynchus mykiss) were conducted to examine the combined effects of energy intake as manipulated by ration and pulp and paper mill effluent exposure over either one, or two consecutive reproductive cycles. This study demonstrated that the level of energy intake affected the full range of measured parameters from energy allocation to somatic growth and the gonadal development, steroid production and hematology. Increasing ration level expectedly increased growth, condition, liver and gonad size. Female trout in the higher ration treatments produced more follicles and had larger eggs, investing the same relative proportion of total energy into ovarian development. Sex steroid levels and hematological parameters were also positively influenced by increasing ration level in males and females. By far, the most dramatic impact of reduced ration on reproduction was to substantially reduce the frequency of sexually maturing fish. The effects of effluent exposure were not as marked as those linked to ration level and typically did not manifest unless fish were exposed through two consecutive reproductive cycles. The physiological effects of pulp and paper effluent exposure observed in these experiments were not consistent between the two experiments conducted herein, nor were they consistent with previously observed impacts in similar experiments with this effluent. Effluent exposure over one reproductive cycle did not impact physiological parameters in trout. However, when effluent exposure was maintained over two reproductive cycles, a new pattern of effluent response emerged including increased condition factor in both sexes, a decrease in the potential ability of the blood of females to transport oxygen, and increased sex steroids and reproductive investment in males. Effluent was also observed to cause reduced growth in male trout over two years. The effects of ration on gonad and liver size were far more obvious and consistent when a longer exposure was employed, thus, it appears to take more than one full year for energy intake changes to be reflected in those particular physiological endpoints.


Genomic epidemiology of meticillin-resistant Staphylococcus aureus ST22 widespread in communities of the Gaza Strip, 2009.
BackgroundRemarkably high carriage prevalence of a community-associated meticillin-resistant Staphylococcus aureus (MRSA) strain of sequence type (ST) 22 in the Gaza strip was reported in 2012. This strain is linked to the pandemic hospital-associated EMRSA-15. The origin and evolutionary history of ST22 in Gaza communities and the genomic elements contributing to its widespread predominance are unknown. Methods: We generated high-quality draft genomes of 61 ST22 isolates from Gaza communities and, along with 175 ST22 genomes from global sources, reconstructed the ST22 phylogeny and examined genotypes unique to the Gaza isolates. Results: The Gaza isolates do not exhibit a close relationship with hospital-associated ST22 isolates, but rather with a basal population from which EMRSA-15 emerged. There were two separate resistance acquisitions by the same MSSA lineage, followed by diversification of other genetic determinants. Nearly all isolates in the two distinct clades, one characterised by staphylococcal cassette chromosome mec (SCCmec) IVa and the other by SCCmec V and MSSA isolates, contain the toxic shock syndrome toxin-1 gene. Discussion: The genomic diversity of Gaza ST22 isolates is not consistent with recent emergence in the region. The results indicate that two divergent Gaza clones evolved separately from susceptible isolates. Researchers should not assume that isolates identified as ST22 in the community are examples of EMRSA-15 that have escaped their healthcare roots. Future surveillance of MRSA is essential to the understanding of ST22 evolutionary dynamics and to aid efforts to slow the further spread of this lineage.


Role of phospholipids in endocytosis, phagocytosis, and macropinocytosis.
Endocytosis, phagocytosis, and macropinocytosis are fundamental processes that enable cells to sample their environment, eliminate pathogens and apoptotic bodies, and regulate the expression of surface components. While a great deal of effort has been devoted over many years to understanding the proteins involved in these processes, the important contribution of phospholipids has only recently been appreciated. This review is an attempt to collate and analyze the rapidly emerging evidence documenting the role of phospholipids in clathrin-mediated endocytosis, phagocytosis, and macropinocytosis. A primer on phospholipid biosynthesis, catabolism, subcellular distribution, and transport is presented initially, for reference, together with general considerations of the effects of phospholipids on membrane curvature and charge. This is followed by a detailed analysis of the critical functions of phospholipids in the internalization processes and in the maturation of the resulting vesicles and vacuoles as they progress along the endo-lysosomal pathway.


The role of microtubule dynamics in growth cone motility and axonal growth.
The growth cone contains dynamic and relatively stable microtubule populations, whose function in motility and axonal growth is uncharacterized. We have used vinblastine at low doses to inhibit microtubule dynamics without appreciable depolymerization to probe the role of these dynamics in growth cone behavior. At doses of vinblastine that interfere only with dynamics, the forward and persistent movement of the growth cone is inhibited and the growth cone wanders without appreciable forward translocation; it quickly resumes forward growth after the vinblastine is washed out. Direct visualization of fluorescently tagged microtubules in these neurons shows that in the absence of dynamic microtubules, the remaining mass of polymer does not invade the peripheral lamella and does not undergo the usual cycle of bundling and splaying and the growth cone stops forward movement. These experiments argue for a role for dynamic microtubules in allowing microtubule rearrangements in the growth cone. These rearrangements seem to be necessary for microtubule bundling, the subsequent coalescence of the cortex around the bundle to form new axon, and forward translocation of the growth cone.


Inhibition of transcription by adriamycin is a consequence of the loss of negative superhelicity in DNA mediated by topoisomerase II.
Adriamycin is commonly used as a chemotherapeutic agent and is known to intercalate into the major groove of DNA and inhibit DNA and RNA synthesis. Results presented in this communication suggest that adriamycin affects topoisomerase cleavage of DNA. The resultant change in negative superhelicity (decrease) is responsible for the decrease in transcription. This process is not dependent on the continued presence of adriamycin. The reaction between topoisomerases, DNA and adriamycin is dose-dependent. The results help to explain the relatively enhanced cytotoxicity of this drug to tumor cells.


Chromosome 22q11 in a Xhosa schizophrenia population.
Chromosome 22q11 aberrations substantially increase the risk for developing schizophrenia. Although micro-deletions in this region have been extensively investigated in different populations across the world, little is known of their prevalence in African subjects with schizophrenia. We screened 110 African Xhosa-speaking participants with schizophrenia for the presence of micro-deletions. As further verification for the presence or absence of 22q11 microdeletions, we screened 238 Xhosa schizophrenia patients and 240 healthy Xhosa individuals from a larger schizophrenia candidate 22q11 gene study using molecular analyses. Data from molecular and cytogenetic analyses confirmed the absence of 22q11 microdeletions in the Xhosa schizophrenia samples. Although the absence of chromosome 22q11 micro-deletions in this group of patients does not exclude the possibility that it may occur in Xhosa schizophrenia patients, we concluded an extremely low prevalence. Our findings suggest that unique susceptibility loci may be present in this group.


Identification and molecular evolution of new dynein-like protein sequences in rat brain.
RT-PCR cloning was performed to find unknown members of the dynein superfamily expressed in rat brain. Six kinds of degenerate primers designed for the dynein catalytic domain consensuses were used for extensive PCR amplifications. We have sequenced 550 plasmid clones which turned out to include 13 kinds of new dynein-like sequences (DLP1-8, 9A/B, 10-12) and cytoplasmic dynein heavy chain. In these clones, alternative splicing was detected for a 105 nt-domain containing the CFDEFNRI consensus just downstream of the most N-terminal P-loop (DLP9A and 9B). By using these obtained sequences, initial hybridization studies were performed. Genomic Southern blotting showed each sequence corresponds to a single copy of the gene, while northern blotting of adult brain presented more than one band for some subtypes. We further accomplished molecular evolutionary analysis to recognize their phylogenetic origins for the axonemal and non-axonemal (cytoplasmic) functions. Different methods (UPGMA, NJ and MP) presented well coincident phylogenetic trees from 44 partial amino acid sequences of dynein heavy chain from various eukaryotes. The trunk for all the cytoplasmic dynein heavy chain homologues diverged directly from the root of the phylogenetic tree, suggesting that the first dynein gene duplication defined two distinct functions as respective subfamilies. Of particular interest, we found a duplication event of the cytoplasmic dynein heavy chain gene giving rise to another subtype, DLP4, located between the divergence of yeast and that of Dictyostelium. Such evolutionary topology builds up an inceptive hypothesis that there are at least two non-axonemal dynein heavy chains in mammals.


Lasing properties of polymerized chiral nematic Bragg onion microlasers.
Dye doped photocurable cholesteric liquid crystal was used to produce solid Bragg onion omnidirectional lasers. The lasers were produced by dispersing and polymerizing chiral nematic LC with parallel surface anchoring of LC molecules at the interface, extracted and transferred into another medium. Lasing characteristics were studied in carrier medium with different refractive index. The lasing in spherical cholesteric liquid crystal was attributed to two mechanisms, photonic bandedge lasing and lasing of whispering-gallery modes. The latter can be suppressed by using a higher index carrier fluid to prevent total internal reflection on the interface of the spheres. Pulse-to-pulse stability and threshold characteristics were also studied and compared to non-polymerized lasers. The polymerization process greatly increases the lasing stability.


The analgesic effect of thermal therapy after total knee arthroplasty.
Pain induced by surgery is a dynamic symptom, which may be quite variable even in the same surgical procedures. The purpose of this study was to investigate the analgesic effect of far infrared rays on the patients during the postoperative period of total knee arthroplasty (TKA). The selection and application of analgesic methods after the orthopedic surgery are therefore valuable for advanced studies. The quasi-experimental design with a total five consecutive days of far infrared ray (FIR) thermal therapy was employed in this study. The study involved 41 participants assigned by register code entry on computer to either the intervention or the control group. The FIR pads were applied on the acupoints of ST37 (Shang Chu Hsu), ST38 (Tiao Kou), ST39 (Hsia Chu Hsu), and ST40 (Feng Lung) of the patients involved in the experimental group from the third day to the fifth day after the TKA. The analgesic effect was evaluated via the pain intensity of the numeric rating scale (NRS) level and serum concentration of interleukin-6 (IL-6) and endothelin-1 (ET-1). The FIR showed that the significant effects are on relieving pain and lowering the levels of IL-6 and ET-1. The results cannot only be the reference for the postoperative pain relief of TKA, but it can also be the database of another clinical application. This study demonstrated that the FIR can lower the NRS of pain and thus reduce the discomfort experienced by the patient. Findings indicated that effective application of FIR decreased the serum level of IL-6 and ET-1, which represent the subjective indicator of pain.


Paralogs of Common Carp Granulocyte Colony-Stimulating Factor (G-CSF) Have Different Functions Regarding Development, Trafficking and Activation of Neutrophils.
Mammalian granulocyte colony-stimulating factor (G-CSF; CSF3) is a primary cytokine that promotes the development, mobilization, and activation of neutrophils and their precursors. Teleosts have been reported to possess two paralogs as a likely result of the teleost-wide whole genome duplication (WGD) event, but functional divergence of G-CSF paralogs remains poorly understood. Common carp are an allotetraploid species owing to an additional WGD event in the carp lineage and here, we report on genomic synteny, sequence similarity, and phylogeny of four common carp G-CSF paralogs (g-csfa1 and g-csfa2; g-csfb1 and g-csfb2). G-csfa1 and g-csfa2 show differential and relatively high gene expression levels, while g-csfb1 and g-csfb2 show low basal gene expression levels in most tissues. All paralogs are expressed higher in macrophages than in other leukocyte sub-types and are highly up-regulated by treatment of macrophages with mitogens. Recombinant G-CSFa1 and G-CSFb1 both promoted the proliferation of kidney hematopoietic cells, while only G-CSFb1 induced the differentiation of kidney cells along the neutrophil-lineage. Colony-forming unit assays revealed that G-CSFb1 alone stimulates the formation of CFU-G colonies from head- and trunk-kidney whereas the combination of G-CSFa1 and G-CSFb1 stimulates the formation of both CFU-G and CFU-GM colonies. Recombinant G-CSFa1 and G-CSFb1 also exhibit chemotactic activity against kidney neutrophils and up-regulation of cxcr1 mRNA expression was highest in neutrophils after G-CSFb1 stimulation. Furthermore, G-CSFb1 more than G-CSFa1 induced priming of kidney neutrophils through up-regulation of a NADPH-oxidase component p47 phox . In vivo administration of G-CSF paralogs increased the number of circulating blood neutrophils of carp. Our findings demonstrate that gene duplications in teleosts can lead to functional divergence between paralogs and shed light on the sub-functionalization of G-CSF paralogs in cyprinid fish.


Variations in the response of interleukins in neurosurgical intensive care patients monitored using intracerebral microdialysis.
The aim of this study was to make a preliminary evaluation of whether microdialysis monitoring of cytokines and other proteins in severely diseased neurosurgical patients has the potential of adding significant information to optimize care, thus broadening the understanding of the function of these molecules in brain injury. Paired intracerebral microdialysis catheters with high-cutoff membranes were inserted in 14 comatose patients who had been treated in a neurosurgical intensive care unit following subarachnoidal hemorrhage or traumatic brain injury. Samples were collected every 6 hours (for up to 7 days) and were analyzed at bedside for routine metabolites and later in the laboratory for interleukin (IL)-l and IL-6; in two patients, vascular endothelial growth factor and cathepsin-D were also checked. Aggregated microprobe data gave rough estimations of profound focal cytokine responses related to morphological tissue injury and to anaerobic metabolism that were not evident from the concomitantly collected cerebrospinal fluid data. Data regarding tissue with no macroscopic evidence of injury demonstrated that IL release not only is elicited in severely compromised tissue but also may be a general phenomenon in brains subjected to stress. Macroscopic tissue injury was strongly linked to IL-6 but not IL- lb activation. Furthermore, IL release seems to be stimulated by local ischemia. The basal tissue concentration level of IL-lb was estimated in the range of 10 to 150 pg/ml; for IL-6, the corresponding figure was 1000 to 20,000 pg/ml. Data in the present study indicate that catheters with high-cutoff membranes have the potential of expanding microdialysis to the study of protein chemistry as a routine bedside method in neurointensive care.


Evidence for Stress-like Alterations in the HPA-Axis in Women Taking Oral Contraceptives.
Using oral contraceptives has been implicated in the aetiology of stress-related disorders like depression. Here, we followed the hypothesis that oral contraceptives deregulate the HPA-axis by elevating circulating cortisol levels. We report for a sample of 233 pre-menopausal women increased circulating cortisol levels in those using oral contraceptives. For women taking oral contraceptives, we observed alterations in circulating phospholipid levels and elevated triglycerides and found evidence for increased glucocorticoid signalling as the transcript levels of the glucocorticoid-regulated genes DDIT4 and FKBP5 were increased in whole blood. The effects were statistically mediated by cortisol. The associations of oral contraceptives with higher FKBP5 mRNA and altered phospholipid levels were modified by rs1360780, a genetic variance implicated in psychiatric diseases. Accordingly, the methylation pattern of FKBP5 intron 7 was altered in women taking oral contraceptives depending on the rs1360780 genotype. Moreover, oral contraceptives modified the association of circulating cortisol with depressive symptoms, potentially explaining conflicting results in the literature. Finally, women taking oral contraceptives displayed smaller hippocampal volumes than non-using women. In conclusion, the integrative analyses of different types of physiological data provided converging evidence indicating that oral contraceptives may cause effects analogous to chronic psychological stressors regarding the regulation of the HPA axis.


Lung Disease, Oxidative Stress, and Oxygen Requirements in Preterm Infants.
The role of oxidative stress remains unclear in the multifactorial pathophysiologic mechanism of lung disease in preterm infants. The aim of this study was to examine the associations among chronic lung disease (CLD), oxidative stress, and oxygen requirements in preterm infants. Prospective, longitudinal, and correlational design. Preterm infants born at <32 weeks' gestation (N = 31), median gestation of 29.0 weeks (range 24.9-31.7). The diagnosis of CLD was obtained from the medical record. Oxidative stress was measured using 8-hydroxydeoxyguanosine (8-OHdG) in the cord blood at birth and urine on Days 1 and 7. Oxygen requirements were measured using fraction of inspired oxygen (FIO2) recorded in the first hour after birth/admission and the average FIO2 during the first 12 hr and 7 days after birth. Descriptive statistics are presented. Comparison analyses were performed using Kruskal-Wallis and Fisher's exact tests. Infants with CLD (n = 12) had lower gestational age (p = .04) and weight (p = .04) at birth, more days on the ventilator (p = .004), and longer neonatal intensive care unit stay (p = .04) compared to infants without CLD (n = 19). CLD was associated with lower oxidative stress levels (p = .03) and higher oxygen requirements during the first 12 hr (p = .025) and on Day 7 (p = .001). Lower oxidative stress levels on Day 7 were associated with higher oxygen requirements in the first 12 hr (p = .01) and on Day 7 (p = .03). Our results linking CLD and higher oxygen requirements with low oxidative stress contradict previous reports. Findings identify a gap in knowledge for postresuscitation oxygen therapy in preterm infants and expose the role of oxidative stress from inflammation and intermittent hypoxia in the etiology of CLD.


Oxidized low-density lipoprotein induces apoptotic insults to mouse cerebral endothelial cells via a Bax-mitochondria-caspase protease pathway.
Cerebral endothelial cells (CECs) are crucial components of the blood-brain barrier. Oxidized low-density lipoprotein (oxLDL) can induce cell injuries. In this study, we attempted to evaluate the effects of oxLDL on mouse CECs and its possible mechanisms. Mouse CECs were isolated from brain tissues and identified by immunocytochemical staining of vimentin and Factor VIII. oxLDL was prepared from LDL oxidation by copper sulfate. Exposure of mouse CECs to oxLDL decreased cell viability in concentration- and time-dependent manners. oxLDL time-dependently caused shrinkage of cell morphologies. Administration of oxLDL to CECs induced DNA fragmentation in concentration- and time-dependent manners. Analysis of the cell cycle revealed that oxLDL concentration- and time-dependently increased the proportion of CECs which underwent apoptosis. Analysis of confocal microscopy and immunoblot revealed that oxLDL significantly increased cellular and mitochondrial Bax levels as well as the translocation of this proapoptotic protein from the cytoplasm to mitochondria. In parallel with the increase in the levels and translocation of Bax, oxLDL time-dependently decreased the mitochondrial membrane potential. Exposure of mouse CECs to oxLDL decreased the amounts of mitochondrial cytochrome c, but enhanced cytosolic cytochrome c levels. The amounts of intracellular reactive oxygen species were significantly augmented after oxLDL administration. Sequentially, oxLDL increased activities of caspase-9, -3, and -6 in time-dependent manners. Pretreatment with Z-VEID-FMK, an inhibitor of caspase-6, significantly decreased caspase-6 activity and the oxLDL-induced DNA fragmentation and cell apoptosis. This study showed that oxLDL induces apoptotic insults to CECs via signal-transducing events, including enhancing Bax translocation, mitochondrial dysfunction, cytochrome c release, increases in intracellular reactive oxygen species, and cascade activation of caspase-9, -3, and -6. Therefore, oxLDL can damage the blood-brain barrier through induction of CEC apoptosis via a Bax-mitochondria-caspase protease pathway.


Productive Ecosystems and the arrow of development.
Economic growth is associated with the diversification of economic activities, which can be observed via the evolution of product export baskets. Exporting a new product is dependent on having, and acquiring, a specific set of capabilities, making the diversification process path-dependent. Taking an agnostic view on the identity of the capabilities, here we derive a probabilistic model for the directed dynamical process of capability accumulation and product diversification of countries. Using international trade data, we identify the set of pre-existing products, the product Ecosystem, that enables a product to be exported competitively. We construct a directed network of products, the Eco Space, where the edge weight corresponds to capability overlap. We uncover a modular structure, and show that low- and middle-income countries move from product communities dominated by small Ecosystem products to advanced (large Ecosystem) product clusters over time. Finally, we show that our network model is predictive of product appearances.


Voluntary Prone Position for Acute Hypoxemic Respiratory Failure in Unintubated Patients.
Severe hypoxemic respiratory failure is frequently managed with invasive mechanical ventilation with or without prone position (PP). We describe 13 cases of nonhypercapnic acute hypoxemic respiratory failure (AHRF) of varied etiology, who were treated successfully in PP without the need for intubation. Noninvasive ventilation (NIV), high-flow oxygen via nasal cannula, supplementary oxygen with venturi face mask, or nasal cannula were used variedly in these patients. Mechanical ventilatory support is offered to patients with AHRF when other methods, such as NIV and oxygen via high-flow nasal cannula, fail. Invasive mechanical ventilation is fraught with complications which could be immediate, ranging from worsening of hypoxemia, worsening hemodynamics, loss of airway, and even death. Late complications could be ventilator-associated pneumonia, biotrauma, tracheal stenosis, etc. Prone position is known to improve oxygenation and outcome in adult respiratory distress syndrome. We postulated that positioning an unintubated patient with AHRF in PP will improve oxygenation and avoid the need for invasive mechanical ventilation and thereby its complications. Here, we describe a series of 13 patients with hypoxemic respiratory of varied etiology, who were successfully treated in the PP without endotracheal intubation. Two patients (15.4%) had mild, nine (69.2%) had moderate, and two (15.4%) had severe hypoxemia. Oxygenation as assessed by PaO2/FiO2 ratio in supine position was 154 ± 52, which improved to 328 ± 65 after PP. Alveolar to arterial (A-a) O2 gradient improved from a median of 170.5 mm Hg interquartile range (IQR) (127.8, 309.7) in supine position to 49.1 mm Hg IQR (45.0, 56.6) after PP. This improvement in oxygenation took a median of 46 hours, IQR (24, 109). Thus, voluntary PP maneuver improved oxygenation and avoided endotracheal intubation in a select group of patients with hypoxemic respiratory failure. This maneuver may be relevant in the ongoing novel coronavirus disease pandemic by potentially reducing endotracheal intubation and the need for ventilator and therefore better utilization of critical care services. Rao SV, Udhayachandar R, Rao VB, Raju NA, Nesaraj JJJ, Kandasamy S, et al. Voluntary Prone Position for Acute Hypoxemic Respiratory Failure in Unintubated Patients. Indian J Crit Care Med 2020;24(7):557-562.


Airway inflammatory and spirometric measurements in obese children.
To investigate the association between obesity and airway inflammation and spirometric parameters in local children. Cross-sectional and observational study. Paediatric clinics of a university-affiliated teaching hospital in Hong Kong. Chinese subjects aged 6 to 18 years were recruited from the paediatric clinics. Obesity was defined as being 120% or more of the median weight-for-height. Airway inflammation assessed by exhaled nitric oxide concentration; lung function evaluated by measuring forced expiratory flow in 1-second and forced vital capacity using spirometry; and peak expiratory flow rate measured by using a mini-Wright peak flow meter. Fifty-five subjects were recruited into four groups as follows: 13 non-obese controls, 16 obese non-asthmatics, 15 non-obese asthmatics, and 11 obese asthmatics. The median (interquartile range) exhaled nitric oxide concentrations of these groups were 17.6 (14.4-20.9), 33.3 (26.1-75.4), 65.7 (32.0-110.0) and 49.2 (41.1-82.6) parts per billion, respectively (P=0.001 for trend). Post-hoc analysis revealed higher exhaled nitric oxide concentration in the latter three groups (obese and/or asthmatic subjects) than controls (P< or =0.002). Exhaled nitric oxide concentration did not differ among obese non-asthmatics, non-obese asthmatics, and obese asthmatics (P>0.1 for all). In non-asthmatics, exhaled nitric oxide concentration correlated positively with age (P=0.048), weight-for-height z-score (P=0.001), and forced vital capacity (P=0.009). Weight-for-height z-score correlated positively with forced vital capacity (P=0.041), but inversely with the forced expiratory flow in 1-second/forced vital capacity ratio (P=0.049). Such correlations were not observed in asthmatic children. Increased airway inflammation as revealed by exhaled nitric oxide concentration was found in obese non-asthmatic children. Weight-for-height z-score as an indicator of childhood obesity correlated with exhaled nitric oxide concentration and spirometric parameters in children without asthma. Nonetheless, concomitant obesity does not influence exhaled nitric oxide concentration in asthmatic children. Further studies are needed to identify the pathophysiologic mechanisms for such associations.


Passive ventricular mechanics in tight-skin mice.
Although changes in the extracellular matrix have been associated with changes in ventricular compliance in certain diseased states, this relationship has not been entirely established. Accordingly, we studied passive ventricular mechanics in the tight-skin (TSk) mouse, a mutant strain known to have increased cardiac collagen. In the arrested left ventricle, we determined the pressure-volume relationship and the stress-free state, as defined by the "opening angle" of an equatorial ring with a radial cut. The results showed the mean opening angle in the TSk mouse to be smaller than that in phenotypic negative controls (7 +/- 6 vs. 21 +/- 9 degrees), and there was no statistical difference in the pressure-volume curves. Histological quantification of the transmural collagen showed a uniform increase of collagen area fraction across the wall in TSk mouse, and a significantly thicker superficial epicardial collagen layer (4.68 +/- 0.87 vs. 3.34 +/- 0.76 micron). Thus, although there appears to be a decrease of residual stress in the TSk mouse heart, which may be related to the thicker epicardial collagen layer, the combination of increased myocardial collagen and the change in stress-free state did not seem to affect the passive pressure-volume relationship of the left ventricle.


Tracking health seeking behavior during an Ebola outbreak via mobile phones and SMS.
The recent Ebola outbreak in West Africa was an exemplar for the need to rapidly measure population-level health-seeking behaviors, in order to understand healthcare utilization during emergency situations. Taking advantage of the high prevalence of mobile phones, we deployed a national SMS-poll and collected data about individual-level health and health-seeking behavior throughout the outbreak from 6694 individuals from March to June 2015 in Liberia. Using propensity score matching to generate balanced subsamples, we compared outcomes in our survey to those from a recent household survey (the 2013 Liberian Demographic Health Survey). We found that the matched subgroups had similar patterns of delivery location in aggregate, and utilizing data on the date of birth, we were able to show that facility-based deliveries were significantly decreased during, compared to after the outbreak (p < 0.05) consistent with findings from retrospective studies using healthcare-based data. Directly assessing behaviors from individuals via SMS also enabled the measurement of public and private sector facility utilization separately, which has been a challenge in other studies in countries including Liberia which rely mainly on government sources of data. In doing so, our data suggest that public facility-based deliveries returned to baseline values after the outbreak. Thus, we demonstrate that with the appropriate methodological approach to account for different population denominators, data sourced via mobile tools such as SMS polling could serve as an important low-cost complement to existing data collection strategies especially in situations where higher-frequency data than can be feasibly obtained through surveys is useful.


"Why do I always see double?" A misdiagnosed case of ocular myasthenia gravis for 10 years.
A 58-year-old man presented with diplopia and partial ptosis for 10 years. It was non-progressive in nature, despite inadequate medical attention the patient received from non-specialists/general practitioners. He did not have fatigability or diurnal variation in weakness and was clinically stable without exacerbations of disease for a decade. He did not have features of Graves's disease, oculopharyngeal dystrophy, cranial nerve paralysis, polymyositis and stroke. The possibility of an atypical presentation of myasthenia gravis (MG) was considered and the patient was evaluated. Ice pack test was negative, Cogan's lid twitch (CLT) test was positive and high titres of acetylcholine receptor antibodies (AChR Ab) suggestive of MG were found. He was treated accordingly with a very good response.


A robust optimization approach for the breast cancer targeted design of PEtOx-b-PLA polymersomes.
The equipping of nanoparticles with the peptide moiety recognizing a particular receptor, enables cell or tissue-specific targeting, therefore the optimization of the targeted nanoparticles is a key factor in the formulation design process. In this paper, we report the optimization concept of Doxorubicin encapsulating PEtOx-b-PLA polymersome formulation equipped with Peptide18, which is a breast cancer recognizing tumor homing peptide, and the unveiling of the cell-specific delivery potential. The most dominant formulation parameters, which are the polymer to Doxorubicin mass ratio (w/w) and the aqueous to organic phase ratio (v/v), were optimized using Central Composite Design (CCD) based Response Surface Methodology. The characteristics of optimum polymersome formulation were determined as the hydrodynamic diameter of 146.35 nm, the PDI value of 0.136, and the encapsulation efficiency of 57.11% and TEM imaging, which are in agreement with the DLS data, showed the spherical morphology of the polymersomes. In order to demonstrate the breast cancer-specific delivery of targeted polymersomes, the flow cytometry and confocal microscopy analyses were carried out. The targeted polymersomes were accumulated 8 times higher in AU565 cells compared to MCF10A cells and the intracellular Doxorubicin was almost 10 times higher in AU565 cells. The CCD-mediated optimized targeted polymersomes proposed in this report holds the promise of targeted therapy for breast cancer and can be potentially used for the development of novel treatments.


Mistletoe lectin I in complex with galactose and lactose reveals distinct sugar-binding properties.
The structures of mistletoe lectin I (ML-I) from Viscum album complexed with lactose and galactose have been determined at 2.3 A resolution and refined to R factors of 20.9% (Rfree = 23.6%) and 20.9 (Rfree = 24.6%), respectively. ML-I is a heterodimer and belongs to the class of ribosome-inactivating proteins of type II, which consist of two chains. The A-chain has rRNA N-glycosidase activity and irreversibly inhibits eukaryotic ribosomes. The B-chain is a lectin and preferentially binds to galactose-terminated glycolipids and glycoproteins on cell membranes. Saccharide binding is performed by two binding sites in subdomains alpha1 and gamma2 of the ML-I B-chain separated by approximately 62 A from each other. The favoured binding of galactose in subdomain alpha1 is achieved via hydrogen bonds connecting the 4-hydroxyl and 3-hydroxyl groups of the sugar moiety with the side chains of Asp23B, Gln36B and Lys41B and the main chain of 26B. The aromatic ring of Trp38B on top of the preferred binding pocket supports van der Waals packing of the apolar face of galactose and stabilizes the sugar-lectin complex. In the galactose-binding site II of subdomain gamma2, Tyr249B provides the hydrophobic stacking and the side chains of Asp235B, Gln238B and Asn256B are hydrogen-bonding partners for galactose. In the case of the galactose-binding site I, the 2-hydroxyl group also stabilizes the sugar-protein complex, an interaction thus far rarely detected in galactose-specific lectins. Finally, a potential third low-affinity galactose-binding site in subunit beta1 was identified in the present ML-I structures, in which a glycerol molecule from the cryoprotectant buffer has bound, mimicking the sugar compound.


Life-History Variation Predicts the Effects of Demographic Stochasticity on Avian Population Dynamics.
Comparative analyses of avian population fluctuations have shown large interspecific differences in population variability that have been difficult to relate to variation in general ecological characteristics. Here we show that interspecific variation in demographic stochasticity, caused by random variation among individuals in their fitness contributions, can be predicted from a knowledge of the species' position along a "slow-fast" gradient of life-history variation, ranging from high reproductive species with short life expectancy at one end to species that often produce a single offspring but survive well at the other end of the continuum. The demographic stochasticity decreased with adult survival rate, age at maturity, and generation time or the position of the species toward the slow end of the slow-fast life-history gradient. This relationship between life-history characteristics and demographic stochasticity was related to interspecific differences in the variation among females in recruitment as well as to differences in the individual variation in survival. Because reproductive decisions in birds are often subject to strong natural selection, our results provide strong evidence for adaptive modifications of reproductive investment through life-history evolution of the influence of stochastic variation on avian population dynamics.


Determination of Ultra-trace Metal Impurities in High-purity Cadmium Using Inductively Coupled Plasma Mass Spectrometry after Matrix Separation with Anion Exchange Resin.
The analytical method for ultra-trace metal impurities at μg kg-1 level in high-purity Cd was examined by inductively coupled plasma mass spectrometry (ICP-MS) combined with matrix separation by Bio-Rad AG MP-1M anion exchange resin. After the separation of Cd, the metal impurities such as Li, In, Cr, Mn, Fe, Co, Ni, Cu, Ga, Sr, Ba and Pb were measured by an ICP-quadrupole mass spectrometer (ICP-QMS) and ICP-sector field mass spectrometer (ICP-SFMS). From the comparison of measured results, it was evaluated that the analytical sensitivity by ICP-SFMS was 10 times higher than ICP-QMS. In addition, ICP-SFMS could obtain determined values of Li and Fe that could not be determined by ICP-QMS. These results suggest the ICP-SFMS combined with matrix separation by anion exchange resin could be utilized for the determination of ultra-trace metal impurities in high-purity materials for the assessment of the purity of the materials.


Technologies to Support Community-Dwelling Persons With Dementia: A Position Paper on Issues Regarding Development, Usability, Effectiveness and Cost-Effectiveness, Deployment, and Ethics.
With the expected increase in the numbers of persons with dementia, providing timely, adequate, and affordable care and support is challenging. Assistive and health technologies may be a valuable contribution in dementia care, but new challenges may emerge. The aim of our study was to review the state of the art of technologies for persons with dementia regarding issues on development, usability, effectiveness and cost-effectiveness, deployment, and ethics in 3 fields of application of technologies: (1) support with managing everyday life, (2) support with participating in pleasurable and meaningful activities, and (3) support with dementia health and social care provision. The study also aimed to identify gaps in the evidence and challenges for future research. Reviews of literature and expert opinions were used in our study. Literature searches were conducted on usability, effectiveness and cost-effectiveness, and ethics using PubMed, Embase, CINAHL, and PsycINFO databases with no time limit. Selection criteria in our selected technology fields were reviews in English for community-dwelling persons with dementia. Regarding deployment issues, searches were done in Health Technology Assessment databases. According to our results, persons with dementia want to be included in the development of technologies; there is little research on the usability of assistive technologies; various benefits are reported but are mainly based on low-quality studies; barriers to deployment of technologies in dementia care were identified, and ethical issues were raised by researchers but often not studied. Many challenges remain such as including the target group more often in development, performing more high-quality studies on usability and effectiveness and cost-effectiveness, creating and having access to high-quality datasets on existing technologies to enable adequate deployment of technologies in dementia care, and ensuring that ethical issues are considered an important topic for researchers to include in their evaluation of assistive technologies. Based on these findings, various actions are recommended for development, usability, effectiveness and cost-effectiveness, deployment, and ethics of assistive and health technologies across Europe. These include avoiding replication of technology development that is unhelpful or ineffective and focusing on how technologies succeed in addressing individual needs of persons with dementia. Furthermore, it is suggested to include these recommendations in national and international calls for funding and assistive technology research programs. Finally, practitioners, policy makers, care insurers, and care providers should work together with technology enterprises and researchers to prepare strategies for the implementation of assistive technologies in different care settings. This may help future generations of persons with dementia to utilize available and affordable technologies and, ultimately, to benefit from them.


An evolutionarily conserved coiled-coil protein implicated in polycystic kidney disease is involved in basal body duplication and flagellar biogenesis in Trypanosoma brucei.
Trypanosoma brucei is a flagellated protozoan with a highly polarized cellular structure. TbLRTP is a trypanosomal protein containing multiple SDS22-class leucine-rich repeats and a coiled-coil domain with high similarity to a mammalian testis-specific protein of unknown function. Homologues are present in a wide range of higher eukaryotes including zebra fish, where the gene product has been implicated in polycystic kidney disease. Western blot analysis and immunofluorescence with antibodies against recombinant TbLRTP indicate that the protein is expressed throughout the trypanosome life cycle and localizes to distal zones of the basal bodies. Overexpression and RNA interference demonstrate that TbLRTP is important for faithful basal body duplication and flagellum biogenesis. Expression of excess TbLRTP suppresses new flagellum assembly, while reduction of TbLRTP protein levels often results in the biogenesis of additional flagellar axonemes and paraflagellar rods that, most remarkably, are intracellular and fully contained within the cytoplasm. The mutant flagella are devoid of membrane and are often associated with four microtubules in an arrangement similar to that observed in the normal flagellar attachment zone. Aberrant basal body and flagellar biogenesis in TbLRTP mutants also influences cell size and cytokinesis. These findings demonstrate that TbLRTP suppresses basal body replication and subsequent flagellar biogenesis and indicate a critical role for the LRTP family of proteins in the control of the cell cycle. These data further underscore the role of aberrant flagellar biogenesis as a disease mechanism.


Cancer across the tree of life: cooperation and cheating in multicellularity.
Multicellularity is characterized by cooperation among cells for the development, maintenance and reproduction of the multicellular organism. Cancer can be viewed as cheating within this cooperative multicellular system. Complex multicellularity, and the cooperation underlying it, has evolved independently multiple times. We review the existing literature on cancer and cancer-like phenomena across life, not only focusing on complex multicellularity but also reviewing cancer-like phenomena across the tree of life more broadly. We find that cancer is characterized by a breakdown of the central features of cooperation that characterize multicellularity, including cheating in proliferation inhibition, cell death, division of labour, resource allocation and extracellular environment maintenance (which we term the five foundations of multicellularity). Cheating on division of labour, exhibited by a lack of differentiation and disorganized cell masses, has been observed in all forms of multicellularity. This suggests that deregulation of differentiation is a fundamental and universal aspect of carcinogenesis that may be underappreciated in cancer biology. Understanding cancer as a breakdown of multicellular cooperation provides novel insights into cancer hallmarks and suggests a set of assays and biomarkers that can be applied across species and characterize the fundamental requirements for generating a cancer.


A case of complex odontoma associated with an impacted lower deciduous second molar and analysis of the 107 odontomas.
Odontoma is a comparatively common odontogenic tumor, and it may lead to interference with the eruption of its associated tooth. Odontomas are mostly associated with permanent teeth, and they are rarely associated with deciduous teeth. The purpose of this report is to analyze 107 odontomas and to present a case of complex odontoma associated with a lower deciduous second molar. The 106 cases were analyzed with regard to the following parameters: age, gender, location, erupted teeth, congenital missing teeth, radiological features, histopathological features and prognosis. Of the 106 cases, 41 were complex odontoma, 62 were compound odontoma, and three were immature odontoma. Compound odontoma had a predilection for the anterior. Complex odontoma occurred more often at the mandible. Odontoma located above the tooth crown of lower deciduous molar did not behave clinically different from that associated with permanent tooth. An odontoma could be related with a supernumerary tooth or a missing tooth. If odontomas, which interfered with tooth eruption, were extirpated early, the impacted teeth would probably erupt normally and be normal in shape.


Chromatin-remodelling factor BRG1 selectively activates a subset of interferon-alpha-inducible genes.
Brahma-related gene 1 (BRG1 ) is a key component of the ATP-dependent chromatin-remodelling SWI2-SNF2 complex and has been implicated in regulating gene expression, cell-cycle control and tumorigenesis. Here we report that BRG1 interacts with signal transducer and activator of transcription 2 (STAT2) - a transcription factor that regulates gene expression mediated by interferon-alpha (IFN-alpha). BRG1 enhances the IFN-alpha-induced expression of 9-27 and IFI27 but not that of four other target genes tested, showing that the activation of different target genes by STAT2 may involve alternative chromatin modifiers. Our results also suggest that the recruitment and activation of BRG1 may require other cis-acting and trans-acting elements in addition to STAT2. Our study links the SWI2-SNF2 complex to the regulation of cytokine-induced gene expression and may identify a molecular mechanism of BRG1-mediated gene activation and tumorigenesis.


Automatic Classification of Structured Product Labels for Pregnancy Risk Drug Categories, a Machine Learning Approach.
With regular expressions and manual review, 18,342 FDA-approved drug product labels were processed to determine if the five standard pregnancy drug risk categories were mentioned in the label. After excluding 81 drugs with multiple-risk categories, 83% of the labels had a risk category within the text and 17% labels did not. We trained a Sequential Minimal Optimization algorithm on the labels containing pregnancy risk information segmented into standard document sections. For the evaluation of the classifier on the testing set, we used the Micromedex drug risk categories. The precautions section had the best performance for assigning drug risk categories, achieving Accuracy 0.79, Precision 0.66, Recall 0.64 and F1 measure 0.65. Missing pregnancy risk categories could be suggested using machine learning algorithms trained on the existing publicly available pregnancy risk information.


Organic semiconductors for artificial vision.
Organic semiconductors have emerged in the past two decades as promising materials for many technological applications. Thanks to their unique optoelectronic properties, they represent an ideal system to mimic natural photoreceptor functioning. This similarity has been exploited, on one hand, to realize organic-based devices for image detection, taking advantage of typical features of natural visual systems, such as trichromatic sensing; on the other hand, these materials can be interfaced with biological tissues for cell photo-stimulation, with the main goal of restoring light sensitivity in the case of retinas affected by photoreceptor degeneration.


Low-Quality Nursing Homes Were More Likely Than Other Nursing Homes To Be Bought Or Sold By Chains In 1993-2010.
Two defining features of the nursing home industry are the tremendous churn in chain ownership and the perception of low-quality care at many facilities. We examined whether nursing homes that underwent chain-related transactions, such as mergers and acquisitions, experienced a larger number of health deficiency citations than nursing homes that maintained common ownership over the same period. Using facility-level data for the period 1993-2010, we found that those nursing homes that underwent chain-related transactions had more deficiency citations in the years preceding and following a transaction than those nursing homes that maintained common ownership. Thus, we did not find that these transactions led to a decline in quality. Instead, we found that chains targeted nursing homes that were already having quality problems and that these problems persisted after the transaction. Given the high frequency of nursing home chain transactions, policy makers will need to continue to invest in tracking, reporting, and overseeing these transactions. One important step would be to report more detailed data on chain ownership, transactions, and aggregate chain quality on the Nursing Home Compare website, the federal government's online report card for nursing homes.


Persistent organochlorine pollutants in eggs of colonial waterbirds from Galveston Bay and East Texas, USA.
Eggs of neotropic cormorants (Phalacrocorax brasilianus), black-crowned night herons (Nycticorax nycticorax), and great egrets (Ardea alba) nesting on several locations in Galveston Bay (TX, USA) and at two control sites outside the bay were collected during April-May 1996 and analyzed for chlorinated pesticides, PCBs, polychlorinated dibenzo-p-dioxins, and polychlorinated dibenzofurans. Additionally, concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (TCDD-EQs) were determined by use of relative potency factors (TEQs) or the H4IIE-luc bioassay TCDD-EQs. Concentrations of 1,1,-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) were greater in eggs of neotropic cormorants from Alexander Island (mean = 1,040 ng/g wet wt) in the Houston Ship Channel (Houston, TX, USA) and in those from Telfair Island (mean = 1,460 ng/g wet wt), a reference location outside the bay, than in most locations inside the bay (mean range = 119-453 ng/g wet wt). Mean PCB concentrations were greater in eggs of neotropic cormorants from Alexander Island (mean = 5,720 ng/g wet wt) than in eggs of cormorants from areas farther away from the ship channel, including two reference sites outside the bay (mean range = 404-3,140 ng/g wet wt). The TCDD was the main dioxin congener detected in eggs from all locations within Galveston Bay. Instrumental TEQs in eggs ranged from 67 pg/g wet weight at control sites to 452 pg/g wet weight at Alexander Island. Concentrations of TCDD-EQs determined in the H4IIE assay were correlated with instrumental TEQs and were greater in eggs of cormorants from islands within the bay, although these were farther away from the ship channel. Overall, concentrations of DDE, PCBs, TCDD, and TCDD-EQs were less than the threshold levels known to affect reproduction. However, some eggs contained concentrations of total PCBs or DDE greater than what would elicit adverse effects on birds. No identifiable deformities or abnormalities were detected in embryos collected from all sites.


A functional-structural modelling approach to autoregulation of nodulation.
Autoregulation of nodulation is a long-distance shoot-root signalling regulatory system that regulates nodule meristem proliferation in legume plants. However, due to the intricacy and subtleness of the signalling nature in plants, molecular and biochemical details underlying mechanisms of autoregulation of nodulation remain largely unknown. The purpose of this study is to use functional-structural plant modelling to investigate the complexity of this signalling system. There are two major challenges to be met: modelling the 3D architecture of legume roots with nodulation and co-ordinating signalling-developmental processes with various rates. Soybean (Glycine max) was chosen as the target legume. Its root system was observed to capture lateral root branching and nodule distribution patterns. L-studio, a software tool supporting context-sensitive L-system modelling, was used for the construction of the architectural model and integration with the internal signalling. A branching pattern with regular radial angles was found between soybean lateral roots, from which a root mapping method was developed to characterize the laterals. Nodules were mapped based on 'nodulation section' to reveal nodule distribution. A root elongation algorithm was then developed for simulation of root development. Based on the use of standard sub-modules, a synchronization algorithm was developed to co-ordinate multi-rate signalling and developmental processes. The modelling methods developed here not only allow recreation of legume root architecture with lateral branching and nodulation details, but also enable parameterization of internal signalling to produce different regulation results. This provides the basis for using virtual experiments to help in investigating the signalling mechanisms at work.


KCNQ potassium channels: physiology, pathophysiology, and pharmacology.
KCNQ genes encode a growing family of six transmembrane domains, single pore-loop, K(+) channel alpha-subunits that have a wide range of physiological correlates. KCNQ1 (KvLTQ1) is co-assembled with the product of the KCNE1 (minimal K(+)-channel protein) gene in the heart to form a cardiac-delayed rectifier-like K(+) current. Mutations in this channel can cause one form of inherited long QT syndrome (LQT1), as well as being associated with a form of deafness. KCNQ1 can also co-assemble with KCNE3, and may be the molecular correlate of the cyclic AMP-regulated K(+) current present in colonic crypt cells. KCNQ2 and KCNQ3 heteromultimers are thought to underlie the M-current; mutations in these genes may cause an inherited form of juvenile epilepsy. The KCNQ4 gene is thought to encode the molecular correlate of the I(K,n) in outer hair cells of the cochlea and I(K,L) in Type I hair cells of the vestibular apparatus, mutations in which lead to a form of inherited deafness. The recently identified KCNQ5 gene is expressed in brain and skeletal muscle, and can co-assemble with KCNQ3, suggesting it may also play a role in the M-current heterogeneity. This review will set this family of K(+) channels amongst the other known families. It will highlight the genes, physiology, pharmacology, and pathophysiology of this recently discovered, but important, family of K(+) channels.


Consumer visual preference and value for beef steaks differing in marbling level and color.
To determine visual preference and value for fresh beef steaks differing in marbling level and color, consumers in Chicago and San Francisco (n = 124 per city) evaluated two pairs of steaks in a retail case. Steaks differing in marbling level (Modest/Moderate vs. Slight) and color (bright, cherry-red vs. dark red) were purchased at retail stores in each city. Consumers selected their preferred steak in each pair, described their selection criteria, and provided the price they were willing to pay for each of the four steaks. There was a difference in visual preference in each city, with most consumers preferring (P < 0.01) low (Slight) over high (Moderate/Modest) marbling; however, more (P < 0.01) consumers in Chicago (86.7%) preferred low marbling than in San Francisco (67.0%). Selection criteria were categorized into five groups: marbling, fat, color, appearance, and palatability. Marbling was mentioned by 65.4% of consumers who preferred high marbling, whereas 64.9% of consumers who preferred low marbling mentioned fat as a selection criterion. Bright, cherry-red color was preferred by a higher (P < 0.01) percentage of consumers in both Chicago and San Francisco (67.6 and 76.5%, respectively). Color was mentioned both by consumers who preferred bright, cherry-red color (64.8%) and those who preferred dark red color (63.9%). All preference groups were willing to pay more for their preferred steak (P < 0.01), but consumers who preferred low marbling were willing to pay more (P < 0.01) for their preferred steak than consumers who preferred high marbling. Consumers who preferred bright, cherry-red color were willing to pay more (P < 0.01) for their preferred steak than consumers who preferred dark red color. Consumers who preferred low marbling seemed to desire lean products, and consumers who preferred high marbling seemed to desire products with high eating quality. In this study, consumers were willing to pay more to purchase their preferred product; however, most consumers preferred low marbling and bright, cherry-red color.


Transcriptional ontogeny of the developing liver.
During embryogenesis the liver is derived from endodermal cells lining the digestive tract. These endodermal progenitor cells contribute to forming the parenchyma of a number of organs including the liver and pancreas. Early in organogenesis the fetal liver is populated by hematopoietic stem cells, the source for a number of blood cells including nucleated erythrocytes. A comprehensive analysis of the transcriptional changes that occur during the early stages of development to adulthood in the liver was carried out. We characterized gene expression changes in the developing mouse liver at gestational days (GD) 11.5, 12.5, 13.5, 14.5, 16.5, and 19 and in the neonate (postnatal day (PND) 7 and 32) compared to that in the adult liver (PND67) using full-genome microarrays. The fetal liver, and to a lesser extent the neonatal liver, exhibited dramatic differences in gene expression compared to adults. Canonical pathway analysis of the fetal liver signature demonstrated increases in functions important in cell replication and DNA fidelity whereas most metabolic pathways of intermediary metabolism were under expressed. Comparison of the dataset to a number of previously published microarray datasets revealed 1) a striking similarity between the fetal liver and that of the pancreas in both mice and humans, 2) a nucleated erythrocyte signature in the fetus and 3) under expression of most xenobiotic metabolism genes throughout development, with the exception of a number of transporters associated with either hematopoietic cells or cell proliferation in hepatocytes. Overall, these findings reveal the complexity of gene expression changes during liver development and maturation, and provide a foundation to predict responses to chemical and drug exposure as a function of early life-stages.


Excessive weight gain during peritoneal dialysis.
The authors carried out a retrospective chart review in 114 patients treated for at least two years at the Toronto Western Hospital Peritoneal Dialysis Unit and identified eight, who gained an "excessive" amount of weight equal to or greater than 10 kg of their initial weight. These patients had gained an average of 13.1 kg over the preceding two years. They are mostly males and their average age is 51 years. They are well-nourished normotenseive nondiabetics with mostly normal cardiac function. They are adequately dialyzed (per KT/V urea), have little residual renal function and typically have peritoneal membranes characterized by high average transport. According to BIA analysis, this weight gain was likely due to an increase in fat mass accompanied by a trend toward decreasing body-cell mass. This weight gain may be due to increased caloric intake secondary to dialysate glucose absorption in the setting of high average (peritoneal membrane) transport. Such excessive weight gain also may occur if these patients have polymorphism of the UCP-2 gene, which can alter metabolic rate.


Expression of the glycoprotein of vesicular stomatitis virus by infectious adenovirus vectors.
We have constructed recombinant human adenovirus (Ad) vectors containing the glycoprotein gene of vesicular stomatitis virus (VSV). The structural gene of the VSV glycoprotein was modified by the addition of promoter and poly(A) addition sequences from the herpes simplex virus type 1 thymidine kinase (TK) gene and inserted, in either orientation, into early region 3 (E3) of human Ad type 5. The recombinant vectors were fully infectious and replicated in HeLa cells in culture. The TK promoter was functional in both insert orientations and responsive to trans-activation by herpes virus infection; however production of VSV glycoprotein in readily detectable amounts was only obtained with the vector having an insert in the E3 parallel orientation (AdG12), and depended principally on transcripts initiating within upstream Ad sequences. The onset of expression of the glycoprotein in AdG12-infected cells was detectable at about the same time as the Ad 72K DNA-binding protein encoded by E2, and its synthesis was not prevented by blocking viral DNA synthesis. The VSV glycoprotein produced by AdG12 was fully processed and could function to direct low pH-induced fusion of infected cells. These Ad vectors have considerable potential utility for the expression of antigens in cell culture and for the immunization of animals in studies of immunity and protection.


Molecular Evidence of Distinct Introductions of the European Race of Gremmeniella abietina into North America.
ABSTRACT The presence of the European (EU) race of Gremmeniella abietina var. abietina, the causal agent of Scleroderris canker of conifers, was first reported in North America in 1975 in the northeastern United States and subsequently in southern Quebec and Newfoundland during the late 1970s, where it quickly became established. We analyzed DNA profiles in samples from a historic collection of G. abietina var. abietina that included some of the first isolates of the EU race reported in the United States to test hypotheses concerning the G. abietina var. abietina epidemic in North America. Genetic diversity was partitioned by an analysis of molecular variance with haplotype frequencies and distances. Genetic differentiation was high between populations in continental North America and Newfoundland (between region differentiation, Phi(ct) = 0.665, P < 0.001). This result was not consistent with the hypothesis of a single introduction of the pathogen into the northeastern United States followed by secondary spread into northeastern Canada. In contrast, small levels of genetic differentiation were observed among continental North American populations (Phi(ct) = 0.047, P = 0.079), suggesting gene flow among these populations. A single haplotype of G. abietina var. abietina dominated the continental populations (80% of the isolates) but was absent from Newfoundland and Europe. Five haplotypes were found in the New-foundland population, all of which were either absent or very rare on the continent. Populations from continental North America clustered together and were distinct from a second cluster composed of European and Newfoundland populations. A phylogenetic analysis of the haplotypes indicated that some of the rare haplotypes may have derived from somatic mutations, whereas others probably occurred as the result of new introductions. The results are consistent with a scenario of distinct primary introductions of this pathogen into Newfoundland and continental eastern North America followed by secondary asexual propagation.


Transcriptional profiling reveals that C5a alters microRNA in brain endothelial cells.
Blood-brain barrier (BBB) disturbance is a crucial occurrence in many neurological diseases, including systemic lupus erythematosus (SLE). Our previous studies showed that experimental lupus serum altered the integrity of the mouse brain endothelial layer, an important constituent of the BBB. Complement activation occurs in lupus with increased circulating complement components. Using a genomics approach, we identified the microRNA (miRNA) altered in mouse brain endothelial cells (bEnd3) by lupus serum and the complement protein, C5a. Of the 318 miRNA evaluated, 23 miRNAs were altered by lupus serum and 32 were altered by C5a alone compared with controls. Seven miRNAs (P < 0 · 05) were differentially expressed by both treatments: mmu-miR-133a*, mmu-miR-193*, mmu-miR-26b, mmu-miR-28*, mmu-miR-320a, mmu-miR-423-3p and mmu-miR-509-5p. The microarray results were validated by quantitative RT-PCR. In line with the in vitro results, expression of miR-26b and miR-28* were also significantly up-regulated in lupus mouse brain which was reduced by C5a receptor inhibition. Target prediction analysis revealed miR gene targets encoding components involved in inflammation, matrix arrangement, and apoptosis, pathways known to play important roles in central nervous system lupus. Our findings suggest that the miRNAs reported in this study may represent novel therapeutic targets in central nervous system lupus and other similar neuroinflammatory settings.


Palaeoecological inferences for the fossil Australian snakes Yurlunggur and Wonambi (Serpentes, Madtsoiidae).
Madtsoiids are among the most basal snakes, with a fossil record dating back to the Upper Cretaceous (Cenomanian). Most representatives went extinct by the end of the Eocene, but some survived in Australia until the Late Cenozoic. Yurlunggur and Wonambi are two of these late forms, and also the best-known madtsoiids to date. A better understanding of the anatomy and palaeoecology of these taxa may shed light on the evolution and extinction of this poorly known group of snakes and on early snake evolution in general. A digital endocast of the inner ear of Yurlunggur was compared to those of 81 species of snakes and lizards with known ecological preferences using three-dimensional geometric morphometrics. The inner ear of Yurlunggur most closely resembles both that of certain semiaquatic snakes and that of some semifossorial snakes. Other cranial and postcranial features of this snake support the semifossorial interpretation. While the digital endocast of the inner ear of Wonambi is too incomplete to be included in a geometric morphometrics study, its preserved morphology is very different from that of Yurlunggur and suggests a more generalist ecology. Osteology, palaeoclimatic data and the palaeobiogeographic distribution of these two snakes are all consistent with these inferred ecological differences.


Genetic organization of the Vibrio harveyi DnaA gene region and analysis of the function of the V. harveyi DnaA protein in Escherichia coli.
The Vibrionaceae family is distantly related to Enterobacteriaceae within the group of bacteria possessing the Dam methylase system. We have cloned, sequenced, and analyzed the dnaA gene region of Vibrio harveyi and found that although the organization of the V. harveyi dnaA region differs from that of Escherichia coli, the expression of both genes is autoregulated and ATP-DnaA binds cooperatively to ATP-DnaA boxes in the dnaA promoter region. The DnaA proteins of V. harveyi and E. coli are interchangeable and function nearly identically in controlling dnaA transcription and the initiation of chromosomal DNA replication despite the evolutionary distance between these bacteria.


Effects of altitude on mood, behaviour and cognitive functioning. A review.
Alterations in psychological mood, personality, behaviour and cognitive functioning associated with altitude have been recognised for many years. Psychological and behavioural changes resulting from the effects of hypoxia often include increases in euphoria, irritability, hostility and impairment of neuropsychological functions such as vision and memory. There is limited research to indicate that some decrements may persist for up to a year, or longer, after return to lower elevation. However, generalisations of the effects of altitude on mood, behaviour and cognitive function are complicated by differences between studies including the specific tasks or dimensions measured, methods of measurement, degree of altitude, duration of exposure and types of participants. There also appear to be wide individual differences in the response to altitude sojourns. Investigations designed to measure symptoms and mood changes during actual mountain climbs are needed, since most of the systematic research has been conducted in altitude chambers. The extent to which these simulations can be generalised to actual altitude settings remains to be documented.


Neural control of leg movements in a metamorphic insect: persistence of larval leg motor neurons to innervate the adult legs of Manduca sexta.
During metamorphosis of the hawkmoth Manduca sexta, the larval thoracic legs along with their associated sensory organs and muscles degenerate and new adult legs develop. The larval legs are small and relatively simple structures capable of lateral extension and medial flexion allowing them to grasp the substrate as the caterpillar crawls along. By contrast, the adult legs are used for walking with an alternating gait. They are much larger than the larval legs and articulate such that they are capable of movement in several directions. This change in form and function is accompanied by a reorganization of the neural circuits controlling leg movements. In a previous report (Kent and Levine: J. Comp. Neurol. 271:559-576, '88) we described motor neurons innervating the larval prothoracic legs, and here we describe motor neurons innervating the prothoracic legs of the adult. Using a combination of cobalt staining methods and the persistent fluorescent dye Fluoro-Gold, we have found that some, if not all, larval leg motor neurons are retained and innervate the new adult leg muscles. Moreover, we have been able to discover the fate of individual larval leg motor neurons by marking a single larval neuron with Fluoro-Gold and using a second fluorescent dye to double label the same neuron in the adult. Our results suggest that specific larval leg motor neurons innervate corresponding muscles in the adult stage, although their apparent function is significantly different. In addition, the motor neurons undergo significant remodeling of their dendritic branching patterns during metamorphosis, alterations which doubtless contribute to their new roles in adult behavior.


Vaccine effect of intact metacestodes of Taenia crassiceps against T. taeniaeformis infection in rats.
Wistar rats inoculated intraperitoneally with 10 viable metacestodes of Taenia crassiceps without adjuvant once on day 0 showed strong resistance to challenge with 200 eggs of T. taeniaeformis on day 30. When rats were killed one month after challenge, there were 80.4% and 46.1% reductions in the number of cystic and total metacestodes of T. taeniaeformis in the liver, respectively. When five rats were killed 16 months after challenge, they showed almost complete immunity against the challenge, with 99.4% and 91.1% reductions in the number of cystic and total metacestodes, respectively. There were only a few degenerated, pin-point metacestodes of T. taeniaeformis in the liver of all five rats; one harbored one cystic metacestode as well. However, there were no such reductions in rats injected initially with cyst fluid antigens of T. crassiceps with Freund's complete adjuvant. An additional experiment was carried out using 500 eggs of T. taeniaeformis in order to confirm the vaccine effect against higher egg dose. There were 96.6%, 87.9%, 83.9%, and 79.3% reductions in the number of cystic metacestodes in rats initially inoculated with 10 viable, 10 formalized, and 10 frozen metacestodes, and injected with sodium deoxycholate-solubilized metacestode antigens, respectively. It is strongly suggested that rats singly dosed with 10 viable or non-viable, intact metacestodes of T. crassiceps without adjuvant became highly resistant to challenge infection with eggs of T. taeniaeformis, which resulted in almost no cystic metacestode establishment.


Predicting Quality of Overnight Glycaemic Control in Type 1 Diabetes Using Binary Classifiers.
In type 1 diabetes management, maintaining nocturnal blood glucose within target range can be challenging. Although semi-automatic systems to modulate insulin pump delivery, such as low-glucose insulin suspension and the artificial pancreas, are starting to become a reality, their elevated cost and performance below user expectations is hindering their adoption. Hence, a decision support system that helps people with type 1 diabetes, on multiple daily injections or insulin pump therapy, to avoid undesirable overnight blood glucose fluctuations (hyper- or hypoglycaemic) is an attractive alternative. In this paper, we introduce a novel data-driven approach to predict the quality of overnight glycaemic control in people with type 1 diabetes by analyzing commonly gathered data during the day-time period (continuous glucose monitoring data, meal intake and insulin boluses). The proposed approach is able to predict whether overnight blood glucose concentrations are going to remain within or outside the target range, and therefore allows the user to take the appropriate preventive action (snack or change in basal insulin). For this purpose, a number of popular established machine learning algorithms for binary classification were evaluated and compared on a publicly available clinical dataset (i.e., OhioT1DM). Although there is no clearly superior classification algorithm, this study indicates that, by using commonly gathered data in type 1 diabetes management, it is possible to predict the quality of overnight glycaemic control with reasonable accuracy (AUC-ROC = 0.7).


Prevalence, incidence, and recurrence of oral lesions among HIV-infected patients on HAART in Alabama: a two-year longitudinal study.
Our aim was to quantify prevalence, incidence, and recurrence of oral lesions (OL) among a population in the Southeast. A retrospective study based on chart review was conducted among patients (n = 744) who were ≥19 years of age and initiated highly active antiretroviral therapy (HAART) between January 2000 and June 2006 at the University of Alabama at Birmingham (UAB) 1917 Clinic. Patients' laboratory data and oral conditions were recorded for 2 years after enrollment into the study. During 2 years of follow-up, the period prevalence of individuals experienced at least one OL was 35.6% (266/744). Among all of the 374 episodes of OL, 183 were new cases, while 57 were recurrences. The OL person-visit incidence rate was 0.02 per 100 person-visits. Oropharyngeal candidiasis (OPC) was the most frequent manifestation in terms of period prevalence (74.9%) with a person-visit incident rate of 0.01 per 100 person-visits. Patients undergoing HAART continue to be affected by HIV-related oral conditions, especially OPC. These results clearly indicate that OL during HIV infection are still highly prevalent in spite of the improvements in medical care and the availability of HAART.


Prospective Multicenter Study of Myocardial Recovery Using Left Ventricular Assist Devices (RESTAGE-HF [Remission from Stage D Heart Failure]): Medium-Term and Primary End Point Results.
Left ventricular assist device (LVAD) unloading and hemodynamic support in patients with advanced chronic heart failure can result in significant improvement in cardiac function allowing LVAD removal; however, the rate of this is generally considered to be low. This prospective multicenter nonrandomized study (RESTAGE-HF [Remission from Stage D Heart Failure]) investigated whether a protocol of optimized LVAD mechanical unloading, combined with standardized specific pharmacological therapy to induce reverse remodeling and regular testing of underlying myocardial function, could produce a higher incidence of LVAD explantation. Forty patients with chronic advanced heart failure from nonischemic cardiomyopathy receiving the Heartmate II LVAD were enrolled from 6 centers. LVAD speed was optimized with an aggressive pharmacological regimen, and regular echocardiograms were performed at reduced LVAD speed (6000 rpm, no net flow) to test underlying myocardial function. The primary end point was the proportion of patients with sufficient improvement of myocardial function to reach criteria for explantation within 18 months with sustained remission from heart failure (freedom from transplant/ventricular assist device/death) at 12 months. Before LVAD, age was 35.1±10.8 years, 67.5% were men, heart failure mean duration was 20.8±20.6 months, 95% required inotropic and 20% temporary mechanical support, left ventricular ejection fraction was 14.5±5.3%, end-diastolic diameter was 7.33±0.89 cm, end-systolic diameter was 6.74±0.88 cm, pulmonary artery saturations were 46.7±9.2%, and pulmonary capillary wedge pressure was 26.2±7.6 mm Hg. Four enrolled patients did not undergo the protocol because of medical complications unrelated to the study procedures. Overall, 40% of all enrolled (16/40) patients achieved the primary end point, P<0.0001, with 50% (18/36) of patients receiving the protocol being explanted within 18 months (pre-explant left ventricular ejection fraction, 57±8%; end-diastolic diameter, 4.81±0.58 cm; end-systolic diameter, 3.53±0.51 cm; pulmonary capillary wedge pressure, 8.1±3.1 mm Hg; pulmonary artery saturations 63.6±6.8% at 6000 rpm). Overall, 19 patients were explanted (19/36, 52.3% of those receiving the protocol). The 15 ongoing explanted patients are now 2.26±0.97 years after explant. After explantation survival free from LVAD or transplantation was 90% at 1-year and 77% at 2 and 3 years. In this multicenter prospective study, this strategy of LVAD support combined with a standardized pharmacological and cardiac function monitoring protocol resulted in a high rate of LVAD explantation and was feasible and reproducible with explants occurring in all 6 participating sites. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01774656.