Does early second-trimester sonography predict adverse perinatal outcomes in monochorionic diamniotic twin pregnancies?
To determine whether intertwin discordant abdominal circumference, femur length, head circumference, and estimated fetal weight sonographic measurements in early second-trimester monochorionic diamniotic twins predict adverse obstetric and neonatal outcomes. We conducted a multicenter retrospective cohort study involving 9 regional perinatal centers in the United States. We examined the records of all monochorionic diamniotic twin pregnancies with two live fetuses at the 16- to 18-week sonographic examination who had serial follow-up sonography until delivery. The intertwin discordance in abdominal circumference, femur length, head circumference, and estimated fetal weight was calculated as the difference between the two fetuses, expressed as a percentage of the larger using the 16- to 18-week sonographic measurements. An adverse composite obstetric outcome was defined as the occurrence of 1 or more of the following in either fetus: intrauterine growth restriction, twin-twin transfusion syndrome, intrauterine fetal death, abnormal growth discordance (≥20% difference), and very preterm birth at or before 28 weeks. An adverse composite neonatal outcome was defined as the occurrence of 1 or more of the following: respiratory distress syndrome, any stage of intraventricular hemorrhage, 5-minute Apgar score less than 7, necrotizing enterocolitis, culture-proven early-onset sepsis, and neonatal death. Receiver operating characteristic and logistic regression-with-generalized estimating equation analyses were constructed. Among the 177 monochorionic diamniotic twin pregnancies analyzed, intertwin abdominal circumference and estimated fetal weight discordances were only predictive of adverse composite obstetric outcomes (areas under the curve, 79% and 80%, respectively). Receiver operating characteristic curves showed that intertwin discordances in abdominal circumference, femur length, head circumference, and estimated fetal weight were not acceptable predictors of twin-twin transfusion syndrome or adverse neonatal outcomes. In our cohort, only second-trimester abdominal circumference and estimated fetal weight discordances in monochorionic diamniotic twin pregnancies were predictive of adverse composite obstetric outcomes. Twin-twin transfusion syndrome and adverse neonatal outcomes were not predicted by any of the intertwin discordances measured.


Effect of cyclosporin A on the allergen-induced late asthmatic reaction.
The allergen-induced late asthmatic reaction (LAR) is associated with mucosal inflammation involving several cell types including activated T lymphocytes and eosinophils. In contrast, the early asthmatic reaction (EAR) is considered to results from rapid allergen-induced release of bronchoconstrictor mediators from IgE sensitised mast cells. Cyclosporin A has efficacy in chronic severe corticosteroid-dependent asthma and is believed to act principally by inhibiting cytokine mRNA transcription in T lymphocytes. However, it has effects on other cell types in vitro, including the inhibition of exocytosis/degranulation events in mast cells. It was therefore hypothesised that cyclosporin A would attenuate both the EAR and LAR in subjects with mild asthma. Twelve sensitised atopic asthmatic subjects with documented dual asthmatic responses were studied in a double blind, placebo controlled, crossover trial. On two separate study visits subjects received two oral doses of either cyclosporin A or matched placebo before inhaled allergen challenges. The forced expiratory volume in one second (FEV1) was measured half hourly for eight hours and blood eosinophil counts were analysed three, six, and 24 hours after the challenge. Treatment effects on blood eosinophil counts as well as the EAR and LAR, respectively defined as the areas under the curve (AUC) of FEV1 changes from baseline between 0-1 and 4-8 hours after challenge, were compared by non-parametric crossover analysis. Cyclosporin A reduced both the LAR (median AUC -41.9 1.h (interquartile range -82.7 to -12.4) for cyclosporin A and -84.5 1.h (-248.9 to -39.1) for placebo; p = 0.007) and the late increase in blood eosinophils (median 0.2 x 10(9)/1 (0.15 to 0.4) for cyclosporin A and 0.4 x 10(9)/1 (0.25 to 0.55) for placebo; p = 0.024) but had no effect on the EAR. The reduction of the LAR by cyclosporin A correlated significantly with prechallenge blood concentrations of cyclosporin A (r = 0.6, p = 0.028). These data are consistent with the concept that cyclosporin A has anti-inflammatory actions in asthma resulting from inhibition of mRNA transcription of eosinophil-active cytokines, predominantly in T lymphocytes. Cyclosporin A, possibly in its inhaled form, or other agents which prevent cytokine gene transcription may therefore have potential in ameliorating the inflammatory component of asthma.


Effect of organic matter concentration and characteristics on mercury mobilization and methylmercury production at an abandoned mine site.
Thousands of abandoned mines throughout the western region of North America contain elevated total-mercury (THg) concentrations. Mercury is mobilized from these sites primarily due to erosion of particulate-bound Hg (THg-P). Organic matter-based soil amendments can promote vegetation growth on mine tailings, reducing erosion and subsequent loading of THg-P into downstream waterbodies. However, the introduction of a labile carbon source may stimulate microbial activity that can produce methylmercury (MeHg)-the more toxic and bioaccumulative form of Hg. Our objectives were to investigate how additions of different organic matter substrates impact Hg mobilization and methylation using a combination of field observations and controlled experiments. Field measurements of water, sediment, and porewater were collected downstream of the site and multi-year monitoring (and load calculations) were conducted at a downstream gaging station. MeHg production was assessed using stable isotope methylation assays and mesocosm experiments that were conducted using different types of organic carbon soil amendments mixed with materials from the mine site. The results showed that >80% of the THg mobilized from the mine was bound to particles and that >90% of the annual Hg loading occurred during the period of elevated discharge during spring snowmelt. Methylation rates varied between different types of soil amendments and were correlated with the components of excitation emission matrices (EEMs) associated with humic acid fractions of organic matter. The mesocosm experiments showed that under anoxic conditions carbon amendments to tailings could significantly increase porewater MeHg concentrations (up to 13 ± 3 ng/L). In addition, the carbon amendments significantly increased THg partitioning into porewater. Overall, these results indicate that soil amendment applications to reduce surface erosion at abandoned mine sites could be effective at reducing particulate Hg mobilization to downstream waterbodies; however, some types of carbon amendments can significantly increase Hg methylation as well as increase the mobilization of dissolved THg from the site.


Atmospheric Neutron Monitoring through Optical Fiber-Based Sensing.
The potential of fiber-based sensors to monitor the fluence of atmospheric neutrons is evaluated through accelerated tests at the TRIUMF Neutron Facility (TNF) (BC, Canada), offering a flux approximatively 109 higher than the reference spectrum observed under standard conditions in New York City, USA. The radiation-induced attenuation (RIA) at 1625 nm of a phosphorus-doped radiation sensitive optical fiber is shown to linearly increase with neutron fluence, allowing an in situ and easy monitoring of the neutron flux and fluence at this facility. Furthermore, our experiments show that the fiber response remains sensitive to the ionization processes, at least up to a fluence of 7.1 × 1011 n cm-², as its radiation sensitivity coefficient (~3.36 dB km-1 Gy-1) under neutron exposure remains very similar to the one measured under X-rays (~3.8 dB km-1 Gy-1) at the same wavelength. The presented results open the way to the development of a point-like or even a distributed dosimeter for natural or man-made neutron-rich environments. The feasibility to measure the dose caused by the neutron exposure during stratospheric balloon experiments, or during outer space missions, is presented as a case study of a potential future application.


[Septic shock--a condition with great potential for improvement. Management and therapy].
There is a recent focus upon treatment of septic shock, related to the publication of a number of interesting studies during the last two years. These studies indicate that patient outcome can be improved, provided care is organized so as to optimize and expedite initial treatment of the patient in septic shock. In parallel, new drugs have been launched using rather aggressive marketing, which calls for recommendations and advice from professional experts who are independent of the pharmaceutical industry. This article reviews the studies that have engendered a new optimism in the treatment of septic shock. These "new" therapies are presented in a total context with a temporal perspective. It is suggested that emergency sepsis teams be instituted at hospitals.


Oral health-related quality of life in patients with temporomandibular disorders: A case-control study considering psychological aspects.
This case-control study aimed to compare patients with temporomandibular disorders (TMD) and healthy controls in terms of oral health-related quality of life (OHRQoL) considering Graded Chronic Pain Scale (GCPS) scores, pain duration, psychological impairment and demographic characteristics. A total of 75 patients with TMD and 75 healthy controls were recruited. The short version of Oral Health Impact Profile (OHIP-14) was administered for evaluating the OHRQoL. Psychosocial impairments were assessed using the General Health Questionnaire-28 (GHQ-28). The Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) axis I and II were also used for patient diagnosis and collecting GCPS scores, pain duration, age and gender. Independent-sample t tests, Pearson's chi-square tests and multiple logistic and linear regression models were applied for statistical analysis. The mean age of the patients was 34.3±12.4 years. A female-to-male ratio of 6:1 was seen in the TMD group. The prevalence and severity of the OHIP were significantly different between the TMD and control groups (66.7% vs 12.0% and 18.0 vs 9.2, respectively). According to multiple logistic regression for OHIP prevalence and multiple linear regression for OHIP severity in the TMD group, GCPS scores and pain duration, followed by psychological impairment, were the most important predictors of the OHRQoL. TMD negatively affected the OHRQoL, particularly in patients with psychological impairments. Meanwhile, age and gender did not seem to have a serious effect. Hence, promoting the quality of life of patients with TMD requires emphasis on chronic pain management and maintaining good mental health.


Disseminated cutaneous granulomatous eruption occurring in the setting of myelodysplasia.
A 66-year-old woman with a myelodysplastic syndrome developed a widespread, pruritic, nodular eruption. A skin-biopsy specimen showed a granulomatous infiltrate, with no evidence of clonality; a bone-marrow biopsy showed possible transition to acute myeloid leukemia. This presentation is consistent with two prior reports of granulomatous eruptions occurring in the setting of myelodysplasia.


Ecological limitations on aquatic mosquito predator colonization in the urban environment.
Urban malaria cases are becoming common in Africa as more people move into cities and industrialization proceeds. While many species of Anopheles mosquitoes vector malaria in rural areas, only a few are found within cities. The success of anthropophilic species in cities, such as members of the An. gambiae complex, may be explained by limitations on colonization by predator species in urban environments. Habitats that are temporal or structurally simple have lower predator survivorship in a variety of ecosystems, but these have not been investigated previously in an urban area. Areas within and around the Kenyan coastal town of Malindi were previously sampled for the presence of standing water using a geographic sampling strategy with probability proportional to size sampling of planned well-drained, unplanned poorly-drained, planned poorly-drained, unplanned well-drained, and peri-urban locations. Standing aquatic habitats in these areas were reassessed. During monthly sampling, presence/absence of mosquitoes and predator taxa were noted, as were ecological habitat variables: structural complexity and presence of water. Lambda statistics were calculated to associate predator guilds, habitat types, location variables, and ecological variables. All predator guilds found in habitats were strongly associated with habitat type, as were the structural complexity and temporal nature of the habitats. Types of habitat were heterogeneously distributed throughout Malindi, with swimming pools as a common habitat type in planned urban areas and tire track pools a common habitat type in peri-urban areas of Malindi. Predator colonization of aquatic habitats in Malindi was strongly influenced by habitat type, and not associated with location characteristics. Ecological variables were affected by the type of habitats, which are co-associated with planning and drainage in Malindi. While habitat types are distributed heterogeneously within Malindi, habitats with low predation pressure are available for mosquito colonization in both urban and peri-urban areas. The temporal, peri-urban tire track pools and the structural simplicity of urban swimming pools may discourage predator colonization, thereby increasing the probability of malaria vectors in these areas of Malindi. Future studies should evaluate habitats for use in malaria surveillance and experimentally test the effects of structural complexity and temporal nature of urban habitats on the densities of mosquito larvae and their aquatic predators.


"We, mothers of autistic people": between knowledge of the experience and collective memories in videos on YouTube.
This paper results from research that analyzed the narratives of mothers of autistic children about their experiences with their children, produced and shared by them through videos on YouTube. We used a qualitative methodology to debate the logic and meanings attributed to illness, health, motherhood, and childcare, towards a narrative reconstruction produced by us researchers. We observed that these women spoke primarily about their experiences as mothers of autistic children and directly addressed the emotional difficulties of having a child with autism, such as mourning the ideal child promoted by the diagnosis and the construction of care for an autistic child. Through the videos, the mothers form an identification group based on the premise that they lived everyday experiences, generating significant value and becoming an existential capital. Talking about such experiences in public and far-reaching spaces like YouTube produces, among other things, collective memories that develop a caring community. We understand that the individual story reported and produced in the videos can emotionally and pragmatically help others with a similar experience, re-inhabiting daily life.


Contribution of disruption of the nuclear factor-kappaB pathway to induction of apoptosis in human leukemia cells by histone deacetylase inhibitors and flavopiridol.
Interactions between the cyclin-dependent kinase inhibitor flavopiridol and the histone deacetylase inhibitors (HDACIs) sodium butyrate (NaB) and suberoylanilide hydroxamic acid (SAHA) have been examined in human leukemia cells in relation to effects on nuclear factor kappaB (NF-kappaB) activation. Exposure (24 h) of U937 human leukemia cells to NaB (1 mM) or SAHA (1.5 microM) resulted in a marked increase in NF-kappaB DNA binding, effects that were essentially abrogated by coadministration of flavopiridol (100 nM). These events were accompanied by a marked increase in mitochondrial injury, caspase activation, and apoptosis. Mutant cells expressing an IkappaBalpha super-repressor exhibited impairment of NF-kappaB DNA binding in response to HDACIs and a significant although modest increase in apoptosis. However, disruption of the NF-kappaB pathway also increased mitochondrial injury and caspase activation in response to flavopiridol and to an even greater extent to the combination of flavopiridol and HDACIs. Coadministration of flavopiridol with HDACIs down-regulated the X-linked inhibitor of apoptosis (XIAP), Mcl-1, and p21CIP1/WAF1 and activated c-Jun NH2-terminal kinase; moreover, these effects were considerably more pronounced in IkappaBalpha mutants. Similar responses were observed in U937 mutant cells stably expressing RelA/p65 small interfering RNA. In all cases, flavopiridol was significantly more potent than genetic interruption of the NF-kappaB cascade in promoting HDACI-mediated lethality. Together, these findings are consistent with the notion that although inhibition of NF-kappaB activation by flavopiridol contributes to antileukemic interactions with HDACIs, other NF-kappaB-independent flavopiridol actions (e.g., down-regulation of Mcl-1, XIAP, and p21CIP1/WAF1) play particularly critical roles in this phenomenon.


Tissue-specific regulation of epidermal contraction during Caenorhabditis elegans embryonic morphogenesis.
Actin and myosin mediate the epidermal cell contractions that elongate the Caenorhabditis elegans embryo from an ovoid to a tubular-shaped worm. Contraction occurs mainly in the lateral epidermal cells, while the dorsoventral epidermis plays a more passive role. Two parallel pathways trigger actinomyosin contraction, one mediated by LET-502/Rho kinase and the other by PAK-1/p21 activated kinase. A number of genes mediating morphogenesis have been shown to be sufficient when expressed either laterally or dorsoventrally. Additional genes show either lateral or dorsoventral phenotypes. This led us to a model where contractile genes have discrete functions in one or the other cell type. We tested this by examining several genes for either lateral or dorsoventral sufficiency. LET-502 expression in the lateral cells was sufficient to drive elongation. MEL-11/Myosin phosphatase, which antagonizes contraction, and PAK-1 were expected to function dorsoventrally, but we could not detect tissue-specific sufficiency. Double mutants of lethal alleles predicted to decrease lateral contraction with those thought to increase dorsoventral force were previously shown to be viable. We hypothesized that these mutant combinations shifted the contractile force from the lateral to the dorsoventral cells and so the embryos would elongate with less lateral cell contraction. This was tested by examining 10 single and double mutant strains. In most cases, elongation proceeded without a noticeable alteration in lateral contraction. We suggest that many embryonic elongation genes likely act in both lateral and dorsoventral cells, even though they may have their primary focus in one or the other cell type.


Sensitive and rapid reversed-phase liquid chromatography-fluorescence method for determining bisphenol A diglycidyl ether in aqueous-based food simulants.
A method has been developed for determination of bisphenol A diglycidyl ether (BADGE) in 3 aqueous-based food simulants: water, 15% (v/v) ethanol, and 3% (w/v) acetic acid. BADGE is extracted with C18 cartridges and the extract is concentrated under a stream of nitrogen. BADGE is quantitated by reversed-phase liquid chromatography with fluorescence detection. Relative precision at 200 micrograms/L was 3.4%, the detection limit of the method was 0.1 micrograms/L, and recoveries of spiking concentrations from 1 to 8 micrograms/L were nearly 100%. Relative standard deviations for the method ranged from 3.5 to 5.9%, depending on the identity of the spiked aqueous-based food simulant.


Opinion leaders' support for tobacco control policies and participation in tobacco control activities.
Because opinion leaders hold positions from which they may influence tobacco control efforts, this study examined their support for tobacco control policies and their involvement in tobacco control activities. A telephone survey was administered to 712 California opinion leaders who were randomly selected from constructed lists representing 8 types of organizations: health, education, law enforcement, media, government, business, ethnic, and youth. Hierarchical regression analysis was used to identify predictors of support for and participation in tobacco control activities. Approximately one half to two thirds of opinion leaders supported the tobacco control policies queried; 60% reported involvement in tobacco control-related activities during the previous year. Organizational affiliation was a strong predictor of support and involvement, with leaders from health and educational organizations reporting the highest levels and business and media leaders reporting the lowest. Tobacco issue involvement variables (e.g., having a friend or family member with a smoking-related illness) were significantly associated with the outcomes, while sociodemographics, for the most part, were not. Study results can be used to mobilize opinion leaders' support for tobacco control more effectively.


Hereditary dysplastic nevus syndrome: lymphoid cell ultraviolet hypermutability in association with increased melanoma susceptibility.
The hereditary dysplastic nevus syndrome (DNS) is a well-characterized disorder in which affected individuals have increased numbers of premalignant (dysplastic) nevi and a markedly increased risk of developing cutaneous melanoma. Seeking evidence of a systemic disorder in DNS, we examined the effect of ultraviolet radiation on cultured lymphoid cells. Epstein-Barr virus-transformed lymphoblastoid cell lines from patients with hereditary DNS had similar survival values following treatment with 2.3 to 9.0 J of 254-nm ultraviolet radiation per m2 as did lines from control individuals. Mutagenesis at the hypoxanthineguanine phosphoribosyltransferase locus was assessed by measuring the induction of resistance to thioguanine using a microtiter well assay. Three lymphoblastoid cell lines from patients with hereditary DNS and melanoma had a 2- to 3-fold greater frequency of induced mutants per clonable cell than three normal lines following exposure to 4.5 to 9.0 J of ultraviolet radiation per m2. Expanded clones of mutated DNS lymphoblastoid cell lines had less than 6% of normal hypoxanthine-guanine phosphoribosyltransferase activity. Inhibition and recovery of DNA synthesis following ultraviolet exposure were similar in 2 DNS and 2 normal lines. Repair by DNS lines of ultraviolet-induced DNA damage was in the normal range as measured by alkaline elution. Thus, hereditary DNS exhibits in vitro hypermutability which may reflect increased susceptibility to ultraviolet-induced somatic mutations in vivo. This abnormality may be related to the increased melanoma susceptibility of patients with hereditary DNS.


Apolipoprotein A-I Mimetic Peptides: Discordance Between In Vitro and In Vivo Properties-Brief Report.
Apolipoprotein A-I (apoA-I) mimetic peptides have antiatherogenic properties of high-density lipoprotein in vitro and have been shown to inhibit atherosclerosis in vivo. It is unclear, however, if each in vitro antiatherogenic property of these peptides translates to a corresponding activity in vivo, and if so, which of these contributes most to reduce atherosclerosis. The effect of 7 apoA-I mimetic peptides, which were developed to selectively reproduce a specific component of the antiatherogenic properties of apoA-I, on the development of atherosclerosis was investigated in apolipoprotein E-deficient mice fed a high-fat diet for 4 or 12 weeks. The peptides include those that selectively upregulate cholesterol efflux, or are anti-inflammatory, or have antioxidation properties. All the peptides studied effectively inhibited the in vivo development of atherosclerosis in this model to the same extent. However, none of the peptides had the same selective effect in vivo as they had exhibited in vitro. None of the tested peptides affected plasma lipoprotein profile; capacity of plasma to support cholesterol efflux was increased modestly and similarly for all peptides. There is a discordance between the selective in vitro and in vivo functional properties of apoA-I mimetic peptides, and the in vivo antiatherosclerotic effect of apoA-I-mimetic peptides is independent of their in vitro functional profile. Comparing the properties of apoA-I mimetic peptides in plasma rather than in the lipid-free state is better for predicting their in vivo effects on atherosclerosis.


Spindle pole body components are reorganized during fission yeast meiosis.
During meiosis, the centrosome/spindle pole body (SPB) must be regulated in a manner distinct from that of mitosis to achieve a specialized cell division that will produce gametes. In this paper, we demonstrate that several SPB components are localized to SPBs in a meiosis-specific manner in the fission yeast Schizosaccharomyces pombe. SPB components, such as Cut12, Pcp1, and Spo15, which stay on the SPB during the mitotic cell cycle, disassociate from the SPB during meiotic prophase and then return to the SPB immediately before the onset of meiosis I. Interestingly, the polo kinase Plo1, which normally localizes to the SPB during mitosis, is excluded from them in meiotic prophase, when meiosis-specific, horse-tail nuclear movement occurs. We found that exclusion of Plo1 during this period was essential to properly remodel SPBs, because artificial targeting of Plo1 to SPBs resulted in an overduplication of SPBs. We also found that the centrin Cdc31 was required for meiotic SPB remodeling. Thus Plo1 and a centrin play central roles in the meiotic SPB remodeling, which is essential for generating the proper number of meiotic SPBs and, thereby provide unique characteristics to meiotic divisions.


Clozapine Increases Nestin Concentration in the Adult Male Rat Hippocampus: A Preliminary Study.
Patients with schizophrenia, and rodent models of the disease, both exhibit suppressed neurogenesis, with antipsychotics possibly enhancing neurogenesis in pre-clinical models. Nestin, a cytoskeletal protein, is implicated in neuronal differentiation and adult neurogenesis. We hypothesized that schizophrenia pathogenesis involves nestin downregulation; however, few studies have related nestin to schizophrenia. We assessed nestin protein concentration, prepulse inhibition (PPI), and social interaction in the MK-801 model of schizophrenia, with or without antipsychotic (clozapine) treatment. Adult male Sprague-Dawley rats were intraperitoneally administered saline or MK-801 (0.1 mg/kg) to produce a schizophrenia-like phenotype, with concomitant subcutaneous injections of vehicle or clozapine (5 mg/kg). PPI was assessed on days 1, 8, and 15, and social interaction was assessed on day 4. Hippocampus tissue samples were dissected for Western blotting of nestin concentration. MK-801 alone did not alter nestin concentration, while clozapine alone enhanced hippocampal nestin concentration; this effect was not apparent in animals with MK-801 and clozapine co-administration. MK-801 also produced schizophrenia-like PPI disruptions, some of which were reversed by clozapine. Social interaction deficits were not detected in this model. This is the first report of clozapine-induced enhancements of hippocampal nestin concentration that might be mediated by NMDA receptors. Future studies will explore the impact of neurodevelopmental nestin concentration on symptom onset and antipsychotic treatment.


Psychiatric disorder in a rural and an urban population: 2. Sensitivity to loss.
In an earlier paper we found that a model of depression developed on a sample of women in a London population was confirmed in a female population in the Outer Hebrides. Differences in the rates of onset and chronic cases between the two populations, however, suggested that the Scottish women might be more likely to become depressed after the death or intimation of death of close relatives; furthermore, it seemed that such depressions were more likely to remain chronic in the Scottish islands than in London, and to contain a strong anxiety component. This difference is discussed in the light of socio-cultural differences between the two populations, particularly in terms which relate family structure, marital position and contact with relatives to affective disorder in terms of theories of attachment.


[Ultrastructure and functions of the cells of proximal and distal segments of the nephron of anadromous and freshwater fishes].
In the carp kidney, the proximal tubule cells have no infoldings of the basilar plasmatic membrane. In the Salmonidae nephrons the numerous parallel membranes of proximal tubule cell are formed by foldings of the basilar plasmatic membrane with numerous mitochondria in between. In O. nerka and S. malma experiments with MgCl2 injection showed that their kidneys secrete magnesium in contrast to the carp kidney. The numerous invaginations of proximal tubule cells membrane are suggested to be a morphological equivalent of the Na/Mg exchange mechanism.


Modelling and genetic dissection of staygreen under heat stress.
Staygreen traits are associated with heat tolerance in bread wheat. QTL for staygreen and related traits were identified across the genome co-located with agronomic and physiological traits associated to plant performance under heat stress. Plant chlorophyll retention-staygreen-is considered a valuable trait under heat stress. Five experiments with the Seri/Babax wheat mapping population were sown in Mexico under hot-irrigated environments. Normalized difference vegetation index (NDVI) during plant growth was measured regularly and modelled to capture the dynamics of plant greenness decay, including staygreen (Stg) at physiological maturity which was estimated by regression of NDVI during grainfilling. The rate of senescence, the percentage of plant greenness decay, and the area under the curve were also estimated based on NDVI measurements. While Stg and the best fitted curve were highly environment dependent, both traits showed strong (positive for Stg) correlations with yield, grainfilling rates, and extended grainfilling periods, while associations with kernel number and kernel weight were weak. Stg expression was largely dependent on rate of senescence which was related to the pattern of the greenness decay curve and the initial NDVI. QTL analyses revealed a total of 44 loci across environments linked to Stg and related traits, distributed across the genome, with the strongest and most repeatable effects detected on chromosomes 1B, 2A, 2B, 4A, 4B and 7D. Of these, some were common with regions controlling phenology but independent regions were also identified. The co-location of QTL for Stg and performance traits in this study confirms that the staygreen phenotype is a useful trait for productivity enhancement in hot-irrigated environments.


TEMPO-Mediated Interrupted 6π-Photocyclization of ortho-Biaryl-Appended 1,3-Dicarbonyl Compounds toward 10-Phenanthrenols.
In this paper, we present an example of a photoinduced catalyst, halogen-, and base-free TEMPO-mediated interrupted 6π-photocyclization/dehydrogenative aromatization of ortho-biaryl-appended 1,3-dicarbonyl compounds for the preparation of 10-phenanthrenols. The reaction involves rapid photocycloaddition via a 1,2-biradical of 1,3-dicarbonyl compounds, followed by subsequent dehydrogenative aromatization of 1,4-biradical intermediates using TEMPO as the commercially available oxidant rather than trapped by TEMPO to form an alkoxyamine product.


Does high-intensity resistance training maintain bone mass during moderate weight loss in older overweight adults with type 2 diabetes?
The aim was to investigate whether the addition of supervised high intensity progressive resistance training to a moderate weight loss program (RT+WLoss) could maintain bone mineral density (BMD) and lean mass compared to moderate weight loss (WLoss) alone in older overweight adults with type 2 diabetes. We also investigated whether any benefits derived from a supervised RT program could be sustained through an additional home-based program. This was a 12-month trial in which 36 sedentary, overweight adults aged 60 to 80 years with type 2 diabetes were randomized to either a supervised gymnasium-based RT+WLoss or WLoss program for 6 months (phase 1). Thereafter, all participants completed an additional 6-month home-based training without further dietary modification (phase 2). Total body and regional BMD and bone mineral content (BMC), fat mass (FM) and lean mass (LM) were assessed by DXA every 6 months. Diet, muscle strength (1-RM) and serum total testosterone, estradiol, SHBG, insulin and IGF-1 were measured every 3 months. No between group differences were detected for changes in any of the hormonal parameters at any measurement point. In phase 1, after 6 months of gymnasium-based training, weight and FM decreased similarly in both groups (P<0.01), but LM tended to increase in the RT+WLoss (n=16) relative to the WLoss (n=13) group [net difference (95% CI), 1.8% (0.2, 3.5), P<0.05]. Total body BMD and BMC remained unchanged in the RT+WLoss group, but decreased by 0.9 and 1.5%, respectively, in the WLoss group (interaction, P<0.05). Similar, though non-significant, changes were detected at the femoral neck and lumbar spine (L2-L4). In phase 2, after a further 6 months of home-based training, weight and FM increased significantly in both the RT+WLoss (n=14) and WLoss (n=12) group, but there were no significant changes in LM or total body or regional BMD or BMC in either group from 6 to 12 months. These results indicate that in older, overweight adults with type 2 diabetes, dietary modification should be combined with progressive resistance training to optimize the effects on body composition without having a negative effect on bone health.


Detecting epileptic seizures in long-term human EEG: a new approach to automatic online and real-time detection and classification of polymorphic seizure patterns.
Epileptic seizures can cause a variety of temporary changes in perception and behavior. In the human EEG they are reflected by multiple ictal patterns, where epileptic seizures typically become apparent as characteristic, usually rhythmic signals, often coinciding with or even preceding the earliest observable changes in behavior. Their detection at the earliest observable onset of ictal patterns in the EEG can, thus, be used to start more-detailed diagnostic procedures during seizures and to differentiate epileptic seizures from other conditions with seizure-like symptoms. Recently, warning and intervention systems triggered by the detection of ictal EEG patterns have attracted increasing interest. Since the workload involved in the detection of seizures by human experts is quite formidable, several attempts have been made to develop automatic seizure detection systems. So far, however, none of these found widespread application. Here, we present a novel procedure for generic, online, and real-time automatic detection of multimorphologic ictal-patterns in the human long-term EEG and its validation in continuous, routine clinical EEG recordings from 57 patients with a duration of approximately 43 hours and additional 1,360 hours of seizure-free EEG data for the estimation of the false alarm rates. We analyzed 91 seizures (37 focal, 54 secondarily generalized) representing the six most common ictal morphologies (alpha, beta, theta, and delta- rhythmic activity, amplitude depression, and polyspikes). We found that taking the seizure morphology into account plays a crucial role in increasing the detection performance of the system. Moreover, besides enabling a reliable (mean false alarm rate<0.5/h, for specific ictal morphologies<0.25/h), early and accurate detection (average correct detection rate>96%) within the first few seconds of ictal patterns in the EEG, this procedure facilitates the automatic categorization of the prevalent seizure morphologies without the necessity to adapt the proposed system to specific patients.


Effect of yerba mate (Ilex paraguariensis) tea on topoisomerase inhibition and oral carcinoma cell proliferation.
Tea flavonoids have antitopoisomerase activity and can inhibit cell proliferation. The objectives of this study were to determine the phenolic content of yerba mate tea products (MT) (Ilex paraguariensis) and evaluate their capacity to inhibit topoisomerase I (Topo I) and II (Topo II) activities and oral carcinoma cell proliferation. Total polyphenols of aqueous extracts of dried MT leaves were measured by the Folin-Ciocalteau assay, using chlorogenic (CH) and gallic (GA) acids as standards. Topoisomerase inhibition was determined by a clone-forming assay, which uses yeast (Saccharomyces cerevisiae) strains as a model. Controls included dimethyl sulfoxide (1.66%); camptothecin (50 microg/mL), a Topo I inhibitor; and amsacrine (100 microg/mL), a Topo II inhibitor. Cytotoxicity studies were conducted using a nontumorigenic human keratinocyte cell line HaCaT and two human squamous cancer cell lines (SCC-61 and OSCC-3). MT was found to be a rich source of phenolic compounds. Total polyphenol content of various commercially available traditional MT products ranged from 236 to 490 mg equiv of CH/g of dry leaves. Such levels were significantly different among products depending on their origin (P < 0.001). Higher anti-topoisomerase II activity was observed against JN394t(2-4) strain for Nobleza Gaucha MT (IC50 = 0.43 microg equiv of CH) in comparison to GA (IC50 = 112 mM) and CH (IC50 > 1500 mM). MT showed catalytic anti-topoisomerase activity against Topo II but not against Topo I. In addititon, MT exhibited dose-dependent cytotoxicity against all squamous cell lines tested. In comparison to premalignant cell line HaCaT [28 microg equiv of (+)-catechin mL(-1)], the cell line SCC-61 [21 microg equiv of (+)-catechin mL(-1)] was the most sensitive to MT, resulting in 50% inhibition of net cell growth. It is concluded that MT is rich in phenolic constituents and can also inhibit oral cancer proliferation. The effect on cancer cell proliferation may be mediated via inhibition of topoisomerase II. The lack of correlation between polyphenol content and the inhibition of topoisomerases suggests that the effect of MT on topoisomerase inhibition may be due to other still unidentified biologically active phytochemicals constituents.


Survey of parallel slat collimator designs for hybrid PET imaging.
Hybrid PET gamma cameras with coincidence detection electronics are commonly equipped with parallel slat collimators in order to reduce detection of singles and scattered photons, and create a pseudo-2D imaging geometry. The objective of this work was to survey a broad range of parallel slat collimator designs using a series of Monte Carlo simulated PET acquisitions. Collimator properties including septal height, septal thickness and pitch were independently examined over a wide range of values. Simulations were performed for hybrid PET imaging of a long cylindrical phantom uniformly filled with water and radioactivity. The performance for each collimator design was evaluated in terms of the trues-to-singles ratio, scatter fraction, and noise equivalent count rate for a wide range of camera trigger rates. Results indicate that increasing septal height offers the biggest performance gain. Septal thickness should be at least 0.5 mm, and should be optimized in conjunction with pitch to obtain the best performance. This survey provides the groundwork necessary for optimizing slat collimators, and provides a starting point for investigating new slat collimator designs.


Neuroimaging Biomarkers in Schizophrenia.
Schizophrenia is a complex neuropsychiatric syndrome with a heterogeneous genetic, neurobiological, and phenotypic profile. Currently, no objective biological measures-that is, biomarkers-are available to inform diagnostic or treatment decisions. Neuroimaging is well positioned for biomarker development in schizophrenia, as it may capture phenotypic variations in molecular and cellular disease targets, or in brain circuits. These mechanistically based biomarkers may represent a direct measure of the pathophysiological underpinnings of the disease process and thus could serve as true intermediate or surrogate endpoints. Effective biomarkers could validate new treatment targets or pathways, predict response, aid in selection of patients for therapy, determine treatment regimens, and provide a rationale for personalized treatments. In this review, the authors discuss a range of mechanistically plausible neuroimaging biomarker candidates, including dopamine hyperactivity, N-methyl-d-aspartate receptor hypofunction, hippocampal hyperactivity, immune dysregulation, dysconnectivity, and cortical gray matter volume loss. They then focus on the putative neuroimaging biomarkers for disease risk, diagnosis, target engagement, and treatment response in schizophrenia. Finally, they highlight areas of unmet need and discuss strategies to advance biomarker development.


Retroviral vector gene expression in F9 embryonal carcinoma cells.
When F9 embryonal carcinoma (EC) cells are infected with retroviral vectors, the efficiency of expression of selectable genes is considerably lower than that in mouse fibroblasts infected with the same retroviral vectors. In this study, several retroviral vectors with regulatory sequences placed immediately 5' to a selectable gene were constructed, packaged, and used to infect mouse fibroblasts and F9 EC cells. With selection as an assay, there was a hierarchy of relative expression in F9 cells compared with that in mouse fibroblasts. These internally placed regulatory sequences are the source of the mRNAs detected in F9 EC cells, while both retroviral long-terminal-repeat promoters and internal promoters are the source of steady-state mRNAs in mouse fibroblasts. This effect was observable with both the internally placed herpes simplex virus thymidine kinase promoter and the Moloney murine leukemia virus promoter.


Leave no stone unturned: defining recurrence in kidney stone formers.
Established guidelines provide recommendations on the management of kidney stones to prevent recurrence. However, clear and clinically useful terminology for recurrence of kidney stones is needed. This review describes the various manifestations of kidney stone recurrence and the reported rates of kidney stone recurrence in various clinical settings. Kidney stone recurrence has a wide range of symptomatic and radiographic presentations. Symptomatic recurrence may include characteristic symptoms of stone passage via the ureter (renal colic and gross hematuria). This may be self-managed or result in clinical care, with or without confirmation of an obstructing stone on imaging. Radiographic recurrence has been variably defined as new stone formation, stone growth, or stone disappearance (from passage with or without symptoms). Studies have used inconsistent definitions of recurrence, and recurrence rates vary substantially. Stone free rates and residual stone fragment size after surgical interventions are useful predictors of symptomatic recurrence. The recurrence rate of kidney stones has been assessed in stone formers from sub-specialty clinics, the general community, and clinical trials. The definition of recurrence is quite heterogenous between studies, but the rate of recurrence generally increases as more manifestations are included in the definition.


[Sexual differences in the reaction of the thyroid gland and its sensitivity to thyrotropic hormone following administration of estradiol, testosterone and progesterone].
After the administration of estradiol benzoate (EB), testosterone propionate (TP) and progesterone (P)to Sprague-Dawley rats it was revealed that both the thyroid gland weight and the thyroxin-binding capacity of protein (TBCP) of the blood plasma were higher in the female than in the male animals. The female animals responsed to TP and P with lower values for total (TT4) and free thyrotoxin (T4)than the male animals. In the males EB elevated the level of TT4 and free T4, and in the females--the level of TT4 and TBCP. TP decreased the sensitivity of the thyroid gland to thyrotropic hormone. The stimulating effect of P on the thyroid gland resulted in its functional overstrain and exhaustion, which was stronger and more rapid in the female than in the male animals.


Augmentation of transvascular transport of macromolecules and nanoparticles in tumors using vascular endothelial growth factor.
The goal of this investigation was to measure changes in vascular permeability, pore cutoff size, and number of transvascular transport pathways as a function of time and in response to vascular endothelial growth factor (VEGF), placenta growth factor (PIGF-1 and PIGF-2), or basic fibroblast growth factor (bFGF). Two human and two murine tumors were implanted in the dorsal skin chamber or cranial window. Vascular permeability to BSA (approximately 7 nm in diameter) and extravasation of polyethylene glycol-stabilized long-circulating liposomes (100-400 nm) and latex microspheres (approximately 800 nm) were determined by intravital microscopy. Vascular permeability was found to be temporally heterogeneous. VEGF superfusion (100 ng/ml) significantly increased vascular permeability to albumin in normal s.c. vessels, whereas a 30-fold higher dose of VEGF (3000 ng/ml) was required to increase permeability in pial vessels, suggesting that different tissues exhibit different dose thresholds for VEGF activity. Furthermore, VEGF superfusion (1000 ng/ml) increased vascular permeability to albumin in a hypopermeable human glioma xenograft in cranial window, whereas VEGF superfusion (10-1000 ng/ml) failed to increase permeability in a variety of hyperpermeable tumors grown in dorsal skin chamber. Interestingly, low-dose VEGF treatment (10 ng/ml) doubled the maximum pore size (from 400 to 800 nm) and significantly increased the frequency of large (400 nm) pores in human colon carcinoma xenografts. PIGF-1, PIGF-2, or bFGF did not show any significant effect on permeability or pore size in tumors. These findings suggest that exogenous VEGF may be useful for augmenting the transvascular delivery of larger antineoplastic agents such as gene targeting vectors and encapsulated drug carriers (typical range, 100-300 nm) into tumors.


Biosynthesis of the thiazole moiety of thiamin pyrophosphate (vitamin B1).
While most of the proteins required for the biosynthesis of thiamin pyrophosphate have been known for more than a decade, the reconstitution of this biosynthesis in a defined biochemical system has been difficult due to the novelty of the chemistry involved. Here we demonstrate the first successful enzymatic synthesis of the thiazole moiety of thiamin from glycine, cysteine, and deoxy-D-xylulose-5-phosphate using overexpressed Bacillus subtilis ThiF, ThiS, ThiO, ThiG, and a NifS-like protein. This has facilitated the identification of the biochemical function of each of the proteins involved: ThiF catalyzes the adenylation of ThiS; NifS catalyzes the transfer of sulfur from cysteine to the acyl adenylate of ThiS; ThiO catalyzes the oxidation of glycine to the corresponding imine; and ThiG catalyzes the formation of the thiazole phosphate ring. The complex oxidative cyclization reaction involved in the biosynthesis of the thiamin thiazole has been greatly simplified by replacing ThiF, ThiS, ThiO, and NifS with defined biosynthetic intermediates in a reaction where ThiG is the only required enzyme.


Role of the Na(+)/H(+) exchanger in short-term atrial electrophysiological remodeling.
The pathophysiology underlying electrophysiological remodeling (ER) from rapid atrial rates is unknown. We tested the hypothesis that activation of the Na(+)/H(+) exchanger (NHE) by ischemia contributes to ER. Twenty-eight dogs were studied under autonomic blockade. In 15 closed-chest dogs, atrial fibrillation was simulated by right atrial pacing at 600 bpm over 5 hours. Of these, 9 (pace/NHEI) received HOE642, a selective inhibitor of the NHE, and 6 (pace/control) received saline. In pace/controls, atrial effective refractory period (AERP) at a drive cycle length (DCL) of 400 ms shortened from 143+/-7 to 118+/-5 ms (1 hour) and to 122+/-17 ms (5 hours). Shortening of AERP was prevented in the pace/NHEI group (P=0.02 compared with pace/controls). At baseline in all 15 dogs, pacing at shorter DCL resulted in shortening of AERP (physiological rate adaptation), which was lost at 5 hours in pace/controls. In pace/NHEI animals, rate adaptation was maintained despite 5 hours of pacing (P=0.02). In 13 other open-chest dogs, right atrial ERP was determined before and after occlusion of the right coronary artery. Five received HOE642 (ischemia/NHEI), 5 saline (ischemia/control), and 3 intravenous glibenclamide. In ischemia/controls, AERP(400) decreased (156+/-30 to 130+/-32 ms). Shortening of AERP was not prevented by glibenclamide (180+/-20 to 153+/-33 ms) but was prevented in ischemia/NHEI dogs (169+/-12 to 184+/-19 ms, P=0.001 compared with ischemia/controls and ischemia/glibenclamide). Rate adaptation was lost in ischemia/controls and preserved in ischemia/NHEI dogs (P=0. 02). Activation of the NHE is one mechanism underlying short-term ER.


[Slow Ca2'-binding Mg2+- EDTA buffer for intracellular perfusion].
In studies of currents in perfused cells or their membrane fragments containing potential-dependent Ca channels and Ca2+-activated channels, a buffer slowly binding Ca2+ appears useful in some cases. A buffer with EDTA in excess of Mg2+ has been proposed, and its kinetic characteristics have been calculated. It has been shown that this buffer, depending on its component proportions, may provide Ca2+ binding with a characteristic time of up to tens of milliseconds. For comparison, in the cytoplasm, this time does not exceed 1 ms even with a large calcium signal, as follows from calculations.


Structural evidence that the 32-kilodalton lipoprotein (Tp32) of Treponema pallidum is an L-methionine-binding protein.
A structure-to-function approach was undertaken to gain insights into the potential function of the 32-kDa membrane lipoprotein (Tp32) of Treponema pallidum, the syphilis bacterium. The crystal structure of rTp32 (determined at a resolution of 1.85 A) shows that the organization of rTp32 is similar to other periplasmic ligand-binding proteins (PLBPs), in that it consists of two alpha/beta domains, linked by two crossovers, with a binding pocket between them. In the pocket, a molecule of L-methionine was detected in the electron density map. Residues from both domains interact with the ligand. One of the crossover regions is comprised of a 3(10)-helix, a feature not typical in other ligand-binding proteins. Sequence comparison shows strong similarity to other hypothetical methionine-binding proteins. Together, the data support the notion that rTp32 is a component of a periplasmic methionine uptake transporter system in T. pallidum.


ATTITUDE STATEMENTS AS POSITIVE AND NEGATIVE REINFORCEMENTS.
The finding that attraction is a function of attitude similarity has been interpreted as a special case of the effect of positive and negative reinforcements on attraction. A simple discrimination learning task was employed in which the reinforcements were attitude statements similar and dissimilar to the opinions of the subject. The presentation of similar attitude statements after each correct response and dissimilar attitude statements after each incorrect response significantly changed response probability. The hypothesis that such statements could be used as reinforcers in a learning situation was thus confirmed.


Predictive factors for recurrence from a series of 74 children and adolescents with differentiated thyroid cancer.
The influence of clinical and treatment factors on the risk of recurrence was analyzed from a retrospective series of 74 children and adolescents with thyroid cancer (55 girls, 19 boys; age 2-20 years). Two groups, comparable in terms of age, sex, and previous radiotherapy, were compared according to the presence (group 1) or absence (group 2) of cervical lymph nodes identified by palpation or ultrasonography. Total thyroidectomy (TT) with lymph node dissection (LND) was performed in the 19 group 1 patients, whereas in group 2 patients (n = 55) lobectomy was performed in 29, TT in 26, and LND in 7. Pathology studies showed papillary thyroid carcinoma in 95% of cases. In group 1, tumors were more frequently multifocal (89% vs. 16% in group 2), invasive with extension beyond the thyroid capsule (68% vs. 5% in group 2), and of the diffuse sclerosing variety (63% vs. 4% in group 2) (p < 0.001). With a median follow-up of 61 months, lymph node recurrence was seen in 53% of group 1 patients and in no patients in group 2. Three group 2 patients (10%) were reoperated for a local recurrence after lobectomy. Risk factors for reintervention were young age (< 15 years) (p < 0.01) and cervical lymph nodes (p < 0.001). Survivals without reintervention at 5 and 10 years were, respectively, 58% and 38% for group 1 and 94% and 90% for group 2 (p < 0.001). At the time of analysis, 68% of group 1 patients and 98% of group 2 patients were in remission. In conclusion, the presence of palpable cervical lymph nodes at diagnosis is associated with more invasive forms of malignancy and is a predictive factor of recurrence regardless of the extent of the initial surgery.


Impact of lincosamides antibiotics on the composition of the rat gut microbiota and the metabolite profile of plasma and feces.
The importance of the gut microorganisms and their wide range of interactions with the host are well-acknowledged. In this study, lincomycin and clindamycin were used to modulate microbial communities of Wistar rats to gain a comprehensive understanding of the implications of microbiome alterations. A metabolomics approach and taxonomic profiling were applied to characterize the effects of these antibiotics on the functionality of the microbiome and to identify microbiome-related metabolites. After treatment, the diversity of the microbial community was drastically reduced. Bacteroidetes and Verrucomicrobia were drastically reduced, Tenericutes and Deferribacteres completely disappeared, while abundance of Firmicutes and Proteobacteria were highly increased. Changes in plasma and feces metabolites were observed for metabolites belonging mainly to the class of complex lipids, fatty acids and related metabolites as well as amino acids and related compounds. Bile acid metabolism was markedly affected: taurocholic acid, glycochenodeoxycholic acid and cholic acid presented abrupt changes showing a specific metabolite pattern indicating disruption of the microbial community. In both plasma and feces taurocholic acid was highly upregulated upon treatment whereas glycochenodeoxycholic acid was downregulated. Cholic acid was upregulated in feces but downregulated in plasma. These results show that changes in the gut microbial community lead to alterations of the metabolic profile in blood and feces of the host and can be used to identify potentially microbiome-related metabolites. This implies that metabolomics could be a suitable tool to estimate the extent of changes induced in the intestinal microbiome with respect to consequences for the host.


New implications on genomic adaptation derived from the Helicobacter pylori genome comparison.
Helicobacter pylori has a reduced genome and lives in a tough environment for long-term persistence. It evolved with its particular characteristics for biological adaptation. Because several H. pylori genome sequences are available, comparative analysis could help to better understand genomic adaptation of this particular bacterium. We analyzed nine H. pylori genomes with emphasis on microevolution from a different perspective. Inversion was an important factor to shape the genome structure. Illegitimate recombination not only led to genomic inversion but also inverted fragment duplication, both of which contributed to the creation of new genes and gene family, and further, homological recombination contributed to events of inversion. Based on the information of genomic rearrangement, the first genome scaffold structure of H. pylori last common ancestor was produced. The core genome consists of 1186 genes, of which 22 genes could particularly adapt to human stomach niche. H. pylori contains high proportion of pseudogenes whose genesis was principally caused by homopolynucleotide (HPN) mutations. Such mutations are reversible and facilitate the control of gene expression through the change of DNA structure. The reversible mutations and a quasi-panmictic feature could allow such genes or gene fragments frequently transferred within or between populations. Hence, pseudogenes could be a reservoir of adaptation materials and the HPN mutations could be favorable to H. pylori adaptation, leading to HPN accumulation on the genomes, which corresponds to a special feature of Helicobacter species: extremely high HPN composition of genome. Our research demonstrated that both genome content and structure of H. pylori have been highly adapted to its particular life style.


DNA from non-viable bacteria biases diversity estimates in the corals Acropora loripes and Pocillopora acuta.
Nucleic acid-based analytical methods have greatly expanded our understanding of global prokaryotic diversity, yet standard metabarcoding methods provide no information on the most fundamental physiological state of bacteria, viability. Scleractinian corals harbour a complex microbiome in which bacterial symbionts play critical roles in maintaining health and functioning of the holobiont. However, the coral holobiont contains both dead and living bacteria. The former can be the result of corals feeding on bacteria, rapid swings from hyper- to hypoxic conditions in the coral tissue, the presence of antimicrobial compounds in coral mucus, and an abundance of lytic bacteriophages. By combining propidium monoazide (PMA) treatment with high-throughput sequencing on six coral species (Acropora loripes, A. millepora, A. kenti, Platygyra daedalea, Pocillopora acuta, and Porites lutea) we were able to obtain information on bacterial communities with little noise from non-viable microbial DNA. Metabarcoding of the 16S rRNA gene showed significantly higher community evenness (85%) and species diversity (31%) in untreated compared with PMA-treated tissue for A. loripes only. While PMA-treated coral did not differ significantly from untreated samples in terms of observed number of ASVs, > 30% of ASVs were identified in untreated samples only, suggesting that they originated from cell-free/non-viable DNA. Further, the bacterial community structure was significantly different between PMA-treated and untreated samples for A. loripes and P. acuta indicating that DNA from non-viable microbes can bias community composition data in coral species with low bacterial diversity. Our study is highly relevant to microbiome studies on coral and other host organisms as it delivers a solution to excluding non-viable DNA in a complex community. These results provide novel insights into the dynamic nature of host-associated microbiomes and underline the importance of applying versatile tools in the analysis of metabarcoding or next-generation sequencing data sets.


Estradiol Sensitizes the Transient Receptor Potential Vanilloid 1 Receptor in Pain Responses.
Sex differences exist in chronic pain pathologies, and gonadal estradiol (E2) alters the pain sensation. The nocisensor transient receptor potential vanilloid 1 (TRPV1) receptor plays a critical role in triggering pain. Here we examined the impact of E2 on the function of TRPV1 receptor in mice sensory neurons in vitro and in vivo. Both mechano- and thermonociceptive thresholds of the plantar surface of the paw of female mice were significantly lower in proestrus compared with the estrus phase. These thresholds were higher in ovariectomized (OVX) mice and significantly lower in sham-operated mice in proestrus compared with the sham-operated mice in estrus phase. This difference was absent in TRPV1 receptor-deficient mice. Furthermore, E2 potentiated the TRPV1 receptor activation-induced mechanical hyperalgesia in OVX mice. Long pretreatment (14 hours) with E2 induced a significant increase in TRPV1 receptor messenger RNA expression and abolished the capsaicin-induced TRPV1 receptor desensitization in primary sensory neurons. The short E2 incubation (10 minutes) also prevented the desensitization, which reverted after coadministration of E2 and the tropomyosin-related kinase A (TrkA) receptor inhibitor. Our study provides in vivo and in vitro evidence for E2-induced TRPV1 receptor upregulation and sensitization mediated by TrkAR via E2-induced genomic and nongenomic mechanisms. The sensitization and upregulation of TRPV1 receptor by E2 in sensory neurons may explain the greater pain sensitivity in female mice.


Purpura fulminans manifesting with Staphylococcus aureus endocarditis: a case report.
Purpura fulminans (PF) is a haematologic emergency that can occur in the setting of severe septic shock. Its pathophysiology is not well-understood; however, some evidence suggests it may be mediated by excessive protein C consumption. In this case report, we describe a patient with PF secondary to methicillin-resistant Staphylococcus aureus endocarditis. She presented with severe septic shock and, despite haemodynamic improvement, developed a significant purpuric rash. Diagnostic work-up was notable for severely decreased serum levels of protein C. This patient was successfully treated with protein C concentrate and surgical valve replacement. While PF is rarely associated with S. aureus infection, this presentation may be more frequently encountered among clinicians in the current opioid epidemic. Quick recognition is crucial and a multidisciplinary approach, including intravenous infusion of protein C, may be considered.


HoughFeature, a novel method for assessing drug effects in three-color cDNA microarray experiments.
Three-color microarray experiments can be performed to assess drug effects on the genomic scale. The methodology may be useful in shortening the cycle, reducing the cost, and improving the efficiency in drug discovery and development compared with the commonly used dual-color technology. A visualization tool, the hexaMplot, is able to show the interrelations of gene expressions in normal-disease-drug samples in three-color microarray data. However, it is not enough to assess the complicated drug therapeutic effects based on the plot alone. It is important to explore more effective tools so that a deeper insight into gene expression patterns can be gained with three-color microarrays. Based on the celebrated Hough transform, a novel algorithm, HoughFeature, is proposed to extract line features in the hexaMplot corresponding to different drug effects. Drug therapy results can then be divided into a number of levels in relation to different groups of genes. We apply the framework to experimental microarray data to assess the complex effects of Rg1 (an extract of Chinese medicine) on Hcy-related HUVECs in details. Differentially expressed genes are classified into 15 functional groups corresponding to different levels of drug effects. Our study shows that the HoughFeature algorithm can reveal natural cluster patterns in gene expression data of normal-disease-drug samples. It provides both qualitative and quantitative information about up- or down-regulated genes. The methodology can be employed to predict disease susceptibility in gene therapy and assess drug effects on the disease based on three-color microarray data.


Estimates of the duration of untreated acute malnutrition in children from Niger.
Expected incidence of acute malnutrition is the most appropriate measure for projecting the needs of a nutritional treatment program over time in terms of staffing, food, and other treatments, but direct estimation of incidence is rarely feasible at the onset of an intervention. While incidence may be approximated as prevalence/average duration, ethical constraints preclude measurement of the duration of acute malnutrition in the absence of treatment. The authors used a compartmental model to estimate the duration of untreated moderate acute malnutrition (MAM) and severe acute malnutrition (SAM) in children aged 6-60 months. The model was informed by data from a community-based cohort of children in Niger followed from August 2006 to March 2007. Maximum likelihood estimates for the duration of untreated MAM, defined by weight-for-height z score and middle upper arm circumference, were 75-81 days and 101-116 days, respectively. The duration of untreated SAM, defined by weight-for-height z score, was 45 days. The duration of untreated MAM appears to have been shorter among children aged 6-35 months compared with those aged 36-60 months. Such estimates of the duration, and thus incidence, of untreated malnutrition can be used to improve projections of program needs and estimates of the global burden of acute malnutrition.


Upper and lower limb length equalization: diagnosis, limb lengthening and curtailment, epiphysiodesis.
This article contains notions and guidelines derived from the current therapeutic approach used in the Pediatric Orthopedics Clinic of "M.S. Curie" Hospital, Bucharest. The purpose of this work is to illustrate the clinic's experience theoretically and by means of images. This article is based on 25 years of clinical experience (1986-2011), gained at Mangalia Regional Hospital and the Pediatric Orthopedics Clinic of "M.S. Curie" Hospital in Bucharest, having treated more than 250 such cases. In post-traumatic shortenings with associated soft tissue injuries we used double leveled corticotomies and lengthening. The lengthening rarely exceeded 10 cm, especially for congenital deformities and repeated lengthening. From 2001 onwards, all lengthening operations included the intramedullary implantation of one or two TEN rods, with the purpose of reducing the time to fixator removal and to shrink the healing index. In the last five years we frequently used minimally invasive osteotomies after the placement of TEN implants, achieving the separation of a small fragment that sites itself between the major fragments. The lengthening rate was 1 mm per day, broken down in four steps (0.25 mm every 6 hours). For difficult cases, such as congenital pseudarthroses or the presence of scar tissue around the osteotomy site, we recommended 0.75 mm of lengthening per day (0.25 mm every 8 hours). For congenital pseudarthroses we used controlled epiphysiolysis and bone transport. For inequalities ranging 3 to 5 cm we used temporary epiphysiodesis, initially with staples, and subsequently with "8", "H" and "I" plates. Limb shortening followed by locked intramedullary fixation was reserved for those patients who did not follow through with the evaluation program and who could not benefit from temporary epiphysiodesis. The amount of lengthening per segment varied between 3 and 17 cm. The longest staged lengthening measured 20 cm, in two stages, and the greatest overall lengthening was 25 cm for an entire lower limb. An appropriate stabilization, followed by the adequate choice of osteotomy site and the postoperative weight loading of the limb ensured a quick and qualitative healing process. Less than half of the patients suffered complications, most of them being minor ones. Pseudarthroses have been treated by compaction of the site, followed by distraction, and/or the injection of BMP (Bone Morphogenic Protein). We saw no complications after epiphysiodesis or limb shortening. Limb lengthening procedures up to 5 cm lead to rapid consolidation and minimal complications. Lengthenings exceeding 5 cm require a good psychological preparation and careful monitoring. In lengthenings more than 10 cm, a faster rate of consolidation requires a double corticotomy, the use of intramedullary fixation and the immobilization of adjacent joints. In Lobstein's disease, good results can be obtained by the use of an Ilizarov external fixator. Restoring limb length equality by temporary epiphysiodesis, around the age of 10-12, is the least aggressive method and is very effective. Limb shortening by segmental resection should become obsolete.


Prevalence and correlates of psychotropic drug use in community-dwelling people with young-onset dementia: the NeedYD-study.
Young-onset dementia (YOD) is defined as dementia that develops before the age of 65 years. The prevalence and type of neuropsychiatric symptoms (NPS) in YOD differ from patients with late onset dementia. NPS in dementia patients are often treated with psychotropic drugs. The aim of this study was to investigate psychotropic drug use (PDU) in Dutch community-dwelling YOD patients and the association between age, gender, dementia etiology and severity, symptoms of depression, disease awareness, unmet needs, and type of NPS. Psychotropic drug use in 196 YOD patients was registered. Drugs were categorized according to the Anatomical Therapeutical Chemical classification. The association between age, gender, dementia type, dementia stage, type of NPS, depressive symptoms, disease awareness, and amount of unmet needs on total PDU was analyzed using binomial logistic regression analysis. Fifty-two percent of the patients were prescribed at least one psychotropic drug; 36.2% of patients used one drug, and 12.2% used two different drugs. Antidepressants (36.2%) and antipsychotic drugs (17.3%) were the most frequently prescribed psychotropic drugs. Anti-dementia drugs were prescribed in 51.5% of the patients. Increasing age and moderate to severe depressive symptoms were positively associated with the total use of psychotropic drugs. Community-dwelling YOD patients have a high prevalence of PDU. More research is needed to study the association between unmet needs, NPS, and PDU, and psychosocial interventions have to be developed to limit the use of psychotropic drugs in YOD.


Phylogeography and pleistocene evolution in the North American black bear.
To determine the extent of phylogeographic structuring in North American black bear (Ursus americanus) populations, we examined mitochondrial DNA sequences (n = 118) and restriction fragment length polymorphism profiles (n = 258) in individuals from 16 localities. Among the bears examined, 19 lineages falling into two highly divergent clades were identified. The clades differ at 5.0% of nucleotide positions, a distance consistent with an origin 1.8 MYA, and have different but overlapping geographical distributions. Areas of clade cooccurrence show that eastern and western populations are currently mixing, but regional differences in lineage distribution suggest that mixing has begun only recently. The long-term population history of black bears appears to be characterized predominantly by long-term regional isolation followed by recent contact and hybridization. Congruence between the pattern of diversity observed in black bears and patterns of forest refuge formation during the Pleistocene supports earlier speculation that Pleistocene forest fragmentations underlie a common pattern in the phylogeography of North American forest taxa.


Effects of patulin on thymus capillary of rats.
Patulin is a mycotoxin that is produced by species of Penicillum, Aspergillus, and Byssochylamys molds that may grow on a variety of foods including fruit, grains and cheese. Patulin, at a dose of 0.1 mg kg(-1) bw day(-1) was administered orally to growing male rats aged 5-6 weeks for a period of 60 or 90 days. The dose of patulin used in the present study was based on estimated human exposure levels. At the end of these periods, the thymus glands of patulin-treated and control Wistar rats were removed and ultrastructural changes in capillary cells of the thymus of patulin-treated Wistar rats were determined by electron microscopy. The walls of thymus capillaries of the 60-day patulin-treated rat groups (P-60) exhibited degeneration observable in electron microscopic sections. For example, loss of cytoplasm and mitochondrial cristae of cells, swollen endothelial cells, increased thickness of the basement membrane, closed lumen of capillaries, accumulation of fibrous material at the periphery of the capillaries and nuclear anomalies were seen in these sections. Such degeneration and changes were also observed in sections of capillaries of the 90-day patulin-treated rat groups (P-90). The levels of degeneration of endothelial cell nucleus of P-90 were greater than those of P-60. This study demonstrated the ultrastructural degeneration of thymus capillary cells of patulin-treated rats. The results obtained from this study may provide a guide to research dealing with the toxic effects of patulin on tissue and organ ultrastructure.


Age affects over-marking of opposite-sex scent marks in meadow voles, Microtus pennsylvanicus.
Models of age-related effects on behavior predict that among short-lived species younger adults are more attractive and attracted to opposite-sex conspecifics than are older adults, whereas the converse is predicted for long-lived species. Although most studies of age-related effects on behavior support these predictions, they are not supported by many studies of scent marking, a behavior used in mate attraction. Over-marking, a form of scent marking, is a tactic used by many terrestrial mammals to convey information about themselves to opposite-sex conspecifics. The present study tested the hypothesis that the age of meadow voles, Microtus pennsylvanicus; a microtine rodent, affects their over- and scent marking behaviors when they encounter the marks of opposite-sex conspecifics. Sex differences existed in the over-marking behavior of adult voles among the three different age groups that were tested. Male voles that were 5-7 mo-old and 10-12 mo-old over-marked a higher proportion of the marks of females than did 2-3 mo-old male voles. Female voles that were 2-3 mo-old, 5-7 mo-old, and 10-12 mo-old over-marked a similar number of marks deposited by male voles. Overall, the data were not consistent with models predicting the behavior of short-lived animals such as rodents when they encounter the opposite sex. The differences in over-marking displayed by older and younger adult male voles may be associated with life history tradeoffs, the likelihood that they will encounter sexually receptive females, and being selected as mates.


Changes in 24 h ambulatory blood pressure and effects of angiotensin II receptor blockade during acute and prolonged high-altitude exposure: a randomized clinical trial.
Many hypertensive subjects travel to high altitudes, but little is known on ambulatory blood pressure (ABP) changes and antihypertensive drugs' efficacy under acute and prolonged exposure to hypobaric hypoxia. In particular, the efficacy of angiotensin receptor blockers in this condition is unknown. This may be clinically relevant considering that renin-angiotensin system activity changes at altitude. The HIGHCARE-HIMALAYA study assessed changes in 24 h ABP under acute and prolonged exposure to increasing altitude and blood pressure-lowering efficacy and safety of an angiotensin receptor blockade in this setting. Forty-seven healthy, normotensive lowlanders were randomized to telmisartan 80 mg or placebo in a double-blind, parallel group trial. Conventional and Ambulatory BPs were measured at baseline and on treatment: after 8 weeks at sea level, and under acute exposure to 3400 and 5400 m altitude, the latter upon arrival and after 12 days (Mt. Everest base camp). Blood samples were collected for plasma catecholamines, renin, angiotensin, and aldosterone. In both groups, exposure to increasing altitude was associated with: (i) significant progressive increases in conventional and 24 h blood pressure, persisting throughout the exposure to 5400 m; (ii) increased plasma noradrenaline and suppressed renin-angiotensin-aldosterone system. Telmisartan lowered 24 h ABP at the sea level and at 3400 m (between-group difference 4.0 mmHg, 95% CI: 2.2-9.5 mmHg), but not at 5400 m. Ambulatory blood pressure increases progressively with increasing altitude, remaining elevated after 3 weeks. An angiotensin receptor blockade maintains blood pressure-lowering efficacy at 3400 m but not at 5400 m.


Repeatedly Northwards and Upwards: Southern African Grasslands Fuel the Colonization of the African Sky Islands in Helichrysum (Compositae).
The Afromontane and Afroalpine areas constitute some of the main biodiversity hotspots of Africa. They are particularly rich in plant endemics, but the biogeographic origins and evolutionary processes leading to this outstanding diversity are poorly understood. We performed phylogenomic and biogeographic analyses of one of the most species-rich plant genera in these mountains, Helichrysum (Compositae-Gnaphalieae). Most previous studies have focused on Afroalpine elements of Eurasian origin, and the southern African origin of Helichrysum provides an interesting counterexample. We obtained a comprehensive nuclear dataset from 304 species (≈50% of the genus) using target-enrichment with the Compositae1061 probe set. Summary-coalescent and concatenation approaches combined with paralog recovery yielded congruent, well-resolved phylogenies. Ancestral range estimations revealed that Helichrysum originated in arid southern Africa, whereas the southern African grasslands were the source of most lineages that dispersed within and outside Africa. Colonization of the tropical Afromontane and Afroalpine areas occurred repeatedly throughout the Miocene-Pliocene. This timing coincides with mountain uplift and the onset of glacial cycles, which together may have facilitated both speciation and intermountain gene flow, contributing to the evolution of the Afroalpine flora.


Quantitative cross-species translators of cardiac myocyte electrophysiology: Model training, experimental validation, and applications.
Animal experimentation is key in the evaluation of cardiac efficacy and safety of novel therapeutic compounds. However, interspecies differences in the mechanisms regulating excitation-contraction coupling can limit the translation of experimental findings from animal models to human physiology and undermine the assessment of drugs' efficacy and safety. Here, we built a suite of translators for quantitatively mapping electrophysiological responses in ventricular myocytes across species. We trained these statistical operators using a broad dataset obtained by simulating populations of our biophysically detailed computational models of action potential and Ca2+ transient in mouse, rabbit, and human. We then tested our translators against experimental data describing the response to stimuli, such as ion channel block, change in beating rate, and β-adrenergic challenge. We demonstrate that this approach is well suited to predicting the effects of perturbations across different species or experimental conditions and suggest its integration into mechanistic studies and drug development pipelines.


Barriers to reporting medication errors: a measurement equivalence perspective.
To demonstrate a statistical analysis for testing the measurement equivalence of a patient safety survey instrument. The survey instrument examined in the present study is the Medication Administration Error Reporting Survey. Surveys were posted to a random sample of registered nurses in the State of Texas, with 435 nurses completing the survey. The surveys contained questions about various error reporting issues, including the 16-item, Medication Administration Error Reporting scale. Nurses were divided into one of two samples--calibration and holdout--to ensure replicability of the results. Within each sample, two groups were created based on nurse tenure on the job. Multiple Group Confirmatory Factor Analysis was conducted across nurses with varying levels of experience for the calibration and holdout samples. For each sample, a baseline model was estimated, where model parameters were allowed to vary across the nursing groups, and compared with more restrictive models. The results provided support for the factor structure of the Medication Administration Error Reporting System but yielded mixed results concerning the equivalence of the measure across nursing groups. The present study provides an explanation of how to examine the measurement equivalence of survey instruments and demonstrated that the Medication Administration Error Reporting scale might not be equivalent across nurses who differ with respect to experience levels.


The Rad51 paralog Rad51B promotes homologous recombinational repair.
The highly conserved Saccharomyces cerevisiae Rad51 protein plays a central role in both mitotic and meiotic homologous DNA recombination. Seven members of the Rad51 family have been identified in vertebrate cells, including Rad51, Dmc1, and five Rad51-related proteins referred to as Rad51 paralogs, which share 20 to 30% sequence identity with Rad51. In chicken B lymphocyte DT40 cells, we generated a mutant with RAD51B/RAD51L1, a member of the Rad51 family, knocked out. RAD51B(-/-) cells are viable, although spontaneous chromosomal aberrations kill about 20% of the cells in each cell cycle. Rad51B deficiency impairs homologous recombinational repair (HRR), as measured by targeted integration, sister chromatid exchange, and intragenic recombination at the immunoglobulin locus. RAD51B(-/-) cells are quite sensitive to the cross-linking agents cisplatin and mitomycin C and mildly sensitive to gamma-rays. The formation of damage-induced Rad51 nuclear foci is much reduced in RAD51B(-/-) cells, suggesting that Rad51B promotes the assembly of Rad51 nucleoprotein filaments during HRR. These findings show that Rad51B is important for repairing various types of DNA lesions and maintaining chromosome integrity.


A CD45-based barcoding approach to multiplex mass-cytometry (CyTOF).
CyTOF enables the study of the immune system with a complexity, depth, and multidimensionality never achieved before. However, the full potential of using CyTOF can be limited by scarce cell samples. Barcoding strategies developed based on direct labeling of cells using maleimido-monoamide-DOTA (m-DOTA) provide a very useful tool. However, using m-DOTA has some inherent problems, mainly associated with signal intensity. This may be a source of uncertainty when samples are multiplexed. As an alternative or complementary approach to m-DOTA, conjugating an antibody, specific for a membrane protein present on most immune cells, with different isotopes could address the issues of stability and signal intensity needed for effective barcoding. We chose for this purpose CD45, and designed experiments to address different types of cultures and the ability to detect extra- and intra-cellular targets. We show here that our approach provides an useful alternative to m-DOTA in terms of sensitivity, specificity, flexibility, and user-friendliness. Our manuscript provides details to effectively barcode immune cells, overcoming limitations in current technology and enabling the use of CyTOF with scarce samples (for instance precious clinical samples).


Potentially inappropriate use of benzodiazepines and z-drugs in the older population-analysis of associations between long-term use and patient-related factors.
The long-term use of benzodiazepines (BZD) and z-drugs in older populations is associated with a variety of sociodemographic and health-related factors. Recent studies reported that long-term BZD and z-drugs use is associated with increased age, female sex, and severe negative psychological (e.g., depression) and somatic (e.g., chronic disease) factors. The current study explores the sociodemographic and health-related factors associated with long-term BZD and z-drugs use in the elderly. We conducted a cross-sectional survey among randomly selected patients of one health insurance plan ("AOK North-West") with BZD and z-drugs prescriptions in the past 12 months. The sample was stratified by appropriate German prescription guidelines (yes vs. no) and age (50-65 vs. >65 years). To examine the association of selected sociodemographic and psychological variables (e.g., sex, employment status, quality of life, depression) with long-term use, a binary logistic regression analysis was conducted. In total, data from 340 patients were analyzed. The mean age was 72.1 (SD = 14.5) years, and the most commonly used substances were zopiclon (38.1%), oxazepam (18.1%), and lorazepam (13.8%). The mean defined daily dose (DDD) was 0.73 (SD = 0.47). Insomnia was the main reason for prescribing BZD and z-drugs. The long-term use of BZD and z-drugs was significantly associated with unemployment (OR = 2.9, 95% CI [1.2-7.1]) and generally problematic medication use (OR = 0.5, 95% CI [0.2-1.0]). Unemployment status and problematic medication use had a significant association with the patient-reported, long-term use of BZD and z-drugs. Divergent prescription patterns might suggest problematic patterns of BZD and z-drugs use. The causal connection between the identified factors and problematic BZD and z-drugs prescription is not discussed in this paper. Nevertheless, employment status and possible evidence of general problematic drug use may be a warning signal to the prescribers of BZD and z-drugs.


Diffusion-weighted MRI in head and neck cancer.
Diffusion-weighted magnetic resonance imaging (MRI) is an imaging technique showing molecular diffusion. Cell size, density and integrity influence the signal intensity seen on diffusion-weighted images. This technique is a helpful complementary tool to distinguish tumoral from non-tumoral tissue, and has several interesting applications in the evaluation of head and neck cancer.


Inhibition of poly(ADP-ribose) polymerase enhances the effect of chemotherapy in an animal model of regional therapy for the treatment of advanced extremity malignant melanoma.
Poly(ADP-ribose) polymerase (PARP) is an important regulator of programmed cell death in response to alkylating agents such as temozolomide (TMZ). The goal of this study was to determine if a systemically administered PARP-inhibitor (INO-1001) could augment the efficacy of TMZ in a rat model of extremity malignant melanoma. PARP activity was measured in vitro across a panel of 5 human malignant melanoma-derived cell lines. To evaluate tumor response to PARP inhibition in combination with regional isolated limb infusion (ILI) therapy with TMZ, two TMZ-resistant malignant melanoma cell lines were grown as xenografts in the hind limb of rats. INO-1001 (400 mg/kg) was injected intraperitoneally 7 times every 8 hours prior to ILI. Tumor volume was measured for up to 40 days. In vitro inhibition of PARP activity by INO-1001 ranged from 25.5% to 65.6%. In a mismatch repair (MMR)-deficient xenograft, treatment with INO-1001 prior to ILI significantly (P < .04) increased the efficacy of TMZ. The increase in tumor volume at day 40 following TMZ-ILI with INO-1001 was only 22.6% compared with 322.8% with TMZ-ILI alone. In a xenograft that was MMR-proficient and had high levels of O(6)-methylguanine-DNA methyltransferase (MGMT) activity, there was little improvement in TMZ efficacy with INO-1001 treatment. The PARP-inhibitor, INO-1001, can enhance the response of TMZ-resistant, MMR-deficient, malignant melanoma xenografts to intra-arterially administered TMZ in a regional treatment model of advanced extremity malignant melanoma.


Age and disability affect dietary intake.
The purpose of the study was to provide information on dietary intake in the InCHIANTI study population, a representative sample (n = 1453) of persons living in two towns of Tuscany (Italy), including a large number of old and very old individuals (79.5% >65 y old). We also investigated whether difficulties in nutrition-related activities were associated with inadequate intake of selected nutrients. The percentage of persons with an inadequate intake of nutrients according to Italian Recommended Nutrients Levels (LARN) was higher in the older age groups. Older persons tended to adapt their diets in response to individual functional difficulties, often leading to monotonous food consumption and, as a consequence, to inadequate nutrient intakes. Multiple logistic models were used to evaluate whether inadequate intake of selected nutrients could be predicted by nutrition-related difficulties. Reporting difficulties in three or more nutrition-related activities (chewing, self-feeding, shopping for basic necessities, carrying a shopping bag, cooking a warm meal, using fingers to grasp or handle) significantly increased the risk of inadequate intake of energy [odds ratio (OR) = 3.8, 95% CI = 1.9-7.8) and vitamin C (OR = 2.2, 95% CI = 1.2-4.2, after adjustment for energy intake). More attention to functional problems in the elderly population and the provision of formal or informal help to those who have difficulty in purchasing, processing and eating food may reduce, at least in part, the percentage of older persons with poor nutrition.


The region adjacent to the C-end of the inner gate in transient receptor potential melastatin 8 (TRPM8) channels plays a central role in allosteric channel activation.
The ability of transient receptor potential (TRP) channels to sense and respond to environmental and endogenous cues is crucial in animal sensory physiology. The molecular mechanism of channel gating is yet elusive. The TRP box, a conserved region in the N-end of the C terminus domain, has been signaled as pivotal for allosteric activation in TRP channels. Here, we have examined the role of the linker region between the TRPM8 inner gate and the TRP box (referred to as the S6-TRP box linker) to identify structural determinants of channel gating. Stepwise substitutions of segments in the S6-TRP box linker of TRPM8 channel with the cognate TRPV1 channel sequences produced functional chimeric channels, and identified Tyr(981) as a central molecular determinant of channel function. Additionally, mutations in the 986-990 region had a profound impact on channel gating by voltage and menthol, as evidenced by the modulation of the conductance-to-voltage (G-V) relationships. Simulation of G-V curves using an allosteric model for channel activation revealed that these mutations altered the allosteric constants that couple stimuli sensing to pore opening. A molecular model of TRPM8, based on the recently reported TRPV1 structural model, showed that Tyr(981) may lie in a hydrophobic pocket at the end of the S6 transmembrane segment and is involved in inter-subunit interactions with residues from neighbor subunits. The 986-990 region holds intrasubunit interactions between the TRP domain and the S4-S5 linker. These findings substantiate a gating mechanism whereby the TRP domain acts as a coupling domain for efficient channel opening. Furthermore, they imply that protein-protein interactions of the TRP domain may be targets for channel modulation and drug intervention.


Anti-tumor effect of vitamin A and D on head and neck squamous cell carcinoma.
Vitamin A and D(3) have a very strong differentiation induction effect. We examined the anti tumor effect on head and neck squamous cell carcinoma (HNSCC) by treatment with several vitamins having strong differentiation induction effects in vitro. We used KB cell that an oral floor squamous cell carcinoma, vitamins as all-trans retinoic acid (ATRA), 4-[3,5-bis (trimethylsilyl) benzamido] benzoic acid (TAC-101), 1alpha,25(OH)(2)D(3) (calcitriol) and 22-oxa-1,25-(OH)(2)D(3) (OCT). We determined receptors of vitamin A and D(3) using RT-PCR. Furthermore, we investigated the proliferation of tumor cells in concentration dependency using [3H]TdR uptake method, apoptosis and apoptosis related factors using TUNEL method and real-time PCR, cell cycle changes using flow cytometry, changing of the sensitivity of using MTT method, cytokine production and the angiogenesis factor using ELISA, by treatment with these vitamins. The deficit of RAR-beta was found in the KB cell. Each vitamin suppressed the cell proliferation, induced apoptosis, and cell cycle arrest, upregulated sensitivity of the chemotherapeutics drugs and downregulated several angiogenesis factors and an apoptotic factor; survivin. These results support the idea that vitamin A, D(3) and their derivatives are useful for preventing and/or treating patients with HNSCC.


Granulocyte macrophage colony-stimulating factor and interleukin 4 enhance the number and antigen-presenting activity of circulating CD14+ and CD83+ cells in cancer patients.
Antigen-presenting cells (APCs) are essential for stimulating antigen-specific immunity, including immunity against tumor cells. We hypothesized that systemic administration of granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4, which promote monocytes to differentiate into dendritic cells in vitro, might enhance the number and antigen-presenting activity of CD14+ cells in vivo. Patients with metastatic solid malignancies were treated with daily s.c. injections of either GM-CSF alone (2.5 microg/kg/day) or GM-CSF in combination with IL-4 (0.5-6.0 microg/kg/day) in a multicohort study. When given alone, GM-CSF increased the number of CD14+ cells but did not enhance the cells' expression of APC markers or antigen-presenting activity. In contrast, combination therapy with GM-CSF and IL-4 stimulated CD14+ cells to acquire several APC characteristics including increased expression of HLA-DR and CD11c, decreased CD14, increased endocytotic activity, and the ability to stimulate T cells in a mixed leukocyte reaction. Combination therapy also induced a dose-dependent increase in the number of CD14-/CD83+ cells with APC activity. Clinically significant and sustained tumor regression was observed in one patient. Systemic therapy with GM-CSF and IL-4 may provide a mechanism for increasing the number and function of APCs in patients with cancer.


Intestinal transplantation.
Intestinal transplantation has now emerged as a lifesaving therapeutic option and standard of care for patients with irreversible intestinal failure. Improvement in survival over the years has justified expansion of the indications for intestinal transplantation beyond the original indications approved by Center for Medicare and Medicaid services. Management of patients with intestinal failure is complex and requires a multidisciplinary approach to accurately select candidates who would benefit from rehabilitation versus transplantation. Significant strides have been made in patient and graft survival with several advancements in the perioperative management through timely referral, improved patient selection, refinement in the surgical techniques and better understanding of the immunopathology of intestinal transplantation. The therapeutic efficacy of the procedure is well evident from continuous improvements in functional status, quality of life and cost-effectiveness of the procedure. This current review summarizes various aspects including current practices and evidence based recommendations of intestinal transplantation.


Targeted nasal vaccination provides antibody-independent protection against Staphylococcus aureus.
Despite showing promise in preclinical models, anti-Staphylococcus aureus vaccines have failed in clinical trials. To date, approaches have focused on neutralizing/opsonizing antibodies; however, vaccines exclusively inducing cellular immunity have not been studied to formally test whether a cellular-only response can protect against infection. We demonstrate that nasal vaccination with targeted nanoparticles loaded with Staphylococcus aureus antigen protects against acute systemic S. aureus infection in the absence of any antigen-specific antibodies. These findings can help inform future developments in staphylococcal vaccine development and studies into the requirements for protective immunity against S. aureus.


Adaptive median filters: new algorithms and results.
Based on two types of image models corrupted by impulse noise, we propose two new algorithms for adaptive median filters. They have variable window size for removal of impulses while preserving sharpness. The first one, called the ranked-order based adaptive median filter (RAMF), is based on a test for the presence of impulses in the center pixel itself followed by a test for the presence of residual impulses in the median filter output. The second one, called the impulse size based adaptive median filter (SAMF), is based on the detection of the size of the impulse noise. It is shown that the RAMF is superior to the nonlinear mean L(p) filter in removing positive and negative impulses while simultaneously preserving sharpness; the SAMF is superior to Lin's (1988) adaptive scheme because it is simpler with better performance in removing the high density impulsive noise as well as nonimpulsive noise and in preserving the fine details. Simulations on standard images confirm that these algorithms are superior to standard median filters.


ShapeWordle: Tailoring Wordles using Shape-aware Archimedean Spirals.
We present a new technique to enable the creation of shape-bounded Wordles, we call ShapeWordle, in which we fit words to form a given shape. To guide word placement within a shape, we extend the traditional Archimedean spirals to be shape-aware by formulating the spirals in a differential form using the distance field of the shape. To handle non-convex shapes, we introduce a multi-centric Wordle layout method that segments the shape into parts for our shape-aware spirals to adaptively fill the space and generate word placements. In addition, we offer a set of editing interactions to facilitate the creation of semantically-meaningful Wordles. Lastly, we present three evaluations: a comprehensive comparison of our results against the state-of-the-art technique (WordArt), case studies with 14 users, and a gallery to showcase the coverage of our technique.