Association between physical activity and risk of fracture.
Prospective studies that have examined the association between physical activity and fracture risks have reported conflicting findings. We performed a meta-analysis to evaluate this association. We searched MEDLINE (1966 to February 1, 2013), EMBASE (1980 to February 1, 2013), and OVID (1950 to February 1, 2013) for prospective cohort studies with no restrictions. Categorical, heterogeneity, publication bias, and subgroup analyses were performed. There were 22 cohort studies with 1,235,768 participants and 14,843 fractures, including 8874 hip, 690 wrist, and 927 vertebral fractures. The pooled relative risk (RR) of total fractures for the highest versus lowest category of physical activity was 0.71 (95% confidence interval [CI], 0.63-0.80). The analysis of fracture subtypes showed a statistically significant inverse relationship between a higher category of physical activity and risk of hip and wrist fracture. The risk of hip or wrist fracture was 39% and 28% lower, respectively, among individuals with the highest category of physical activity than among those with the lowest category (95% CI, 0.54-0.69 and 0.49-0.96, respectively). The association between physical activity and vertebral fracture risk was not statistically related (RR, 0.87; 95% CI, 0.72-1.03). There was no evidence of publication bias. There was a statistically significant inverse association between physical activity and total fracture risk, especially for hip and wrist fractures. Additional subject-level meta-analyses are required for a more reliable assessment of subgroups and types of physical activity.


RNA sequence analysis defines Dicer's role in mouse embryonic stem cells.
Short RNA expression was analyzed from Dicer-positive and Dicer-knockout mouse embryonic [corrected] stem (ES) cells, using high-throughput pyrosequencing. A correlation of miRNA quantification with sequencing frequency estimates that there are 110,000 miRNAs per ES cell, the majority of which can be accounted for by six distinct miRNA loci. Four of these miRNA loci or their human homologues have demonstrated roles in cell cycle regulation or oncogenesis, suggesting that a major function of the miRNA pathway in ES cells may be to shape their distinct cell cycle. Forty-six previously uncharacterized miRNAs were identified, most of which are expressed at low levels and are less conserved than the set of known miRNAs. Low-abundance short RNAs matching all classes of repetitive elements were present in cells lacking Dicer, although the production of some SINE- and simple repeat-associated short RNAs appeared to be Dicer-dependent. These and other Dicer-dependent sequences resembled miRNAs. At a depth of sequencing that approaches the total number of 5' phosphorylated short RNAs per cell, miRNAs appeared to be Dicer's only substrate. The results presented suggest a model in which repeat-associated miRNAs serve as host defenses against repetitive elements, a function canonically ascribed to other classes of short RNA.


Treatment with liposome-encapsulated clodronate as a new strategic approach in the management of immune thrombocytopenic purpura in a mouse model.
Immune thrombocytopenic purpura (ITP) is an autoimmune disease related to the presence of elevated levels of platelet-associated immunoglobulin, or autoantibodies. In recent years the importance of macrophage Fc gamma receptors in the uptake of platelets in ITP has been confirmed. Although in patients with ITP the platelet destruction occurs in liver and spleen, in this present experimental mouse model the liver was the principal organ of sequestration of sensitized platelets. The uptake in the spleen, bone marrow, lung, and kidneys was negligible and not different from that in control animals. In addition, the trapped platelets did not return to circulation, and new cells derived from the platelet-storage pool or new thrombocytogenesis were necessary to restore the platelet count. The depletion of splenic and hepatic murine macrophages by liposome-encapsulated clodronate (lip-clod) was studied as a new strategy for ITP treatment. Lip-clod inhibits, in a dose-dependent manner, the antibody-induced thrombocytopenia. Moreover, lip-clod treatment rapidly restored (24 hours) the platelet count in thrombocytopenic animals to hematologic safe values, and despite additional antiplatelet antiserum treatment, mice were able to maintain this level of platelets at least up to 48 hours. The bleeding times in lip-clod-treated animals was not different from those in controls, demonstrating that the hemostasis was well controlled in these animals. The results presented in this study demonstrate that lip-clod treatment can be effective in the management of experimental ITP. (Blood. 2000;96:2834-2840)


Reconstruction of difference in sequential CT studies using penalized likelihood estimation.
Characterization of anatomical change and other differences is important in sequential computed tomography (CT) imaging, where a high-fidelity patient-specific prior image is typically present, but is not used, in the reconstruction of subsequent anatomical states. Here, we introduce a penalized likelihood (PL) method called reconstruction of difference (RoD) to directly reconstruct a difference image volume using both the current projection data and the (unregistered) prior image integrated into the forward model for the measurement data. The algorithm utilizes an alternating minimization to find both the registration and reconstruction estimates. This formulation allows direct control over the image properties of the difference image, permitting regularization strategies that inhibit noise and structural differences due to inconsistencies between the prior image and the current data. Additionally, if the change is known to be local, RoD allows local acquisition and reconstruction, as opposed to traditional model-based approaches that require a full support field of view (or other modifications). We compared the performance of RoD to a standard PL algorithm, in simulation studies and using test-bench cone-beam CT data. The performances of local and global RoD approaches were similar, with local RoD providing a significant computational speedup. In comparison across a range of data with differing fidelity, the local RoD approach consistently showed lower error (with respect to a truth image) than PL in both noisy data and sparsely sampled projection scenarios. In a study of the prior image registration performance of RoD, a clinically reasonable capture ranges were demonstrated. Lastly, the registration algorithm had a broad capture range and the error for reconstruction of CT data was 35% and 20% less than filtered back-projection for RoD and PL, respectively. The RoD has potential for delivering high-quality difference images in a range of sequential clinical scenarios including image-guided surgeries and treatments where accurate and quantitative assessments of anatomical change is desired.


Role of growth factor receptor bound protein 7 in hepatocellular carcinoma.
The human growth factor receptor-bound protein 7 (Grb7) is an adaptor molecule and is related to cell invasion. In this present study, we investigated the clinical and biological significance of Grb7 expression in human hepatocellular carcinoma (HCC). We reviewed 64 consecutive patients who had undergone liver resection for HCC, and we investigated the correlation between Grb7 expression and clinical outcome. To analyze the biological behavior of Grb7 in vitro and in vivo, we established Grb7 stable knockdown HCC cells using RNA interference technology. The positive staining of Grb7 protein was correlated with portal venous invasion (P < 0.01), hepatic venous invasion (P < 0.01), and intrahepatic metastasis (P < 0.05). Positive expression of Grb7 was significantly correlated with focal adhesion kinase (FAK) protein levels in HCC (P < 0.01). The Grb7- and FAK-positive group showed a significantly poorer prognosis as compared with the Grb7- and FAK-negative group (P < 0.05). Grb7 knockdown HCC cells exhibited significantly lower levels of invasion potential (P < 0.05) and motility (P < 0.05) than the control cells in vitro; moreover, Grb7 knockdown HCC cells showed delayed onset of the tumors compared with the control cells in vivo. Grb7 expression can modulate the invasive phenotype of HCC. Grb7 plays an important role in HCC progression and is strongly associated with expression of FAK. Grb7 could be a therapeutic target in HCC.


The effects of carbon trading on resident income: a theoretical and empirical study on the pilot carbon market in China.
Establishing an efficient carbon emissions trading market is a priority to achieve the goal of carbon peaking and carbon neutrality. In the context of income inequality and emissions inequality, this study examined the efficiency of carbon trading in China from the perspective of resident income. First, this paper used the Cobb-Douglas (C-D) production function to incorporate carbon intensity into the production network model and obtained the expression of household income by solving the Walras equilibrium. Secondly, this study put forward a theory that Carbon trading affects the income level of individuals. Finally, in order to test the theory, the study used the differences-in-differences (DID) method, provincial panel data from 2005 to 2019, and the quasi-natural experiment of China's carbon emissions trading pilot. The results indicated that this policy could reduce the per capita disposable income level. Further heterogeneity research showed that although the emission reduction effect was significant, the pilot policy failed to save emission reduction costs and improve residents' welfare. The low efficiency of the carbon market was mainly attributed to the insufficient liquidity of the pilot carbon market. Therefore, it not only failed to achieve efficiency but also increased unnecessary costs, which had a negative impact on income. In addition, the consumption patterns of residents and the industrial-oriented economic structure exacerbated the decline in income.


The inferior, anterior temporal lobes and semantic memory clarified: novel evidence from distortion-corrected fMRI.
The neural basis of semantic memory generates considerable debate. Semantic dementia results from bilateral anterior temporal lobe (ATL) atrophy and gives rise to a highly specific impairment of semantic memory, suggesting that this region is a critical neural substrate for semantic processing. Recent rTMS experiments with neurologically-intact participants also indicate that the ATL are a necessary substrate for semantic memory. Exactly which regions within the ATL are important for semantic memory are difficult to detect from these methods (because the damage in SD covers a large part of the ATL). Functional neuroimaging might provide important clues about which specific areas exhibit activation that correlates with normal semantic performance. Neuroimaging studies, however, have not consistently found anterior temporal lobe activation in semantic tasks. A recent meta-analysis indicates that this inconsistency may be due to a collection of technical limitations associated with previous studies, including a reduced field-of-view and magnetic susceptibility artefacts associated with standard gradient echo fMRI. We conducted an fMRI study of semantic memory using a combination of techniques which improve sensitivity to ATL activations whilst preserving whole-brain coverage. As expected from SD patients and ATL rTMS experiments, this method revealed bilateral temporal activation extending from the inferior temporal lobe along the fusiform gyrus to the anterior temporal regions, bilaterally. We suggest that the inferior, anterior temporal lobe region makes a crucial contribution to semantic cognition and utilising this version of fMRI will enable further research on the semantic role of the ATL.


Equilibrium freezing of leaf water and extracellular ice formation in Afroalpine 'giant rosette' plants.
The water potentials of frozen leaves of Afroalpine plants were measured psychrometrically in the field. Comparison of these potentials with the osmotic potentials of an expressed cellular sap and the water potentials of ice indicated almost ideal freezing behaviour and suggested equilibrium freezing. On the basis of the osmotic potentials of expressed cellular sap, the fractions of frozen cellular water which correspond to the measured water potentials of the frozen leaves could be determined (e.g. 74% at -3.0° C). The freezing points of leaves were found to be in the range between 0° C and -0.5° C, rendering evidence for freezing of almost pure water and thus confirming the conclusions drawn from the water-potential measurements. The leaves proved to be frost resistant down to temperatures between -5° C and -15° C, as depending on the species. They tolerated short supercooling periods which were necessary in order to start ice nucleation. Extracellular ice caps and ice crystals in the intercellular space were observed when cross sections of frozen leaves were investigated microscopically at subfreezing temperatures.


The outcome of full-intensity and reduced-intensity conditioning matched sibling or unrelated donor transplantation in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first and second complete remission.
We examined the efficacy of reduced-intensity conditioning (RIC) and compared outcomes of 93 patients older than 16 years after RIC with 1428 patients receiving full-intensity conditioning for allografts using sibling and unrelated donors for Philadelphia-negative acute lymphoblastic leukemia (ALL) in first or second complete remission. RIC conditioning included busulfan 9 mg/kg or less (27), melphalan 150 mg/m(2) or less (23), low-dose total body irradiation (TBI; 36), and others (7). The RIC group was older (median 45 vs 28 years, P < .001) and more received peripheral blood grafts (73% vs 43%, P < .001) but had similar other prognostic factors. The RIC versus full-intensity conditioning groups had slightly, but not significantly, less acute grade II-IV graft-versus-host disease (39% vs 46%) and chronic graft-versus-host disease (34% vs 42%), yet similar transplantation-related mortality. RIC led to slightly more relapse (35% vs 26%, P = .08) yet similar age-adjusted survival (38% vs 43%, P = .39). Multivariate analysis showed that conditioning intensity did not affect transplantation-related mortality (P = .92) or relapse risk (P = .14). Multivariate analysis demonstrated significantly improved overall survival with: Karnofsky performance status more than 80, first complete remission, lower white blood count, well-matched unrelated or sibling donors, transplantation since 2001, age younger than 30 years, and conditioning with TBI, but no independent impact of conditioning intensity. RIC merits further investigation in prospective trials of adult ALL.


Retinopathy of prematurity: incidence and risk factors.
A high incidence of retinopathy of prematurity (ROP) was found in the very low-birth-weight infants discharged from the neonatal intensive care unit during the years 1977 to 1980, in spite of frequent monitoring of oxygen use. Although the yearly incidence of ROP in infants weighing less than 1,500 g varied between 35% to 36%, none were blind. The medical records of 65 infants with a birth weight between 501 and 1,250 g; surviving in 1979 to 1980, were reviewed in order to find risk factors for ROP. There were no significant differences between the 34 infants with ROP and the 31 infants who did not have ROP in mean birth weight or mean gestational age. Of 32 possible risk factors examined, the factors significantly associated with ROP were: apnea with mask and bag ventilation; prolonged parenteral nutrition; number of blood transfusions; and episodes of hypoxemia, hypercarbia, and hypocarbia. A highly significant association between hypocarbia and the development of severe ROP was found.


Sedation-related complications in gastrointestinal endoscopy.
Sedation practices for gastrointestinal endoscopic (GIE) procedures vary widely in different countries depending on health system regulations and local circumstances. The goal of procedural sedation is the safe and effective control of pain and anxiety, as well as to provide an appropriate degree of memory loss or decreased awareness. Sedation-related complications in gastrointestinal endoscopy, once occurred, can lead to significant morbidity and occasional mortality in patients. The risk factors of these complications include the type, dose and mode of administration of sedative agents, as well as the patient's age and underlying medical diseases. Complications attributed to moderate and deep sedation levels are more often associated with cardiovascular and respiratory systems. However, sedation-related complications during GIE procedures are commonly transient and of a mild degree. The risk for these complications while providing any level of sedation is greatest when caring for patients already medically compromised. Significant unwanted complications can generally be prevented by careful pre-procedure assessment and preparation, appropriate monitoring and support, as well as post-procedure management. Additionally, physicians must be prepared to manage these complications. This article will review sedation-related complications during moderate and deep sedation for GIE procedures and also address their appropriate management.


Effects of replacing roughage with soy hulls on feeding behavior and milk production of dairy cows under hot weather conditions.
Two total mixed rations (TMR) containing different proportions of roughage neutral detergent fiber (NDF) were fed to lactating cows under Israeli summer conditions, and the effects on feeding behavior and milk production were measured. Forty-two lactating cows were divided into 2 groups fed ad libitum a TMR containing either 18% NDF of roughage origin (control group) or only 12% roughage NDF, in which the corn silage component (16.5% of dry matter [DM]) was replaced with soy hulls (experiment group). This and additional adjustments in TMR were reflected in higher net energy for lactation and in vitro digestibility of the experimental TMR. Cow behavior was investigated at the feeding lane during June 2001; about 11,000 cow visits were analyzed. Feed intake per meal and average meal duration were significantly higher in the experiment group (1.51 kg of DM per meal and 12.1 min per meal, respectively) as compared with the control group (1.22 kg of DM per meal and 9.47 min per meal, respectively). However, number of meals per day recorded in the feeding lane was significantly higher in the control group (21.0 vs. 16.6 meals/d per cow). Distribution of meals and feed intake along the day depended more on management practices, such as milking and feed dispensing times, than on feed composition or weather conditions. These differences between groups were expressed in similar daily eating duration (approximately 200 min), and because the rate of feed consumption was similar for both treatments (approximately 127 g DM/min), the daily average DM intake was also similar (25.0 to 25.7 kg). However, NDF intake was higher in the experiment group. Consequently, the average milk yield was higher in the experimental group, and production of milk fat, 4% fat-corrected milk, and economically corrected milk were significantly higher in the experiment group than in the control group. Data imply that the experimental TMR containing only 12% NDF of roughage origin is more suitable for cows under hot climate conditions compared with the control TMR.


Intracellular plutonium: removal by liposome-encapsulated chelating agent.
Chelating agents, such as ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA) were successfully encapsulated within lipid spherules (that is, liposomes). Encapsutlated [(14)C]EDTA, given intravenously to mice, was retained longer in tissues that nonencapsulated [(14)C]EDTA. Encapsulated DTPA, given to mice 3 days after pluttonium injection, removed an additional fraction of plutonium in the liver, presumably intracellular, not available to nonencapslulated DTPA. It also further increased urinary excretion of plutonium. Introduction of chelating agents into cells by liposomal encapsulation is a promising new approach to the treatment of metal poisoning


Choline: high-affinity uptake by rat brain synaptosomes.
Synaptosomes from rat brain accumulate choline by two kinetically distinct processes, a high-affinity uptake system [Michaelis constant (K(m)) = 1 x 10(-6)M], and a low-affinity system (K(m) = 9 x 10(-5)M). The high-affinity uptake system requires sodium, and is associated with considerable formation of acetylcholine. The low-affinity uptake system is less dependent on sodium, and does not appear to be associated with a marked degree of acetylcholine formation. The high-affinity choline uptake appears to represent selective choline accumulation by cholinergic neurons.


Development of spray dried liposomal dry powder inhaler of Dapsone.
This investigation was undertaken to evaluate practical feasibility of site specific pulmonary delivery of liposomal encapsulated Dapsone (DS) dry powder inhaler for prolonged drug retention in lungs as an effective alternative in prevention of Pneumocystis carinii pneumonia (PCP) associated with immunocompromised patients. DS encapsulated liposomes were prepared by thin film evaporation technique and resultant liposomal dispersion was passed through high pressure homogenizer. DS nano-liposomes (NLs) were separated by ultra centrifugation and characterized. NLs were dispersed in phosphate buffer saline (PBS) pH 7.4 containing different carriers like lactose, sucrose, and hydrolyzed gelatin, and 15% L-leucine as antiadherent. The resultant dispersion was spray dried and spray dried formulation were characterized to ascertain its performance. In vitro pulmonary deposition was assessed using Andersen Cascade Impactor as per USP. NLs were found to have average size of 137 +/- 15 nm, 95.17 +/- 3.43% drug entrapment, and zeta potential of 0.8314 +/- 0.0827 mV. Hydrolyzed gelatin based formulation was found to have low density, good flowability, particle size of 7.9 +/- 1.1 microm, maximum fine particle fraction (FPF) of 75.6 +/- 1.6%, mean mass aerodynamic diameter (MMAD) 2.2 +/- 0.1 microm, and geometric standard deviation (GSD) 2.3 +/- 0.1. Developed formulations were found to have in vitro prolonged drug release up to 16 h, and obeys Higuchi's Controlled Release model. The investigation provides a practical approach for direct delivery of DS encapsulated in NLs for site specific controlled and prolonged release behavior at the site of action and hence, may play a promising role in prevention of PCP.


Diagnostic value of PET/CT for giant cell arteritis combined with pulmonary embolism presenting: Case report and literature review.
Giant cell arteritis (GCA) combined with concomitant pulmonary embolism (PE) is extremely difficult to diagnose because of its low incidence and atypical clinical presentations. A 62-year-old male developed fever of unknown origin. Positron emission tomography/computed tomography (PET/CT) revealed increased glucose metabolism in the vascular walls of the ascending and descending aorta and pulmonary artery, leading to a diagnosis of GCA combined with PE. The patient did not respond to regular antiviral and antibacterial treatment but was remised after steroid treatment. No specific autoantibodies were positive for this patient, and the patient did not respond to regular antiviral and antibacterial treatment. After diagnosed by PET/CT, the patient responded well to steroid treatment. Literature review found 16 cases of GCA diagnosed by PET/CT. Their median age was 68.5 (range, 21-87) years and 13 cases were female. PET/CT showed significantly increased metabolism in the ascending and descending aorta, abdominal aorta, and carotid artery. In 4 cases (including our own case), the mean maximum standardized uptake value was 4.2 ± 1.7 (range, 2.5-7.2). Six cases of GCA also had PE and 5 (6/7, 85.7%) cases were females, and the current case is the first male case of GCA combined with PE. Steroid therapy was initiated in all 5 cases. Complete remission was achieved in 4 cases and 2 patients died and the outcome of 1 patient was unknown. Our case and the review highlight the value of PET/CT in diagnosing GCA combined with PE, suggesting that PET/CT is the preferred diagnostic tool for atypical patients presenting with fever or muscle pain.


[Evaluation of the effect of long term valproic acid treatment on plasma levels of carnitine, ammonia and amino acids related to the urea cycle in pediatric epileptic patients].
Valproic acid (VPA) is an antiepileptic drug widely used in paediatrics. In spite of being a safe and effective anticonvulsant, VPA has been involved in the onset of changes in the metabolism of ammonia and carnitine, although few prospective studies have been made of this. To evaluate the effect of long-term VPA administration, particularly on the metabolism of carnitine, ammonia and plasma amino-acids and the possible clinical repercussions of this in a group of epileptic patients studied prospectively and retrospectively. A study was made of 102 epileptic children on long term anticonvulsant treatment mainly with VPA. These patients were divided into two groups: group I (n = 25) were studied prospectively (basal sample, after one, six and twelve months of treatment) and group II (n = 77) or long term treatment group (a single sample extraction). In each epileptic patient and in 56 children from a control group (group III) studies were made of free plasma carnitine, ammonia and amino-acids related to the urea cycle and the plasma levels of each anticonvulsant drug. It was observed that in group I there was a fall in plasma carnitine concentrations with time and a progressive rise which was statistically significant (p = 0.001) in plasma levels, mainly of ammonia, glutamine, glycine and ornithine, from the basal levels to those after a year of treatment in practically 100% of the children studied. In group II children on antiepileptic drugs, mainly VPA, were seen to have lower plasma carnitine levels than those in the control group and higher serum ammonia, glutamine and glycine levels than the healthy population not treated with anticonvulsants. These differences were statistically significant (p = 0.001). No relationship was found between the parameters studied and the plasma levels of the drug, type of epilepsy or presence of side effects. These changes show the negative effects of VPA on the metabolism of carnitine and ammonia. It would therefore seem advisable to monitor these parameters in epileptic children on long term antiepileptic treatment.


Treatment of conduct problem youth with interpersonal callous traits using mental models: measurement of risk and change.
The present study examined a newly developed intervention for conduct problem youth with callous unemotional (CU) traits. Specifically, we examined the effects of a mental models intervention designed to increase motivation, raise positive emotion, and decrease interpersonal callousness in youth. We then measured change on the treatment scale of a risk and management measure for young offenders, namely the Risk-Sophistication-Treatment Inventory - Self Report (RSTI-SR; Iselin & Salekin, 2008). The design of the study involved administering a test battery to youth in a secure residential facility pre-, mid-, and post-treatment. Findings showed increases in positive emotion and treatment amenability scores and reduced psychopathy scores across the intervention. Reductions in symptoms were evidenced across the facets of interpersonal, callous and impulsive psychopathy traits. Similarly, gains on the RSTI-SR treatment scale were multidimensional. The current study revealed three important findings. First, positive emotion was shown to increase in youth across the intervention. Second, the new intervention was effective at reducing interpersonal callous traits in youth, as well as improving their amenability to treatment. Third, the RSTI-SR appeared to be an effective measure for indexing change.


Influenza virus vaccination induces interleukin-12/23 receptor beta 1 (IL-12/23R beta 1)-independent production of gamma interferon (IFN-gamma) and humoral immunity in patients with genetic deficiencies in IL-12/23R beta 1 or IFN-gamma receptor I.
To investigate whether protective immune responses can be induced in the absence of normal interleukin-12/23/gamma interferon (IL-12/23/IFN-gamma) axis signaling, we vaccinated with the seasonal influenza virus subunit vaccine two patients with complete IL-12/23 receptor beta1 (IL-12/23R beta 1) deficiencies, two patients with partial IFN-gamma receptor I (pIFN-gamma RI) deficiencies, and five healthy controls. Blood samples were analyzed before, 7 days after, and 28 days after vaccination. In most cases, antibody titers reached protective levels. Moreover, although T-cell responses in patients were lower than those observed in controls, significant influenza virus-specific T-cell proliferation, IFN-gamma production, and numbers of IFN-gamma-producing cells were found in all patients 7 days after the vaccination. Interestingly, influenza virus-specific IFN-gamma responses were IL-12/23 independent, in striking contrast to mycobacterium-induced IFN-gamma production. In conclusion, influenza virus vaccination induces IL-12/23-independent IFN-gamma production by T cells and can result in sufficient humoral protection in both IL-12/23R beta 1- and pIFN-gamma RI-deficient individuals.


Phase I/II trial of outpatient docetaxel, cisplatin, 5-fluorouracil, leucovorin (opTPFL) as induction for squamous cell carcinoma of the head and neck (SCCHN).
The purpose of this study was to establish the maximum tolerated dose (MTD) of docetaxel in an outpatient docetaxel (T), cisplatin (P), 5-fluorouracil (5-FU) (F), and leucovorin (L) (opTPFL) regimen and to obtain preliminary assessment of opTPFL efficacy. Thirty-four patients with stage III or IV squamous cell carcinoma of the head and neck were treated with opTPFL. Docetaxel was escalated from 60 to 95 mg/m(2) in combination with 100 mg/m(2) cisplatin intravenous bolus, and 2,800 mg/m(2) 5-FU continuous infusion and 2,000 mg/m(2) leucovorin continuous infusion with prophylactic growth factors and antibiotics. Patients who achieved a complete (CR) or partial (PR) response to three cycles received definitive twice-daily radiation therapy. A total of 97 cycles were administered to 34 patients. The major acute toxicities were neutropenia and mucositis. The MTD of docetaxel was 90 mg/m(2) . Seventy-seven of 97 cycles of were administered on an outpatient basis. The overall clinical response rate to opTPFL was 94%, with 44% CRs and 50% PRs. The MTD of opTPFL is 90 mg/m(2) docetaxel. Outpatient administration of opTPFL is tolerable, feasible, and does not alter the ability to administer definitive radiation therapy on schedule.


Regional Disparities in the Uptake of Differentiated Influenza Vaccines in the United States.
Significant racial/ethnic inequities in the uptake of differentiated influenza vaccines (DIVs) have been previously reported, though less is known about regional disparities. We conducted a retrospective longitudinal study (2014/15-2017/18 influenza seasons) among privately insured adults aged 65 + years in the US. The exposure was the beneficiary's area of residence (US Census Bureau division) and the outcome was the type of influenza vaccine: differentiated (high-dose [HDV], adjuvanted, recombinant, and cell-based) versus conventional standard-dose egg-based. Multilevel logistic regression modeling, guided by a causal diagram, was used to assess the influence of socio-demographics, medical, healthcare utilization, community, and vaccinator characteristics in confounding or mediating regional disparities. Among those vaccinated in physician offices, beneficiaries in the East North Central region were twice as likely to receive a DIV vs those in the South Atlantic, whereas those in the East and West South Central were least likely. Disparities became more pronounced in models adjusted for individual and community characteristics, suggesting that crude uptake estimates understate the true magnitude of disparities. A vaccinator's previous HDV use was most influential in explaining regional differences. Similar but less pronounced patterns emerged for vaccinations in pharmacies/facilities. Regional disparities remained even in fully adjusted models, pointing to currently poorly understood factors that may include quality of healthcare, client health literacy and engagement, and other political and cultural factors.


Sycrp2 Is Essential for Twitching Motility in the Cyanobacterium Synechocystis sp. Strain PCC 6803.
Two cAMP receptor proteins (CRPs), Sycrp1 (encoded by sll1371) and Sycrp2 (encoded by sll1924), exist in the cyanobacterium Synechocystis sp. strain PCC 6803. Previous studies have demonstrated that Sycrp1 has binding affinity for cAMP and is involved in motility by regulating the formation of pili. However, the function of Sycrp2 remains unknown. Here, we report that sycrp2 disruption results in the loss of motility of Synechocystis sp. PCC 6803, and that the phenotype can be recovered by reintroducing the sycrp2 gene into the genome of sycrp2-disrupted mutants. Electron microscopy showed that the sycrp2-disrupted mutant lost the pilus apparatus on the cell surface, resulting in a lack of cell motility. Furthermore, the transcript level of the pilA9-pilA11 operon (essential for cell motility and regulated by the cAMP receptor protein Sycrp1) was markedly decreased in sycrp2-disrupted mutants compared with the wild-type strain. Moreover, yeast two-hybrid analysis and a pulldown assay demonstrated that Sycrp2 interacted with Sycrp1 to form a heterodimer and that Sycrp1 and Sycrp2 interacted with themselves to form homodimers. Gel mobility shift assays revealed that Sycrp1 specifically binds to the upstream region of pilA9 Together, these findings indicate that in Synechocystis sp. PCC 6803, Sycrp2 regulates the formation of pili and cell motility by interacting with Sycrp1.IMPORTANCE cAMP receptor proteins (CRPs) are widely distributed in cyanobacteria and play important roles in regulating gene expression. Although many cyanobacterial species have two cAMP receptor-like proteins, the functional links between them are unknown. Here, we found that Sycrp2 in the cyanobacterium Synechocystis sp. strain PCC 6803 is essential for twitching motility and that it interacts with Sycrp1, a known cAMP receptor protein involved with twitching motility. Our findings indicate that the two cAMP receptor-like proteins in cyanobacteria do not have functional redundancy but rather work together.


[AIDS and intravenous drug abuse].
The importance of intravenous drug-abuse as a vehicle of HIV and AIDS is evidenced on the basis of recent epidemiological data gathered in the USA. The rate of seropositivity among intravenous drug-addicts (whose total number i is close to one million) is estimated at more than 20 percent. Besides direct contamination, risks of contamination of sexual partners and their offspring can be evaluated from these figures. The programme developed by the National Institute on Drug Abuse against AIDS, aimed at that particular target population, is presented in its various aspects, including basic research, treatment and prevention.


Technical problems in determining safe re-entry intervals.
Organophosphate pesticide residues have been responsible for periodic outbreaks of acute intoxication among California fieldworkers for over 30 years. In 1971, California established 're-entry intervals' to protect workers against overexposure to these residues. These intervals are stipulated times which must elapse between pesticide application and entry into the field for work involving substantial foliar or soil contact. The re-entry strategy depends upon a relatively predictable relation between time post-application and the level of the pesticide residue. It now appears that there are thiophosphates for which the residue hazard is not related to time in a stable way. This circumstance and the continued occurrence of poisoning incidents have focused attention on the quantitative aspects of the relationships between pesticide residue and toxicological response in humans. In the last decade, considerable progress has been made in elucidating these relationships and it now appears to be possible to outline the data requirements for a comprehensive regulatory solution to this longstanding occupational health problem.


Chemokine CCL18 predicts intraventricular hemorrhage in very preterm infants.
Intraventricular hemorrhage (IVH) in very preterm infants is a common disease associated with long-term consequences. Risk factors of IVH remain to be further defined. To determine whether specific immunoproteins at birth predict the risk of IVH and whether their receptors are localized at the bleeding site. A prospective cohort consisted of 163 infants born before 32 weeks of gestation. Altogether 107 cord blood immunoproteins and 12 cytokines from peripheral blood obtained 1 and 7 days after birth were analyzed. Serial brain ultrasounds were assessed. Immunohistochemistry of a chemokine receptor from 14 autopsies was studied. Low levels of cord chemokine CCL18 (chemokine (C-C motif) ligand 18) robustly predicted the risk of IVH grade II-IV when ante- and neonatal risk factors were considered. Cord CCL18 increased from 32 weeks to term. During the first week after very preterm birth CCL18 increased as the risk of new IVH cases decreased. CCL18 receptor, CCR3, was detectable in choroid plexus, periventricular capillary endothelium, ependymal cells, and in germinal matrix. Low cord blood CCL18 is an independent risk factor of IVH. CCL18 may inhibit signal transduction of its receptor in periventricular cells. Defining the function and regulation of CCL18 may help to decrease the risk of IVH.


Enjoyment, Exploration and Education: Understanding the Consumption of Pornography among Young Men with Non-Exclusive Sexual Orientations.
This qualitative research examines the influence of pornography consumption on young men with non-exclusive sexual orientations. Drawing on 35 in-depth interviews with young men from an elite university in the north-eastern United States, we examine how pornography was experienced as a leisure activity to be consumed in free time. Rather than focusing on the potential harms of pornography, we use an inductive analytic approach to explore the broader range of experiences that participants had, since the time they first consumed pornography. We demonstrate that pornography had educational benefits for these young men, related to their sexual desires, emerging sexual identities and for developing new sexual techniques. This study is part of a growing body of research that seeks to develop a holistic understanding of pornography in society, addressing the absence of the lived experience of the consumer in most pornography research.


Jugular bulb desaturation during coronary artery surgery: a comparison of off-pump and on-pump procedures.
Conventional coronary artery bypass surgery has been associated with cerebral injury attributed to cardiopulmonary bypass (CPB) and surgical manipulation of the ascending aorta. Off-pump coronary artery surgery avoids these factors and could prevent cerebral injury. However, moving the heart from its natural position affects the circulation and could compromise cerebral oxygenation and perfusion. We set out to compare episodes of poor global cerebral oxygenation, defined as a jugular bulb saturation less than 50%, between patients randomized to off-pump or (conventional) on-pump coronary artery surgery. One hundred and eighty-seven patients were assigned randomly to off-pump or on-pump coronary artery surgery. Oxygen saturation in the jugular bulb (SjO2) was measured during revascularization of the three main coronary vessels in the off-pump group, and at the start of CPB, before rewarming, and after rewarming in the on-pump group. We compared samples with jugular bulb with desaturation (SjO2) < or = 50%) between treatment groups. One hundred and seventy-five patients (81 in the off-pump group [93%] and 94 in the on-pump group [94%]) had complete jugular oxygen saturation data. Thirty-nine patients in the off-pump group (48%) and 25 patients in the on-pump group (27%) had one or more samples with desaturation during revascularization or CPB (odds ratio after adjustment for other factors, 0.39; 95% confidence interval, 0.21-0.73, P<0.01). Jugular bulb desaturation occurs more frequently during off-pump coronary artery surgery than during conventional coronary artery surgery.


Unraveling the Microbial Interactions and Metabolic Potentials in Pre- and Post-treated Sludge from a Wastewater Treatment Plant Using Metagenomic Studies.
Sewage waste represents an ecosystem of complex and interactive microbial consortia which proliferate with different kinetics according to their individual genetic as well as metabolic potential. We performed metagenomic shotgun sequencing on Ion-Torrent platform, to explore the microbial community structure, their biological interactions and associated functional capacity of pre-treated/raw sludge (RS) and post-treated/dried sludge (DS) of wastewater treatment plant. Bacterial phylotypes belonging to Epsilonproteobacteria (∼45.80%) dominated the RS with relatively few Archaea (∼1.94%) whereas DS has the dominance of beta- (30.23%) and delta- (13.38%) classes of Proteobacteria with relatively greater abundance of Archaea (∼7.18%). In particular, Epsilonproteobacteria appears as a primary energy source in RS and sulfur-reducing bacteria with methanogens seems to be in the potential syntrophic association in DS. These interactions could be ultimately responsible for carrying out amino-acid degradation, aromatic compound degradation and degradation of propionate and butyrate in DS. Our data also reveal the presence of key genes in the sludge microbial community responsible for degradation of polycyclic aromatic hydrocarbons. Potential pathogenic microbes and genes for the virulence factors were found to be relatively abundant in RS which clearly reflect the necessity of treatment of RS. After treatment, potential pathogens load was reduced, indicating the sludge hygienisation in DS. Additionally, the interactions found in this study would reveal the biological and environmental cooperation among microbial communities for domestic wastewater treatment.


UDP-glucuronosyltransferase activity and bilirubin conjugation in the bullfrog.
Bile pigments of bile and serum of Rana catesbeiana were investigated by means of high-pressure liquid chromatography. The major pigment in both bile and serum was bilirubin IX alpha. Bilirubin UDP-glucuronosyltransferase activity was found in the livers of all animals examined, but no conjugated bilirubin was detectable in the bile. Frog bile was found to contain large amounts of beta-glucuronidase. When the beta-glucuronidase inhibitor saccharo-1,4-lactone was introduced into the gall bladder followed by an exogenous bilirubin load, bilirubin glucuronide appeared in the bile.


Towards a two tier health system in the Netherlands: how to put theory into practice.
The Dutch health care system is developing a two, or multiple, tier system. How can moral principles be of help in assessing whether this is the right track? Instead of dismissing as unhelpful the principles that have been suggested so far and exchanging them for other, usually more complex, principles, it is suggested that the methods of moral inquiry be reconsidered.


Social and economic burden of recurrent urinary tract infections and quality of life: a patient web-based study (GESPRIT).
Uncomplicated lower urinary tract infections (UTIs) occur in approximately 50% of women, and 20-30% experience recurrent UTI. Data on UTIs and quality of life (QoL) in Europe are limited. This was an anonymous, self-administered web-based survey conducted in 5 countries (Germany, Switzerland, Poland, Russia and Italy), on adult women who had experienced recurrent UTI and were affected by acute UTI currently or within 4 weeks of study entry. Questions covered disease course; management; social and economic burden; education, income, and health insurance status. QoL was evaluated using the SF-12v2. Participants reported a mean of 5.15 UTI symptoms, ranging from 4.85 - 5.38 in Russia and Germany. There was a mean of 2.78 doctor visits per year (1.74 - 3.71 in Russia and Germany; p < 0.0001). 80.3% of participants had been treated with antibiotics, mean prescriptions ranged from 2.17 (Poland) to 3.36 (Germany) per person per year. A mean of 3.09 days sick leave due to UTIs, and 3.45 days of limited activities, were reported. Although 73.8% of participants had tried prophylaxis recurrence was common and associated with mental stress for a high proportion of women. Our results indicate that recurrent UTIs have a significant impact on QoL of women in Europe.


Effect of soy protein on nonheme iron absorption in man.
The absorption of iron was measured from a hamburger in which half of the meat protein was substituted with various soy protein products (textured soy flour or defatted soy flour). Thge reduction of the meat content per se in the hamburgers reduced the percentage nonheme iron absorption by 25% from 11.2 to 8.4% The addition of defatted soy flour reduced the percentage absorption further from 8.4% to 5.2%. The amount of nonheme iron absorbed, however, was unchanged due to the high iron content of soy flour. A removal of phytates from soy flour did not increase the nonheme iron absorption. The total amount of iron absorbed, including the heme iron, is much lower when the content of meat was reduced by half in the soy-meat hamburgers. The addition of heme iron as blood to these hamburgers fully restored the total amount of iron absorbed to the level measured in hamburger meals prepared of meat only.


Gastrointestinal stromal tumors (GISTs) with KIT and PDGFRA mutations have distinct gene expression profiles.
Most GISTs require oncogenic activation of the KIT or PDGFRA receptor tyrosine kinase proteins, and the genomic mechanisms of oncogene activation are heterogeneous. Notably, the kinase mutation type correlates with both tumor biology and imatinib response. For example, GISTs with KIT exon 11 mutations are typically gastric and have excellent imatinib response, whereas those with KIT exon 9 mutations generally arise in the small bowel and are less responsive to imatinib. To identify genes that might contribute to these biological differences, we carried out gene expression profiling of 26 GISTs with known KIT and PDGFRA mutational status. Expression differences were then evaluated further by RNA in situ hybridization, immunohistochemistry, and immunoblotting. Unsupervised hierarchical clustering grouped tumors with similar mutations together, but the distinction between the different groups was not absolute. Differentially expressed genes included ezrin, p70S6K, and PKCs, which are known to have key roles in KIT or PDGFRA signaling, and which might therefore contribute to the distinctive clinicopathological features in GISTs with different mutation types. These gene products could serve as highly selective therapeutic targets in GISTs containing the KIT or PDGFRA mutational types with which they are associated.


Prevalence, Characteristics, and Epidemiology of Microbial Hand Contamination Among Minnesota State Fair Attendees (2014).
Background: Many antimicrobial-resistant infections are community-acquired, yet community carriage of microorganisms by healthy individuals is poorly characterized. We assessed microorganism carriage on the hands of Minnesota State Fair attendees and explored associated factors. Methods: Minnesota State Fair attendees (in 2014) from households with ≥2 members (≥1 member being <19 years old [a child]) were eligible to participate. Participants provided biological samples via a hand plating technique and completed a questionnaire on factors potentially related to microorganism carriage. Using presumptive taxonomic identifications and disk-diffusion-determined resistance phenotypes, hand-culture isolates were classified by microbial type; types were grouped into four broad categories based on inferred pathogenicity and consistency with the skin microbiota. Descriptive statistics, X2 tests, and generalized linear mixed-effects models were used to explore associations between survey and culture data. Results: We enrolled 206 participants from 82 households during 2 days; 50% of subjects were children. Overall, 99.5% (205/206) of hand samples yielded microorganisms. Most were non-pathogenic, whether skin microbiota (98.5% of participants) or non-skin microbiota (93.2% of participants). Only 2.4% (5/206) of samples yielded antibiotic-resistant bacteria. Children were more likely than adults to carry potentially pathogenic (OR = 3.63, 95% CI: 1.66-7.93) and presumably non-pathogenic (OR = 6.61, 95% CI: 1.67-26.15) non-skin microorganisms. Conclusions: Large community gatherings can serve as efficient sites for estimating the prevalence of microorganism carriage. A small proportion of participants carried antimicrobial-resistant pathogens on their hands; most carried non-pathogenic microorganisms, and no exposures specific to the state fair were associated with microorganism carriage.


A neural-network appearance-based 3-D object recognition using independent component analysis.
This paper presents results on appearance-based three-dimensional (3-D) object recognition (3DOR) accomplished by utilizing a neural-network architecture developed based on independent component analysis (ICA). ICA has already been applied for face recognition in the literature with encouraging results. In this paper, we are exploring the possibility of utilizing the redundant information in the visual data to enhance the view based object recognition. The underlying premise here is that since ICA uses high-order statistics, it should in principle outperform principle component analysis (PCA), which does not utilize statistics higher than two, in the recognition task. Two databases of images captured by a CCD camera are used. It is demonstrated that ICA did perform better than PCA in one of the databases, but interestingly its performance was no better than PCA in the case of the second database. Thus, suggesting that the use of ICA may not necessarily always give better results than PCA, and that the application of ICA is highly data dependent. Various factors affecting the differences in the recognition performance using both methods are also discussed.


Use of a combination of diaphragmatic ultrasound and muscle relaxation monitoring in predicting post-extubation adverse respiratory events among elderly patients in an anesthesia intensive care unit.
The purpose of this study was to examine the feasibility of using a combination of diaphragmatic ultrasound and muscle relaxation monitoring in predicting adverse respiratory events after extubation among elderly patients in an anesthetic intensive care unit (AICU). The study participants were 120 elderly patients who were in the AICU after laparoscopic radical resection for colorectal cancer. Based on whether there were critical respiratory events (CREs) after extubation, they were divided into the adverse event group and the non-adverse event group. We used logistic regression to identify factors influencing the occurrence of CREs post-extubation in elderly patients. Using the receiver operating characteristic (ROC) curve, we analyzed the value of each indicator in predicting CREs post-extubation. We included 109 patients in the final analysis. In the adverse event group (n = 19), the age, proportion of females, and proportion of preoperative respiratory diseases were higher than in the non-adverse event group (n = 90). The muscle relaxation value, quiet breathing diaphragmatic excursion during extubation (DE-QB), deep breathing diaphragmatic excursion during extubation (DE-DB), and deep breathing diaphragmatic thickening fraction during extubation (DTF-DB) of patients in the adverse event group were significantly lower than those in the non-adverse event group (P < 0.05). Using binary logistic regression analysis, we identified muscle relaxation value, DE-DB, and DTF-DB during extubation as significant predictors of CREs post-extubation in elderly patients (P < 0.05). The area under the curve (AUC) of the combination of the muscle relaxation value, DE-DB, and DTF-DB during extubation for predicting CREs after extubation in elderly patients was 0.949, which was higher than that of any single indicator. The combination of diaphragmatic ultrasound and muscle relaxation monitoring was more accurate in predicting CREs post-extubation among elderly patients in the AICU.


A university challenge: responding to continuing professional education and development needs.
Educational institutions have a pivotal role in identifying and responding to emerging health human resource needs. However, the educational context for pre-registration qualification is not the same as that required for continuing professional education. This short paper suggests that a structured framework similar to that proposed by Tzountzouris and Gilbert for strategic analysis be applied to encourage universities to be more responsive in their post-registration education of healthcare professionals. Further, it proposes that universities set a goal of becoming learning organizations and encourage staff to challenge their thinking and adaptability to meet the needs of employers.


Cathepsin K-sensitive poly(ethylene glycol) hydrogels for degradation in response to bone resorption.
We propose a new strategy of biomaterial design to achieve selective cellular degradation by the incorporation of cathepsin K-degradable peptide sequences into a scaffold structure so that scaffold biodegradation can be induced at the end of the bone formation process. Poly(ethylene glycol) diacrylate (PEGDA) hydrogels were used as a model biomaterial system in this study. A cathepsin K-sensitive peptide, GGGMGPSGPWGGK (GPSG), was synthesized and modified with acryloyl-PEG-succinimidyl carbonate to produce a cross-linkable cathepsin K-sensitive polymer that can be used to form a hydrogel. Specificity of degradation of the GPSG hydrogels was tested with cathepsin K and proteinase K as a positive control, with both resulting in significant degradation compared to incubation with nonspecific collagenases over a 24-h time period. No degradation was observed when the hydrogels were incubated with plasmin or control buffers. Cell-induced degradation was evaluated by seeding differentiated MC3T3-E1 osteoblasts and RAW264.7 osteoclasts on GPSG hydrogels that were also modified with the cell adhesion peptide RGDS. Resulting surface features and resorption pits were analyzed by differential interference contrast (DIC) and fluorescent images obtained with confocal microscopy. Results from both analyses demonstrated that GPSG hydrogels can be degraded specifically in response to osteoclast attachment but not in response to osteoblasts. In summary, we have demonstrated that by incorporating a cathepsin K-sensitive peptide into a synthetic polymer structure, we can generate biomaterials that specifically respond to cues from the natural process of bone remodeling.


Effects of pre- and postpartum dietary starch content on productivity, plasma energy metabolites, and serum inflammation indicators of dairy cows.
The objective of this study was to evaluate the effects of the starch content of pre- and postpartum diets on productivity, plasma energy metabolites, and serum markers of inflammation of dairy cows during the calving transition period. Eighty-eight primiparous and multiparous cows were randomly assigned to pre- and postpartum dietary treatments balanced for parity and pretrial body condition score at d 28 ± 3 before expected calving date. Cows were fed either a control [Control; 14.0% starch, dry matter (DM) basis] or high-starch (High; 26.1% starch, DM basis) prepartum diet commencing 28 ± 3 d before expected calving date. Following calving, cows were fed either a high-fiber (HF; 33.8% neutral detergent fiber, 25.1% starch, DM basis) or high-starch (HS; 27.2% neutral detergent fiber, 32.8% starch, DM basis) postpartum diet for the first 20 ± 2 d following calving. Cows fed the High prepartum diet had greater DM intake (12.4 vs. 10.2 kg/d), plasma concentrations of insulin (1.72 vs. 14.2 ng/mL), glucose (68.1 vs. 65.0 mg/dL), and glucagon-like peptide-2 (0.41 vs. 0.32 ng/mL) before parturition, but increased plasma free fatty acid concentration (452 vs. 363 µEq/L) and milk fat yield (1.64 vs. 1.48 kg/d) after parturition. Cows fed the HS postpartum diet had lower plasma free fatty acid (372 vs. 442 µEq/L) and serum haptoglobin (0.46 vs. 0.70 mg/mL) concentrations over a 3-wk period after calving. In addition, there was a tendency for interaction between prepartum and postpartum diets for milk yield, where feeding the HS postpartum diet increased milk yield compared with the HF diet for cows fed the Control prepartum diet (40.8 vs. 37.9 kg/d) but not for cows fed the High prepartum diet. These results suggest that management efforts to minimize the change in diet fermentability during the calving transition by feeding the High prepartum diet, the HF postpartum diet, or both did not increase productivity of dairy cows but increased fat mobilization after calving. Our findings also suggest that feeding high-starch postpartum diets can decrease fat mobilization and serum indicators of systemic inflammation and increase milk production even with the transition from a low-starch prepartum diet.


Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking.
Alcohol dependence is a disease that impacts millions of individuals worldwide. There has been some progress with pharmacotherapy for alcohol-dependent individuals; however, there remains a critical need for the development of novel and additional therapeutic approaches. Alcohol and nicotine are commonly abused together, and there is evidence that neuronal nicotinic acetylcholine receptors (nAChRs) play a role in both alcohol and nicotine dependence. Varenicline, a partial agonist at the alpha4beta2 nAChRs, reduces nicotine intake and was recently approved as a smoking cessation aid. We have investigated the role of varenicline in the modulation of ethanol consumption and seeking using three different animal models of drinking. We show that acute administration of varenicline, in doses reported to reduce nicotine reward, selectively reduced ethanol but not sucrose seeking using an operant self-administration drinking paradigm and also decreased voluntary ethanol but not water consumption in animals chronically exposed to ethanol for 2 months before varenicline treatment. Furthermore, chronic varenicline administration decreased ethanol consumption, which did not result in a rebound increase in ethanol intake when the varenicline was no longer administered. The data suggest that the alpha4beta2 nAChRs may play a role in ethanol-seeking behaviors in animals chronically exposed to ethanol. The selectivity of varenicline in decreasing ethanol consumption combined with its reported safety profile and mild side effects in humans suggest that varenicline may prove to be a treatment for alcohol dependence.


Neuropsychiatric and Cognitive Symptoms Across the Alzheimer Disease Clinical Spectrum: Cross-sectional and Longitudinal Associations.
To investigate the prevalence and trajectories of neuropsychiatric symptoms (NPS) in relation to cognitive functioning in a cohort of β-amyloid-positive (A+) individuals across the Alzheimer disease (AD) clinical spectrum. In this single-center observational study, we included all individuals who visited the Alzheimer Center Amsterdam and had a clinical diagnosis of subjective cognitive decline (SCD), mild cognitive impairment (MCI), or probable AD dementia and were A+. We measured NPS with the Neuropsychiatric Inventory (NPI), examining total scores and the presence of specific NPI domains. Cognition was assessed across 5 cognitive domains and with the Mini-Mental State Examination (MMSE). We examined trajectories including model-based trends for NPS and cognitive functioning over time. We used linear mixed models to relate baseline NPI scores to cognitive functioning at baseline (whole-sample) and longitudinal time points (subsample n = 520, mean 1.8 [SD 0.7] years follow-up). We included 1,524 A+ individuals from the Amsterdam Dementia Cohort with A+ SCD (n = 113), A+ MCI (n = 321), or A+ AD dementia (n = 1,090). NPS were prevalent across all clinical AD stages (≥1 NPS 81.4% in SCD, 81.2% in MCI, 88.7% in dementia; ≥1 clinically relevant NPS 54.0% in SCD, 50.5% in MCI, 66.0% in dementia). Cognitive functioning showed a uniform gradual decline; while in contrast, large intraindividual heterogeneity of NPS was observed over time across all AD groups. At baseline, we found associations between NPS and cognition in dementia that were most pronounced for NPI total scores and MMSE (range β = -0.18 to -0.11, false discovery rate [FDR]-adjusted p < 0.05), while there were no cross-sectional relationships in SCD and MCI (range β = -0.32 to 0.36, all FDR-adjusted p > 0.05). There were no associations between baseline NPS and cognitive functioning over time in any clinical stage (range β = -0.13 to 0.44, all FDR-adjusted p > 0.05). NPS and cognitive symptoms are both prevalent across the AD clinical spectrum, but show a different evolution during the course of the disease.


Training allied health professionals to deliver breast-feeding services to women in the pre- and postnatal periods.
Results of a recently completed project at Baylor College of Medicine suggest that schools of allied health could incorporate a breast-feeding education program into existing allied health curricula. The need for such programs is the medical indication for the increased use of human milk for all segments of the population, especially for infants in the lower socioeconomic strata because of their higher risk to nutritionally related problems and infectious diseases. Paradoxically, increases in breast-feeding are occurring almost exclusively in the middle and upper classes. The benefits of breast-feeding to both mother and child are great: lower incidence of certain disease processes, enhanced psychological adjustment, and increased economic savings. Training allied health professionals in breast-feeding could help alleviate the problem of higher risks of nutritional deficiencies and infectious diseases among groups that do not traditionally breast-feed their infants.


Chlamydia Psittaci ST24: Clonal Strains of One Health Importance Dominate in Australian Horse, Bird and Human Infections.
Chlamydia psittaci is traditionally regarded as a globally distributed avian pathogen that can cause zoonotic spill-over. Molecular research has identified an extended global host range and significant genetic diversity. However, Australia has reported a reduced host range (avian, horse, and human) with a dominance of clonal strains, denoted ST24. To better understand the widespread of this strain type in Australia, multilocus sequence typing (MLST) and ompA genotyping were applied on samples from a range of hosts (avian, equine, marsupial, and bovine) from Australia. MLST confirms that clonal ST24 strains dominate infections of Australian psittacine and equine hosts (82/88; 93.18%). However, this study also found novel hosts (Australian white ibis, King parrots, racing pigeon, bovine, and a wallaby) and demonstrated that strain diversity does exist in Australia. The discovery of a C. psittaci novel strain (ST306) in a novel host, the Western brush wallaby, is the first detection in a marsupial. Analysis of the results of this study applied a multidisciplinary approach regarding Chlamydia infections, equine infectious disease, ecology, and One Health. Recommendations include an update for the descriptive framework of C. psittaci disease and cell biology work to inform pathogenicity and complement molecular epidemiology.


[The modulation of Plasmodium falciparum virulence as a factor in the self-regulation of the malarial parasitic system].
Higher Plasmodium falciparum virulence is one of the major factors that contributes to the development of severe malaria and leads to death. However, the nature of virulence and its time course are not so far fully understood. The authors have made a published data-based hypothesis that the virulence of P. falciparum strains circulating in the malaria endemic areas of tropical Africa is not strictly genetically determined. The virulence of P. falciparum increases with its passage through the non-immune organisms of the infected persons. This mechanism of virulence modulation ensures the survival of the parasite in the human population with a considerable communal immunity. To test the validity of the hypothesis, the authors have used a mathematical analytical method to assess the published data on malaria mortality in some areas of tropical Africa. The results of the analysis have shown close values of actual and expected data.


Potential application of an Aspergillus strain in a pilot biofilter for benzene biodegradation.
A biofilter with fungus was developed for efficient degradation of benzene, which can overcome the potential risk of leakage commonly found in such services. Results indicated that the optimum parameter values were temperature 40 °C, pH 6, and 500 mg L-1 of the initial benzene concentration. Besides, the empty bed residence time and inlet load range of biofilter were set to 20 s and 21.23-169.84 g m-3 h-1 respectively. Under these conditions, this biofilter can obtain the maximum removal efficiency of more than 90%, the eliminating capacity could be up to 151.67 g m-3 h-1. Furthermore, scanning electron microscopy was used to investigate three filler materials for packing fungus biofilm. This is the first study introducing an Aspergillus strain for benzene removal and these results highlight that the development of this biofilter has the potential scaling-up application as gas-processing of industrial wastes.


Gene-regulatory networks in the Ciona embryos.
Ascidians belong to the subphylum Urochordata or Tunicata, which is the sister group of the vertebrates. The simple architecture of the ascidian larva represents the basic chordate body plan. Recent analyses have shown many instances of developmental mechanisms conserved during evolution, while these studies have also revealed a much larger number of instances of divergence. However, to precisely determine the degree of conservation and divergence, that is, how many ways are used to make tadpole-like larvae, we need a systems-level understanding of development. Because animal development is organized by the genome and the minimal functional unit of development is a cell, comprehensiveness and single-cell resolution are necessary for a systems-biological understanding of the development. In the ascidian Ciona intestinalis, gene-regulatory networks responsible for the embryonic development have been studied on a genome-wide scale and at single-cell resolution. The simplicity and compactness of the genome facilitates genome-wide studies. In the Ciona genome, only approximately 670 transcription factor genes are encoded, and their expression profiles during the embryonic development have been analyzed. Gene-knockdown analyses of the transcription factor genes expressed during the embryonic development have been performed. The simplicity of the embryo permits these analyses to be done at single-cell resolution. Actually, these simple embryos are now being modeled in the computer, which allows us to understand the gene-regulatory networks very precisely in three dimensions.


After providing end of life care to relatives, what care options do family caregivers prefer for themselves?
We examined how caregivers who had cared for a relative at end of life (EoL) wished to be cared for in the event that they experienced advanced dementia or physical disability in the future, and what factors influenced their preferences for EoL care. In this mixed-methods study, 83 participants, recruited from multiple sources in Israel, were interviewed concerning socio-demographic factors, health status, past experience with EoL, preference for extension of life vs. quality of life (QoL), willingness to be dependent on others, and preferences for EoL care. In case of advanced dementia, 58% preferred euthanasia or suicide; around a third chose those for physical disability. Care by family members was the least desired form of care in the advanced dementia scenario, although more desirable than institutional care in the physical disability scenario. QoL was rated as the highest factor impacting preferences for EoL care. Men demonstrated a higher preference than women for extension of life over QoL. Our study points to the need for society to consider solutions to the request of participants to reject the type of EoL experienced by their relatives. Those solutions include investing in improving the quality of life at the end of life, and offering alternatives such as euthanasia, which a large proportion of our participants found ethically and medically appropriate within the current system of care in the event of severe physical disability, and more so in the event of advanced dementia.


Neuroprotective effect of erythropoietin after experimental cold injury-induced vasogenic brain edema in rats.
The aims of this study were to evaluate the efficiency of EPO in the treatment of cold injury-induced brain edema, apoptosis, and inflammation and to compare its effectiveness with DSP. One hundred fifteen adult male Sprague-Dawley rats weighing between 280 and 300 g were used for the study. Rats were divided into 5 groups. Controls received craniotomy only. The injury group underwent cold injury and had no medication. In the EPO group, a single dose of 1000 IU/kg body weight of EPO was administered. The DSP group received 0.2 mg/kg body weight of DSP. The vehicle group received a vehicle solution containing human serum albumin, which is the solvent for EPO. Brain edema was formed by cold injury using metal sterile rods with a diameter of 4 mm that were previously cooled at -80 degrees C. Twenty-four hours after the injury, animals were decapitated and brain tissues were investigated for brain edema, tissue MPO and caspase-3 levels, and ultrastructure. A significant increase in brain water content was revealed in injury group of rats at 24 hours after cold injury. Injury significantly increased tissue MPO and caspase-3 levels and resulted in ultrastructural damage. Both EPO and DSP markedly decreased tissue MPO and caspase-3 levels and preserved ultrastructure of the injured brain cortex. Erythropoietin and DSP were found to be neuroprotective in cold injury-induced brain edema model in rats via anti-apoptotic and anti-inflammatory actions.


Thermodynamic consequences of grafting enhanced affinity toward the mutated antigen onto an antibody. The case of anti-lysozyme antibody, HyHEL-10.
In order to address the mechanism of enhancement of the affinity of an antibody toward an antigen from a thermodynamic viewpoint, anti-hen lysozyme (HEL) antibody HyHEL-10, which also recognize the mutated antigen turkey lysozyme (TEL) with reduced affinity, was examined. Grafting high affinity toward TEL onto HyHEL-10 was performed by saturation mutagenesis into four residues (Tyr(53), Ser(54), Ser(56), and Tyr(58)) in complementarity-determining region 2 of the heavy chain (CDR-H2) followed by selection with affinity for TEL. Several clones enriched have a Phe residue at site 58. Thermodynamic analyses showed that the clones selected had experienced a greater than 3-fold affinity increase toward TEL in comparison with wild-type Fv, originating from an increase in negative enthalpy change. Substitution of HyHEL-10 HTyr(58) with Phe led to the increase in negative enthalpy change and to almost identical affinity for TEL in comparison with mutants selected, indicating that mutations at other sites decrease the entropy loss despite little contribution to the affinity for TEL. These results suggest that the affinity of an antibody toward the antigen is enhanced by the increase in enthalpy change by some limited mutation, and excess entropy loss due to the mutation is decreased by other energetically neutral mutations.


Using Multilevel Structural Equation Modeling (MSEM) to Identify the Predictors and Influencing Mechanism of Technology Use Among Chinese Physicians: An Example from Des-Gamma-Carboxy Prothrombin (DCP).
Since expanding the use of appropriate and effective health technologies will greatly benefit the diagnosis and treatment of some major diseases at an early stage, understanding the mechanism of technology use is crucial for its successful implementation. Few previous studies focused on the healthcare providers and involved multi-facets factors at individual, technical, organizational, and environmental levels. To examine the influencing mechanism of technology use among Chinese physicians by integrating multilevel factors, Des-gamma-Carboxy Prothrombin (DCP) was taken as an example. Through multistage random sampling, a cross-sectional questionnaire survey was conducted among physicians in charge of direct use of DCP of sampled secondary and tertiary hospitals. Since the sample data comprised two hierarchical levels (physicians and hospitals), multilevel structural equation modeling was used to link five aspects of factors with physicians' technology use and estimate the effects. Totally, 229 physicians completed the investigation. The use of DCP appears to be at a relatively low level. Intra-class coefficients of the null model (unadjusted baseline model) suggested that physicians' DCP use has a significant variation between hospitals. The final model identified that value cognition (B = 0.447, P < 0.01), experienced organizational practice (B = 0.203, P < 0.05), and perceived organizational atmosphere (B = -0.237, P < 0.01) contributed directly to physicians' DCP use. Additionally, technical assessment, perceived organizational atmosphere, and perceived environmental pressure had indirect impacts on physicians' DCP use that were mediated by value cognition and experienced organizational practice (P < 0.05). This study incorporated and determined the significant direct or indirect role of value cognition, technical assessment, experienced organizational practice, perceived organizational atmosphere, and perceived environmental pressure. This influencing mechanism with integrated multilevel factors could serve as a theoretical basis for tailoring interventions to promote technology use among Chinese physicians.


Antiviral activity and tolerability of amdoxovir with zidovudine in a randomized double-blind placebo-controlled study in HIV-1-infected individuals.
Amdoxovir acts synergistically with zidovudine in vitro and the combination prevents or delays the selection of thymidine analogue and K65R mutations. In silico studies have shown that a reduced dose of zidovudine (200 mg) results in decreased zidovudine-monophosphate levels, associated with toxicity, while maintaining zidovudine-triphosphate levels, which are associated with antiviral effects. Here, we aimed to assess the short-term tolerability and antiviral activity of amdoxovir in combination with reduced and standard doses of zidovudine. The study was a double-blind, placebo-controlled study in HIV-1-infected patients not receiving antiretroviral therapy and with plasma HIV-1 RNA > or =5,000 copies/ml. Patients were randomized to 10 days of twice-daily treatment with 200 mg zidovudine, 300 mg zidovudine, 500 mg amdoxovir, 500 mg amdoxovir plus 200 mg zidovudine or 500 mg amdoxovir plus 300 mg zidovudine. The mean change in viral load (VL) log(10) and area under the virus depletion curve (AUC(VL)) from baseline to day 10 were determined. Laboratory and clinical safety monitoring were performed. Twenty-four patients were enrolled. The mean VL log(10) change was 0.10 with placebo, -0.69 with zidovudine 200 mg, -0.55 with zidovudine 300 mg, -1.09 with amdoxovir, -2.00 with amdoxovir plus zidovudine (200 mg) and -1.69 with amdoxovir plus zidovudine (300 mg). Amdoxovir plus zidovudine (200 mg) was significantly more potent than amdoxovir monotherapy in AUC(VL) and mean VL decline (P=0.019 and P=0.021, respectively), suggesting synergy. There was markedly decreased VL variability with the combination compared with amdoxovir alone. All adverse events were mild to moderate. The combination of amdoxovir plus zidovudine appeared synergistic with reduced VL variability. This combined therapy, including the use of a lower zidovudine dosage, warrants further development for the therapy of HIV infection.


Drug development and IBS drugs: experience from the past, current challenges, and proposal for the future.
Over the past decade, the failed promise of animal models and preclinical pharmacology, and a changing landscape in the regulatory perspectives have impacted the development of drugs for the treatment of irritable bowel syndrome (IBS). In general, animal models have failed to predict efficacy of medications developed for visceral pain. On the contrary, extensive experience with different endpoints in large, randomized, and controlled trials has generated some data on psychometric validation and unprecedented information about responsiveness of binary or global endpoints. However, it has now become necessary to pursue further validation studies in the run-up to or during pivotal trials. Guidance documents from regulatory agencies in Europe and the United States have focused on patient response outcomes (PROs) and associated impact on quality of life. These extra validation steps will undoubtedly result in delays in drug development. Providing relief to patients should galvanize all parties to achieve effective and fair strategies for regulatory approval.


Stress induces the assembly of RNA granules in the chloroplast of Chlamydomonas reinhardtii.
Eukaryotic cells under stress repress translation and localize these messenger RNAs (mRNAs) to cytoplasmic RNA granules. We show that specific stress stimuli induce the assembly of RNA granules in an organelle with bacterial ancestry, the chloroplast of Chlamydomonas reinhardtii. These chloroplast stress granules (cpSGs) form during oxidative stress and disassemble during recovery from stress. Like mammalian stress granules, cpSGs contain poly(A)-binding protein and the small, but not the large, ribosomal subunit. In addition, mRNAs are in continuous flux between polysomes and cpSGs during stress. Localization of cpSGs within the pyrenoid reveals that this chloroplast compartment functions in this stress response. The large subunit of ribulosebisphosphate carboxylase/oxygenase also assembles into cpSGs and is known to bind mRNAs during oxidative stress, raising the possibility that it plays a role in cpSG assembly. This discovery within such an organelle suggests that mRNA localization to granules during stress is a more general phenomenon than currently realized.


How should fetal surgery for congenital diaphragmatic hernia be implemented in the post-TOTAL trial era: A discussion.
Following prenatal diagnosis of congenital diaphragmatic hernia, severity can be predicted based on the presence of associated abnormalities, and in isolated cases, on lung size and position of the liver. Severe hypoplasia is defined by a contralateral lung size <25% on ultrasound; moderate hypoplasia is when that lung measures between 25% and 45% of the normal. In fetuses with predicted poor postnatal outcome a procedure that reverses pulmonary hypoplasia may be considered. In uncontrolled studies, fetoscopic endoluminal tracheal occlusion (FETO) improved neonatal outcome. Recently, two randomized controlled trials compared the neonatal and infant outcomes in fetuses with isolated CDH (www.totaltrial.eu). In severe cases, FETO was carried out at 27+0 -29+6 weeks' gestation (referred to as "early") and in moderate at 30+0 -31+6 weeks ("late"). Survival to discharge from the neonatal intensive care unit increased by 25% (95%-CI:+6 to +46; p = 0.0091) and 13% (-1 to +28; p = 0.059), in fetuses with severe and moderate cases, respectively. Following FETO gestational age at delivery was on average 3.2 (2.3-4.1) weeks earlier following early and 1.7 (1.1-2.3) following late FETO. Here the strengths and weaknesses of the TOTAL trials and their translation to the clinic are debated. Discussants are the lead for the trial (JD) and a colleague (AF) not involved. The discussant notes that the observed survival, both in treated and expectantly managed fetuses, was overall less than what is reported by some high volume centers, particularly in North America. Additional criticisms are the potential effects of prematurity on the long term, the inclusion of low-volume centers, and the potential of FETO for severe iatrogenic complications. Therefore results may not be generalizable. The discussants concluded that although FETO may have its value it remains a procedure with a high risk for prematurity and it can be lethal when the balloon cannot be removed prior to delivery. CLINICAL TRIAL REGISTRATION: The TOTAL trials were registered at www.clinicaltrials.gov as NCT01240057 (severe) and NCT00763737 (moderate).


Rapid and near-complete dissolution of wood lignin at ≤80°C by a recyclable acid hydrotrope.
We report the discovery of the hydrotropic properties of a recyclable aromatic acid, p-toluenesulfonic acid (p-TsOH), for potentially low-cost and efficient fractionation of wood through rapid and near-complete dissolution of lignin. Approximately 90% of poplar wood (NE222) lignin can be dissolved at 80°C in 20 min. Equivalent delignification using known hydrotropes, such as aromatic salts, can be achieved only at 150°C or higher for more than 10 hours or at 150°C for 2 hours with alkaline pulping. p-TsOH fractionated wood into two fractions: (i) a primarily cellulose-rich water-insoluble solid fraction that can be used for the production of high-value building blocks, such as dissolving pulp fibers, lignocellulosic nanomaterials, and/or sugars through subsequent enzymatic hydrolysis; and (ii) a spent acid liquor stream containing mainly dissolved lignin that can be easily precipitated as lignin nanoparticles by diluting the spent acid liquor to below the minimal hydrotrope concentration. Our nuclear magnetic resonance analyses of the dissolved lignin revealed that p-TsOH can depolymerize lignin via ether bond cleavage and can separate carbohydrate-free lignin from the wood. p-TsOH has a relatively low water solubility, which can facilitate efficient recovery using commercially proven crystallization technology by cooling the concentrated spent acid solution to ambient temperatures to achieve environmental sustainability through recycling of p-TsOH.


Fetal sheep pituitary proopiomelanocortin in late gestation: effect of bilateral lesions of the paraventricular nucleus on regional and cellular messenger ribonucleic acid levels.
Previous experiments have clearly indicated that the successful completion of ovine gestation is dependent upon fetal adrenocortical maturation and the associated preterm rise in fetal plasma cortisol. The purposes of this study were to: 1) examine pituitary POMC messenger RNA (mRNA) levels during normal fetal development; and 2) examine the effects of bilateral lesion of the fetal paraventricular nucleus (PVN) on levels and spatial distribution of pituitary POMC mRNA. Pituitary glands were collected from intact fetal sheep of four gestational ages [100-107 days gestational age (dga), n = 8; 117-121 dga, n = 9; 126-130 dga, n = 9; 144-147 dga, n = 8]. Lesions of the PVN (PVN Lx; n = 4) or sham lesions (Sham; n = 5) were performed at 118-122 dga. Pituitary glands from PVN Lx and Sham fetuses were collected at 139-142 dga (term approximately 147 dga). POMC mRNA levels were determined by in situ hybridization. POMC transcript levels were determined by both regional analysis (20x magnification) and analysis of individual corticotropes (400x magnification). There was no difference among gestational age groups in superior anterior pituitary (AP) POMC mRNA levels determined by regional or cellular analysis. POMC mRNA levels were significantly greater in the inferior AP at 144-147 dga, compared with other gestational ages, using regional analysis (P = 0.003) or analysis of individual corticotropes (P < 0.01). POMC mRNA levels in the neurointermediate lobe in 126- to 130-dga fetuses were significantly greater than those in younger fetuses (P = 0.005) but not those in 144- to 147-dga fetuses. There was no difference in POMC mRNA levels in the superior AP between PVN Lx and Sham, using regional analysis or analysis of individual corticotropes. In the inferior AP, there was a significant decrease in POMC mRNA levels in PVN Lx, compared with Sham, using both regional analysis (P < 0.01) and cellular analysis (P < 0.01). There was no difference in POMC mRNA levels in the neurointermediate lobe as the result of bilateral PVN Lx. Our findings support that basal AP POMC mRNA levels are heterogenously distributed in the ovine fetal AP, with POMC mRNA levels in the inferior AP being significantly greater than in superior AP, by 144-147 dga. We further found that the higher POMC mRNA levels in the inferior AP reflect significantly higher corticotrope POMC transcripts and not simply a greater density of corticotropes in this AP region. The increase in POMC mRNA levels at 144-147 dga in the inferior AP seems unrelated to the onset of adrenocortical maturation (at approximately 125-130 dga). Finally, we report that increase in corticotrope POMC transcripts during late gestation in the inferior AP requires an intact PVN.


A method for intratracheal instillation in the rat.
A method was developed to provide safe, rapid, and accurate intratracheal instillation of radionuclides into the rat lung. Rats were anesthetized with halothane and suspended vertically on an animal support stand with rubber bands attached to the incisor teeth, holding the mouth open. A speculum was inserted into the trachea and the radionuclide was injected from a syringe through tubing inserted through the tracheal speculum into the trachea. The amount of radionuclide retained in the lung varied by less than a factor of 2 within groups of rats observed 4 hr-20 da after employing this method of instillation. When a volume of 2 ml was instilled, the radionuclide distribution between the left and right lung was similar to that observed following incorporation by inhalation. Instillations of less than 2 ml showed unequal distribution of radionuclide between the right and left lung.


[Differential voltametry: a new method for studying the cerebral metabolism of monoamines].
In vivo electrochemistry by differential pulse voltammetry represents an interesting option for functional neurochemistry or neuropharmacology. This paper successively presents the principle of the method and the technical bases of the measurement. The particular points of the specificity of the method and the necessary identification procedure of the different species detected in vivo are discussed (see fig. 1 to 7) with special reference to the detection of ascorbic acid and catechol compounds. Success for analysis of 5-hydroxy-indolic compounds are also referenced. In a second part of the paper an example of an in vivo metabolic exploration is presented. The detection of a catechol compound in the rat locus coeruleus, its identification as being extracellular DOPAC, its origin in noradrenergic cell bodies, its relationship with the activity of this group of noradrenaline containing perikarya are discussed (see fig. 8 to 15).


Purification and characterization of hypoxanthine-guanine phosphoribosyltransferase from Schistosoma mansoni. A potential target for chemotherapy.
Hypoxanthine phosphoribosyltransferase and guanine phosphoribosyltransferase activities are essential for the supply of guanine nucleotides in Schistosoma mansoni schistosomules. In crude extracts of adult S. mansoni, these two activities co-elute in size exclusion, ion exchange, and chromatofocusing chromatography and exhibit similar stabilities to heat treatment, suggesting that they are associated in one enzyme protein hypoxanthine-guanine phosphoribosyltransferase. This enzyme has been purified by a combination of heat treatment at 85 degrees C and chromatofocusing chromatography with elution at an apparent pI of 5.27 +/- 0.15. Pore gradient electrophoresis of the native enzyme followed by subsequent activity staining demonstrate an enzyme molecular weight of 105,000. The activity staining pattern remains the same whether hypoxanthine or guanine is used as the substrate, further supporting the existence of a single protein, hypoxanthine-guanine phosphoribosyltransferase. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the purified protein results in a single protein band with a subunit molecular weight estimate of 64,000, suggesting that the native enzyme is a dimer. Preliminary kinetic studies showed that the purified hypoxanthine-guanine phosphoribosyltransferase reacted with guanine at a rate twice as fast as it did with hypoxanthine, but it did not act on xanthine at all. A full-length mouse neuroblastoma hypoxanthine-guanine phosphoribosyltransferase cDNA clone pHPT5 and a plasmid pSV2-gpt containing the xanthine-guanine phosphoribosyltransferase gene for Escherichia coli were utilized as probes on Southern blots of S. mansoni DNA digests, and no significant hybridization was found under relatively relaxed conditions. Polyclonal antibodies made against human erythrocyte hypoxanthine-guanine phosphoribosyltransferase and E. coli xanthine-guanine phosphoribosyltransferase were tested in enzyme-linked immunosorbent assays of S. mansoni protein extracts, and no detectable cross-reacting protein was found. S. mansoni hypoxanthine-guanine phosphoribosyltransferase thus may bear rather limited homology to mammalian hypoxanthine-guanine phosphoribosyltransferase or bacterial xanthine-guanine phosphoribosyltransferase and could be an attractive target for antischistosomal chemotherapeutic drug design.


Aging, dementia, and brain atrophy: a longitudinal computed tomographic study.
Studies involving linear measurements of ventricular size and a volumetric measurement of the cerebrospinal fluid (CSF) space were performed on elderly subjects with mild dementia of the Alzheimer type and on age-matched controls. Forty-five subjects were studied twice at a 1 year interval; linear ventricular measurements showed not only a greater degree but a more rapid evolution of brain atrophy in individuals with mild dementia as compared with controls. An additional 12 normal subjects were studied twice over a 1 year period with volumetric estimates of the CSF space, which demonstrated development of significant brain atrophy within 1 year, while linear measurements on the same scans showed no significant change. The volumetric method is regarded as a more sensitive indicator of brain volume and is potentially useful in further studies in dementia.


Examining a New Scale for Evaluating Taste in Children (TASTY).
Pediatric medication taste impacts adherence, and current recommendations advocate for direct input from pediatric patients on medication taste during drug development. However, the lack of a widely used, validated measurement tool limits taste assessments. This protocol examines the validity of, and preferences for, a newly created self-report taste rating scale designed with images centered on taste (TASTY), compared with 2 existing hedonic taste scales. This study was a prospective, single-center, randomized survey of child-parent dyads recruited from pediatric ambulatory care clinics and ancillary service waiting rooms. Parents facilitated the survey by identifying foods that they perceived their child would recall as pleasant, neutral, and unpleasant. Children were asked to rate each of the 3 food items on each of 3 different faces scales presented in random order. Parents and children were also asked which scale they preferred and why. Ninety child-parent dyads completed this study (mean child age was 6.7 ± 2.9 years, 58% female). All 3 scales performed comparably with no significant differences (p > 0.05). However, concordance between parental assignment and child rankings was markedly lower in 3-year-olds (r < 0.4) and 4-year-olds (r < 0.6) than for children 5 years and older (r > 0.9). TASTY was preferred by both parents and children when compared with the other scales. This novel hedonic taste scale for pediatric use is equally valid and preferred to comparable faces scales. The TASTY scale may be beneficial in developing standardized methodology for evaluating drug palatability.


[68Ga]NODAGA-RGD for imaging αvβ3 integrin expression.
A molecular target involved in the angiogenic process is the α(v)β(3) integrin. It has been demonstrated in preclinical as well as in clinical studies that radiolabelled RGD peptides and positron emission tomography (PET) allow noninvasive monitoring of α(v)β(3) expression. Here we introduce a (68)Ga-labelled NOTA-conjugated RGD peptide ([(68)Ga]NODAGA-RGD) and compare its imaging properties with [(68)Ga]DOTA-RGD using small animal PET. Synthesis of c(RGDfK(NODAGA)) was based on solid phase peptide synthesis protocols using the Fmoc strategy. The (68)Ga labelling protocol was optimized concerning temperature, peptide concentration and reaction time. For in vitro characterization, partition coefficient, protein binding properties, serum stability, α(v)β(3) binding affinity and cell uptake were determined. To characterize the in vivo properties, biodistribution studies and microPET imaging were carried out. For both in vitro and in vivo evaluation, α(v)β(3)-positive human melanoma M21 and α(v)β(3)-negative M21-L cells were used. [(68)Ga]NODAGA-RGD can be produced within 5 min at room temperature with high radiochemical yield and purity (> 96%). In vitro evaluation showed high α(v)β(3) binding affinity (IC(50) = 4.7 ± 1.6 nM) and receptor-specific uptake. The radiotracer was stable in phosphate-buffered saline, pH 7.4, FeCl(3) solution, and human serum. Protein-bound activity after 180 min incubation was found to be 12-fold lower than for [(68)Ga]DOTA-RGD. Biodistribution data 60 min post-injection confirmed receptor-specific tumour accumulation. The activity concentration of [(68)Ga]NODAGA-RGD was lower than [(68)Ga]DOTA-RGD in all organs and tissues investigated, leading to an improved tumour to blood ratio ([(68)Ga]NODAGA-RGD: 11, [(68)Ga]DOTA-RGD: 4). MicroPET imaging confirmed the improved imaging properties of [(68)Ga]NODAGA-RGD compared to [(68)Ga]DOTA-RGD. The introduced [(68)Ga]NODAGA-RGD combines easy accessibility with high stability and good imaging properties making it an interesting alternative to the (18)F-labelled RGD peptides currently used for imaging α(v)β(3) expression.


Burnout and Time Perspective of Blue-Collar Workers at the Shipyard.
Background: The aim of the research was to investigate the association between time perspective in relation to burnout and successful ageing of blue-collar workers with physically highly demanding work and low autonomy. Shipyard blue-collar workers usually do predominantly manual labor versus white-collar workers, whose jobs do not usually involve physical work. Methods: 497 participants workers in a shipyard in the north of Spain. Ages were between 20 and 69 (M = 46.62, SD = 10.79). We used the Zimbardo Time Perspective Instrument (ZTPI), Spanish version, and the Maslach Burnout Inventory-General Survey (MBI-GS). Results: Emotional exhaustion factor obtained a coefficient of 0.97; cynicism factor of 0.83; and professional efficacy factor of p = 0.86. The mean of the three reliability coefficients was 0.887. With respect to the five factors of the ZTPI questionnaire: the negative past factor obtained a coefficient of p = 0.91; that of positive past p = 0.81; the present hedonistic of 0.878; the future of p = 0.83; and the fatalistic present of p = 0.90. The mean of the five coefficients, was p = 0.86. Conclusions: Within shipyard workers, burnout is associated with a negative past and negative future time perspective. This makes shipyard workers at a higher risk of developing burnout and this can have serious consequences for the sustainable employability of these blue-collar workers.


Retrieval of absorption and backscattering coefficients from HJ-1A/CCD imagery in coastal waters.
A simple semi-analytical model (SAB) was developed for computing a(560) and b(b)(550) from HJ-1A/CCD images. By comparison with field measurements, the SAB model produces 5.3-23.5% uncertainty for a(560) and b(b)(550) retrievals. The a(560) and b(b)(550) are also retrieved from satellite images. The match-up analysis results indicate that a(560) and b(b)(550) may be derived from the HJ-1A/CCD images with respective uncertainties of 29.84 and 21.35%. These findings imply that, provided that an atmospheric correction scheme for the green bands is available, the extensive database of HJ-1A/CCD imagery may be used for the quantitative monitoring of optical properties in coastal waters.