Phosphatidylserine enhancement of [3H]gamma-aminobutyric acid uptake by rat whole brain synaptosomes.
[3H]gamma-Aminobutyric acid ([3H]GABA) binding to purified lipids was examined in an organic solvent-aqueous partition system. In addition, the [3H]GABA binding capacity in the partition system was compared with the capacity of lipids to alter sodium-dependent [3H]GABA uptake into synaptosomes isolated from rat whole brains. [3H]GABA was found to bind to all of the lipids studied in the organic solvent-aqueous partition system [phosphatidic acid (PA), phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylserine (PS), gangliosides, and sulfatide], although PS exhibited the greatest binding capacity. [3H]GABA uptake into synaptosomes was enhanced by PS (48.0%) but was not altered by any other lipid. PS enhancement of [3H]GABA uptake required the presence of sodium and was blocked by nipecotic acid (10 microM). These results suggest that PS may play a role in the sodium-dependent GABA reuptake process in the presynaptic nerve end.


Regulatory mechanisms controlling expression of the DAN/TIR mannoprotein genes during anaerobic remodeling of the cell wall in Saccharomyces cerevisiae.
The DAN/TIR genes of Saccharomyces cerevisiae encode homologous mannoproteins, some of which are essential for anaerobic growth. Expression of these genes is induced during anaerobiosis and in some cases during cold shock. We show that several heme-responsive mechanisms combine to regulate DAN/TIR gene expression. The first mechanism employs two repression factors, Mox1 and Mox2, and an activation factor, Mox4 (for mannoprotein regulation by oxygen). The genes encoding these proteins were identified by selecting for recessive mutants with altered regulation of a dan1::ura3 fusion. MOX4 is identical to UPC2, encoding a binucleate zinc cluster protein controlling expression of an anaerobic sterol transport system. Mox4/Upc2 is required for expression of all the DAN/TIR genes. It appears to act through a consensus sequence termed the AR1 site, as does Mox2. The noninducible mox4Delta allele was epistatic to the constitutive mox1 and mox2 mutations, suggesting that Mox1 and Mox2 modulate activation by Mox4 in a heme-dependent fashion. Mutations in a putative repression domain in Mox4 caused constitutive expression of the DAN/TIR genes, indicating a role for this domain in heme repression. MOX4 expression is induced both in anaerobic and cold-shocked cells, so heme may also regulate DAN/TIR expression through inhibition of expression of MOX4. Indeed, ectopic expression of MOX4 in aerobic cells resulted in partially constitutive expression of DAN1. Heme also regulates expression of some of the DAN/TIR genes through the Rox7 repressor, which also controls expression of the hypoxic gene ANB1. In addition Rox1, another heme-responsive repressor, and the global repressors Tup1 and Ssn6 are also required for full aerobic repression of these genes.


Structure-from-motion without correspondence from tomographic projections by Bayesian inversion theory.
In conventional tomography, the interior of an object is reconstructed from tomographic projections such as X-ray or transmission electron microscope images. All the current reconstruction methods assume that projection geometry of the imaging device is either known or solved in advance by using e.g., fiducial or nonfiducial feature points in the images. In this paper, we propose a novel approach where the imaging geometry is solved simultaneously with the volume reconstruction problem while no correspondence information is needed. Our approach is a direct application of Bayesian inversion theory and produces the maximum likelihood or maximum a posteriori estimates for the motion parameters under the selected noise and prior distributions. In this paper, the method is implemented for a two-dimensional model problem with one-dimensional affine projection data. The performance of the method is tested with simulated and measured X-ray projection data.


Theoretical construct into blocks of actigraphic-derived sleep parameters.
Actigraphic parameters can provide indication of people's sleep quality during their daily lives. However, there is a need for clear guidelines on the understanding of the different actigraphic parameters. The present study aims to propose a conceptual and theoretical framework for known actigraphic-derived parameters, which is able to describe the alternation between rest and wake phases during the nocturnal sleep, explaining their main characteristics and interrelations that can be replicated in future studies. Forty Sport Sciences students at the University of Milan (20 males; mean age ± SD, 22 ± 3 y) completed the validated Italian version of Morningness-Eveningness Questionnaire (MEQ) and wore an actigraph (Motion Watch 8®, Cambridge Neurotechnology, Cambridge, UK) for seven days. A framework was developed to depict the interactions between the actigraphic parameters and how they objectively describe sleep, according to which the parameters are organized into three different functional blocks related to different aspects of sleep. Correlations analyses were conducted to explore the relationships among the primary actigraphic parameters within and across the functional blocks. The proposed framework is a purely theoretical construct that provides a simple interpretation of known actigraphic parameters guiding researchers and practitioners in the use of these parameters either for research or clinical purposes.


Efficient functional localization of language regions in the brain.
Important recent advances in the cognitive neuroscience of language have been made using functional localizers to demarcate language-selective regions in individual brains. Although single-subject localizers offer insights that are unavailable in classic group analyses, they require additional scan time that imposes costs on investigators and participants. In particular, the unique practical challenges of scanning children and other special populations has led to less adoption of localizers for neuroimaging research with these theoretically and clinically important groups. Here, we examined how measurements of the spatial extent and functional response profiles of language regions are affected by the duration of an auditory language localizer. We compared how parametrically smaller amounts of data collected from one scanning session affected (i) consistency of group-level whole-brain parcellations, (ii) functional selectivity of subject-level activation in individually defined functional regions of interest (fROIs), (iii) sensitivity and specificity of subject-level whole-brain and fROI activation, and (iv) test-retest reliability of subject-level whole-brain and fROI activation. For many of these metrics, the localizer duration could be reduced by 50-75% while preserving the stability and reliability of both the spatial extent and functional response profiles of language areas. These results indicate that, for most measures relevant to cognitive neuroimaging studies, the brain's language network can be localized just as effectively with 3.5 minutes of scan time as it can with 12 minutes. Minimizing the time required to reliably localize the brain's language network allows more effective localizer use in situations where each minute of scan time is particularly precious.


The INSIG2 rs7566605 genetic variant does not play a major role in obesity in a sample of 24,722 individuals from four cohorts.
In a genome-wide association study performed in the Framingham Offspring Cohort, individuals homozygous for the rs7566605 C allele located upstream of insulin-induced gene 2 (INSIG2) were reported to incur an increased risk of obesity. This finding was later replicated in four out of five populations examined. The goal of the study reported here was to assess the role of the INSIG2 single nucleotide polymorphism (SNP) in susceptibility to obesity in the prospective longitudinal Atherosclerosis Risk in Communities (ARIC) study (n = 14,566) and in three other cohorts: the Coronary Artery Risk Development in Young Adults (CARDIA) study (n = 3,888), the Genetic Epidemiology Network of Arteriopathy (GENOA) study (n = 4,766), and extremely obese and lean individuals ascertained at the University of Ottawa (n = 1,502). The combined study sample is comprised of 24,722 white, African-American, and Mexican-American participants. Differences in mean body mass index (BMI) and other anthropometric measures including weight, waist circumference, and waist-to-hip ratio were assessed by a general linear model in individuals categorized by INSIG2 rs7566605 genotype. Multivariable logistic regression was used to predict the risk of obesity (BMI >or= 30 kg/m2). There was no discernable variation in the frequencies of the three INSIG2 SNP genotypes observed between white, Hispanic, and African-American obese individuals and non-obese study subjects. When the relationship between rs7566605 and BMI considered either as a categorical variable or a continuous variable was examined, no significant association with obesity was found for participants in any of the four study populations or in a combined analysis (p = 0.38) under a recessive genetic model. There was also no association between the INSIG2 polymorphism and the obesity-related quantitative traits except for a reduced waist-to-hip ratio in white ARIC study participants homozygous for the C allele, and an increased waist-to-hip ratio in African-Americans in the ARIC cohort with the same genotype (p = 0.04 and p = 0.01, respectively). An association with waist-to-hip ratio was not seen when the combined study sample was analyzed (p = 0.74). These results suggest that the INSIG2 rs7566605 variant does not play a major role in determining obesity risk in a racially and ethnically diverse sample of 24,722 individuals from four cohorts.


Brønsted acid-catalyzed cycloisomerization of but-2-yne-1,4-diols with or without 1,3-dicarbonyl compounds to tri- and tetrasubstituted furans.
A Brønsted acid-catalyzed method to prepare tri- and tetrasubstituted furans efficiently from cycloisomerization of but-2-yne-1,4-diols with or without 1,3-dicarbonyl compounds is described. By taking advantage of the orthogonal modes of reactivity of the alcoholic substrate through slight modification of the reaction conditions, a divergence in product selectivity was observed. At room temperature, p-TsOH·H(2)O-mediated tandem alkylation/cycloisomerization of the propargylic 1,4-diol with the β-dicarbonyl compound was found to selectively occur to provide the tetrasubstituted furan product. On the other hand, increasing the reaction temperature to 80 °C was discovered to result in preferential p-TsOH·H(2)O-catalyzed dehydrative rearrangement of the unsaturated alcohol and formation of the 2,3,5-trisubstituted furan adduct.


Fullerene C60-silver nanoparticles hybrid structures: optical and photoelectric characterization.
A detailed optical and photoelectric characterization of pristine fullerene C60 films deposited onto n-silicon substrates (C60/Si), C60 films crosslinked by means of the solvent-free chemical functionalization with 1,8-diaminooctane (C60-DA/Si), and the pristine and crosslinked films decorated with silver nanoparticles (C60-Ag/Si and C60-DA-Ag/Si), was carried out. The reflectance spectra obtained allowed to calculate the absorption coefficient (alpha = 4pik/lamda) spectral dependencies and the spectra of light transmittance in layered barrier structures metal(Au)/fullerene/Si. Photoelectric properties of the films were investigated as well. The experimentally measured values of band gap were in a good agreement with mobility gap values (2.3 +/- 0.1 eV). The decoration of fullerene films (both pristine and chemically crosslinked) with silver nanoparticles did not change the photocurrent spectra as compared to those for undecorated fullerene films, but lowered the values of internal quantum efficiency Qint. The photocurrent generated in fullerene/Si heterostructure, showed a maximum value at lamda to appromimately 450 nm (Qint max approximately = 0.25 for decorated and undecorated C60-DA/Si films), and it was higher for the samples based on pristine C60 films, in accordance with their higher absorption coefficient. Diminishing of Qint for C60-DA/Si and C60-DA-Ag/Si films was observed for the spectral range of photocurrent generated in Si layer. The analysis of dark current-voltage characteristics showed that the barrier properties differ insignificantly, though a certain increase of series resistance was observed for the C60-DA/Si samples.


New opportunities to treat the T315I-Bcr-Abl mutant in chronic myeloid leukaemia: tyrosine kinase inhibitors and molecules that act by alternative mechanisms.
Resistance to the Bcr-Abl inhibitors approved for the treatment of chronic myeloid leukaemia (CML) may arise from different mechanisms, including Bcr-Abl amino acid mutations, gene amplification and mechanisms independent of Bcr-Abl. The T315I mutation at the gatekeeper residue is very frequent in advanced phases of the disease and is one of the main causes of resistance, disrupting important contact points between the inhibitors and the enzyme. Different strategies have been implemented to overcome this resistance, including the synthesis of new Bcr-Abl ATPcompetitive or non-ATP-competitive inhibitors, dual Aurora/Bcr-Abl inhibitors and multi-targeted kinase inhibitors. An alternative approach is the use of other compounds that do not bind directly to the Bcr-Abl protein; instead, these molecules act on several downstream pathways, regulated by or linked in different ways to Bcr-Abl, that lead to the malignant transformation of the cells. For this reason, farnesyl transferase inhibitors, MAPK inhibitors, Rac guanosine triphosphatase inhibitors, PI3K inhibitors, JAK inhibitors, Hsp90 inhibitors, mTOR inhibitors, PP2A activators and apoptosis inducers have been tested, alone or in combination with ATP-competitive inhibitors, against CML cell lines. This review discusses compounds that act on Bcr-Abl or different cell pathways and reports on the molecules active against the T315I mutation, particularly the most recent findings in this field. New molecules that are claimed by recent patents to be active on this mutation are also reported. When possible, the review will focus on medicinal chemistry in terms of chemical structure, mechanism of action and structure-activity relationships.


The effects of seaward distance on above and below ground carbon stocks in estuarine mangrove ecosystems.
Mangrove forests have gained recognition for their potential role in climate change mitigation due to carbon sequestration in live trees, and carbon storage in the sediments trapped by mangrove tree roots and pneumatophores. Africa hosts about 19% of the world's mangroves, yet relatively few studies have examined the carbon stocks of African mangroves. The available studies report considerable differences among sites and amongst the different pools of carbon stocks. None considered the effects of seaward distance. We present details of AGC and SOC carbon stocks for Lindi in Tanzania, and focus on how these values differ with increasing seaward distance and, how our results compare to those reported elsewhere across Africa. AGC ranged between 11 and 55 Mg C ha-1, but was not significantly affected by seaward distance. SOC for 0-1 m depth ranged from 154 to 484, with a mean of 302 Mg C ha-1. SOC was significantly negatively correlated with seaward distance. Mangrove type (estuarine/oceanic), soil erosion, soil depth may explain these differences We note important methodological differences in previous studies on carbon stocks in mangroves in Africa. This study indicates that seaward distance has an important effect on SOC stocks in the Lindi region of Tanzania. SOC should be fully incorporated into national climate change mitigation policies. Studies should report seaward distance and to describe the type of mangrove stand to make results easily comparable across sites and to assess the true value of Blue Carbon in Africa. We recommend focusing on trees > 10 cm diameter for AGC, and sampling soils to at least 1 m depth for SOC, which would provide a more complete assessment of the potentially considerable mangrove carbon store.


Spatial ecotoxicology: migratory Arctic seabirds are exposed to mercury contamination while overwintering in the northwest Atlantic.
Arctic organisms are exposed to various levels of pollutants, among which mercury (Hg) has raised important environmental concerns. Previous studies examining Hg levels, trends, and effects on Arctic marine top predators have focused on the Arctic region. However, many of these top predators, such as seabirds, migrate to spend a large part of their life cycle far from the Arctic in areas where their exposure to contaminants is largely unknown. By combining biotelemetry and Hg and stable isotope analyses, we studied the seasonal Hg contamination of little auks (Alle alle, the most abundant Arctic seabird) in relation to their distribution and marine foraging habitat, as well as its potential impacts on bird reproduction. We show that little auks were ∼ 3.5 times more contaminated when outside the breeding season, and that Hg that accumulated during this nonbreeding non-Arctic period was related to egg size the following season, with females having more Hg laying smaller eggs. Our results highlight that ecotoxicological studies should be expanded to yield a comprehensive understanding of contamination risks and associated threats to top predators over their entire annual cycle. Furthermore, we show that an important nonbreeding area located in the northwest Atlantic was associated with greater Hg contamination and demonstrate the utility of bird-borne miniaturized technology for evaluating the contamination of marine systems on large spatial scales.


Ontogeny of apoptosis during lung development.
Apoptosis has been shown to be involved in several processes during embryogenesis, but the ontogeny of apoptosis during lung development ahs not been studied. The goals of the current study were to determine if apoptosis occurs during lung development, and to determine the ontogeny of the changes in apoptosis that occur. We studied the ontogeny of apoptosis in vivo using lungs from 14-18-d gestation fetal rats, newborn rats, and 1-d-, 2-d-, 5-d-, and 10-d-old rat pups. Apoptosis was assessed by electron microscopy and the terminal deoxyribonucleotidyl transferase dUTP nick end-labeling assay. We compared the in vivo results with explants of 14-d gestation fetal rat lung placed in culture for 1-4 d because the biochemical development of the lung in organ culture has been shown to closely parallel the development of the lung in vivo. We found apoptosis of mesenchymal cells at the periphery of distal lung buds in early fetal lung (14-16-d gestation). Apoptosis of both mesenchyme and epithelium was present in later fetal lung (18-d gestation). There were no qualitative differences in apoptosis between in vivo fetal lung and explant cultures of fetal lung. There was a 14-fold increase in apoptosis at birth and in the first postnatal day of life (9-12% of cells) compared with fetal lung (0.6-1% of cells). This was followed by a rapid decline in the percentage of apoptotic cells to fetal levels at postnatal d 2-10. We conclude that apoptosis occurs in a spatially, temporally, and cell-specific manner during lung development. The number of cells undergoing apoptosis increases dramatically in the first day after birth.


Exploring reversible quenching of fluorescence from a pyrazolo[3,4-b]quinoline derivative by protonation.
Pyrazolo[3,4-b]quinoline derivatives are reported to be highly efficient organic fluorescent materials suitable for applications in light-emitting devices. Although their fluorescence remains stable in organic solvents or in aqueous solution even in the presence of H(2)O, halide salts (LiCl), alkali (NaOH) and weak acid (acetic acid), it suffers an efficient quenching process in the presence of protic acid (HCl) in aqueous or ethanolic solution. This quenching process is accompanied by a change in the UV spectrum, but it is reversible and can be fully recovered. Both steady-state and transient fluorescence spectra of 1-phenyl-3,4-dimethyl-1H-pyrazolo-[3,4-b]quinoline (PAQ5) during quenching are measured and analyzed. It is found that a combined dynamic and static quenching mechanism is responsible for the quenching processes. The ground-state proton-transfer complex [PAQ5H(+)] is responsible for static quenching. It changes linearly with proton concentration [H(+)] with a bimolecular association constant K(S)=1.95 M(-1) controlled by the equilibrium dissociation of HCl in ethanol. A dynamic quenching constant K(D)=22.4 M(-1) is obtained by fitting to the Stern-Volmer equation, with a bimolecular dynamic quenching rate constant k(d)=1.03x10(9) s(-1) M(-1) under ambient conditions. A change in electron distribution is simulated and explains the experiment results.


Estimates of leaf vein density are scale dependent.
Leaf vein density (LVD) has garnered considerable attention of late, with numerous studies linking it to the physiology, ecology, and evolution of land plants. Despite this increased attention, little consideration has been given to the effects of measurement methods on estimation of LVD. Here, we focus on the relationship between measurement methods and estimates of LVD. We examine the dependence of LVD on magnification, field of view (FOV), and image resolution. We first show that estimates of LVD increase with increasing image magnification and resolution. We then demonstrate that estimates of LVD are higher with higher variance at small FOV, approaching asymptotic values as the FOV increases. We demonstrate that these effects arise due to three primary factors: (1) the tradeoff between FOV and magnification; (2) geometric effects of lattices at small scales; and; (3) the hierarchical nature of leaf vein networks. Our results help to explain differences in previously published studies and highlight the importance of using consistent magnification and scale, when possible, when comparing LVD and other quantitative measures of venation structure across leaves.


Characterization of endogenous and exogenous mouse mammary tumor virus proviral DNA with site-specific molecular clones.
Restriction fragments of the mouse mammary tumor virus (MMTV) proviral DNA were obtained by molecular cloning procedures. A 4-kilobase fragment delimited by two PstI sites was isolated from unintegrated, linear MMTV DNA and amplified in the pBr322 plasmid vector. EcoRI fragments of proviral DNA, integrated into the genome of a GR mammary tumor cell line, were isolated as lambda recombinant molecules. Five different recombinant phages which contained the 3' region of the MMTV proviral DNA and adjacent host DNA sequences were isolated. Heteroduplex analysis and S1 nuclease digestion suggested that there is no extensive sequence homology in the host DNA flanking the different proviral genes. The cloned DNA was fractionated into site-specific restriction fragments which served as molecular probes in the analysis of the endogenous MMTV proviral copies of C3H, GR, BALB/c, and feral mice. This allowed the correlation of MMTV-specific EcoRI fragments obtained from genomic DNA of these strains with the 5' and 3' ends of the proviral gene. Restriction fragments of two clones which contained the proviral sequences adjacent to the flanking host DNA as well as 1 to 2 kilobases of host DNA were used as hybridization probes, and the results allow the following conclusions: the proviral DNA of both clones contains nucleotide sequences complementary to the 5' and 3' ends of proviral DNA; and the host DNA flanking one clone belongs to the unique class of genomic DNA, whereas the DNA flanking the second clone is reiterated at least 15 times within the mouse genome.


Immunosuppressants.
Immunosuppressants are prescribed to prevent rejection of transplanted tissues and organs and are also used in the treatment of autoimmune disorders. Consultation-liaison psychiatrists increasingly encounter patients taking these agents as the number of transplant recipients increases and the indications for the use of immunosuppressants expands. These drugs have potentially deleterious physical, mental, and biochemical side effects. In addition, transplant recipients and patients with autoimmune disorders commonly have comorbid illnesses that require pharmacologic treatment. The management of these patients is challenging secondary to the severity of these illnesses, the number of medications prescribed, and the potential for adverse drug-drug interactions. Knowledge of the pharmacokinetic properties of these drugs and the potential for serious drug-drug interactions that cause alterations in serum levels of the immunosuppressant medications is essential. Increased serum levels may cause serious toxic effects and decreased serum levels may lead to rejection of the transplanted organ or worsening of the autoimmune disorder. Adverse events may also occur when serum levels of medications prescribed for comorbid illnesses are altered by administration of immunosuppressants. The pharmacokinetic drug-drug interaction profiles of the glucocorticoids, cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, azathioprine, and monoclonal antibodies are discussed in this review.


Hyper-CVAD and high-dose methotrexate/cytarabine followed by stem-cell transplantation: an active regimen for aggressive mantle-cell lymphoma.
Diffuse and nodular forms of mantle-cell lymphoma (MCL) are consistently associated with poor prognosis. In an effort to improve the outcome, we adopted a treatment plan that consisted of four courses of fractionated cyclophosphamide (CY) 1,800 mg/m2 administered with doxorubicin (DOX), vincristine (VCR), and dexamethasone (Hyper-CVAD) that alternated with high-dose methotrexate (MTX) and cytarabine (Ara-C). After four courses, patients were consolidated with high-dose CY, total-body irradiation, and autologous or allogeneic blood or marrow stem-cell transplantation. Forty-five patients were enrolled; 25 patients were previously untreated, 43 patients had Ann Arbor stage IV disease, and 42 patients had marrow involvement. Forty-one patients had diffuse histology, two patients had nodular, and two patients had blastic variants. Hyper-CVAD/MTX-Ara-C induced a response rate of 93.5% (complete response [CR], 38%; partial response [PR], 55.5%) after four cycles of pretransplantation induction chemotherapy. All patients who went on to undergo transplantation achieved CRs. For the 25 previously untreated patients, the overall survival (OS) and event-free survival (EFS) rates at 3 years were 92% (95% confidence interval [CI], 80 to 100) and 72% (95% CI, 45 to 98) compared with 25% (95% CI, 12 to 62; P = .005) and 17% (95% CI, 10 to 43; P = .007), respectively, for the previously treated patients. When compared with a historic control group who received a CY, DOX, VCR, and prednisone (CHOP)-like regimen, untreated patients in the study had a 3-year EFS rate of 72% versus 28% (P = .0001) and a better OS rate (92% v 56%; P = .05). Treatment-related death occurred in five patients: all were previously treated and two received allogeneic transplants. The Hyper-CVAD/MTX-Ara-C program followed by stem-cell transplantation is a promising new therapy for previously untreated patients with MCL.


Activation of natural killer cells by newcastle disease virus hemagglutinin-neuraminidase.
The avian paramyxovirus Newcastle disease virus (NDV) selectively replicates in tumor cells and is known to stimulate T-cell-, macrophage-, and NK cell-mediated responses. The mechanisms of NK cell activation by NDV are poorly understood so far. We studied the expression of ligand structures for activating NK cell receptors on NDV-infected tumor cells. Upon infection with the nonlytic NDV strain Ulster and the lytic strain MTH-68/H, human carcinoma and melanoma cells showed enhanced expression of ligands for the natural cytotoxicity receptors NKp44 and NKp46, but not NKp30. Ligands for the activating receptor NKG2D were partially downregulated. Soluble NKp44-Fc and NKp46-Fc, but not NKp30-Fc, chimeric proteins bound specifically to NDV-infected tumor cells and to NDV particle-coated plates. Hemagglutinin-neuraminidase (HN) of the virus serves as a ligand structure for NKp44 and NKp46, as indicated by the blockade of binding to NDV-infected cells and viral particles in the presence of anti-HN antibodies and by binding to cells transfected with HN cDNA. Consistent with the recognition of sialic acid moieties by the viral lectin HN, the binding of NKp44-Fc and NKp46-Fc was lost after desialylation. NKp44- and NKp46-CD3zeta lacZ-inducible reporter cells were activated by NDV-infected cells. NDV-infected tumor cells stimulated NK cells to produce increased amounts of the effector lymphokines gamma interferon and tumor necrosis factor alpha. Primary NK cells and the NK line NK-92 lysed NDV-infected tumor cells with enhanced efficiency, an effect that was eliminated by the treatment of target cells with the neuraminidase inhibitor Neu5Ac2en. These results suggest that direct activation of NK cells contributes to the antitumor effects of NDV.


Multilineage cells from human adipose tissue: implications for cell-based therapies.
Future cell-based therapies such as tissue engineering will benefit from a source of autologous pluripotent stem cells. For mesodermal tissue engineering, one such source of cells is the bone marrow stroma. The bone marrow compartment contains several cell populations, including mesenchymal stem cells (MSCs) that are capable of differentiating into adipogenic, osteogenic, chondrogenic, and myogenic cells. However, autologous bone marrow procurement has potential limitations. An alternate source of autologous adult stem cells that is obtainable in large quantities, under local anesthesia, with minimal discomfort would be advantageous. In this study, we determined if a population of stem cells could be isolated from human adipose tissue. Human adipose tissue, obtained by suction-assisted lipectomy (i.e., liposuction), was processed to obtain a fibroblast-like population of cells or a processed lipoaspirate (PLA). These PLA cells can be maintained in vitro for extended periods with stable population doubling and low levels of senescence. Immunofluorescence and flow cytometry show that the majority of PLA cells are of mesodermal or mesenchymal origin with low levels of contaminating pericytes, endothelial cells, and smooth muscle cells. Finally, PLA cells differentiate in vitro into adipogenic, chondrogenic, myogenic, and osteogenic cells in the presence of lineage-specific induction factors. In conclusion, the data support the hypothesis that a human lipoaspirate contains multipotent cells and may represent an alternative stem cell source to bone marrow-derived MSCs.


Is survival improved by the use of NIV and PEG in amyotrophic lateral sclerosis (ALS)? A post-mortem study of 80 ALS patients.
Non-invasive ventilation (NIV) and percutaneous gastrostomy (PEG) are guideline-recommended interventions for symptom management in amyotrophic lateral sclerosis (ALS). Their effect on survival is controversial and the impact on causes of death is unknown. To investigate the effect of NIV and PEG on survival and causes of death in ALS patients. Eighty deceased ALS patients underwent a complete post mortem analysis for causes of death between 2003 and 2015. Forty-two of these patients consented for genetic testing. Effects of NIV and PEG on survival and causes of death were analyzed in a multivariable Cox proportional hazard regression. Six patients, who requested assisted suicide causing drug-induced hypoxia, were excluded from final analysis. Respiratory failure was the main cause of death in 72 out of 74 patients. Fifteen out of 74 died of aspiration pneumonia 23/74 of bronchopneumonia and 8/74 of a combination of aspiration pneumonia and bronchopneumonia. Twenty died of hypoxia without concomitant infection, and six patients had pulmonary embolism alone or in combination with pneumonia. NIV (p = 0.01) and PEG (p<0.01) had a significant impact on survival. In patients using NIV bronchopneumonia was significantly more frequent (p <0.04) compared to non-NIV patients. This effect was even more pronounced in limb onset patients (p<0.002). Patients with C9orf72 hexanucleotide repeat expansions showed faster disease progression and shorter survival (p = 0.01). The use of NIV and PEG prolongs survival in ALS. This study supports current AAN and EFNS guidelines which recommend NIV and PEG as a treatment option in ALS. The risk of bronchopneumonia as cause of death may be increased by NIV.


[Fetuin A and matrix GLA protein in long standing type I diabetic patients without ischaemic heart disease].
Fetuin A and matrix GLA protein--MGP are known as extraosseus calcification inhibitors. The aim of the study was to assess the dependence between metabolic status and fetuin A and matrix GLA protein levels in type 1 diabetic patients without ischaemic heart disease. The study was performed in a group consisting of 35 patients with type 1 diabetes mellitus (22 women and 13 men). Mean age of the studied group equaled 38.8 +/- 11.24 years, duration of diabetes mellitus 20.77 +/- 10.11 years. Fetuin A significantly correlated with HDL-cholesterol (r = 0.45; p = 0.007). Total cholesterol, LDL-chol and triglicerides correlated with HbA1c (r = 0.40, p = 0.03; r = 0.41, p = 0.03 and r = 0.37, p = 0.05), HDL-chol significantly correlated with glucose level at the examination day (r = 0.52, p = 0.04). There were also positive correlations of trigliceride with uric acid (r = 0.47, p = 0.09) and cystatin C (r = 0.44, p = 0.02). There were no correlation of MGP with other examined parameters. Initial results of fetuin A and MGP levels in long-term type 1 diabetic patients without ischaemic heart disease draws attention to new parameters in macroangiopathy development.


CD100/Sema4D Increases Macrophage Infection by Leishmania (Leishmania) amazonensis in a CD72 Dependent Manner.
Leishmaniasis is caused by trypanosomatid protozoa of the genus Leishmania, which infect preferentially macrophages. The disease affects 12 million people worldwide, who may present cutaneous, mucocutaneous or visceral forms. Several factors influence the form and severity of the disease, and the main ones are the Leishmania species and the host immune response. CD100 is a membrane bound protein that can also be shed. It was first identified in T lymphocytes and latter shown to be induced in macrophages by inflammatory stimuli. The soluble CD100 (sCD100) reduces migration and expression of inflammatory cytokines in human monocytes and dendritic cells, as well as the intake of oxidized low-density lipoprotein (oxLDL) by human macrophages. Considering the importance of macrophages in Leishmania infection and the potential role of sCD100 in the modulation of macrophage phagocytosis and activation, we analyzed the expression and distribution of CD100 in murine macrophages and the effects of sCD100 on macrophage infection by Leishmania (Leishmania) amazonensis. Here we show that CD100 expression in murine macrophages increases after infection with Leishmania. sCD100 augments infection and phagocytosis of Leishmania (L.) amazonensis promastigotes by macrophages, an effect dependent on macrophage CD72 receptor. Besides, sCD100 enhances phagocytosis of zymosan particles and infection by Trypanosoma cruzi.


Zinc porphyrins: potent inhibitors of hematopoieses in animal and human bone marrow.
The effects of selected heme analogues on heme oxygenase activity in tissues and on human and rabbit bone marrow hematopoietic colony growth were examined. Zinc protoporphyrin (ZnPP) and zinc mesoporphyrin (ZnMP), at concentrations ranging between 1 and 20 microM, produced significant inhibition of human and rabbit bone marrow erythroid (CFU-E, BFU-E) and myeloid (CFU-GM) colony growth. The growth inhibition produced by ZnPP or ZnMP was not overcome with exposure of cultures to elevated levels of the growth factors erythropoietin and granulocyte-macrophage colony stimulating factor. In contrast, tin protoporphyrin and tin mesoporphyrin did not display any significant bone marrow toxicity when used at similar concentrations. In other studies, differential effects of tin mesoporphyrin and ZnMP administered intravenously on kidney heme oxygenase were demonstrated. Chromium mesoporphyrin administered intravenously proved lethal to animals. These results indicate that exposure of bone marrow to ZnPP and ZnMP can be deleterious to hematopoietic cells and raise the possibility that ZnPP, which is endogenously formed and found in high concentration in red blood cells in lead-poisoned children, may itself participate in the bone marrow toxicity produced by this metal.


Abscisic acid, cold and salt stimulate conserved metabolic regulation in the moss Physcomitrella patens.
Salt and cold are major abiotic stresses that have adverse effects on plant growth and development. To cope with these stresses and their detrimental effects plants have evolved several metabolic, biochemical and physiological processes that are mainly triggered and mediated by the plant hormone abscisic acid (ABA). To elucidate the metabolic responses of the moss Physcomitrella patens, which serves as a model plant for abiotic stress adaptation, we performed GC-MS-based metabolic profiling of plants challenged for 5 and 28 h with either salt, cold or ABA. Our results indicate significant changes in the accumulation of several sugars including maltose, isomaltose and trehalose, amino acids including arginine, histidine, ornithine, tryptophan and tyrosine, and organic acids mainly citric acid and malonic acid. The metabolic responses provoked by ABA, cold and salt show considerable similarities. The accumulation of certain metabolites positively correlates with gene expression data whereas some metabolites do not show correlation with cognate transcript abundance. To place our results into an evolutionary context we compared the ABA- and stress-induced metabolic changes in moss to available metabolic profiles of the seed plant Arabidopsis thaliana. We detected considerable conservation between the species, indicating early evolution of stress-associated metabolic adaptations that probably occurred at the plant water-to-land transition.


Developmental Iron Deficiency Dysregulates TET Activity and DNA Hydroxymethylation in the Rat Hippocampus and Cerebellum.
Iron deficiency (ID) during neurodevelopment is associated with lasting cognitive and socioemotional deficits and increased risk for neuropsychiatric disease throughout the lifespan. These neurophenotypical changes are underlain by gene dysregulation in the brain that outlasts the period of ID; however, the mechanisms by which ID establishes and maintains gene expression changes are incompletely understood. The epigenetic modification of 5-hydroxymethylcytosine (5hmC), or DNA hydroxymethylation, is one candidate mechanism because of its dependence on iron-containing TET enzymes. The aim of the present study was to determine the effect of fetal-neonatal ID on regional brain TET activity, Tet expression, and 5hmC in the developing rat hippocampus and cerebellum and to determine whether changes are reversible with dietary iron treatment. Timed pregnant Sprague Dawley rats were fed iron-deficient diet (ID; 4 mg/kg Fe) from gestational day 2 to generate iron-deficient anemic (IDA) offspring. Control dams were fed iron-sufficient diet (IS; 200 mg/kg Fe). At postnatal day (P)7, a subset of ID-fed litters was randomized to IS diet, generating treated IDA (TIDA) offspring. At P15, the hippocampus and cerebellum were isolated for subsequent analysis. TET activity was quantified by ELISA from nuclear proteins. Expression of Tet1, Tet2, and Tet3 was quantified by qPCR from total RNA. Global %5hmC was quantified by ELISA from genomic DNA. ID increased DNA hydroxymethylation (p = 0.0105), with a corresponding increase in TET activity (p < 0.0001) and Tet3 expression (p < 0.0001) in the P15 hippocampus. In contrast, ID reduced TET activity (p = 0.0016) in the P15 cerebellum, with minimal effect on DNA hydroxymethylation. Neonatal dietary iron treatment resulted in partial normalization of these changes in both brain regions. These results demonstrate that the TET/DNA hydroxymethylation system is disrupted by developmental ID in a brain region-specific manner. Differential regional disruption of this epigenetic system may contribute to the lasting neural circuit dysfunction and neurobehavioral dysfunction associated with developmental ID.


[OCULO-ORBITAL TUMOURS AT THE NATIONAL UNIVERSITY HOSPITAL CENTRE OF BANGUI (CNHUB), CENTRAL AFRICAN REPUBLIC, IN 2022].
Oculo-orbital tumors are common. Their clinical and histological features are multiple. The management of oculo-orbital tumors is a real challenge in sub-Saharan Africa, especially in our context. The aim of this study was to contribute to the improvement of the management of oculo-orbital tumors at the Bangui Teaching Hospital (CNHUB). This was a prospective, observational study of oculo-orbital tumors over 12 months from January 1 to December 31, 2022 in the ophthalmology department of the CNHUB. All consenting patients with histologically proven tumors of the eyeball and/or its adnexa were included in this study, regardless of age and sex.The parameters studied were:epidemiological: age, sex, occupation, origin;clinical: time of consultation, functional signs and associated signs, physical examination signs, risk factors;paraclinical: report of the anatomopathological examination of the operating room;therapeutic: treatment modalities (chemotherapy, surgery, palliative treatment, radiotherapy).These data were collected on a pre-established survey form for direct administration. The processing and the production of the results were carried out with Excel and Epi Info 7.0 software. We included 97 patients with a mean age of 37.5 years, ranging from 2 to 70 years. There was a male predominance (sex-ratio = 1.8). Almost all patients lived in Bangui (96%). Patients under 40 years of age were most commonly affected (55%). The majority of tumors were benign (55%). Ocular pain (24%), lacrimation (22%) and orbital swelling (16%) were the main symptoms. Risk factors were mainly age (23%), diabetes (22%), HIV infection (16%) and alcohol and tobacco use (37%). The most common treatments were surgical removal (68%) and enucleation (16%). Chemotherapy was combined with surgery in 37% of cases. Oculo-orbital tumors are frequent in our context. Their morpho-histological presentations are varied. A multidisciplinary approach is important for a good management.


Antimicrobial susceptibility testing and phenotyping of Neisseria gonorrhoeae isolated from patients with ophthalmia neonatorum in Nairobi, Kenya.
Antimicrobial susceptibility testing, auxotyping-serotyping, and plasmid analysis were performed on 41 ocular isolates, 7 nasopharyngeal isolates, and 18 cervical isolates of Neisseria gonorrhoeae obtained during a recent treatment trial of gonococcal ophthalmia neonatorum in Nairobi, Kenya. Fourteen distinct serovar-auxotype patterns were observed with IB-1/Pro-strains which accounted for 59% of the isolates. Infection with multiple types of gonococci appeared to occur in 22% of the mothers since 4 of 18 paired maternal cervical and neonatal ocular isolates had mismatched serovar-auxotype patterns. Among 10 treatment failure isolates only 1 had a mismatched serovar-auxotype pattern. Six (15%) of the ocular isolates were penicillinase-producing N. gonorrhoeae (PPNG). Five had the 4.4-megadalton (Md) beta-lactamase plasmid and one had the 3.2-Md beta-lactamase plasmid. The 24.5-Md plasmid was found in 5 of 6 PPNG strains and in 8 of 35 non-PPNG strains (P less than 0.02). For most antimicrobial agents, PPNG and non-PPNG strains showed similar patterns of susceptibility. Ceftriaxone was the most active of the antibiotics tested, with all strains having an MIC less than or equal to 0.06 mg/liter. Among non-PPNG strains, 15 (43%) had a penicillin MIC greater than or equal to 2 mg/liter and were considered intrinsically resistant to penicillin. Overall, non-PPNG intrinsically resistant strains had greater resistance to other antibiotics than did non-intrinsically resistant strains (P less than or equal to 0.006). The Mtr phenotype was found in 53% of these strains.


[Characterization of amino acid composition of lectin from noduleless soybean].
The amino acid composition of lectin from noduleless soybean has been investigated. It is shown that contents of threonine, serine and proline are higher but contents of tyrosine, phenylalanine and histidine are lower as compared with those in lectin from common soybean. The conclusion is made about the significance of amino acid composition of soybean lectin for its symbiotic properties.


Impact of recombinant activated factor VII on health-related quality of life after intracerebral hemorrhage.
We recently demonstrated that recombinant activated factor VII (rFVIIa) given to patients presenting within 3 h of acute spontaneous intracerebral hemorrhage (ICH) reduces mortality (18% vs. 29%) and poor outcome (modified Rankin Scale, mRS, 4-6, 53 vs. 69%). This analysis was performed to determine the impact of rFVIIa on health-related quality of life (HRQoL) in those patients. In a prospective, randomized controlled trial, 399 patients (mean age, 66 years) received placebo, 40, 80 or 160 microg/kg of rFVIIa within 4 h of acute ICH. At 90 days, HRQoL was assessed with the EuroQoL (EQ-5D), a 5-dimensional measure of health which also includes the Visual Analogue Scale. Additionally, each level of the 90-day mRS was adjusted, using 4 different previously published utility values, to obtain a clearer picture of perceived HRQoL. Among the 5 dimensions of EQ-5D, only mobility rating was significantly better for rFVIIa-treated patients (serious problems, 34 vs. 54%; p = 0.01). Yet, the utility value (scaled 1.0 = perfect health and 0.0 = dead) associated with the composite EQ-5D demonstrated significantly better HRQoL (0.48 vs. 0.36; p = 0.01). This was also true for the EQ-5D Visual Analogue Scale score (44 vs. 36; p = 0.04). Finally, all 4 algorithms for applying utility scores to the mRS indicated that rFVIIa was associated with significantly better perceived HRQoL (all p < 0.006). Treatment with rFVIIa within 4 h of acute spontaneous ICH improves HRQoL.


The Role of Accurate Self-Assessments in Optimizing Mate Choice.
Individuals are thought to seek the best possible romantic partner in exchange for their own desirability. We investigated whether individuals' self-evaluations were related to their partner choices and whether the accuracy of these self-evaluations was associated with mating outcomes. Participants (N = 1,354) took part in a speed-dating study where they rated themselves and others on mate value and indicated their willingness to date each potential partner. Individuals were somewhat accurate in their self-evaluations, and these self-evaluations were associated with individuals' revealed minimum and maximum standards for a potential partner, but not the number of partners they were interested in. Participants who overestimated their mate value were accepted by an equivalent number of partners compared with under-estimators, but the over-estimators were choosier and thus ended up with fewer (but similarly attractive) reciprocal matches. Results support social exchange theory and the matching hypothesis, and contrast findings that self-enhancement facilitates positive social outcomes.


Sarcoplasmic reticulum Ca release in intact ventricular myocytes.
Sarcoplasmic reticulum (SR) Ca release in intact ventricular myocytes is the major source of Ca which activates cardiac contraction (although Ca influx makes a non-negligible contribution in most species). The fundamental events of SR Ca release are known as Ca sparks. The twitch Ca transient is composed of approximately 10,000 Ca sparks occurring in a given cell, and they are synchronized by the action potential and Ca current. Many factors influence SR Ca release amplitude and kinetics, and the focus here is on understanding how these factors work in the intact cellular environment. The intracellular [Ca] ([Ca]i) and intra-SR [Ca] ([Ca]SR) are two of the most important dynamic modulators of SR Ca release. Indeed, while [Ca]i (and Ca current which initiates systolic SR Ca release) is widely acknowledged to be important, it is increasingly clear that [Ca]SR changes dynamically under physiological conditions and that this has very important regulatory effects on the SR Ca release process. While elevation of [Ca]SR obviously increases the driving force and amount of SR Ca available for release, it also increases the fractional release and can be responsible for spontaneous diastolic SR Ca release. These issues are discussed in both normal physiological and pathophysiological contexts.


Rational Design of Hyperbranched Nanowire Systems for Tunable Superomniphobic Surfaces Enabled by Atomic Layer Deposition.
Superomniphobic surfaces display contact angles of θ* > 150° and low contact angle hysteresis with virtually all high and low surface tension liquids. The introduction of hierarchical scales of texture can increase the contact angles and decrease the contact angle hysteresis of superomniphobic surfaces by reducing the solid-liquid contact area. Thus far, it has not been possible to fabricate superomniphobic surfaces with three or more hierarchical scales of texture where the size, spacing, and angular orientation of features within each scale of texture can be independently varied and controlled. Here, we report a method for tunable control of geometry in hyperbranched ZnO nanowire (NW) structures, which in turn enables the rational design and fabrication of superomniphobic surfaces. Branched NWs with tunable density and orientation were grown via a sequential hydrothermal process, in which atomic layer deposition was used for NW seeding, disruption of epitaxy, and selective blocking of NW nucleation. This approach allows for the rational design and optimization of three-level hierarchical structures, in which the geometric parameters of each level of hierarchy can be individually controlled. We demonstrate the coupled relationships between geometry and contact angles for a variety of liquids, which is supported by mathematical models. The highest performing superomniphobic surface was designed with three levels of hierarchy and achieved the following advancing/receding contact angles with water 172°/170°, hexadecane 166°/156°, octane 162°/145°, and heptane 160°/130°.


Joint effects of gas bubbles and solid particles on sonochemical inhibition in sonicated aqueous solutions.
Wastewater is a multicomponent and multiphase mixture. Gas bubbles and solid particles in the dispersed phase influence sonochemical efficiency during ultrasonic treatment of wastewater, sometimes unfavorably; however, the influencing factors and mechanisms remain unclear. In this paper, the influence of argon gas bubbles (1.2 mm) and monodisperse silica particles (0.1 mm) on sonochemical effects in an aqueous system using a horn-type reactor (20 kHz) is reported. Triiodide formation decreased with an increase in the volume fraction of either or both phases. The two phases started inhibiting sonoreactions as the total volume fraction approached 3.0-4.0 vol% compared to pure water. The effect of the gas-to-solid ratio is also considered. We propose an acoustic attenuation model, which incorporates the scattering effect of solid particles and the thermal effect of gas bubbles. The agreement between the modeling and experimental results demonstrates that the two phases are jointly responsible for sonochemical inhibition by increasing ultrasound attenuation. This enhances the understanding of sonochemistry in gas-solid-liquid systems and helps regulate gases and solids in sonochemical reactors.


Large-scale mirror-symmetry organization of human occipito-temporal object areas.
We have combined functional maps of retinotopy (eccentricity and meridian mapping), object category, and motion in a group of subjects to explore the large-scale topography of higher-order object areas. Our results reveal seven consistent category-related entities situated in the occipito-temporal cortex adjoining early visual areas. These include two face-related regions, three object-related regions, and two building-related regions. Interestingly, this complex category-related pattern is organized in a large-scale dorso-ventral mirror symmetry of object category. Furthermore, correlating this pattern to the map of visual field eccentricity, we found that the entire network of areas could be related to a single and unified eccentricity map. We hypothesize that this large-scale organization points to a possible development of high-order object areas through extension and specialization of a single proto-representation.


TRPV4 channels contribute to renal myogenic autoregulation in neonatal pigs.
Myogenic response, a phenomenon in which resistance size arteries and arterioles swiftly constrict or dilate in response to an acute elevation or reduction, respectively, in intravascular pressure is a key component of renal autoregulation mechanisms. Although it is well established that the renal system is functionally immature in neonates, mechanisms that regulate neonatal renal blood flow (RBF) remain poorly understood. In this study, we investigated the hypothesis that members of the transient receptor potential vanilloid (TRPV) channels are molecular components of renal myogenic constriction in newborns. We show that unlike TRPV1-3, TRPV4 channels are predominantly expressed in neonatal pig preglomerular vascular smooth muscle cells (SMCs). Intracellular Ca2+ concentration ([Ca2+]i) elevation induced by osmotic cell swelling was attenuated by TRPV4, L-type Ca2+, and stretch-activated Ca2+ channel blockers but not phospholipase A2 inhibitor. Blockade of TRPV4 channels reversed steady-state myogenic tone and inhibited pressure-induced membrane depolarization, [Ca2+]i elevation, and constriction in distal interlobular arteries. A step increase in arterial pressure induced efficient autoregulation of renal cortical perfusion and total RBF in anesthetized and mechanically ventilated neonatal pigs. Moreover, intrarenal arterial infusion of the TRPV4 channel blockers HC 067047 and RN 1734 attenuated renal autoregulation in the pigs. These data suggest that renal myogenic autoregulation is functional in neonates. Our findings also indicate that TRPV4 channels are mechanosensors in neonatal pig preglomerular vascular SMCs and contribute to renal myogenic autoregulation.


Progressive striatal and hippocampal volume loss in initially antipsychotic-naive, first-episode schizophrenia patients treated with quetiapine: relationship to dose and symptoms.
First-generation antipsychotics have been associated with striatal volume increases. The effects of second-generation antipsychotics (SGAs) on the striatum are unclear. Moreover, SGAs may have neuroprotective effects on the hippocampus. Dose-dependent volumetric effects of individual SGAs have scarcely been investigated. Here we investigated structural brain changes in antipsychotic-naive, first-episode schizophrenia patients after 6 months treatment with the SGA, quetiapine. We have recently reported on baseline volume reductions in the caudate nucleus and hippocampus. Baseline and follow-up T1-weighted images (3 T) from 22 patients and 28 matched healthy controls were analysed using tensor-based morphometry. Non-parametric voxel-wise group comparisons were performed. Small volume correction was employed for striatum, hippocampus and ventricles. Dose-dependent medication effects and associations with psychopathology were assessed. Patients had significant bilateral striatal and hippocampal loss over the 6-month treatment period. When compared to controls the striatal volume loss was most pronounced with low quetiapine doses and less apparent with high doses. Post-hoc analyses revealed that the striatal volume loss was most pronounced in the caudate and putamen, but not in accumbens. Conversely, hippocampal volume loss appeared more pronounced with high quetiapine doses than with low doses. Clinically, higher baseline positive symptoms were associated with more striatal and hippocampal loss over time. Although patients' ventricles did not change significantly, ventricular increases correlated with less improvement of negative symptoms. Progressive regional volume loss in quetiapine-treated, first-episode schizophrenia patients may be dose-dependent and clinically relevant. The mechanisms underlying progressive brain changes, specific antipsychotic compounds and clinical symptoms warrant further research.


Lagged kernel machine regression for identifying time windows of susceptibility to exposures of complex mixtures.
The impact of neurotoxic chemical mixtures on children's health is a critical public health concern. It is well known that during early life, toxic exposures may impact cognitive function during critical time intervals of increased vulnerability, known as windows of susceptibility. Knowledge on time windows of susceptibility can help inform treatment and prevention strategies, as chemical mixtures may affect a developmental process that is operating at a specific life phase. There are several statistical challenges in estimating the health effects of time-varying exposures to multi-pollutant mixtures, such as: multi-collinearity among the exposures both within time points and across time points, and complex exposure-response relationships. To address these concerns, we develop a flexible statistical method, called lagged kernel machine regression (LKMR). LKMR identifies critical exposure windows of chemical mixtures, and accounts for complex non-linear and non-additive effects of the mixture at any given exposure window. Specifically, LKMR estimates how the effects of a mixture of exposures change with the exposure time window using a Bayesian formulation of a grouped, fused lasso penalty within a kernel machine regression (KMR) framework. A simulation study demonstrates the performance of LKMR under realistic exposure-response scenarios, and demonstrates large gains over approaches that consider each time window separately, particularly when serial correlation among the time-varying exposures is high. Furthermore, LKMR demonstrates gains over another approach that inputs all time-specific chemical concentrations together into a single KMR. We apply LKMR to estimate associations between neurodevelopment and metal mixtures in Early Life Exposures in Mexico and Neurotoxicology, a prospective cohort study of child health in Mexico City.


Cyclic nucleotides of cone-dominant retinas. Reduction of cyclic AMP levels by light and by cone degeneration.
Dark-adapted retinas or whole eyes of 13-line ground squirrels (Citellus tridecemlineatus) and western fence lizards (Sceloporus occidentalis) contain higher levels of cyclic AMP than of cyclic GMP. In these cone-dominant retinas, light reduces cyclic AMP content selectively. Freezing of dark- or light-adapted retinas or eyes also reduces cyclic AMP content, with only minimal changes in cyclic GMP levels. In addition, exposure of frozen retinas of dark-adapted ground squirrel to light results in a significant decrease in cyclic AMP content. The destruction of cone visual cells of ground squirrel retina by iodoacetic acid injection decreases the cyclic nucleotide content of the dark-adapted retina. Considering the relative loss of cyclic nucleotides from cone degeneration, we estimate that the content of cyclic AMP in visual cells of ground squirrel retina is about four times greater than that of cyclic GMP.


Preparation and reactions of myoglobin mutants bearing both proximal cysteine ligand and hydrophobic distal cavity: protein models for the active site of P-450.
We have reported that H93C human myoglobin (Mb), in which proximal histidine (His93, F8) was replaced by cysteine, gave nearly identical spectroscopic features of P-450 [Adachi, S., Nagano, S., Ishimori, K., Watanabe, Y., Morishima, I., Egawa, T., Kitagawa, T., & Makino R. (1993) Biochemistry 32, 241-252]. More importantly, the thiolate ligand enhanced its oxygenation activities when supported by H2O2 due to the exclusive encouragement of heterolytic O-O bond cleavage of peroxides. While we have attributed the enhanced heterolysis to the electron donation from the thiolate ligand, possible participation of the distal histidine (H64, E7) in H93C Mb cannot be eliminated. In addition, the racemic product formation catalyzed by H93C Mb implied that its distal cavity could prevent substrates from accessing to the heme and the reactions may proceed other than by the P-450 type mechanism (ferryl oxygen transfer). In order to clarify whether the distal histidine is involved in the O-O bond cleavage step and to improve accessibility of substrates, the distal histidine of H93C Mb is replaced by smaller and nonpolar residues, glycine (H64G/H93C Mb) and valine (H64V/H93C Mb), by site-directed mutagenesis. Various spectroscopic studies on these double-mutated Mbs revealed the ligation of cysteine to the ferric heme as a thiolate form. In the reaction with cumene hydroperoxide, the anionic nature of the proximal cysteine in H64G/H93C and H64V/H93C Mbs was found to encourage the heterolytic O-O bond cleavage as observed for H93C Mb. The results clearly demonstrate that the distal histidine of H93C Mb is hardly involved in the O-O bond cleavage step and are in good agreement with the role of thiolate ligation for the formation of the reactive intermediate, equivalent to compound I, in the catalytic cycle of P-450 reactions. In the oxygenation of methyl p-tolyl sulfide, the ratios of ferryl oxygen transfer increased in H64G/H93C Mb (58%) and H64V/H93C Mb (78%) as compared to H93C Mb (53%). The increased ratios of ferryl oxygen transfer imply the active site of H64G/H93C and H64V/H93C Mbs being more accessible for substrates; however, the sulfoxidation by the ferric mutant Mbs/H2O2 system was much slower than that by H93C Mb. The poor activities of these mutant Mbs are attributed to the significantly discouraged binding of H2O2.


Isolation of T cells from the gut.
The lymphocytes of epithelial and lamina proprial compartments of the intestine are phenotypically and functionally distinct and serve a wide range of functions in the intestinal mucosa like regulating intestinal homeostasis, maintaining epithelial barrier function as well as regulating adaptive and innate immune responses. To analyze the role of these cells in different disease states, it is necessary to isolate pure cell populations of the intraepithelial lymphocytes (IEL) and lamina propria lymphocytes (LPL) of the gut. In this protocol we describe a method to isolate T cells from IEL and LPL, which can be used for further investigations like comparative studies of mRNA expression, cell proliferation assay, or protein analysis.


An aza-anthrapyrazole negatively regulates Th1 activity and suppresses experimental autoimmune encephalomyelitis.
Previously we showed that BBR3378, a novel analog of the anticancer drug mitoxantrone, had the ability to ameliorate ascending paralysis in MOG35-55-induced experimental autoimmune encephalomyelitis (EAE), a murine model of human multiple sclerosis, without the drug-induced cardiotoxicity or lymphopenia associated with mitoxantrone therapy. Chemotherapeutic drugs like mitoxantrone, a topoisomerase inhibitor, are thought to provide protection in inflammatory autoimmune diseases like EAE by inducing apoptosis in rapidly proliferating autoreactive lymphocytes. Here, we show that while BR3378 blocked cell division, T cells were still able to respond to antigenic stimulation and upregulate surface molecules indicative of activation. However, in contrast to mitoxantrone, BBR3378 inhibited the production of the proinflammatory cytokine IFN-γ both in recently activated T cell blasts and established Th1 effectors, while sparing the activities of IL-13-producing Th2 cells. IFN-γ is known to be regulated by the transcription factor T-bet. In addition to IFN-γ, in vitro and in vivo exposure to BBR3378 suppressed the expression of other T-bet regulated proteins, including CXCR3 and IL-2Rβ. Microarray analysis revealed BBR3378-induced suppression of additional T-bet regulated genes, suggesting that the drug might disrupt global Th1 programming. Importantly, BBR3378 antagonized ongoing Th1 autoimmune responses in vivo, modulated clinical disease and CNS inflammation in acute and relapsing forms of EAE. Therefore, BBR3378 may be a unique inhibitor of T-bet regulated genes and may have potential as a therapeutic intervention in human autoimmune disease.


Virulence reaction norms across a food gradient.
Host-parasite interactions involve competition for nutritional resources between hosts and the parasites growing within them. Consuming part of a host's resources is one cause of a parasite's virulence, i.e. part of the fitness cost imposed on the host by the parasite. The influence of a host's nutritional conditions on the virulence of a parasite was experimentally tested using the mosquito Aedes aegypti and the microsporidian parasite Vavraia culicis. A condition-dependent expression of virulence was found and a positive relation between virulence and transmissibility was established. Spore production was positively influenced by host food availability, indicating that the parasite's within-host growth is limited by host condition. We also investigated how the fitness of each partner varied across the nutritional gradient and demonstrated that the sign of the correlation between host fitness and parasite fitness depended on the amount of nutritional resources available to the host.


Effect of COVID-19 on the Activity Level of Elderly people with Dementia.
Measures against physical and social frailty after the COVID-19 epidemic in elderly people with dementia are required. However, there are no studies that have systematically examined the level of activity maintained by elderly people with dementia. In this study, we developed an ICT-based steps monitoring system and investigated changes in the number of steps taken by 13 community-dwelling elderly people with dementia from before the COVID-19 epidemic to during the epidemic. Six of the thirteen subjects maintained approximately 7,000 steps, which was the same level as that before the epidemic. However, some subjects showed a significant decrease in their frequency of going out. This system indicated the construction of a health promotion strategy based on quantitative daily step count data for community-dwelling elderly people with dementia.


Smoking habits among italian adolescents: what has changed in the last decade?
Tobacco use, alcohol abuse, overweight and obesity are risk factors for numerous diseases in Italy as elsewhere. However, children and adolescents are not usually included in official national surveys although it is at this stage of life when unhealthy habits are often established. Italian participation in HBSC and GYTS surveys allows our country to implement standardized surveillance systems providing reliable information on tobacco-related behaviors of this population. Data from three HBSC surveys (2002-2010) show that following the drop in the first half of the decade, prevalence of tobacco use stabilized in the second half. The decline was significant for younger age groups, while prevalence of regular tobacco use remained stable among 15-year-olds. Many adolescents reported being exposed to secondhand smoke, to have at least one parent who smokes, and having seen teachers and students smoking at school. Although the sale of tobacco products to minors is prohibited, the vast majority had no trouble in buying cigarettes. Data from GYTS and HBSC surveys provide a wealth of information about attitudes and behaviors of Italian adolescents with respect to smoking. Despite some progress, sizeable gaps remain in meeting standard recommendations for discouraging smoking initiation and motivating adolescent smokers to quit the habit.


[Detection of viruses in raw water as a basic tool for risk assessment].
Human pathogenic viruses may end up in surface waters by fecal contamination. However, the German drinking water ordinance requests that pathogens in drinking water should not be present in concentrations constituting a potential danger to human health. Since many viruses do have a very low dose of infection, they have to be sufficiently eliminated in the process of drinking water purification. Waterborne virus outbreaks in Europe, over the last few decades, were mostly linked to noncompliance with the generally accepted codes of practice for drinking water production. The aimed level of protection of drinking water supplies in Germany, however, exceeds prevention of outbreaks by even protecting against sporadic virus infections. Documentation of such a high level of protection is not achieved by end product control alone but requires a process analysis with risk assessment. To do such an analysis, information regarding the presence of viruses in the raw water used for drinking water production, as well as data of virus elimination rates during purification processes, are of major importance. This paper presents suggestions for implementation of such a risk assessment, focusing on the evaluation of raw water quality.


[Organic pig farming: what about parasitic infections?].
The parasitological problems that may arise in organic pig farming are discussed. The rearing of pigs outdoors increases substantially the chances that several parasite species will complete their life cycle. Moreover, zoonoses may play an important role. Parasite species that may cause problems are discussed, as are control measures, when possible.


[Intestine microbiota and allergic diseases].
In industrialized countries an increased number of diseases due to immune system disorders including connected with allergy is noted. Allergic diseases generally proceed against the background of various common inflammatory diseases arising in childhood. The role of intestine microflora in its interaction with immune system and defining factors in allergization of children are actively studied. A decrease of risk of allergy development later in life for children who had grown up in the countryside was shown to be possibly related with microorganisms present in food. Thus the positive potential of farms is currently examined as a result of innate immunity activation by using microbial components. Acinetobacter lwoffii F78 isolated from cowsheds is able to protect mice from experimental allergy by activating Th1-polarization program of dendritic cells. Moreover, an important role in pathogenesis of allergic diseases belongs to mast cells. Probiotic lactobacilli may weaken activation of mast cells and release of inflammation mediators connected with allergic reactions. The ability of intestine microflora to influence immune response resulted in novel approaches in therapy that use these differences in microbiota for therapy and prophylaxis in allergy patients. And therefore on the basis of "hygiene hypothesis" of allergy emergence, a consideration is expressed that early manipulation with intestinal microbial communities may offer a new strategy of allergic sensibilization prevention.


Sensory nerve conduction velocity: technical requirements and normal values for branches of the radial and ulnar nerves of the dog.
Conduction velocities of compound action potentials of sensory axons of alteral superficial radial (LSR) and dorsal ulnar nerves (DUN) of the dog were determined by averaging potentials evoked and recorded through subcutaneous needle electrodes. Suitable locations for electrodes were identified and specificities of sites for LSR and DUN were verified by recording before and after cutting the nerves. Stimulus rates of 4/second to 20/second did not markedly affect conduction velocities. Increasing stimulus intensity in steps from threshold to 8 X threshold recruited more axons into the compound action potentials but resulted in interference from movement and muscle potentials at 4 X or 8 X threshold. Mean conduction velocities at 2 X threshold were: LSR = 61.7 +/- 0.76 SEM; DUN = 68.1 +/- 2.71 SEM.


Robot-Assisted Simulated Strabismus Surgery.
This study aims to investigate the feasibility of robot-assisted simulated strabismus surgery using the new da Vinci Xi Surgical System and to report what we believe is the first use of a surgical robot in experimental eye muscle surgery. Robot-assisted strabismus surgeries were performed on a strabismus eye model using the robotic da Vinci Xi Surgical System. On the lateral rectus of each eye, we performed a procedure including, successively, a 4-mm plication followed by a 4-mm recession of the muscle to end with a 4-mm resection. Operative time from conjunctival opening to closing and successful completion of the different steps with or without complications or unexpected events were assessed. Robot-assisted strabismus procedures were successfully performed on six eyes. The feasibility of robot-assisted simulated strabismus surgery is confirmed. The da Vinci Xi system provided the appropriate dexterity and operative field visualization necessary to perform conjunctival and Tenon's capsule opening and closing, muscle identification, suturing, desinsertion, sectioning, and resuturing. The mean duration to complete the whole procedure was 27 minutes (range, 22-35). There were no complications or unexpected intraoperative events. Experimental robot-assisted strabismus surgery is technically feasible using the new robotic da Vinci Xi Surgical System. This is, to our knowledge, the first use of a surgical robot in ocular muscle surgery. Further experimentation will allow the advantages of robot-assisted microsurgery to be identified while underlining the improvements and innovations necessary for clinical use.


Properties and determination of serum and bilirubin.
The accurate determination of the types and amounts of bilirubin species in serum is important for diagnostic purposes as well as for therapeutic monitoring. However, of the determinations routinely performed in the clinical laboratory, those for bilirubins are not among the more accurate and exhibit significant method variability. In this review, the structural, stability, solubility, and albumin-binding properties of serum bilirubins are discussed with respect to their impact on analytical methods. Following a consideration of analytical standards, methods for the determination of unconjugated and conjugated bilirubins are reviewed and recent developments are evaluated. Finally, the present capabilities and future potential of the methods for producing information applicable to the development of new or improved methods of determination are summarized.


Rapid preparation of bacterial DNA for pulsed-field gel electrophoresis.
A disadvantage of genotyping bacterial strains by pulsed-field gel electrophoresis is that the procedure requires up to 6 days to complete. We modified a standard pulsed-field gel electrophoresis method (B.E. Murray, K.V. Singh, J.D. Health, B.R. Sharma, and G.M. Weinstock, J.Clin. Microbiol. 28:2059-2063, 1990) so that it could be completed in less than 3 days. We successfully applied this method to the analysis of a variety of gram-positive and gram-negative bacteria.


[Distant thermography in the diagnosis of digestive organ diseases in children].
The authors review the most urgent problems of alimentary diseases in children: diagnosis, differential diagnosis and early detection with the use of remote thermography, an up-to-date noninvasive and atraumatic research method. The method was demonstrated to be highly informative in diseases such as gastroduodenitis, peptic ulcer, chronic pancreatitis and others. The significance of remote thermography in revealing functional pathology of the alimentary organs in children is emphasized.


Suppression of radiation-induced testicular germ cell apoptosis by 2,5-hexanedione pretreatment. I. Histopathological analysis reveals stage dependence of attenuated apoptosis.
In the testis, developing germ cells are dependent on supportive physical and paracrine interactions with Sertoli cells. The intimate nature of this relationship is demonstrated by the fact that a toxic insult compromising the stability of Sertoli cells will have deleterious effects on the associated germ cells. 2,5-Hexanedione (HD) and x-radiation (x-ray) are testicular toxicants, each with a unique cellular target. HD exposure disrupts microtubule function in Sertoli cells, and x-ray exposure causes double-strand breaks in the DNA of germ cells. Despite their differing modes of action, exposure to either toxicant has the similar ultimate effect of increased germ cell apoptosis. In this study, adult male F344 rats were exposed to 1% HD in the drinking water for 18 days with or without coexposure to 2 or 5 Gy x-ray 12 h prior to necropsy. Incidence of retained spermatid heads was increased in the HD and coexposure groups. Germ cell apoptosis was significantly increased in the x-ray and coexposure groups. There was a striking stage-dependent attenuation of apoptosis with coexposure compared with x-ray alone. Detailed histopathological analysis revealed a significant suppression of x-ray-induced germ cell apoptosis by HD pretreatment in stages I-VI of the seminiferous cycle, most noticeably at stages II/III. We hypothesize either that subacute HD pretreatment compromises the ability of the Sertoli cells to eliminate x-ray-damaged germ cells or that germ cells are more resistant to x-ray-induced damage, having adapted to a less supportive environment.


Coffee consumption and breast cancer risk among BRCA1 and BRCA2 mutation carriers.
Although there are several plausible biologic mechanisms whereby coffee consumption might influence the risk of breast cancer, epidemiologic evidence is limited. We assessed the association between coffee consumption and breast cancer risk among high-risk women who carry BRCA mutations. We performed a matched case-control analysis on 1,690 women with a BRCA1 or BRCA2 mutation from 40 centers in 4 countries. Average lifetime coffee consumption was estimated via a self-administered questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. After adjustment for potential confounders, the ORs for breast cancer in BRCA carriers who habitually drank 0, 1-3, 4-5 and 6 or more cups of coffee were 1.00, 0.90 (95% CI 0.72-1.12), 0.75 (95% CI 0.47-1.19) and 0.31 (95% CI 0.13-0.71; p-trend = 0.02). The effect was limited to the consumption of caffeinated coffee. These results suggest that among women with BRCA gene mutation, coffee consumption is unlikely to be harmful and that high levels of consumption may in fact be related to reduced breast cancer risk.


Inhibition of virulence factor expression and swarming differentiation in Proteus mirabilis by p-nitrophenylglycerol.
Proteus mirabilis is a common cause of upper urinary tract infections that can involve invasion of host urothelial cells. The ability to invade urothelial cells is coupled closely to swarming, a form of multicellular behaviour in which vegetative bacteria differentiate into hyperflagellate, filamentous swarming cells capable of co-ordinated and rapid population migration. Co-ordinate expression of virulence factors including urease, protease, haemolysin and flagellin during swarm-cell differentiation in P. mirabilis has been reported. To investigate the effects of p-nitrophenylglycerol (PNPG), a potent anti-swarming agent, on the various swarming-associated traits of P. mirabilis and to elucidate the relationships among them, P. mirabilis growth rate, swarming/swimming activity, cell invasion ability and the ability to express various virulence factors were monitored in the presence or absence of PNPG. It was found that PNPG could inhibit the growth rate, swarming differentiation and swarming/swimming activities of P. mirabilis. The expression of virulence factors such as protease, urease, haemolysin and flagellin in P. mirabilis was also inhibited by PNPG. The ability of P. mirabilis to invade human urothelial cells was reduced dramatically in the presence of PNPG. These results suggest that PNPG has the potential to be developed as an agent active against the effects of P. mirabilis infection.


Dynamics of telomeres and promyelocytic leukemia nuclear bodies in a telomerase-negative human cell line.
Telomerase-negative tumor cells maintain their telomeres via an alternative lengthening of telomeres (ALT) mechanism. This process involves the association of telomeres with promyelocytic leukemia nuclear bodies (PML-NBs). Here, the mobility of both telomeres and PML-NBs as well as their interactions were studied in human U2OS osteosarcoma cells, in which the ALT pathway is active. A U2OS cell line was constructed that had lac operator repeats stably integrated adjacent to the telomeres of chromosomes 6q, 11p, and 12q. By fluorescence microscopy of autofluorescent LacI repressor bound to the lacO arrays the telomere mobility during interphase was traced and correlated with the telomere repeat length. A confined diffusion model was derived that describes telomere dynamics in the nucleus on the time scale from seconds to hours. Two telomere groups were identified that differed with respect to the nuclear space accessible to them. Furthermore, translocations of PML-NBs relative to telomeres and their complexes with telomeres were evaluated. Based on these studies, a model is proposed in which the shortening of telomeres results in an increased mobility that could facilitate the formation of complexes between telomeres and PML-NBs.


What can we learn from the morphology of Hebrew? A masked-priming investigation of morphological representation.
All Hebrew words are composed of 2 interwoven morphemes: a triconsonantal root and a phonological word pattern. the lexical representations of these morphemic units were examined using masked priming. When primes and targets shared an identical word pattern, neither lexical decision nor naming of targets was facilitated. In contrast root primes facilitated both lexical decisions and naming of target words that were derived from these roots. This priming effect proved to be independent of meaning similarity because no priming effects were found when primes and targets were semantically but not morphologically related. These results suggest that Hebrew roots are lexical units whereas word patterns are not. A working model of lexical organization in Hebrew is offered on the basis of these results.


Panitumumab following disease progression on cetuximab in patients with metastatic colorectal cancer: a retrospective review.
Despite advances in treatment options for metastatic colorectal cancer over the past decade, the number of chemotherapy agents available remains limited. We report here a retrospective review of 11 patients who were treated with panitumumab following documented disease progression on cetuximab. Two patients demonstrated minor radiographic responses, albeit only for a short period of time. We conclude that the use of one epidermal growth factor receptor inhibitor following failure on the other may be of benefit to patients who would otherwise have no other treatment options. However, studies to help identify the subset of patients who might benefit from this strategy are needed.


Chronic fatigue syndrome in psychiatric patients: lifetime and premorbid personal history of physical health.
This preliminary report compares a group of chronic fatigue syndrome (CFS) patients and controls on several variables of potential significance in the etiology of CFS. The lifetime prevalence of reported physical disorders was compared among 46 CFS psychiatric patients, 92 relatively physically healthy psychiatric patients (C-I), and 46 psychiatric patients selected without regard to physical health (C-II). All patients were matched on age, sex, and psychiatric diagnosis and were drawn from the same psychiatric practice. The same groups were compared on a 7-point scale of lifetime physical health by three raters independently evaluating physical health narratives of the CFS patients up to the time of onset of CFS and that of the controls up to the corresponding age. The CFS patients had a significantly higher reported lifetime prevalence of irritable bowel syndrome (IBS), infectious mononucleosis-like syndromes (IM), infectious mononucleosis-like syndromes two or more times (IM x 2), and herpes (other than genital or perioral herpes) than one or both control groups. The CFS group also had a higher incidence of allergic rhinitis or asthma, IBS, IM, and IM x 2 than the combined controls. On the independent ratings, the CFS patients had significantly more impaired physical health up to the time of onset of the CFS than C-I at a comparable age. The findings suggest that a general health factor may be involved in the pathogenesis of some cases of CFS.


Furosemide in the intraoperative reduction of intracranial pressure in the patient with subarachnoid hemorrhage.
The effect of furosemide in the intraoperative reduction of intracranial pressure was measured in 25 patients undergoing the operative repair of a ruptured intracranial aneurysm. Seven patients with similar intracranial lesions served as controls. A single bolus of 80 mg of furosemide was administered intravenously after the induction of anesthesia, and sequential measurements were made of intracranial pressure, mean arterial pressure, and arterial blood gases. A mean decrease of intracranial pressure of 56% was measured in the furosemide-treated patients, whereas the control patients demonstrated a mean decline of subarachnoid pressures of 18%. These changes are significant at the P less than 0.005 confidence level, whereas changes in mean arterial pressure, mean arterial pCO2, and base line arterial pCO2 were statistically insignificant. This study suggests that intravenous furosemide is a quick, dependable, and effective mechanism for the intraoperative reduction of intracranial pressure in the postsubarachnoid hemorrhage aneurysm patient.


Dynamics of fractal networks.
Random structures often exhibit fractal geometry, defined in terms of the mass scaling exponent, D, the fractal dimension. The vibrational dynamics of fractal networks are expressed in terms of the exponent d, the fracton dimensionality. The eigenstates on a fractal network are spatially localized for d less than or equal to 2. The implications of fractal geometry are discussed for thermal transport on fractal networks. The electron-fracton interaction is developed, with a brief outline given for the time dependence of the electronic relaxation on fractal networks. It is suggested that amorphous or glassy materials may exhibit fractal properties at short length scales or, equivalently, at high energies. The calculations of physical properties can be used to test the fractal character of the vibrational excitations in these materials.


The role of instrumental emotion regulation in the emotions-creativity link: how worries render individuals with high neuroticism more creative.
Based on the instrumental account of emotion regulation (Tamir, 2005), the current research seeks to offer a novel perspective to the emotions-creativity debate by investigating the instrumental value of trait-consistent emotions in creativity. We hypothesize that emotions such as worry (vs. happy) are trait-consistent experiences for individuals higher on trait neuroticism and experiencing these emotions can facilitate performance in a creativity task. In 3 studies, we found support for our hypothesis. First, individuals higher in neuroticism had a greater preference for recalling worrisome (vs. happy) events in anticipation of performing a creativity task (Study 1). Moreover, when induced to recall a worrisome (vs. happy) event, individuals higher in neuroticism came up with more creative design (Study 2) and more flexible uses of a brick (Study 3) when the task was a cognitively demanding one. Further, Study 3 offers preliminary support that increased intrinsic task enjoyment and motivation mediates the relationship between trait-consistent emotion regulation and creative performance. These findings offer a new perspective to the controversy concerning the emotions-creativity relationship and further demonstrate the role of instrumental emotion regulation in the domain of creative performance.


Importance of a specialty clinic for individuals with fragile X syndrome.
Advances in human genetics have identified a significant number of genetic disorders associated with intellectual disability. As a result, appropriate clinical management of these affected individuals and their family members have become critical in addressing medical needs to improve quality of life. We examine the importance of a Fragile X Clinic for individuals with fragile X syndrome (FXS) and their family members by conducting a retrospective chart review of 123 new patients with FXS evaluated at the Fragile X Clinic at Emory University. After the initial diagnosis of a proband with FXS with cascade testing, there were 345 family members identified with a mutation (70% with premutations; 30% with full mutations). In terms of the impact of the clinic visit, males had a substantial number of new diagnoses in all behavioral disorders (P < 0.001), with anxiety (62%) being the most common. For female probands, the most frequent diagnosis was also anxiety (87%). Prior to the clinic visit, very few patients were prescribed psychotropic medications. After the clinic visit, the most frequently prescribed psychotropic medications for males were stimulants (41%; P < 0.001) and SSRIs (40%; P < 0.001). For females, only stimulants (33%; P = 0.03) and SSRIs (44%; P = 0.008) were statistically significantly prescribed. Our results revealed that there is a gap in care to address the co-morbid behavioral issues, psychopharmacologic medication management, and genetic counseling needs regarding FXS. A multidisciplinary setting and approach, such as that offered by a Fragile X Clinic, is one method of treating the complex needs of patients with FXS. © 2016 Wiley Periodicals, Inc.


Clinical effects of endothelin receptor antagonism with bosentan in patients with severe chronic heart failure: results of a pilot study.
Endothelin receptor antagonism produces favorable short-term hemodynamic effects in heart failure, but the clinical effects of longer term therapy have not been evaluated. Three hundred and seventy patients with symptoms of heart failure at rest or on minimal exertion and a left ventricular ejection fraction <35% were randomly assigned (double-blind) to placebo (n = 126) or the endothelin receptor antagonist bosentan, titrated slowly (n = 121) or rapidly (n = 123) to a target dose of 500 mg twice daily. Treatment with the study drug was to be maintained for 26 weeks, whereas background medications for heart failure were kept constant. Safety concerns led to early termination of the trial when only 174 patients had had an opportunity to complete 26 weeks of therapy. Bosentan exerted no apparent benefit when all randomized patients were analyzed (P = .709). However, in the first 174 patients who were recruited at least 26 weeks before study termination and who could therefore be followed for the planned duration of the trial, patients in the bosentan groups were more likely to be improved (26% versus 19%) and were less likely to be worse (28% versus 43%), P = .045. When compared with placebo-treated patients, bosentan-treated patients had a increased risk of heart failure during the first month of treatment but a decreased risk of heart failure during the fourth, fifth, and sixth months of therapy. The major noncardiac adverse effects of bosentan included an increase in hepatic transaminases (in 15.6% of patients) and a decrease in hemoglobin (of about 1 g/L). Although bosentan exerted no favorable effects in the overall study, our findings suggest that the clinical responses to endothelin antagonism with bosentan in patients with severe chronic heart failure may be dependent on the duration of treatment.


[Computed tomographic colonography: applications, advantages and disadvantages].
Complete preoperative study of the colon is required in the management of colorectal cancer, due to the frequent association of primary colonic neoplasms with colonic adenomas (28%) and/or synchronous carcinomas (5%) of the colon. We present a series of patients who underwent computed tomographic colonography, the indications for this procedure, and the results. We performed a descriptive prospective study. Between May 2003 and August 2004, 50 computed tomographic colonographies were performed in 50 patients with suspected stenosing colorectal cancer and incomplete conventional colonoscopy. Fifty computed tomographic colonographies were performed. The findings were as follows: three were normal (6%), and in the remainder, one was a false positive for a suspected neoplastic pelvic mass (3.125%) and two were false positives (11.7%) for colonic polyps. Fifty percent of the findings (n = 32) were related to peritoneal metastases and colonic neoplasms. There were 12 technical complications [lack of cleaning of the colon (5), lack of distension (2), little air insufflation (5)]. Patient complications included vegetative manifestations in one (vomiting) and rectal bleeding in another. The overall complication rate was 27.4% (23.4% corresponded to technical complications and the remaining 4% were patient-related). There was no mortality related to the procedure. Because computed tomographic colonography is safe, effective and well tolerated by the patient, it should be considered as a technical alternative in the study of stenosing neoplasms of the proximal colon with incomplete colonoscopy. In addition, it allows other associated findings, both intra- and extracolonic, to be obtained and improves the diagnostic and therapeutic management of the patient.


Evaluation of central nervous system involvement in SLE patients. Screening psychiatric manifestations--a systematic review.
Cognitive dysfunction, mood and anxiety disorders are three out of the five psychiatric manifestations included the description of neuropsychiatric Systemic Lupus Erythematosus (SLE). These manifestations are among the most prevalent in SLE having an important impact on patients quality of life. However, the unknown etiology allied to the lack of clarity on the best diagnosis procedure, makes early diagnosis dificult. This manuscript reviews the recent literature on the screening instruments focused on identifying lupus patients with probable psychiatric manifestations.


The zinc finger proteins Pannier and GATA4 function as cardiogenic factors in Drosophila.
The regulation of cardiac gene expression by GATA zinc finger transcription factors is well documented in vertebrates. However, genetic studies in mice have failed to demonstrate a function for these proteins in cardiomyocyte specification. In Drosophila, the existence of a cardiogenic GATA factor has been implicated through the analysis of a cardial cell enhancer of the muscle differentiation gene D-mef2. We show that the GATA gene pannier is expressed in the dorsal mesoderm and required for cardial cell formation while repressing a pericardial cell fate. Ectopic expression of Pannier results in cardial cell overproduction, while co-expression of Pannier and the homeodomain protein Tinman synergistically activate cardiac gene expression and induce cardial cells. The related GATA4 protein of mice likewise functions as a cardiogenic factor in Drosophila, demonstrating an evolutionarily conserved function between Pannier and GATA4 in heart development.


Impulse control disorders in Parkinson's disease patients treated with pramipexole and ropinirole: a systematic review and meta-analysis.
This analysis is the first systematic review and meta-analysis assessing occurrences of ICD in PD patients treated with oral DAs: ropinirole (ROP) and pramipexole (PRX). This study compares the two oral DAs to a transdermal patch, rotigotine (RTG). We performed an extensive systematic search for eligible studies from PubMed, Embase, Cochrane Library, and Google Scholar. The data was analyzed by various software, including EndNote, Rayyan, PRISM, and RevMan. Two studies incorporating 658 patients collectively were assessed. This meta-analysis shows a significant correlation between the usage of PRX (25.3%) or ROP (21.8%) and the development of ICD in PD patients. Compared to the transdermal patch, RTG, PRX was found to have a significant relative risk (P < 0.0001) of 3.46 (95% CI 2.07-5.76), and ROP was found to have a significant relative risk (P < 0.0001) of 2.98 (95% CI 1.77-5.02). The data collected shows RTG is approximately three times less likely to cause ICDs than oral PRX and ROP. The present investigation provides insight into ICD occurrences with PRX, ROP, and RTG to allow physicians to make more informed decisions on risk versus reward when deciding how to treat a PD patient with these drugs. However, related to various disclosed limitations, our conclusion cannot provide definitive practice protocols.