Trait coordination and environmental filters shape functional trait distributions of forest understory herbs.
Understanding the drivers of trait selection is critical for resolving community assembly processes. Here, we test the importance of environmental filtering and trait covariance for structuring the functional traits of understory herbaceous communities distributed along a natural environmental resource gradient that varied in soil moisture, temperature, and nitrogen availability, produced by different topographic positions in the southern Appalachian Mountains.To uncover potential differences in community-level trait responses to the resource gradient, we quantified the averages and variances of both abundance-weighted and unweighted values for six functional traits (vegetative height, leaf area, specific leaf area, leaf dry matter content, leaf nitrogen, and leaf δ13C) using 15 individuals of each of the 108 species of understory herbs found at two sites in the southern Appalachians of western North Carolina, USA.Environmental variables were better predictors of weighted than unweighted community-level average trait values for all but height and leaf N, indicating strong environmental filtering of plant abundance. Community-level variance patterns also showed increased convergence of abundance-weighted traits as resource limitation became more severe.Functional trait covariance patterns based on weighted averages were uniform across the gradient, whereas coordination based on unweighted averages was inconsistent and varied with environmental context. In line with these results, structural equation modeling revealed that unweighted community-average traits responded directly to local environmental variation, whereas weighted community-average traits responded indirectly to local environmental variation through trait coordination.Our finding that trait coordination is more important for explaining the distribution of weighted than unweighted average trait values along the gradient indicates that environmental filtering acts on multiple traits simultaneously, with abundant species possessing more favorable combinations of traits for maximizing fitness in a given environment.


A carbon nanotube gas sensor fabricated by dielectrophoresis and its application for NH3 detection.
Multi-walled carbon nanotubes (MWNTs) were successfully manipulated by dielectrophoresis (DEP) to form electrical connection between interdigitated gold electrodes (IDEs) and were demonstrated to serve as gas sensor for NH(3) detection. The MWNTs were suspended in ethanol and deposited on the IDEs under the effect of DEP. After the evaporation of ethanol, the MWNTs remained between the gaps of the IDEs. The electrical conductivity of the DEP-fabricated MWNTs sensor decreased when exposed to NH(3) at room temperature. There is a good linear correlation between the decreasing amplitude of conductance and the NH(3) concentration, and the detection limit of 10 ppm NH(3) could be achieved.


In Vitro Digestion of Peanut Skin Releases Bioactive Compounds and Increases Cancer Cell Toxicity.
Peanut skin is a rich source of bioactive compounds which may be able to reduce the risk factors associated with metabolic syndromes. This study aimed to characterize bio-compounds from peanut skin (Arachis hypogaea) and their bioactivity (antioxidant activity, inhibition of lipase, and carbohydrase enzymes) and to evaluate their anti-proliferative properties in colorectal cancer cells (HCT116) upon in vitro digestion. Peanut skin was digested in two sequential phases, and the final content, named phase-1 (P1) and phase-2 (P2) extracts, was evaluated. Several bioactive compounds were positively identified and quantified by liquid chromatography, including quinic acid, released especially after in vitro digestion. The total phenolic content and, regardless of the method, the antioxidant activity of P1 was higher than P2. P1 also showed a lower enzyme inhibitory concentration IC50 than P2, lipase, and α-glucosidase. For cell viability in HCT116 cells, lower concentrations of P1 were found for IC50 compared to P2. In conclusion, bioactive compounds were released mainly during the first phase of the in vitro digestion. The digested samples presented antioxidant activity, enzyme inhibitory activity, and cancer cell cytotoxicity, especially those from the P1 extract. The potential applications of such a by-product in human health are reported.


A child of high intelligence with the Johanson-Blizzard syndrome.
In this article, a boy is presented with the Johanson-Blizzard syndrome and high intelligence. In the literature, a wide range of intellectual abilities of children with the Johanson-Blizzard syndrome is reported. To obtain optimal conditions for the development of a child with the Johanson-Blizzard syndrome, early diagnosis of potential problems that may prevent this normal growth and development is recommended. The acquisition of more knowledge concerning the hypothetic reasons for intellectual impairment is of vital importance for families involved, in the light of genetic counseling.


[Method of measuring modulation transfer function in computed tomography using slit method with air gap phantom].
There are several methods for measuring modulation transfer function (MTF) in computed tomography (CT) images. The aluminum slit method, scanning a phantom consisting of a thin aluminum foil sandwiched by flat plastic slabs, is a standard method for measuring field of view (FOV) in clinical CT scan. But this method requires extreme caution when handling metal foil of high precision. Therefore, we devised a more simple method named air gap slit (AS) method. This new technique is based on the aluminum slit method but use air gap instead of metal foil between phantoms. The MTF was calculated from a reversed profile curve of air slit which indicated minimum CT number. The aim of this study was to investigate a possibility of AS method evaluating MTF. We investigated fluctuation of MTF and FOV in clinical CT scan compared with the aluminum slit method. The result showed that the fluctuation of MTF was caused by statistics noise and is more affected by a bone kernel than standard kernel when reconstructing. Also, the MTF value in AS method was slightly higher than in aluminum slit method and did not correspond with. AS method is a useful method for measurement of MTF in clinical CT scan. When we use this method, we have to take into consideration the noise influence of data.


Postexposure prophylaxis of tick-borne relapsing fever: lessons learned from recent outbreaks in Israel.
Tick-borne relapsing fever (TBRF) is endemic in Israel. Military activities pose a particular risk for TBRF, and its prevention is based on heightened awareness and risk stratification by active surveillance of tick bites and selective postexposure prophylaxis (PEP) with doxycycline for tick-bitten individuals. We report three outbreaks of TBRF affecting 35 exposed military personnel, with an average recognized tick bite rate of approximately 50% and an attack rate of 25-50%. Of 10 TBRF cases, 20% had no evidence of tick bites and thus restriction of PEP administration to individuals with recognized tick bites contributed to TBRF occurrence. As a result of a revised policy, 24 soldiers (including eight with recognized and 16 with unrecognized tick bites) received antimicrobials following the diagnosis of TBRF among their cohorts, and none of these individuals subsequently developed TBRF. The probability for TBRF among exposed individuals associated with well-established cases of TBRF warrants that prompt doxycycline administration be considered in all individuals who share risk factors, regardless of tick bite status.


Mass spectrometric identification of bromotryptophan containing conotoxin sequences from the venom of C. amadis.
Four 30 residue conotoxin have been identified from the venom of C. amadis. MS/MS analysis of crude venom subjected to global reduction/alkylation yielded fragmentation patterns, which permitted searching and matching with a database of putative mature toxin sequences obtained from transcriptomic analysis. Of the four sequences identified, Am3408(Am6.1b), Am3452(Am6.1c), Am3136(Am6.2a) and Am3214(Am6.2b), three contain bromotryptophan residues, while an additional post translational modification, gamma carboxylation of glutamic acid, is present in Am3408(Am6.1b)/3452(Am6.1c). The conotoxins belong to the O1/O2 gene superfamily and possess cysteine framework VI/VII. While, the cysteine patterns show a similarity to omega conotoxins, the three C. amadis peptides are highly negatively charged and possess a significant content of hydrophobic residues.


On the plasmonic photovoltaic.
The conversion of sunlight into electricity by photovoltaics is currently a mature science and the foundation of a lucrative industry. In conventional excitonic solar cells, electron-hole pairs are generated by light absorption in a semiconductor and separated by the "built in" potential resulting from charge transfer accompanying Fermi-level equalization either at a p-n or a Schottky junction, followed by carrier collection at appropriate electrodes. Here we report a stable, wholly plasmonic photovoltaic device in which photon absorption and carrier generation take place exclusively in the plasmonic metal. The field established at a metal-semiconductor Schottky junction separates charges. The negative carriers are high-energy (hot) electrons produced immediately following the plasmon's dephasing. Some of the carriers are energetic enough to clear the Schottky barrier or quantum mechanically tunnel through it, thereby producing the output photocurrent. Short circuit photocurrent densities in the range 70-120 μA cm(-2) were obtained for simulated one-sun AM1.5 illumination with devices based on arrays of parallel gold nanorods, conformally coated with 10 nm TiO2 films and fashioned with a Ti metal collector. For the device with short circuit currents of 120 μA cm(-2), the internal quantum efficiency is ∼2.75%, and its wavelength response tracks the absorption spectrum of the transverse plasmon of the gold nanorods indicating that the absorbed photon-to-electron conversion process resulted exclusively in the Au, with the TiO2 playing a negligible role in charge carrier production. Devices fabricated with 50 nm TiO2 layers had open-circuit voltages as high as 210 mV, short circuit current densities of 26 μA cm(-2), and a fill factor of 0.3. For these devices, the TiO2 contributed a very small but measurable fraction of the charge carriers.


Orientation and stereodynamic paths of planar monodentate ligands in square planar nickel N2S complexes.
The well-established presence of histidine donors in binding sites of Ni-containing biomolecules prompts the study of orientational preference and stereodynamic nature of flat monodentate ligands (L = imidazoles, pyridine and an N-heterocyclic carbene) bound to planar N(2)SNi moieties. Square planar [N(2)SNiL](n+) complexes are accessed through bridge-splitting reactions of dimeric, thiolate-S bridged [N(2)SNi](2) complexes. The solid state molecular structures of three mononuclear products, and three monothiolate bridged dinickel complexes, reveal that the plane of the added monodentate ligand orients largely orthogonal to the N(2)SNiL square plane. Variable temperature (1)H NMR characterization of dynamic processes and ground state isomer ratios of imidazole complexes in their stopped exchange limiting spectra, readily correlate with density functional theory (DFT)-guided interpretation of Ni-L rotational activation barriers. Full DFT characterization finds Ni-L bond lengthening as well as a tetrahedral twist distortion in the transition state, reaching a maximum in the NHC complex, and relating mainly to the steric hindrance derived both from the ligand and the binding pocket. In the case of the imidazole ligands a minor electronic contribution derives from intramolecular electrostatic interactions (imidazole C-2 C-H(delta+)- - S(delta-) interaction). Computational studies find this donor-acceptor interaction is magnified in O-analogues, predicting coplanar arrangements in the ground state of N(2)ON(imid)Ni complexes.


Diagnostic and Prognostic Role of Blood and Cerebrospinal Fluid and Blood Neurofilaments in Amyotrophic Lateral Sclerosis: A Review of the Literature.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting upper and lower motor neurons (MNs) that still lacks an efficacious therapy. The failure of recent therapeutic trials in ALS, other than depending on the poor knowledge of pathogenic mechanisms responsible for MNs loss, is largely due to diagnostic delay and the lack of reliable biomarkers for diagnosis, prognosis and response to pharmacologic intervention. Neurofilaments (Nfs) are neuron-specific cytoskeletal proteins, whose levels increased in biological fluids proportionally to the degree of axonal damage, both in normal and in pathologic conditions, representing potential biomarkers in various neurological disorders, such as motor neuron disorder (MND). Growing evidence has shown that phosphorylated neurofilaments heavy chain (p-NfH) and neurofilaments light chain (NfL) are increased in blood and cerebrospinal fluid (CSF) of ALS patients compared to healthy and neurological controls and are found to correlate with disease progression. In this review, we reported the most relevant studies investigating the diagnostic and prognostic role of Nfs in ALS. Given their reliability and reproducibility, we consider Nfs as promising and useful biomarkers in diagnosis of MND, early patient identification for inclusion in clinical trials, prediction of disease progression, and response to pharmacological intervention, and we suggest the validation of their measurement in clinical activity.


Genomewide association study for determinants of HIV-1 acquisition and viral set point in HIV-1 serodiscordant couples with quantified virus exposure.
Host genetic factors may be important determinants of HIV-1 sexual acquisition. We performed a genome-wide association study (GWAS) for host genetic variants modifying HIV-1 acquisition and viral control in the context of a cohort of African HIV-1 serodiscordant heterosexual couples. To minimize misclassification of HIV-1 risk, we quantified HIV-1 exposure, using data including plasma HIV-1 concentrations, gender, and condom use. We matched couples without HIV-1 seroconversion to those with seroconversion by quantified HIV-1 exposure risk. Logistic regression of single nucleotide polymorphisms (SNPs) for 798 samples from 496 HIV-1 infected and 302 HIV-1 exposed, uninfected individuals was performed to identify factors associated with HIV-1 acquisition. In addition, a linear regression analysis was performed using SNP data from a subset (n = 403) of HIV-1 infected individuals to identify factors predicting plasma HIV-1 concentrations. After correcting for multiple comparisons, no SNPs were significantly associated with HIV-1 infection status or plasma HIV-1 concentrations. This GWAS controlling for HIV-1 exposure did not identify common host genotypes influencing HIV-1 acquisition. Alternative strategies, such as large-scale sequencing to identify low frequency variation, should be considered for identifying novel host genetic predictors of HIV-1 acquisition.


Neural sensitivity to interaural envelope delays in the inferior colliculus of the guinea pig.
Interaural time differences (ITDs) are important cues for mammalian sound localization. At high frequencies, sensitivity to ITDs, which are conveyed only by the envelope of the waveforms, has been shown to be poorer than sensitivity to ITDs at low frequencies, which are conveyed primarily by the fine structure of the waveforms. Recently, human psychophysical experiments have demonstrated that sensitivity to envelope-based ITDs in high-frequency transposed tones can be equivalent to low-frequency fine-structure-based ITD sensitivity. Transposed tones are designed to provide high-frequency auditory nerve fibers (ANFs) with similar temporal information to that provided by low-frequency tones. We investigated neural sensitivity to ITDs in high-frequency transposed and sinusoidally amplitude modulated (SAM) tones, in the inferior colliculus of the guinea pig. Neural sensitivity to ITDs in transposed tones was found to be greater than that to ITDs in SAM tones; in response to transposed tones, neural firing rates were more modulated as a function of ITD and discrimination thresholds were found to be lower than those in response to SAM tones. Similar to psychophysical findings, ITD discrimination of single neurons in response to transposed tones for rates of modulation <250 Hz was comparable to neural discrimination of ITDs in low-frequency tones. This suggests that the neural mechanisms that mediate sensitivity to ITDs at high and low frequencies are functionally equivalent, provided that the stimuli result in appropriate temporal patterns of action potentials in ANFs.


Analysis of the K-ras/B-raf/Erk signal cascade, p53 and CMAP as markers for tumor progression in colorectal cancer patients.
Colorectal cancer patients may succumb to their disease because of local recurrence or formation of metastasis. To develop a prognostic tool for these fatal types of progression, 23 patients with colorectal carcinoma were included in this study for the detection at the time of surgery of the incidence of K-ras, B-raf and p53 mutations, the phosphorylation status of Erk and the expression of cystatin-like metastasis-associated protein (CMAP) in tumor, mucosa and liver samples. Polymerase chain reaction-restriction fragment length polymorphism and PCR-SSCP were used to detect the respective mutations. The results of these assays were complemented by sequencing the K-ras, B-raf and p53 mutations. A multiplex RT-PCR assay was used to detect the CMAP mRNA levels and the phosphorylation status of Erk in tumor samples was assessed by Western blot using a phosphospecific Erk antibody. The carcinomas were classified as stages T4 (70%), T3 (17%), T2 (9%) and T1 (4%) and thus represent a group of advanced colorectal carcinomas. The carcinomas (8 out of 23, 39.1%) were mutated in K-ras codons 12 or 13 and two patients had a B-raf (V599) mutation in their tumor. Of 22 tumors, 11 (50%) were positive for pErk, indicating the activation of the RAS/RAF/ERK signaling pathway. Of the 23 tumors, 13 (65.5%) showed an increased CMAP RNA level. Notably, 10 of these 13 patients have already died and two developed liver metastasis. Mutations in p53 were found in only 6 patients (26%), with 6 being detected in carcinoma, 1 in mucosa and 1 in liver tissue. These alterations were classified as non-sense (n=1), mis-sense (n=2) and frame-shift mutations (n=1) as well as intron polymorphisms (n=5). There was a significant correlation between Erk activation and K-ras codon 12 mutation (p=0.016), but not between K-ras codon 13 or B-raf mutations and Erk activation. Furthermore, there was a significant correlation of each positive marker with tumor stage (p=0.001).


An investigation of changes in physical properties of injectable calcium hydroxylapatite in a carrier gel when mixed with lidocaine and with lidocaine/epinephrine.
As physicians incorporate calcium hydroxylapatite (CaHA) into their aesthetic treatment regimens, the question has arisen of whether the addition of anesthetic agents to prefilled CaHA syringes might provide sufficient anesthetic prophylaxis to warrant reduction in conventional anesthetic pretreatment procedures. Investigators sought to determine changes in the physical properties of CaHA induced by the addition of lidocaine and lidocaine with epinephrine into the prefilled CaHA syringe. The CaHA and gel carrier (CHM) were mixed with varying amounts of lidocaine and lidocaine with epinephrine to measure the number of passes back and forth for optimal homogeneity of lidocaine and CaHA in syringes, changes in viscosity, extrusion force, needle jam rates, elasticity, and pH. Ten mixing passes appeared sufficient for homogeneity. Viscosities and extrusion forces of CHM/lidocaine blends decrease with increasing amount of lidocaine. Needle jams do not increase. The pH and elasticity of the CHM/lidocaine blend are essentially equivalent to those of CHM alone. Epinephrine added to lidocaine did not alter the results enough to reach statistical significance. Addition of lidocaine to original CHM can be safely added without harmful changes in physical properties of the original soft tissue filler. Further studies are required to explore whether the addition of lidocaine to CHM alters patient discomfort, durability, and efficacy.


The status of fish conservation in South African estuaries.
Estuary-dependent fish species are defined as those taxa whose populations would be adversely affected by the loss of estuarine habitats. Of the 155 species regularly recorded in South African estuaries, only 32 (21%) are completely dependent on these systems, but this figure increases to 103 species (66%) if partially dependent taxa are included in the analysis. The conservation of fishes in estuaries on the subcontinent is threatened by a number of factors, including habitat degradation, disruption of essential ecological processes, hydrological manipulations, environmental pollution, overexploitation due to fishing activities and, more recently, climate change and the effects of introduced aquatic animals. Although major threats to fishes are usually linked to environmental degradation, there is increasing evidence that the stocks of certain fish species are overexploited or collapsed. Fish conservation and fisheries management does not depend on the implementation of a single action, but rather the co-ordination of a detailed plan, often in a multidisciplinary context. Some examples of innovative means of contributing to estuarine fish conservation in a South African context include the determination and implementation of the ecological freshwater requirements for estuaries, the zoning of estuaries for different uses and the recognition that the maintenance of ecological processes are vital to aquatic ecosystem health. Apart from the designation of protected areas, the main direct means of conserving fish species and stocks include habitat conservation, controls over fishing methods, effort, efficiency and seasonality, pollution control and the prevention of artificial manipulation of estuary mouths. Since becoming a democracy in 1994, environmental legislation, policy and institutional arrangements in South Africa have undergone some major changes, which, if fully implemented, will be very positive for fish conservation in estuaries on the subcontinent.


Biophysical characterisation of neuroglobin of the icefish, a natural knockout for hemoglobin and myoglobin. Comparison with human neuroglobin.
The Antarctic icefish Chaenocephalus aceratus lacks the globins common to most vertebrates, hemoglobin and myoglobin, but has retained neuroglobin in the brain. This conserved globin has been cloned, over-expressed and purified. To highlight similarities and differences, the structural features of the neuroglobin of this colourless-blooded fish were compared with those of the well characterised human neuroglobin as well as with the neuroglobin from the retina of the red blooded, hemoglobin and myoglobin-containing, closely related Antarctic notothenioid Dissostichus mawsoni. A detailed structural and functional analysis of the two Antarctic fish neuroglobins was carried out by UV-visible and Resonance Raman spectroscopies, molecular dynamics simulations and laser-flash photolysis. Similar to the human protein, Antarctic fish neuroglobins can reversibly bind oxygen and CO in the Fe(2+) form, and show six-coordination by distal His in the absence of exogenous ligands. A very large and structured internal cavity, with discrete docking sites, was identified in the modelled three-dimensional structures of the Antarctic neuroglobins. Estimate of the free-energy barriers from laser-flash photolysis and Implicit Ligand Sampling showed that the cavities are accessible from the solvent in both proteins.Comparison of structural and functional properties suggests that the two Antarctic fish neuroglobins most likely preserved and possibly improved the function recently proposed for human neuroglobin in ligand multichemistry. Despite subtle differences, the adaptation of Antarctic fish neuroglobins does not seem to parallel the dramatic adaptation of the oxygen carrying globins, hemoglobin and myoglobin, in the same organisms.


["Palliative" surgical procedures in refractory epilepsy].
In some patients with refractory epilepsy, no resective surgery of the epileptogenic zone can be offered. This is the case when for instance the epileptogenic zone is located in an eloquent region (motor, language or visual) or when there are several epileptogenic zones. When disabling seizures persist despite the medical treatment, several surgical procedures can be proposed with the aim of decreasing the seizure frequency. Among these procedures, we review briefly here vagus nerve stimulation, the various brain stimulations procedures, multiples subpial transsections, and the corpus callosotomy. For each procedure, we will discuss its indication and outcome.


[Mechanical impedance of human parotid area tissues (mastoid)].
Frequency relationship of mechanical impedance of human mastoid has been recorded within the frequency range of 125-15 000 Hz. The technique of measuring mechanical impedance has been described and its error evaluated. From the results obtained equivalent parameters of the mechanical system imitating acoustic properties of human mastoid are calculated. These parameters can serve as the basis for developing the device artificial mastoid.


Highly efficient nonuniform grating coupler for silicon-on-insulator nanophotonic circuits.
We present design, fabrication, and characterization of a silicon-on-insulator grating coupler of high efficiency for coupling between a silicon nanophotonic waveguide and a single mode fiber. By utilizing the lag effect of the dry etching process, a grating coupler consisting of nonuniform grooves with different widths and depths is designed and fabricated to maximize the overlapping between the upward wave and the fiber mode. The measured waveguide-to-fiber coupling efficiency of 64% (-1.9 dB) for the transverse electric polarization is achieved by the present nonuniform grating coupler directly defined on a regular silicon-on-insulator wafer.


Genetic variations in host IL28B links to the detection of peripheral blood mononuclear cells-associated hepatitis C virus RNA in chronically infected patients.
Hepatitis C virus (HCV) is mainly hepatotropic; however, several reports document the presence of genomic viral RNA in extrahepatic sites including peripheral blood mononuclear cells (PBMCs). In this study, the presence of HCV RNA was initially evaluated in the plasma and peripheral blood mononuclear cells (PBMCs) of 53 HCV-infected patients who were treated per protocol. PBMC-associated HCV RNA was detectable in 79% of patients. Early virological response to combined pegylated interferon-α (PegIFN) and ribavirin (RBV) therapy in patients with undetectable levels of PBMCs-associated HCV RNA was 100%, while it was 60% (P = 0.003) in those who had detectable levels of PBMC-associated HCV RNA. A sustained virological response was observed in 35% of patients with detectable PBMC-associated HCV RNA, but was 70% in patients with undetectable levels of PBMC-associated HCV RNA (P = 0.07). In a multivariate analysis incorporating parameters such as HCV genotype, viral load, presence of cirrhosis and absence of PBMC-associated HCV RNA, a significant relationship was observed between the detection of PBMC-associated HCV RNA and the sustained virological response (OR 19.4, 95% CI: 2.1-486.2, P = 0.0061). The association between single nucleotide polymorphism (SNP) in IL28B, known predictor of antiviral therapy outcome, and the occurrence of HCV RNA in PBMC in 84 chronically infected patients was then evaluated. Results suggest that the presence of a G allele in rs8099917, known to associate to a poor response to PegIFN/RBV therapy, also predicts an increased association of HCV RNA with PBMC (OR: 3.564; 95% CI: 1.114-11.40, P = 0.0437).


Is measurement of maternal serum TSH sufficient screening in early pregnancy? A case for more randomized trials.
During the past decades, observational studies have demonstrated a relationship between thyroid dysfunction in pregnancy and a range of adverse outcomes in both mother and offspring. However, results from the few randomized trials of screening for thyroid dysfunction in pregnant women have not shown any benefit for women or their children. Before implementing screening in pregnant women at population level, randomized trials are needed to show that screening with subsequent intervention is effective for mothers or children. Here, we review the literature and argue that the findings from existing trials are not conclusive. Until such conclusive evidence from randomized trials is available, the best advice to the clinician is to screen only high-risk pregnant women. Such women, for example those with symptoms or a history of thyroid problems, should be screened using trimester-specific reference ranges for thyroid stimulating hormone (TSH) levels. We recommend new prospective randomized trials that combine different thyroid parameters as the screening tool, apply trimester-specific ranges for thyroid hormones and examine whether screening and intervention during the first trimester of pregnancy will improve neuropsychological outcomes in the offspring.


Age-related changes in mouse bone permeability.
The determination of lacunar-canalicular permeability is essential for understanding local fluid flow in bone, which may indicate how bone senses changes in the mechanical environment to regulate mechano-adaptation. The estimates of lacunar-canalicular permeability found in the literature vary by up to eight orders of magnitude, and age-related permeability changes have not been measured in non-osteonal mouse bone. The objective of this study is to use a poroelastic approach based on nanoindentation data to characterize lacunar-canalicular permeability in murine bone as a function of age. Nine wild type C57BL/6 mice of different ages (2, 7 and 12 months) were used. Three tibiae from each age group were embedded in epoxy resin, cut in half and indented in the longitudinal direction in the mid-cortex using two spherical fluid indenter tips (R=238 μm and 500 μm). Results suggest that the lacunar-canalicular intrinsic permeability of mouse bone decreases from 2 to 7 months, with no significant changes from 7 to 12 months. The large indenter tip imposed larger contact sizes and sampled larger ranges of permeabilities, particularly for the old bone. This age-related difference in the distribution was not seen for indents with the smaller radius tip. We conclude that the small tip effectively measured lacunar-canalicular permeability, while larger tip indents were influenced by vascular permeability. Exploring the age-related changes in permeability of bone measured by nanoindentation will lead to a better understanding of the role of fluid flow in mechano-transduction. This understanding may help indicate alterations in bone adaptation and remodeling.


Evaluation of NHMRC funded research completed in 1992, 1997 and 2003: gains in knowledge, health and wealth.
To report on strategies for, and outcomes of, evaluation of knowledge (publications), health and wealth (commercial) gains from medical research funded by the Australian Government through the National Health and Medical Research Council (NHMRC). End-of-grant reports submitted by researchers within 6 months of completion of NHMRC funded project grants which terminated in 2003 were used to capture self-reported publication number, health and wealth gains. Self-reported gains were also examined in retrospective surveys of grants completed in 1992 and 1997 and awards primarily supporting people ("people awards") held between 1992 and 2002. The response rate for the 1992 sample was too low for meaningful analysis. The mean number of publications per grant in the basic biomedical, clinical and health services research areas was very similar in 1997 and 2003. The publication output for population health was somewhat higher in the 2003 than in the 1997 analysis. For grants completed in 1997, 24% (31/131) affected clinical practice; 14% (18/131) public health practice; 9% (12/131) health policy; and 41% (54/131) had commercial potential with 20% (26/131) resulting in patents. Most respondents (89%) agreed that NHMRC people awards improved their career prospects. Interpretation is limited by the relatively low response rates (50% or less). A mechanism has been developed for ongoing assessment of NHMRC funded research. This process will improve accountability to the community and to government, and refine current funding mechanisms to most efficiently deliver health and economic returns for Australia.


Importance of subtype in the immune response to the pre-S(2) region of the hepatitis B surface antigen. II. Synthetic Pre-S(2) immunogen.
One purpose of this study was to examine the influence of viral subtype on in vivo antibody production to the pre-S(2) region of the hepatitis B surface Ag. Immunization with hepatitis B surface Ag particles containing the pre-S(2) region of the d or y subtypes identified the B10.M (H-2f) strain as an antibody nonresponder to the pre-S(2) and S regions after immunization with the y subtype, but as an antibody responder to the pre-S(2) and S regions after immunization with the d subtype. Both the S region and pre-S(2) region-specific antibody responses emanated from pre-S(2)/d-specific Th cell function because B10.M mice are T cell nonresponsive to the S region of both subtypes. Although responder/nonresponder status of the B10.M strain was dependent on the pre-S(2) subtype used for immunization, the anti-pre-S(2) antibody produced was totally cross-reactive on both subtypes. This is consistent with the conserved nature of the dominant pre-S(2) antibody-binding site and the highly polymorphic nature of the pre-S(2) sequence that represents the focus of T cell recognition. These data suggest that, to fully benefit from the inclusion of pre-S(2) region sequences, third generation hepatitis B virus vaccines should contain both the d and y subtype sequences of the pre-S(2) region to increase the frequency of pre-S(2) and S-specific antibody responses and to insure Th cell memory relevant to both viral subtypes. A second purpose of this study was to "design" a synthetic pre-S(2) immunogen based on combining the dominant B and T cell recognition sites into a single peptide. A composite peptide consisting of the dominant T cell recognition sequence p151-174 positioned N-terminal to the dominant B cell site p133-143 (i.e., p151-174(133-143] yielded an effective pre-S(2) synthetic immunogen. Interestingly, the orientation of the T and B cell determinants and the context of the T cell site within the larger composite peptide influenced both antibody fine specificity and T cell fine specificity.


Long-term efficacy of tubercidin against schistosomiasis japonica and mansoni in primates.
Schistosomiasis japonica in capuchin msnkeys (Cebus apella) and schistosomiasis mansoni in baboons (Papio cyanocephalus and P. hamadryas) were completely arrested for 6 months in every infected primate receiving a single treatment with tubercidin (Tu), administered after prior absorption into 20% of their red cells. It is very likely that a single treatment with Tu sequestered in only 15% of the hosts' red cells would also be 100% effective for prolonged periods of time, but that with lower doses some relapses would be expected. Babbons with patent Schistosoma mansoni infections were rechallenged with S. mansoni cercariae 4 months after treatment with Tu. Although Tu eliminated almost all the sexually mature female worms from the primary infection but spared most of the males for continuing sojourn within their hosts, the baboons retained their full susceptibility to reinfection, as indicated by worm burdens and fecal egg excretion. However, the granulomatous reaction in the rechallenged Tu-treated baboons to new masses of eggs trapped in their livers appeared to be less intense than was seen in animals with primary infections.


Cancer testis antigen XAGE-1 is a promising marker for the diagnosis and treatment of ovarian cancer.
Cancer testis antigens have been discovered in various cancers, and several studies have suggested that since they exhibit such distinct patterns of expression, these antigens might be attractive targets for cancer detection and immunotherapy. Our work attempted to clarify the function played by cancer-testis antigens in ovarian cancers, notably in the XAGE1 gene. The investigation was conducted on 74 tissue samples from newly diagnosed patients with ovarian cancer. The control group included twenty-eight benign ovarian tumors. The expression of XAGE1 mRNA was assessed using RT-PCR. Compared to benign tumors, cancer samples exhibited higher levels of XAGE1 gene expression, which was statistically significant (P0.01). There were no statistically significant differences between menopausal status and family history. Gene expression was substantially connected with age groups as the higher level of gene expression in patients 50-74 years of age (P 0.01) was seen. Mucinous tumors exhibited significant correlations (P0.01) across histopathological tumor types. In correlation with tumor stages, stage III was substantially linked compared to stage I (P0.01). In conclusion, we referred to the potential to use XAGE1 to discriminate malignant ovarian tumors as a diagnostic biomarker. The connection of high XAGE 1 level with advanced ovarian cancer stages has also been established, supporting XAGE 1's proposed role in poor prognosis. Finally, finding the specific involvement of this gene in ovarian cancer and other kinds of malignancies may require further investigations.


Diverse microbial exposure - consequences for vaccine development.
Numerous epidemiological studies suggest that there is an inverse relationship between "immunologically mediated diseases of affluence", such as allergy, diabetes and inflammatory bowel disease on one hand and few infections encountered in early childhood, on the other hand. Careful analysis of the epidemiological, clinical and animal studies taken together, however, suggests that the protection is mediated by broad exposure to a wealth of commensal, non-pathogenic microorganisms early in life, rather than by infections. Microbial exposure has little relationship with "hygiene" in the usual meaning of the word and the term "hygiene hypothesis" is therefore misleading. A better term would be "microbial deprivation hypothesis". The suggestion that childhood infections would protect against allergic disease led to unfortunate speculations that vaccinations would increase the risk for allergies and diabetes. Numerous epidemiological studies have therefore been conducted, searching for a possible relationship between various childhood vaccinations on one hand and allergy on the other hand. It is reasonable from these studies to conclude that vaccinations against infectious agents neither significantly increase, nor reduce the likelihood of immunologically mediated diseases. It is established that the postnatal maturation of immune regulation is largely driven by exposure to microbes. Germ free animals manifest excessive immune responses when immunised and they do not develop normal immune regulatory function. The gut is by far the largest source of microbial exposure, as the human gut microbiome contains up to 1014 bacteria, i.e. ten times the number of cells in the human body. Several studies in recent years have shown differences in the composition of the gut microbiota between allergic and non-allergic individuals and between infants living in countries with a low and a high prevalence of immune mediated diseases. The administration of probiotic bacteria to pregnant mothers and postnatal to their infants has immune modulatory effects. So far, however, probiotic bacteria do not seem to significantly enhance immune responses to vaccines. The potential to improve vaccine responses by modifying the gut microbiota in infants and the possibility to employ probiotic bacteria as adjuvants and/or delivery vehicles, is currently explored in several laboratories. Although to date few clinical results have been reported, experimental studies have shown some encouraging results.


Etanercept in the treatment of psoriasis and psoriatic arthritis with concomitant hepatitis C virus infection: clinical and virological study in three patients.
Treatment of patients with psoriasis and concomitant hepatitis-C virus (HCV) infection poses a therapeutic challenge because most systemic drugs are associated with potential hepatotoxicity, either due to direct liver damage or to immunosuppression. Among newly available drugs for the treatment of psoriasis and psoriatic arthritis, studies investigating the effect of anti-tumour necrosis factor-α in such patients are still limited. We describe three psoriatic patients with HCV, one with concomitant alcoholic hepatitis, who were treated with etanercept monotherapy for six months. We obtained good clinical responses for both psoriasis and arthritis in all three patients. While no significant changes in viral load and transaminases were observed in two patients, alanine aminotrasferase and gamma-glutamyltransferase levels were raised during treatment in the patient with concomitant alcoholic hepatitis. At baseline, one patient was negative and two were positive for mixed-type cryoglobulins. During treatment, none of the patients developed cryoglobulinemia-related clinical symptoms, and one of the two patients positive at baseline was negative for cryoglobulins at the end of follow-up. Our results add to accumulating data suggesting that etanercept represents a valuable therapeutic option for treatment of HCV-positive psoriatic patients, with an acceptable safety profile in the short-term. However, etanercept treatment of HCV cases with concomitant alcoholic hepatitis must be undertaken with caution.


A chatbot for hypertension self-management support: user-centered design, development, and usability testing.
Health-related chatbots have demonstrated early promise for improving self-management behaviors but have seldomly been utilized for hypertension. This research focused on the design, development, and usability evaluation of a chatbot for hypertension self-management, called "Medicagent." A user-centered design process was used to iteratively design and develop a text-based chatbot using Google Cloud's Dialogflow natural language understanding platform. Then, usability testing sessions were conducted among patients with hypertension. Each session was comprised of: (1) background questionnaires, (2) 10 representative tasks within Medicagent, (3) System Usability Scale (SUS) questionnaire, and (4) a brief semi-structured interview. Sessions were video and audio recorded using Zoom. Qualitative and quantitative analyses were used to assess effectiveness, efficiency, and satisfaction of the chatbot. Participants (n = 10) completed nearly all tasks (98%, 98/100) and spent an average of 18 min (SD = 10 min) interacting with Medicagent. Only 11 (8.6%) utterances were not successfully mapped to an intent. Medicagent achieved a mean SUS score of 78.8/100, which demonstrated acceptable usability. Several participants had difficulties navigating the conversational interface without menu and back buttons, felt additional information would be useful for redirection when utterances were not recognized, and desired a health professional persona within the chatbot. The text-based chatbot was viewed favorably for assisting with blood pressure and medication-related tasks and had good usability. Flexibility of interaction styles, handling unrecognized utterances gracefully, and having a credible persona were highlighted as design components that may further enrich the user experience of chatbots for hypertension self-management.


A preliminary survey of the health behaviors of community leaders.
The purpose of this study was to investigate the health behavior of a town ' s community leaders and other issues associated with that behavior. Structured questionnaires designed by the researchers were used to collect data at a meeting for the announcement of community building; they were filled out in the 10 or 20 minutes before the meeting began and 70 valid responses were received. The SPSS for Window version 10.0 software package was used for data analysis. The results of the study showed that the community leaders demonstrated higher standards of health-protective behaviors (i.e. elder/adult checkups, Pap smear exam and breast self-examination) than others living in the community. Variables such as gender, educational level, self-perceived health status, number of chronic illnesses were correlated with different types of dietary behavior. Subjects who were 40 years old and over, educated to junior high school or lower, who had performed less than one year of community service and were free of chronic illness engaged in relatively regular exercise. Subjects who had performed more than one year of community service were more likely to utilize the preventive services provided by national health insurance. It is recommended that public health nurses improve their cooperation with community leaders over providing health -related activities in order to promote better health behavior on the part of such leaders.


Quantitative diffusion tensor imaging tractography metrics are associated with cognitive performance among HIV-infected patients.
There have been many studies examining HIV-infection-related alterations of magnetic resonance imaging (MRI) diffusion metrics. However, examining scalar diffusion metrics ignores the orientation aspect of diffusion imaging, which can be captured with tractography. We examined five different tractography metrics obtained from global tractography maps (global tractography FA, average tube length, normalized number of streamtubes, normalized weighted streamtube length, and normalized total number of tubes generated) for differences between HIV positive and negative patients and the association between the metrics and clinical variables of disease severity. We also examined the relationship between these metrics and cognitive performance across a wide range of cognitive domains for the HIV positive and negative patient groups separately. The results demonstrated a significant difference between the groups for global tractography FA (t = 2.13, p = 0.04), but not for any of the other tractography metrics examined (p-value range = 0.39 to 0.95). There were also several significant associations between the tractography metrics and cognitive performance (i.e., tapping rates, switching 1 and 2, verbal interference, mazes; r > or = 0.42) for HIV infected patients. In particular, associations were noted between tractography metrics, speed of processing, fine motor control/speed, and executive function for the HIV-infected patients. These findings suggest that tractography metrics capture clinically relevant information regarding cognitive performance among HIV infected patients and suggests the importance of subtle white matter changes in examining cognitive performance.


MolDiA: a novel molecular diversity analysis tool. 1. Principles and architecture.
We introduce the principles and the architecture of a user-friendly software named MOLDIA (Molecular Diversity Analysis) which aims to the comparison of diverse molecular data sets through an XML structured database of predefined fragments. The MOLDIA descriptors are composed of complex fingerprint-like structures, which enclose not only structural information but also physicochemical property data. The system architecture includes the use of customizable weights on molecular descriptors and different choices of similarity/diversity measures to analyze the given data sets. Intermolecular comparisons using Ullmann's algorithm were optimized by the use of fuzzy logic, generic atoms, and a whole system of chemical graph analysis. We have found that customizing the similarity/diversity computation using structural and/or properties weights and choosing the level of fuzziness of the molecular comparison allow the user to adapt the tool to particular needs and increases the possibilities of MolDiA applications. The implementation of XML Web technologies has proven to improve and ease the extraction, processing, and analysis of chemical information.


Becoming a peter pan: omnipotence, dependency and the Ferenczian child.
The aim of this paper is to provide a short history of the changes in Ferenczi's concept of early childhood, during the two decade period, 1913-1932. Initially, Ferenczi mainly emphasized children's feelings of omnipotence, which enable them to perceive themselves as strong, independent and capable human beings. By the mid-1920s, however, he felt that his earlier work did not give a good account of what comes after the stage of omnipotence, and that it did not adequately describe the difficulties in the transition from pleasure to reality principles. However, in his Clinical Diary, Ferenczi became fully aware of how fragile and insecure children are, and therefore how dangerous-yet necessary-it is for them to abandon the "stage of omnipotence" and to gain a "sense of reality". For Ferenczi, traumatized children are children who had not been loved in their early childhood, and therefore could not develop the capacity to make the journey from pleasure principle to that of reality. It will be suggested that a paradigmatic example for this kind of child is Peter Pan.


A Digital Library for Increasing Awareness About Living Donor Kidney Transplants: Formative Study.
It is not common for people to come across a living kidney donor, let alone consider whether they would ever donate a kidney themselves while they are alive. Narrative storytelling, the sharing of first-person narratives based on lived experience, may be an important way to improve education about living donor kidney transplants (LDKTs). Developing ways to easily standardize and disseminate diverse living donor stories using digital technology could inspire more people to consider becoming living donors and reduce the kidney shortage nationally. This paper aimed to describe the development of the Living Donation Storytelling Project, a web-based digital library of living donation narratives from multiple audiences using video capture technology. Specifically, we aimed to describe the theoretical foundation and development of the library, a protocol to capture diverse storytellers, the characteristics and experiences of participating storytellers, and the frequency with which any ethical concerns about the content being shared emerged. This study invited kidney transplant recipients who had received LDKTs, living donors, family members, and patients seeking LDKTs to record personal stories using video capture technology by answering a series of guided prompts on their computer or smartphone and answering questions about their filming experience. The digital software automatically spliced responses to open-ended prompts, creating a seamless story available for uploading to a web-based library and posting to social media. Each story was reviewed by a transplant professional for the disclosure of protected health information (PHI), pressuring others to donate, and medical inaccuracies. Disclosures were edited. This study recruited diverse storytellers through social media, support groups, churches, and transplant programs. Of the 137 storytellers who completed the postsurvey, 105/137 (76.6%) were white and 99/137 (72.2%) were female. They spent 62.5 min, on average, recording their story, with a final median story length of 10 min (00:46 seconds to 32:16 min). A total of 94.8% (130/137) of storytellers were motivated by a desire to educate the public; 78.1% (107/137) were motivated to help more people become living donors; and 75.9% (104/137) were motivated to dispel myths. The ease of using the technology and telling their story varied, with the fear of being on film, emotional difficulty talking about their experiences, and some technological barriers being reported. PHI, most commonly surnames and transplant center names, was present in 62.9% (85/135) of stories and was edited out. With appropriate sensitivity to ensure diverse recruitment, ethical review of content, and support for storytellers, web-based storytelling platforms may be a cost-effective and convenient way to further engage patients and increase the curiosity of the public in learning more about the possibility of becoming living donors.


Serum levels of cytokines and secondary messages after T-cell-depleted and non-T-cell-depleted bone marrow transplantation: influence of conditioning and hematopoietic reconstitution.
Cytokines are increasingly recognized as important mediators of graft-versus-host disease (GVHD). Measurements of cytokine serum levels in patients with GVHD, and successful prevention and treatment of the disease with the use of cytokine antagonists to either the cytokine or its receptor, are only two of several factors demonstrating the involvement of cytokines in GVHD. To further investigate the role of cytokines in the pathomechanism of acute GVHD, we investigated endogenous serum levels of various cytokines and dependent molecules in sera of 14 patients after T-cell-depleted (TCD) bone marrow transplantation (BMT) and compared the results with those of 12 patients undergoing non-TCD BMT. The effect of various conditioning regimens and of hematopoietic reconstitution on cytokine serum levels was analyzed in detail in these cohorts of patients by measuring interferon (IFN)-gamma, IFN-alpha, tumor necrosis factor-alpha, interleukin-6, neopterin, and beta2-microglobulin. The analyses showed that an increase in IFN-gamma and neopterin serum levels was a specific feature of cyclophosphamide administration and was not observed after other cytostatic drugs or total body irradiation, and that an increase in IFN-gamma, neopterin, beta2-microglobulin, and IFN-alpha release depends on the presence of T cells in the graft. We conclude that significant cytokine serum alterations were noted after TCD BMT as compared with after non-TCD BMT. These alterations, besides depletion of cytotoxic effector cells, might be involved in preventing GVHD after TCD BMT. In addition, more attention should be devoted to the cytokine release-inducing capacity of the conditioning regimen, because such a release might influence the occurrence of transplant-related complications after BMT.


Synergy between sulforaphane and selenium in the induction of thioredoxin reductase 1 requires both transcriptional and translational modulation.
Thioredoxin reductases (TrxRs) catalyse the NADPH-dependent reduction of thioredoxin and play an important role in multiple cellular events related to carcinogenesis including cell proliferation, apoptosis and cell signaling. We have used human hepatoma HepG2 cells to examine the regulation of TrxRs by isothiocyanate (sulforaphane) and selenium (Se). We show that TrxR1 mRNA, but not TrxR2 mRNA, is induced up to 4-fold by sulforaphane, and this increase was abolished by actinomycin D, a transcription inhibitor. Se, in the form of sodium selenite, induced TrxR1 at the translational level, as shown by an increase in protein (2.1-fold) and activity (4.8-fold), but not mRNA. In combination, sulforaphane and Se synergistically induced TrxR1 protein (5.5-fold), activity (13-fold) and mRNA (6.5-fold). Although Se does not induce TrxR1 mRNA, Se can delay the degradation of sulforaphane-induced TrxR1 mRNA. Modulation of TrxR1 mRNA by sulforaphane was glutathione and protein kinase C-dependent, as L-buthionine-S,R-sulfoximine (a specific inhibitor of glutathione synthesis), and the protein kinase C inhibitor 1-(5-isoquinolinesulfonyl)-2-methyl-piperazine, significantly reduced the induction. The combination of sulforaphane and Se also efficiently protected HepG2 cells from paraquat-induced cell death, whereas sulforaphane-only and Se-only treatments showed very little if any protective effect. These results demonstrate that synergy can result from a combination of induction at the levels of transcription and translation.


A computational model to predict cell traction-mediated prestretch in the mitral valve.
Prestretch is observed in many soft biological tissues, directly influencing the mechanical behavior of the tissue in question. The development of this prestretch occurs through complex growth and remodeling phenomena, which yet remain to be elucidated. In the present study it was investigated whether local cell-mediated traction forces can explain the development of global anisotropic tissue prestretch in the mitral valve. Towards this end, a model predicting actin stress fiber-generated traction forces was implemented in a finite element framework of the mitral valve. The overall predicted magnitude of prestretch induced valvular contraction after release of in vivo boundary constraints was in good agreement with data reported on valvular retraction after excision from the heart. Next, by using a systematic variation of model parameters and structural properties, a more anisotropic prestretch development in the valve could be obtained, which was also similar to physiological values. In conclusion, this study shows that cell-generated traction forces could explain prestretch magnitude and anisotropy in the mitral valve.


Quantum transport along the armchair and zigzag edges of β12-borophene nanoribbons in the presence of a Zeeman magnetic field and dilute charged impurities.
Tuning the physical properties of nanoribbons is increasing for real applications. We here focus on magnetic and electronic effects to contribute to this matter. We particularly investigate the effects of a Zeeman magnetic field and dilute charged impurities on the quantum transport properties of β12-borophene nanoribbons (BNRs), both in the armchair and zigzag directions, by considering substrate effects. Calculations are done using the five-band tight-binding Hamiltonian, the Green's function approach (for density of states), the Landauer-Büttiker formalism (for quantum transport quantities), and the self-consistent Born approximation (for impurity effects). Our findings show that both electronic transmission probability and current-voltage characteristics of the system can be significantly adjusted in the presence of Zeeman splitting and charged dilute impuritiesy. Interestingly, the Zeeman splitting effect leads to an enhancement of the current that flows through the channel, whereas a reduction is observed in the electrical current of charged impurity-imbrued β12-BNR. Moreover, through a detailed analysis of armchair and zigzag directions, we found that the transport characteristics of impurity-induced armchair β12-BNRs are much more strongly tuned than those of zigzag ones. These results provide useful information for logic nanoelectronics.


Workers exposed to ethylene oxide: a follow up study.
A cohort study has been carried out of 2876 men and women with potential exposure to ethylene oxide. Subjects were identified from employment records at four companies that have produced or used ethylene oxide since the 1950s and at eight hospitals which have had ethylene oxide sterilising units since the 1960s. The cohort represents a substantial proportion of the British workforce with a history of occupational exposure to ethylene oxide. Industrial hygiene data were not available before 1977, but since then time weighted average exposures have been less than 5 ppm in almost all jobs and less than 1 ppm in many. Past exposures were probably somewhat higher. In contrast to some previous studies, no clear excess of leukaemia (three deaths observed, 2.09 expected) and no increase in stomach cancer (five deaths observed, 5.95 expected) were found. This discrepancy with earlier reports may be due in part to differences in levels of exposure. Total cancer mortality was similar to that expected from national and local death rates. Some specific cancers showed small excesses but their relevance to ethylene oxide exposure is doubtful. Again, contrary to some earlier reports, no excess of cardiovascular disease was found. This study does not exclude the possibility that ethylene oxide is a human carcinogen but suggests that any risk of cancer from currently permitted occupational exposures is small.


Role of Entorhinal and Parahippocampal in Diagnosis of Alzheimer's Disease from Resting State EEG.
Alzheimer's disease (AD) poses a significant public health problem. An early diagnosis during the initial development stage of this neurodegenerative brain disorder is a requisite. Initial symptoms of AD involve dysfunctioning in brain memory which later progresses toward language, comprehension, reasoning, and social behavior. The degree of dysfunctionality in AD is accompanied by neuronal damage thereby leading to alteration in functional connectivity of brain regions with AD progression. In literature, substantial studies have focused on topological brain function characteristics, scalp EEG temporal features, and functional MRI or PET scan to diagnose AD. However, source domain based study using EEG is limited. This work establishes the significance of EEG based source domain connectivity in AD diagnosis. In particular, the cortical sources, Parahippocampal and Entorhinal, are particularly studied for cognitive processes and memory in AD and healthy control (HC). A publicly available AD and HC resting state EGG dataset is utilized for this purpose. The dipole imaging method converts surface EEG information into source space. Functional connectivity (FC), supervised classification, frequency analysis, and clustering are then utilized to establish the importance of the entorhinal and parahippocampal in AD diagnosis. The entorhinal source involved in memory is found to be a potential biomarker for AD diagnosis. This memory-associated source dynamics-based approach can further lead to early diagnosis of AD.


Prostate specific antigen in breast cancer, benign breast disease and normal breast tissue.
Prostate specific antigen (PSA) is a tumor marker used widely for the diagnosis and monitoring of prostatic adenocarcinoma. Recently, we provided evidence that PSA may also be produced by breast tumors. In this report we examined quantitatively the PSA levels in 199 breast tumors, 48 tissues with benign breast disease (BBD, 34 fibroadenomas), and 36 normal breast tissues. Significant amounts of PSA (> or = 0.030 ng of PSA per mg of total protein) were found in 28% of breast tumors, 65% of BBD tissues, and 33% of normal breast tissues. PSA positivity in breast tumors was highest in stage I disease (34%) and decreased with disease stage (24% in stage II and 18% in stage III-IV). Using polymerase chain reaction amplification we have shown PSA mRNA presence in patients with PSA protein-positive tissues (benign and malignant) but not in patients with PSA protein-negative tissues. Our data suggest that PSA is expressed frequently by normal breast tissue, by tissue of benign breast diseases, and by breast cancer tissue. Highest expression is seen in benign breast disease and lowest expression in advanced stage cancerous tissue. As PSA production is mediated by steroid hormones and their receptors, we propose that PSA may be a new marker of steroid hormone action in the normal or diseased female breast. The role of this enzyme in the development of breast diseases including breast cancer is currently unknown.


Syntrophus aciditrophicus sp. nov., a new anaerobic bacterium that degrades fatty acids and benzoate in syntrophic association with hydrogen-using microorganisms.
Strain SBT is a new, strictly anaerobic, gram-negative, nonmotile, non-sporeforming, rod-shaped bacterium that degrades benzoate and certain fatty acids in syntrophic association with hydrogen/formate-using microorganisms. Strain SBT produced approximately 3 mol of acetate and 0.6 mol of methane per mol of benzoate in coculture with Methanospirillum hungatei strain JF1. Saturated fatty acids, some unsaturated fatty acids, and methyl esters of butyrate and hexanoate also supported growth of strain SBT in coculture with Desulfovibrio strain G11. Strain SBT grew in pure culture with crotonate, producing acetate, butyrate, caproate, and hydrogen. The molar growth yield was 17 +/- 1 g cell dry mass per mol of crotonate. Strain SBT did not grow with fumarate, iron(III), polysulfide, or oxyanions of sulfur or nitrogen as electron acceptors with benzoate as the electron donor. The DNA base composition of strain SBT was 43.1 mol% G+C. Analysis of the 16 S rRNA gene sequence placed strain SBT in the delta-subdivision of the Proteobacteria, with sulfate-reducing bacteria. Strain SBT was most closely related to members of the genus Syntrophus. The clear phenotypic and genotypic differences between strain SBT and the two described species in the genus Syntrophus justify the formation of a new species, Syntrophus aciditrophicus.


Knuckle cracking and hand osteoarthritis.
Previous studies have not shown a correlation between knuckle cracking (KC) and hand osteoarthritis (OA). However, one study showed an inverse correlation between KC and metacarpophalangeal joint OA. We conducted a retrospective case-control study among persons aged 50 to 89 years who received a radiograph of the right hand during the last 5 years. Patients had radiographically proven hand OA, and controls did not. Participants indicated frequency, duration, and details of their KC behavior and known risk factors for hand OA. The prevalence of KC among 215 respondents (135 patients, 80 controls) was 20%. When examined in aggregate, the prevalence of OA in any joint was similar among those who crack knuckles (18.1%) and those who do not (21.5%; P = .548). When examined by joint type, KC was not a risk for OA in that joint. Total past duration (in years) and volume (daily frequency × years) of KC of each joint type also was not significantly correlated with OA at the respective joint. A history of habitual KC-including the total duration and total cumulative exposure-does not seem to be a risk factor for hand OA.


Developing standards for MRI evaluation of joints in children with juvenile idiopathic arthritis utilizing the temporomandibular joint as a model.
The treatment of a patient with juvenile idiopathic arthritis (JIA) is best monitored with standardized and validated tools to measure joint changes over time. Treatment approaches are best indicated if the clinicians are aware of the structural status of the joint at a given time, especially in anatomically deep joints for which clinical assessment is limited. Magnetic resonance imaging (MRI) is of utmost importance for assessment of deep joints and extra-articular soft tissue of the entire body for which ultrasound may be suboptimal. Because the distinction between pathologic and physiologic joint changes on MRI is key for proper diagnosis and treatment of patients with arthropathies, a comprehensive standardized approach is needed to effectively measure outcomes of growing joints of children with JIA. Such an approach is essential for both clinical assessment and to conduct clinical trials in patients with JIA treated in different centers around the world. To meet this need, several international imaging collaborative research groups have been developing MRI scales over the past years, including the MRI in JIA (JAMRI) special interest group within the Outcome Measures in Rheumatology (OMERACT) research network. This manuscript reviews the efforts of the OMERACT JAMRI working group to generate and validate pediatric MRI scoring systems for different joints in children with JIA that can have ubiquitous utilization anywhere in the world. In particular, it describes the different steps of development and validation of an MRI scale using the TMJ as a model.


Regulation of ribosomal protein S6 phosphorylation by casein kinase 1 and protein phosphatase 1.
Ribosomal protein S6 (rpS6) is a critical component of the 40 S ribosomal subunit that mediates translation initiation at the 5'-m(7)GpppG cap of mRNA. In response to mitogenic stimuli, rpS6 undergoes ordered C-terminal phosphorylation by p70 S6 kinases and p90 ribosomal S6 kinases on four conserved Ser residues (Ser-235, Ser-236, Ser-240, and Ser-244) whose modification potentiates rpS6 cap binding activity. A fifth site, Ser-247, is also known to be phosphorylated, but its function and regulation are not well characterized. In this study, we employed phospho-specific antibodies to show that Ser-247 is a target of the casein kinase 1 (CK1) family of protein kinases. CK1-dependent phosphorylation of Ser-247 was induced by mitogenic stimuli and required prior phosphorylation of upstream S6 kinase/ribosomal S6 kinase residues. CK1-mediated phosphorylation of Ser-247 also enhanced the phosphorylation of upstream sites, which implies that bidirectional synergy between C-terminal phospho-residues is required to sustain rpS6 phosphorylation. Consistent with this idea, CK1-dependent phosphorylation of rpS6 promotes its association with the mRNA cap-binding complex in vitro. Additionally, we show that protein phosphatase 1 (PP1) antagonizes rpS6 C terminus phosphorylation and cap binding in intact cells. These findings further our understanding of rpS6 phospho-regulation and define a direct link between CK1 and translation initiation.


Preventability of 28-Day Hospital Readmissions in General Internal Medicine Patients: A Retrospective Analysis at a Quaternary Hospital.
Unplanned hospital readmissions are associated with increased patient mortality and health care costs, yet only a fraction are likely to be preventable. This study's objective was to identify preventable hospital readmissions of general internal medicine patients, and their common causes. Patients who were discharged from the general internal medicine teaching service and readmitted to hospital within 28 days for 24 hours or more were recruited to the study; they were identified via the hospital electronic medical record system. Data were gathered via structured review of hospital charts/electronic medical records, along with standardized patient interviews. Unique to our study, a multidisciplinary panel of physicians, nurses, and hospital administrators adjudicated preventability and identified common causes of readmission. Fifty-five hospital readmissions were identified; 53% were adjudicated to be preventable. There was no difference in any variable analyzed between preventable and nonpreventable readmissions. The most common causes of preventable readmissions were inadequate coordination of community services upon discharge, insufficient clinical postdischarge follow-up, and suboptimal end-of-life care. This study identified a higher proportion of preventable 28-day hospital readmissions when compared with prior research. Increased involvement of palliative care during initial hospitalization for appropriate conditions and improvements in care after discharge may reduce preventable hospital readmissions.


Neonatal Parotitis: A Case Report.
Acute suppurative parotitis is a rare finding in the neonate. It is commonly caused by Staphylococcus aureus, but other bacterial isolates may be emerging. It is a novel disease for this age group and requires unique management. Only 32 cases of neonatal suppurative parotitis have been described in the English-language literature over the last 35 years. We describe a case of a 14-day-old male who presented to the pediatric emergency department with a 24-hour history of swelling and redness of the right cheek. On examining him, purulent material was seen inside his oral cavity. He was subsequently hospitalized with a diagnosis of neonatal suppurative parotitis and received five days of parenteral antibiotics with improvement in swelling and redness. He was discharged home with oral antibiotics. Although neonatal suppurative parotitis is rare, it should be suspected in newborns presenting with an erythematous pre-auricular mass with or without any predisposing factors. We describe a rare case of acute suppurative parotitis in a neonate and review the published literature.


[Frequency of sex chromosome nondisjunction as affected by microtubule destabilization and heat shock in various lines of Drosophila melanogaster].
Vinblastine (Vb), a drug belonging to a group of mitotic poisons, was shown to induce sexual chromosome nondisjunction and loss (SCNL) in oogenesis of different strains of Drosophila melanogaster. Heat shock (37 degrees C, 45 min) decreases the frequency of these events. The highest level of nondisjunction was demonstrated in the temperature-sensitive strain both after heat shock and Vb treatment. No increase of SCNL frequency in oocytes of females treated with griseofulvin (Gf) and Colchicine (Cl), analogues of Vb.


Strategies for evaluating the environment-public health interaction of long-term latency disease: the quandary of the inconclusive case-control study.
Environmental links to disease are difficult to uncover because environmental exposures are variable in time and space, contaminants occur in complex mixtures, and many diseases have a long time delay between exposure and onset. Furthermore, individuals in a population have different activity patterns (e.g., hobbies, jobs, and interests), and different genetic susceptibilities to disease. As such, there are many potential confounding factors to obscure the reasons that one individual gets sick and another remains healthy. An important method for deducing environmental associations with disease outbreak is the retrospective case-control study wherein the affected and control subject cohorts are studied to see what is different about their previous exposure history. Despite success with infectious diseases (e.g., food poisoning, and flu), case-control studies of cancer clusters rarely have an unambiguous outcome. This is attributed to the complexity of disease progression and the long-term latency between exposure and disease onset. In this article, we consider strategies for investigating cancer clusters and make some observations for improving statistical power through broader non-parametric approaches wherein sub-populations (i.e., whole towns), rather than individuals, are treated as the cases and controls, and the associated cancer rates are treated as the dependent variable. We subsequently present some ecological data for tungsten and cobalt from studies by University of Arizona researchers who document elevated levels of tungsten and cobalt in Fallon, NV. These results serve as candidates for future hybrid ecologic case-control investigations of childhood leukemia clusters.


Semen quality and sexual hormones in greenhouse workers.
This study focused on determining the testicular function of greenhouse workers exposed to pesticides. Semen was examined for 122 of 199 eligible men (61%) from 30 ornamental flower greenhouses. Sperm concentration, morphology, and viability were measured according to World Health Organization guidelines, and the curvilinear sperm velocity was determined by a computer-assisted analysis of video recordings. Three groups were formed according to expert judgment of current exposure to pesticides from cultures, pesticide formulations, and the transfer of pesticide residues from leaves to hands, and also ranked according to years of work in a greenhouse. The risk estimates were adjusted for the effects of sexual abstinence and other potentially confounding factors. According to current exposure the median values of sperm concentration and the proportion of normal spermatozoa were 60% and 14% lower, respectively, in the high-level exposure group (N=13) than in the low-level group (N=44), and the values of the intermediate group fell in between. The adjusted differences between the high-level and low-level exposure groups were statistically significant, while no differences were observed for the viability and velocity of sperm and sexual hormones. The median sperm concentration was 40% lower for the men with > 10 years' experience in a greenhouse than for those with < 5 years' experience. The age-adjusted testosterone/sex-hormone-binding globulin ratio declined 1.9% (95% confidence interval 0.4-3.4%) per year of work. The results are compatible with the hypothesis that male fecundity may be at risk from exposure to pesticides in the manual handling of cultures in greenhouses.


Information processing at the foxa node of the sea urchin endomesoderm specification network.
The foxa regulatory gene is of central importance for endoderm specification across Bilateria, and this gene lies at an essential node of the well-characterized sea urchin endomesoderm gene regulatory network (GRN). Here we experimentally dissect the cis-regulatory system that controls the complex pattern of foxa expression in these embryos. Four separate cis-regulatory modules (CRMs) cooperate to control foxa expression in different spatial domains of the endomesoderm, and at different times. A detailed mutational analysis revealed the inputs to each of these cis-regulatory modules. The complex and dynamic expression of foxa is regulated by a combination of repressors, a permissive switch, and multiple activators. A mathematical kinetic model was applied to study the dynamic response of foxa cis-regulatory modules to transient inputs. This study shed light on the mesoderm-endoderm fate decision and provides a functional explanation, in terms of the genomic regulatory code, for the spatial and temporal expression of a key developmental control gene.


Benzyl and phenylthiomethyl silanes: a new class of bifunctional linchpins for type II anion relay chemistry (ARC).
A new class of bifunctional linchpins bearing electrophilic sites beta or gamma to a silyl group have been designed, synthesized, and demonstrated to be competent in tricomponent unions exploiting Type II Anion Relay Chemistry (ARC). High diastereoselectivities were observed when a phenyl moiety (R(2)) served as an anion-stabilizing group (ASG) adjacent to a methyl susbtituent (R(1)), while diastereomeric mixtures were obtained when a phenylthiol moiety served as the ASG, irrespective of alpha-substitution.


Have giant lobelias evolved several times independently? Life form shifts and historical biogeography of the cosmopolitan and highly diverse subfamily Lobelioideae (Campanulaceae).
The tendency of animals and plants to independently develop similar features under similar evolutionary pressures - convergence - is a widespread phenomenon in nature. In plants, convergence has been suggested to explain the striking similarity in life form between the giant lobelioids (Campanulaceae, the bellflower family) of Africa and the Hawaiian Islands. Under this assumption these plants would have developed the giant habit from herbaceous ancestors independently, in much the same way as has been suggested for the giant senecios of Africa and the silversword alliance of Hawaii. Phylogenetic analyses based on plastid (rbcL, trnL-F) and nuclear (internal transcribed spacer [ITS]) DNA sequences for 101 species in subfamily Lobelioideae demonstrate that the large lobelioids from eastern Africa the Hawaiian Islands, and also South America, French Polynesia and southeast Asia, form a strongly supported monophyletic group. Ancestral state reconstructions of life form and distribution, taking into account phylogenetic uncertainty, indicate their descent from a woody ancestor that was probably confined to Africa. Molecular dating analyses using Penalized Likelihood and Bayesian relaxed clock approaches, and combining multiple calibration points, estimate their first diversification at approximately 25-33 million years ago (Ma), shortly followed by several long-distance dispersal events that resulted in the current pantropical distribution. These results confidently show that lobelioid species, commonly called 'giant', are very closely related and have not developed their giant form from herbaceous ancestors independently. This study, which includes the hitherto largest taxon sampling for subfamily Lobelioideae, highlights the need for a broad phylogenetic framework for testing assumptions about morphological development in general, and convergent evolution in particular.


Trajectories of Mental Health-Related Service Use Among Adolescents With Histories of Early Externalizing Problems.
To inform efforts to reduce costly service utilization, the present study examined longitudinal trajectories of mental health-related outpatient and residential service use among at-risk youth with a history of early externalizing problems. A cohort of 809 children in the Fast Track Project, a multisite longitudinal study of children at risk for conduct disorder, were followed prospectively from kindergarten through 12th grade. They resided in high-risk areas with high rates of poverty, crime, and violence. Their outpatient and residential service use was assessed annually between sixth and 12th grades through parent report. Growth mixture modeling was applied to model individual differences in trajectories of service use during this period. Teacher, parent, and observer-reported childhood predictors of those trajectories were also examined. Most youths had minimal service use during preadolescence into adolescence. However, approximately 31% had moderate probability of using outpatient counseling services, and approximately 8% had elevated probability of seeing a family doctor for mental health needs. For residential services, approximately 6% had moderate to high probability of service use that peaked during transition to high school, whereas close to 5% had service use that dramatically increased during high school. Childhood predictors of these trajectories included earlier externalizing, internalizing, and emotion regulation problems. This study is the first to use person-centered analytic methods to examine longitudinal trajectories in mental health-related service use among at-risk adolescents. Timely treatment for severe externalizing problems, comorbid internalizing problems, and emotion dysregulation during childhood may be crucial for preventing chronic service use.


Tn5 insertion mutations in the mercuric ion resistance genes derived from plasmid R100.
The mercuric resistance (mer) genes of plasmid R100 were cloned into plasmid pBR322. A series of transposon Tn5 insertion mutations in the mer genes were isolated and mapped. The mutants were characterized phenotypically by their sensitivity to Hg2+ and by binding and volatilization of 203Hg2+. Dominance and complementation tests were also performed. Mutations affecting the previously described mer genes merR (regulation), merT (transport), and merA (reductase) were characterized. Evidence was obtained for two new mer genes, which have been called merC and merD. A restriction enzyme map of the mer region was drawn with the gene order merRTCAD. Transcriptional merR-lac and merA-lac fusions were generated by insertion of phage Mu d amp lac into plasmid R100-1. These were used to study regulation of mer gene expression. The merR gene product appears to regulate negatively its own expression as well as acting as both a negative and a positive regulator of the merTCA genes.


Combined Metabolomic Analysis of Plasma and Tissue Reveals a Prognostic Risk Score System and Metabolic Dysregulation in Esophageal Squamous Cell Carcinoma.
Background: Esophageal squamous cell carcinoma (ESCC) is a gastrointestinal malignancy with a poor prognosis. Although studies have shown metabolic reprogramming to be linked to ESCC development, no prognostic metabolic biomarkers or potential therapeutic metabolic targets have been identified. Method: The present study investigated some circulating metabolites associated with overall survival in 276 curatively resected ESCC patients using liquid chromatography/mass spectrometry metabolomics and Kaplan-Meier analysis. Tissue metabolomic analysis of 23-paired ESCC tissue samples was performed to discover metabolic dysregulation in ESCC cancerous tissue. A method consisting of support vector machine recursive feature elimination and LIMMA differential expression analysis was utilized to select promising feature genes within transcriptomic data from 179-paired ESCC tissue samples. Joint pathway analysis with genes and metabolites identified relevant metabolic pathways and targets for ESCC. Results: Four metabolites, kynurenine, 1-myristoyl-glycero-3-phosphocholine (LPC(14:0)sn-1), 2-piperidinone, and hippuric acid, were identified as prognostic factors in the preoperative plasma from ESCC patients. A risk score consisting of kynurenine and LPC(14:0)sn-1 significantly improved the prognostic performance of the tumor-node-metastasis staging system and was able to stratify risk for ESCC. Combined tissue metabolomic analysis and support vector machine recursive feature elimination gene selection revealed dysregulated kynurenine pathway as an important metabolic feature of ESCC, including accumulation of tryptophan, formylkynurenine, and kynurenine, as well as up-regulated indoleamine 2,3-dioxygenase 1 in ESCC cancerous tissue. Conclusions: This work identified for the first time four potential prognostic circulating metabolites. In addition, kynurenine pathway metabolism was shown to be up-regulated tryptophan-kynurenine metabolism in ESCC. Results not only provide a metabolite-based risk score system for prognosis, but also improve the understanding of the molecular basis of ESCC onset and progression, and as well as novel potential therapeutic targets for ESCC.


Cost analysis of photobiomodulation in tibia fracture in the Brazilian public health system.
Managing tibial fractures requires substantial health resources, which costs the health system. This study aimed to describe the costs of photobiomodulation (PBM) with LEDs in the healing process of soft tissue lesions associated with tibial fracture compared to a placebo. Economic analysis was performed based on a randomized controlled clinical trial, with a simulation of the cost-effectiveness and incremental cost model. Adults (n = 27) hospitalized with tibia fracture awaiting definitive surgery were randomized into two distinct groups: the PBM Group (n = 13) and the Control Group with simulated phototherapy (n = 14). To simulate the cost-effectiveness and incremental cost model, the outcome was the evolution of wound resolution by the BATES-JENSEN scale and time of wound resolution in days. The total cost of treatment for the Control group was R$21,164.56, and a difference of R$7,527.10 more was observed when compared to the treatment of the PBM group. The proposed intervention did not present incremental cost since the difference in the costs to reduce measures between the groups was smaller for the PBM group. When analyzing the ICER (Incremental cost-effectiveness ratio), it would be possible to save R$3,500.98 with PBM and decrease by 2.15 points in the daily average on the BATES-JENSEN scale. It is concluded, therefore, that PBM can be a supportive therapy of clinical and economic interest in a hospital setting.


Sulfonylureas in the Current Practice of Type 2 Diabetes Management: Are They All the Same? Consensus from the Gulf Cooperation Council (GCC) Countries Advisory Board on Sulfonylureas.
Since their inception in the commercial market in the mid-twentieth century, sulfonylureas (SUs) have remained a therapeutic option in the management of type 2 diabetes (T2D). Despite their established glucose-lowering effects, there is no consensus among global experts and modern guidelines regarding the priority of SUs in relation to other therapeutic options, given the lack of evidence that SUs are associated with a low risk of macrovascular events and excess mortality. However, findings from recent trials and real-time observations have resolved this contentious issue somewhat, albeit to varying degrees. The present consensus discusses the role of SUs in contemporary diabetes management in the Gulf Cooperation Council (GCC) countries. Regional experts from these countries gathered virtually to formulate a consensus following presentations of topics relevant to SU therapy with an emphasis on gliclazide, including long-term efficacy, cost, end-organ benefits, and side effects, based on up-to-date evidence. The present narrative review reflects the conclusions of this assembly and provides a platform upon which future guidelines for the use of SUs in the GCC can be tailored.


Assessment of a Business-to-Consumer (B2C) model for Telemonitoring patients with Chronic Heart Failure (CHF).
The purpose of this study is to assess the Business-to-Consumer (B2C) model for telemonitoring patients with Chronic Heart Failure (CHF) by analysing the value it creates, both for organizations or ventures that provide telemonitoring services based on it, and for society. The business model assessment was based on the following categories: caveats, venture type, six-factor alignment, strategic market assessment, financial viability, valuation analysis, sustainability, societal impact, and technology assessment. The venture valuation was performed for three jurisdictions (countries) - Singapore, the Netherlands and the United States - in order to show the opportunities in a small, medium-sized, and large country (i.e. population). The business model assessment revealed that B2C telemonitoring is viable and profitable in the Innovating in Healthcare Framework. Analysis of the ecosystem revealed an average-to-excellent fit with the six factors. The structure and financing fit was average, public policy and technology alignment was good, while consumer alignment and accountability fit was deemed excellent. The financial prognosis revealed that the venture is viable and profitable in Singapore and the Netherlands but not in the United States due to relatively high salary inputs. The B2C model in telemonitoring CHF potentially creates value for patients, shareholders of the service provider, and society. However, the validity of the results could be improved, for instance by using a peer-reviewed framework, a systematic literature search, case-based cost/efficiency inputs, and varied scenario inputs.


SAGA/ADA complex subunit Ada2 is required for Cap1- but not Mrr1-mediated upregulation of the Candida albicans multidrug efflux pump MDR1.
Overexpression of the multidrug efflux pump MDR1 is one mechanism by which the pathogenic yeast Candida albicans develops resistance to the antifungal drug fluconazole. The constitutive upregulation of MDR1 in fluconazole-resistant, clinical C. albicans isolates is caused by gain-of-function mutations in the zinc cluster transcription factor Mrr1. It has been suggested that Mrr1 activates MDR1 transcription by recruiting Ada2, a subunit of the SAGA/ADA coactivator complex. However, MDR1 expression is also regulated by the bZIP transcription factor Cap1, which mediates the oxidative stress response in C. albicans. Here, we show that a hyperactive Mrr1 containing a gain-of-function mutation promotes MDR1 overexpression independently of Ada2. In contrast, a C-terminally truncated, hyperactive Cap1 caused MDR1 overexpression in a wild-type strain but only weakly in mutants lacking ADA2. In the presence of benomyl or H2O2, compounds that induce MDR1 expression in an Mrr1- and Cap1-dependent fashion, MDR1 was upregulated with the same efficiency in wild-type and ada2Δ cells. These results indicate that Cap1, but not Mrr1, recruits Ada2 to the MDR1 promoter to induce the expression of this multidrug efflux pump and that Ada2 is not required for MDR1 overexpression in fluconazole-resistant C. albicans strains containing gain-of-function mutations in Mrr1.


Penicillin-induced oxidative stress: effects on antioxidative response of midgut tissues in instars of Galleria mellonella.
Penicillin and other antibiotics are routinely incorporated in insect culture media. Although culturing insects in the presence of antibiotics is a decades-old practice, antibiotics can exert deleterious influences on insects. In this article, we test the hypothesis that one of the effects of dietary penicillin is to increase oxidative stress on insects. The effects of penicillin on midgut concentrations of the oxidative stress indicator malondialdehyde (MDA) and on midgut antioxidant enzyme (superoxide dismutase [SOD], catalase [CAT], glutathione S-transferase [GST], and glutathione peroxidase [GPx]) and transaminases (alanine aminotransferase and aspartate aminotransferase) activities in greater wax moth, Galleria mellonella (L.), were investigated. The insects were reared from first instars on artificial diets containing 0.001, 0.01, 0.1, or 1.0 g penicillin per 100 g of diets. MDA content was significantly increased in the midgut tissues of each larval instar reared in the presence of high penicillin concentrations. Activities of antioxidant and transaminase enzymes did not show a consistent pattern with respect to penicillin concentrations in diet or age of larvae. Despite the increased penicillin-induced oxidative stress in gut tissue, antioxidant and transaminase enzymes did not correlate with oxidative stress level or between each other in larvae of other age stages except for the seventh instar. We found a significant negative correlation of MDA content with SOD and GST activities in seventh instars. SOD activity was also negatively correlated with CAT activity in seventh instars. These results suggest that exposure to dietary penicillin resulted in impaired enzymatic antioxidant defense capacity and metabolic functions in wax moth larval midgut tissues and that the resulting oxidative stress impacts midgut digestive physiology.


Calcium dependence of voltage sensitivity in adenosine 3',5'-cyclic phosphate-stimulated sodium current in Pleurobranchaea.
1. Ionophoretic injection of cyclic AMP into a voltage-clamped molluscan neurone caused a transient slow inward current (Isi) whose amplitude was enhanced by depolarization. Na+-replaced salines abolished the current, placing it with cyclic AMP-stimulated Na+ currents of other gastropod species. 2. Isi amplitude was suppressed by extracellular Ca2+. The amplitude increased up to 4-fold at holding potentials of -50 mV in nominally Ca2+-free saline. Ion substitutions showed that Ca2+ suppressed Isi more effectively than Mg2+, Co2+, Cd2+, Mn2+, Ba2+ or Sr2+. 3. Voltage sensitivity of Isi was abolished by low-Ca2+ salines, by the Ca2+ current blocker Co2+ and by substitution of Ba2+ or Sr2+ as Ca2+ channel current carriers. In such salines Isi showed no appreciable change in amplitude at holding potentials between -70 and -25 mV. 4. Intracellular injection of the Ca2+ chelator EGTA both augmented the amplitude of the current and its duration. EGTA injection failed to suppress the Ca2+-dependent voltage sensitivity of Isi. Intracellular injection of concentrated 3-N-(morpholino) propanesulphonic acid (MOPS) pH buffer to inhibit secondary, Ca2+-dependent intracellular acidification also failed to suppress the voltage sensitivity, as did injections of a mixed EGTA and MOPS solution. 5. While the data indicate a requirement for extracellular Ca2+ in conferring voltage sensitivity, they do not support a role for an intracellular action. An extracellular binding site for Ca2+ could mediate the voltage sensitivity, either by local depolarization-dependent changes in extracellular Ca2+ concentration or through direct voltage-sensitive block of the Isi channel.


Exposure to DDT metabolite p,p'-DDE increases autoimmune type 1 diabetes incidence in NOD mouse model.
The incidence of autoimmune Type 1 diabetes (T1D) has been steadily rising in developed countries. Although the exact cause of T1D remains elusive, it is known that both genetics and environmental factors play a role in its immunopathogenesis. Whereas a positive association between p,p'-DDE, a DDT metabolite, and Type 2 diabetes (T2D) has been well established, its role in T1D development in an experimental animal model has never been elucidated. This study seeks to investigate the effects of DDE exposure on the development of T1D in a NOD mouse model. As T1D is a T-cell-mediated disease, the underlying mechanism of DDE action on T-cells was studied in vitro and, in the context of acute and chronic DDE exposure, in vivo by investigating lymphocytes' viability, proliferation, their subsets and cytokine profiles. Chronic high-dose DDE treatment, initiated in pre-diabetic 8-week-old NOD females administered twice weekly intraperitoneally with 50 mg/kg DDE, significantly increased diabetes incidence and augmented disease severity in treated animals. Whereas T-cell proliferation and cell viability in the spleens of treated mice were not affected, diabetogenic action of chronic DDE exposure was associated with a decrease in regulatory T-cells and a suppression of secretion of protective cytokines, such as IL-4 and IL-10. Interestingly, an acute high-dose in vivo treatment of 8-week-old NOD males with 100 mg DDE/kg, administered intraperitoneally every other day over a period of 10 days, increased T-cell proliferation and potentiated pro-inflammatory and TH1-type cytokine secretion, without affecting the splenocytes viability and the T-cell sub-populations. These results confirm that high-dose DDE treatments affect the immune system, in particularly T-cell function. In conclusion, this study shows for the first time that high-dose chronic DDE exposure exhibits a diabetogenic potential, with an underlying immunomodulatory mechanism of action, in the development of T1D in an experimental mouse NOD model.