Synergistic and Additive Effects of Epigallocatechin Gallate and Digitonin on Plasmodium Sporozoite Survival and Motility

BACKGROUND: Most medicinal plants contain a mixture of bioactive compounds, including chemicals that interact with intracellular targets and others that can act as adjuvants to facilitate absorption of polar agents across cellular membranes. However, little is known about synergistic effects between such potential drug candidates and adjuvants. To probe for such effects, we tested the green tea compound epigallocatechin gallate (EGCG) and the membrane permeabilising digitonin on Plasmodium sporozoite motility and viability. METHODOLOGY/PRINCIPAL FINDINGS: Green fluorescent P. berghei sporozoites were imaged using a recently developed visual screening methodology. Motility and viability parameters were automatically analyzed and IC50 values were calculated, and the synergism of drug and adjuvant was assessed by the fractional inhibitory concentration index. Validating our visual screening procedure, we showed that sporozoite motility and liver cell infection is inhibited by EGCG at nontoxic concentrations. Digitonin synergistically increases the cytotoxicity of EGCG on sporozoite survival, but shows an additive effect on sporozoite motility. CONCLUSIONS/SIGNIFICANCE: We proved the feasibility of performing highly reliable visual screens for compounds against Plasmodium sporozoites. We thereby could show an advantage of administering mixtures of plant metabolites on inhibition of cell motility and survival. Although the effective concentration of both drugs is too high for use in malaria prophylaxis, the demonstration of a synergistic effect between two plant compounds could lead to new avenues in drug discovery

Psychopharmacologic Treatment of Children Prenatally Exposed to Drugs of Abuse

Objective This pilot study compared the pharmacologic treatment history and clinical outcomes observed in pediatric outpatients with psychiatric disorders exposed to drugs of abuse in utero to those of an age-matched, sex-matched and psychiatric disorder-matched, non-drug-exposed group. Methods In this matched cohort study, medical records of children treated at an academic, child and adolescent psychiatry outpatient clinic were reviewed. Children with caregiver-reported history of prenatal drug exposure were compared with a non-drug-exposed control group being cared for by the same providers. Patients were rated with the Clinical Global Impressions—Severity scale (CGI-S) throughout treatment. The changes in pre-treatment and post-treatment CGI-S scores and the total number of medication trials were determined between groups. Results The drug-exposed group (n = 30) had a higher total number of lifetime medication trials compared with the non-drug-exposed group (n = 28) and were taking significantly more total medications, at their final assessment. Unlike the non-drug-exposed group, the drug-exposed group demonstrated a lack of clinical improvement. Conclusions These results suggest that in utero drug-exposed children may be more treatment-refractory to or experience greater side effects from the pharmacologic treatment of psychiatric disorders than controls, although we cannot determine if early environment or drugs exposure drives these findings

Neutron-induced background in the CONUS experiment

CONUS is a novel experiment aiming at detecting elastic neutrino nucleus scattering in the fully coherent regime using high-purity Germanium (Ge) detectors and a reactor as antineutrino ($\bar\nu$) source. The detector setup is installed at the commercial nuclear power plant in Brokdorf, Germany, at a very small distance to the reactor core in order to guarantee a high flux of more than 10$^{13}\bar\nu$/(s$\cdot$cm$^2$). For the experiment, a good understanding of neutron-induced background events is required, as the neutron recoil signals can mimic the predicted neutrino interactions. Especially neutron-induced events correlated with the thermal power generation are troublesome for CONUS. On-site measurements revealed the presence of a thermal power correlated, highly thermalized neutron field with a fluence rate of (745$\pm$30)cm$^{-2}$d$^{-1}$. These neutrons that are produced by nuclear fission inside the reactor core, are reduced by a factor of $\sim$10$^{20}$ on their way to the CONUS shield. With a high-purity Ge detector without shield the $\gamma$-ray background was examined including highly thermal power correlated $^{16}$N decay products as well as $\gamma$-lines from neutron capture. Using the measured neutron spectrum as input, it was shown, with the help of Monte Carlo simulations, that the thermal power correlated field is successfully mitigated by the installed CONUS shield. The reactor-induced background contribution in the region of interest is exceeded by the expected signal by at least one order of magnitude assuming a realistic ionization quenching factor of 0.2.Comment: 28 pages, 28 figure

Impact of acamprosate on plasma amyloid-β precursor protein in youth: a pilot analysis in fragile X syndrome-associated and idiopathic autism spectrum disorder suggests a pharmacodynamic protein marker

BACKGROUND: Understanding of the pathophysiology of autism spectrum disorder (ASD) remains limited. Brain overgrowth has been hypothesized to be associated with the development of ASD. A derivative of amyloid-β precursor protein (APP), secreted APPα (sAPPα), has neuroproliferative effects and has been shown to be elevated in the plasma of persons with ASD compared to control subjects. Reduction in sAPPα holds promise as a novel molecular target of treatment in ASD. Research into the neurochemistry of ASD has repeatedly implicated excessive glutamatergic and deficient GABAergic neurotransmission in the disorder. With this in mind, acamprosate, a novel modulator of glutamate and GABA function, has been studied in ASD. No data is available on the impact of glutamate or GABA modulation on sAPPα function. METHODS: Plasma APP derivative levels pre- and post-treatment with acamprosate were determined in two pilot studies involving youth with idiopathic and fragile X syndrome (FXS)-associated ASD. We additionally compared baseline APP derivative levels between youth with FXS-associated or idiopathic ASD. RESULTS: Acamprosate use was associated with a significant reduction in plasma sAPP(total) and sAPPα levels but no change occurred in Aβ40 or Aβ42 levels in 15 youth with ASD (mean age: 11.1 years). Youth with FXS-associated ASD (n = 12) showed increased sAPPα processing compared to age-, gender- and IQ-match youth with idiopathic ASD (n = 11). CONCLUSIONS: Plasma APP derivative analysis holds promise as a potential biomarker for use in ASD targeted treatment. Reduction in sAPP (total) and sAPPα may be a novel pharmacodynamic property of acamprosate. Future study is required to address limitations of the current study to determine if baseline APP derivative analysis may predict subgroups of persons with idiopathic or FXS-associated ASD who may respond best to acamprosate or to potentially other modulators of glutamate and/or GABA neurotransmission

Initial analysis of peripheral lymphocytic extracellular signal related kinase activation in autism

BACKGROUND: Dysregulation of extracellular signal-related kinase (ERK) activity has been potentially implicated in the pathophysiology of autistic disorder (autism). ERK is part of a central intracellular signaling cascade responsible for a myriad of cellular functions. ERK is expressed in peripheral blood lymphocytes, and measurement of activated (phosphorylated) lymphocytic ERK is commonly executed in many areas of medicine. We sought to conduct the first study of ERK activation in humans with autism by utilizing a lymphocytic ERK activation assay. We hypothesized that ERK activation would be enhanced in peripheral blood lymphocytes from persons with autism compared to those of neurotypical control subjects. METHOD: We conducted an initial study of peripheral lymphocyte ERK activation in 45 subjects with autism and 26 age- and gender-matched control subjects (total n = 71). ERK activation was measured using a lymphocyte counting method (primary outcome expressed as lymphocytes staining positive for cytosolic phosphorylated ERK divided by total cells counted) and additional Western blot analysis of whole cell phosphorylated ERK adjusted for total ERK present in the lymphocyte lysate sample. RESULTS: Cytosolic/nuclear localization of pERK activated cells were increased by almost two-fold in the autism subject group compared to matched neurotypical control subjects (cell count ratio of 0.064 ± 0.044 versus 0.034 ± 0.031; p = 0.002). Elevated phosphorylated ERK levels in whole cell lysates also showed increased activated ERK in the autism group compared to controls (n = 54 total) in Western blot analysis. CONCLUSIONS: The results of this first in human ERK activation study are consistent with enhanced peripheral lymphocytic ERK activation in autism, as well as suggesting that cellular compartmentalization of activated ERK may be altered in this disorder. Future work will be required to explore the impact of concomitant medication use and other subject characteristics such as level of cognitive functioning on ERK activation

Radio Continuum and Recombination Line Study of UC HII Regions with Extended Envelopes

We have carried out 21 cm radio continuum observations of 16 UC HII regions using the VLA (D-array) in search of associated extended emission. We have also observed H76$_\alpha$ recombination line towards all the sources and He76$_\alpha$ line at the positions with strong H76$_\alpha$ line emission. The UC HII regions have simple morphologies and large (>10) ratios of single-dish to VLA fluxes. Extended emission was detected towards all the sources. The extended emission consists of one to several compact components and a diffuse extended envelope. All the UC HII regions but two are located in the compact components, where the UC HII regions always correspond to their peaks. The compact components with UC HII regions are usually smaller and denser than those without UC HII regions. Our recombination line observations indicate that the ultracompact, compact, and extended components are physically associated. The UC HII regions and their associated compact components are likely to be ionized by the same sources on the basis of the morphological relations mentioned above. This suggests that almost all of the observed UC HII regions are not `real' UC HII regions and that their actual ages are much greater than their dynamical age (<10000 yr). We find that most of simple UC HII regions previously known have large ratios of single-dish to VLA fluxes, similar to our sources. Therefore, the `age problem' of UC HII regions does not seem to be as serious as earlier studies argued. We present a simple model that explains extended emission around UC HII regions. Some individual sources are discussed.Comment: 29 pages, 28 postscript figures, Accepted for publication in Ap

HNO Protects the Myocardium against Reperfusion Injury, Inhibiting the mPTP Opening via PKCε Activation

Donors of nitroxyl (HNO), the one electron-reduction product of nitric oxide (NO. ), posi-tively modulate cardiac contractility/relaxation while limiting ischemia-reperfusion (I/R) injury. The mechanisms underpinning HNO anti-ischemic effects remain poorly understood. Using isolated perfused rat hearts subjected to 30 min global ischemia/1 or 2 h reperfusion, here we tested whether, in analogy to NO., HNO protection requires PKCε translocation to mitochondria and KATP channels activation. To this end, we compared the benefits afforded by ischemic preconditioning (IPC; 3 cycles of I/R) with those eventually granted by the NO. donor, diethylamine/NO, DEA/NO, and two chemically unrelated HNO donors: Angeli’s salt (AS, a prototypic donor) and isopropyla-mine/NO (IPA/NO, a new HNO releaser). All donors were given for 19 min before I/R injury. In control I/R hearts (1 h reperfusion), infarct size (IS) measured via tetrazolium salt staining was 66 ± 5.5% of the area at risk. Both AS and IPA/NO were as effective as IPC in reducing IS [30.7 ± 2.2 (AS), 31 ± 2.9 (IPA/NO), and 31 ± 0.8 (IPC), respectively)], whereas DEA/NO was significantly less so (36.2 ± 2.6%, p < 0.001 vs. AS, IPA/NO, or IPC). IPA/NO protection was still present after 120 min of reperfusion, and the co-infusion with the PKCε inhibitor (PKCV1-2500 nM) prevented it (IS = 30 ± 0.5 vs. 61 ± 1.8% with IPA/NO alone, p < 0.01). Irrespective of the donor, HNO anti-ischemic effects were insensitive to the KATP channel inhibitor, 5-OH decanoate (5HD, 100 μM), that, in contrast, abrogated DEA/NO protection. Finally, both HNO donors markedly enhanced the mitochondrial permeability transition pore (mPTP) ROS threshold over control levels (≅35–40%), an action again insensitive to 5HD. Our study shows that HNO donors inhibit mPTP opening, thus limiting myo-cyte loss at reperfusion, a beneficial effect that requires PKCε translocation to the mitochondria but not mitochondrial K+ channels activation

Far infrared mapping of three Galactic star forming regions : W3(OH), S 209 & S 187

Three Galactic star forming regions associated with W3(OH), S209 and S187 have been simultaneously mapped in two trans-IRAS far infrared (FIR) bands centered at ~ 140 and 200 micron using the TIFR 100 cm balloon borne FIR telescope. These maps show extended FIR emission with structures. The HIRES processed IRAS maps of these regions at 12, 25, 60 & 100 micron have also been presented for comparison. Point-like sources have been extracted from the longest waveband TIFR maps and searched for associations in the other five bands. The diffuse emission from these regions have been quantified, which turns out to be a significant fraction of the total emission. The spatial distribution of cold dust (T < 30 K) for two of these sources (W3(OH) & S209), has been determined reliably from the maps in TIFR bands. The dust temperature and optical depth maps show complex morphology. In general the dust around S209 has been found to be warmer than that in W3(OH) region.Comment: Accepted for publication in Journal of Astrophysics and Astronomy (20 pages including 8 figures & 3 tables