Evidence of a Monoaminergic-Cholinergic Imbalance Related to Visual Hallucinations in Lewy Body Dementia

Senile dementia of Lewy body type is characterized clinically by a relatively acute onset of fluctuating memory loss and confusion, frequently accompanied by visual hallucinations. Neurochemical analyses of temporal cortex has revealed a distinction between hallucinating and nonhallucinating patients in both cholinergic and monaminergic transmitter activities. In contrast with the cholinergic enzyme choline acetyltransferase, which was more extensively reduced in hallucinating individuals, serotonergic S2 receptor binding and both dopamine and serotonin metabolites were significantly decreased in nonhallucinating cases. These results suggest that an imbalance between monaminergic and cholinergic transmitters is involved in hallucinogenesis in the human brain.     

The overlooked role of a biotin precursor for marine bacteria - desthiobiotin as an escape route for biotin auxotrophy

Biotin (vitamin B₇) is involved in a wide range of essential biochemical reactions and a crucial micronutrient that is vital for many pro- and eukaryotic organisms. The few biotin measurements in the world’s oceans show that availability is subject to strong fluctuations. Numerous marine microorganisms exhibit biotin auxotrophy and therefore rely on supply by other organisms. Desthiobiotin is the primary precursor of biotin and has recently been detected at concentrations similar to biotin in seawater. The last enzymatic reaction in the biotin biosynthetic pathway converts desthiobiotin to biotin via the biotin synthase (BioB). The role of desthiobiotin as a precursor of biotin synthesis in microbial systems, however, is largely unknown. Here we demonstrate experimentally that bacteria can overcome biotin auxotrophy if they retain the bioB gene and desthiobiotin is available. A genomic search of 1068 bacteria predicts that the biotin biosynthetic potential varies greatly among different phylogenetic groups and that 20% encode solely bioB and thus can potentially overcome biotin auxotrophy. Many Actino- and Alphaproteobacteria cannot synthesize biotin de novo, but some possess solely bioB, whereas the vast majority of Gammaproteobacteria and Flavobacteriia exhibit the last four crucial biotin synthesis genes. We detected high intra- and extracellular concentrations of the precursor relative to biotin in the prototrophic bacterium, Vibrio campbellii, with extracellular desthiobiotin reaching up to 1.09 ± 0.15*10⁶ molecules per cell during exponential growth. Our results provide evidence for the ecological role of desthiobiotin as an escape route to overcome biotin auxotrophy for bacteria in the ocean and presumably in other ecosystems.Subject terms: Water microbiology, Ecosystem ecology, Marine microbiology     

Phorate triggers oxidative stress and mitochondrial dysfunction to enhance micronuclei generation and DNA damage in human lymphocytes

Herein, we studied phorate for its toxicological effects in human lymphocytes. Phorate treatment for 3 h has induced significant increase in the lymphocytic DNA damage. Compared to control, comet data from highest concentration of phorate (1000 µM) showed 8.03-fold increase in the Olive tail moment (OTM). Cytokinesis blocked micronucleus (CBMN) assay revealed 6.4-fold increase in binucleated micronucleated (BNMN) cells following the exposure with phorate (200 µM) for 24 h. The nuclear division index (NDI) in phorate (200 µM) treated cells reduced to 1.8 vis-à-vis control cells showed NDI of 1.94. Comparative to untreated control, 60.43% greater DCF fluorescence was quantitated in lymphocytes treated with phorate (500 µM), affirming reactive oxygen species (ROS) generation and oxidative stress. Flow cytometric data of phorate (200 µM) treated lymphocytes showed 81.77% decline in the fluorescence of rhodamine 123 (Rh123) dye, confirming the perturbation of mitochondrial membrane potential (ΔΨm). Calf thymus DNA (ct-DNA) treated with phorate (1000 µM) exhibited 2.3-fold higher 8-Hydroxy-2′-deoxyguanosine (8-oxodG) DNA adduct formation, signified the oxidative DNA damage. The alkaline unwinding assay revealed 4.0 and 6.5 ct-DNA strand breaks when treated to phorate and phorate-Cu (II) complex. Overall, the data unequivocally suggests the cyto- and genotoxic potential of phorate in human lymphocytes, which may induce comparable toxicological consequences in persons occupationally or non-occupationally exposed to insecticide phorate.     

The pick-up of C14-DDT at different temperatures

Mosquito larvae, Aedes aegypti, picked up progressively greater amounts of C¹⁴ labeled DDT with ascending temperatures. The pick-up relationship contrasted with per cent mortality which showed a negative temperature coefficient. The exposure temperatures were 10°, 20° and 30° C. A similar relationship of pick-up of DDT occurred when heads, thoraces, or abdomens of the larvae were compared separately. The thorax contained greater concentrations than heads or abdomens at 30° and 20° C. At 10° C the heads contain more than thoraces and abdomens, but the amount was still less than that picked up at 20° and 30° C.The results show a positive coefficient of pick-up of DDT but a negative temperature coefficient for per cent mortality provided the concentration of DDT is not too high. The latter relationship agrees with considerable earlier research. The explanation for the negative temperature effect of DDT is still not understood, but we have evidence that the effect is not positively related to pick-up by whole larvae or portions of whole larvae.

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Zusammenfassung Mückenlarven (Aedes aegypti) nahmen um so größere Mengen von ¹⁴C-markiertem DDT auf, je mehr die Temperatur anstieg. Im Gegensatz dazu zeigte die prozentuale Mortalität einen negativen Temperaturkoeffiziente. Die Untersuchungstemperaturen betrugen 10, 20 und 30°. Eine ähnliche DDT-Aufnahme-Beziehung ergab sich, wenn Köpfe, Brustabschnitte oder Abdomina der Larven getrennt verglichen wurden. Bei 30 und 20° wiesen die Brustabschnitte größere Konzentrationen auf als die Köpfe und Abdomina. Bei 10° enthielten die Köpfe mehr als die Abdomina und Brustabschnitte, aber die aufgenommene Menge war doch geringer als bei 20 und 30°.Die Ergebnisse zeigen einen positiven Temperaturkoeffizienten für die DDT-Aufnahme, aber einen negativen für die prozentuale Mortalität unter der Voraussetzung, daß die DDT-konzentration nicht zu hoch ist. Die zweite Beziehung stimmt mit beträchtlich früheren Untersuchungen überein. Eine Erklärung für diesen negativen Temperatureffekt des DDT ist noch nicht gefunden, aber es scheint, daß diese Wirkung keine positive Korrelation zur DDT-Aufnahme ganzer Larven oder bei Teilen ganzer Larven aufweist.

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Paper No. 5188 Scientific Journal Series, Minnesota Agricultural Experiment Station, St. Paul 1, Minnesota.     

Health risk assessment due to exposure of arsenic contamination in drinking water of district Shiekhupura,Punjab, Pakistan

Abstract

The present study was conducted to assess the magnitude and health impacts of As in drinking water. Drinking water samples (n?=?60) were collected from twenty different sites of Shiekhupura District (Pakistan). Health risk assessment through average daily dose (ADD), hazard indices (HI), hazard quotient (HQ), carcinogenic risk (CR), and cancer indices (CI) for dermal and oral exposure were determined. Results revealed that As concentration ranged from 2 to 900?µg?L^?1 in water samples, which was significantly greater than the safe limit of As (10?µg?L^?1) in water. Health risk assessment of As showed that ADD (1.07E?02–9.85E?04), HQ (1.06E+01–9.85E+00), and CR (1.60E?02–9.85E?04) for oral exposure and ADD (1.03E?05–9.69E?06), HQ (1.19E?02–7.96E?03), and CR (1.11E?05–8.98E?05) for dermal exposure which were exceeded the toxic risk index value. Comparison of the two exposure pathways indicated that the oral exposure is much higher risk than the dermal contact. Both values of HI and CI were greater than WHO limit. It is concluded that residents of study area are at higher risk of As induced diseases and carcinogenicity.     

Tumor Necrosis Factor -α, Interleukin-10, Intercellular and Vascular Adhesion Molecules Are Possible Biomarkers of Disease Severity in Complicated Plasmodium vivax Isolates from Pakistan

Background

Cytokine-mediated endothelial activation pathway is a known mechanism of pathogenesis employed by Plasmodium falciparum to induce severe disease symptoms in human host. Though considered benign, complicated cases of Plasmodium vivax are being reported worldwide and from Pakistan. It has been hypothesized that P.vivax utilizes similar mechanism of pathogenesis, as that of P.falciparum for manifestations of severe malaria. Therefore, the main objective of this study was to characterize the role of cytokines and endothelial activation markers in complicated Plasmodium vivax isolates from Pakistan.

Methods and Principle Findings

A case control study using plasma samples from well-characterized groups suffering from P.vivax infection including uncomplicated cases (n=100), complicated cases (n=82) and healthy controls (n=100) were investigated. Base line levels of Tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), Interleukin-10 (IL-10), Intercellular adhesion molecule-1 (ICAM-1), Vascular adhesion molecule-1(VCAM-1) and E-selectin were measured by ELISA. Correlation of cytokines and endothelial activation markers was done using Spearman’s correlation analysis. Furthermore, significance of these biomarkers as indicators of disease severity was also analyzed. The results showed that TNF-α, IL-10, ICAM-1and VCAM-1 were 3-fold, 3.7 fold and 2 fold increased between uncomplicated and complicated cases. Comparison of healthy controls with uncomplicated cases showed no significant difference in TNF-α concentrations while IL-6, IL-10, ICAM-1, VCAM-1 and E-selectin were found to be elevated respectively. In addition, significant positive correlation was observed between TNF-α and IL-10/ ICAM-1, IL-6 and IL-10, ICAM-1 and VCAM-1.A Receiver operating curve (ROC) was generated which showed that TNF-α, IL-10, ICAM-1 and VCAM-1 were the best individual predictors of complicated P.vivax malaria.

Conclusion

The results suggest that though endothelial adhesion molecules are inducible by pro-inflammatory cytokine TNF-α, however, cytokine-mediated endothelial activation pathway is not clearly demonstrated as a mechanism of pathogenesis in complicated P.vivax malaria cases from Pakistan.     

Fungal siderophore biosynthesis is partially localized in peroxisomes

Siderophores play a central role in iron metabolism and virulence of most fungi. Both Aspergillus fumigatus and Aspergillus nidulans excrete the siderophore triacetylfusarinine C (TAFC) for iron acquisition. In A. fumigatus, green fluorescence protein‐tagging revealed peroxisomal localization of the TAFC biosynthetic enzymes SidI (mevalonyl‐CoA ligase), SidH (mevalonyl‐CoA hydratase) and SidF (anhydromevalonyl‐CoA transferase), while elimination of the peroxisomal targeting signal (PTS) impaired both, peroxisomal SidH‐targeting and TAFC biosynthesis. The analysis of A. nidulans mutants deficient in peroxisomal biogenesis, ATP import or protein import revealed that cytosolic mislocalization of one or two but, interestingly, not all three enzymes impairs TAFC production during iron starvation. The PTS motifs are conserved in fungal orthologues of SidF, SidH and SidI. In agreement with the evolutionary conservation of the partial peroxisomal compartmentalization of fungal siderophore biosynthesis, the SidI orthologue of coprogen‐type siderophore‐producing Neurospora crassa was confirmed to be peroxisomal. Taken together, this study identified and characterized a novel, evolutionary conserved metabolic function of peroxisomes.     

Testing of the additivity-based protein sequence to reactivity algorithm

The standard free energies of association (or equilibrium constants) are predicted for 11 multiple variants of the turkey ovomucoid third domain, a member of the Kazal family of protein inhibitors, each interacting with six selected enzymes. The equilibrium constants for 38 of 66 possible interactions are strong enough to measure, and for these, the predicted and measured free energies are compared, thus providing an additional test of the additivity-based sequence to reactivity algorithm. The test appears to be unbiased as the 11 variants were designed a decade ago to study furin inhibition and the specificity of furin differs greatly from the specificities of our six target enzymes. As the contact regions of these inhibitors are highly positive, nonadditivity was expected. Of the 11 variants, one does not satisfy the restriction that either P(2) Thr or P(1)' Glu should be present and all three measurable results on it, as expected, are nonadditive. For the remaining 35 measurements, 22 are additive, 12 are partially additive, and only one is (slightly) nonadditive. These results are comparable to those obtained for a set of 398 equilibrium constants for natural variants of ovomucoid third domains. The expectation that clustering of charges would be nonadditive is modified to the expectation that major nonadditivity will be observed only if the combining sites in both associating proteins involve large charge clusters of the opposite sign. It is also shown here that an analysis of a small variant set can be accomplished with a smaller subset, in this case 13 variants, rather than the whole set of 191 members used for the complete algorithm.     

Effect of Pre‐ and Post–Combined Multidoses of Epigallocatechin Gallate and Coenzyme Q10 on Cisplatin‐Induced Oxidative Stress in Rat Kidney

The nephroprotective effect of coenzyme Q10 and epigallocatechin gallate was investigated in rats with acute renal injury induced by a single nephrotoxic dose of cisplatin. Two days prior to cisplatin administration, epigallocatechin gallate and coenzyme Q10 alone and in four different combinations were given for 6 days. The treatment with antioxidants significantly protected the cisplatin‐induced increase in the levels of blood urea nitrogen and serum creatinine. Both the antioxidants alone or in different combinations significantly compensated the increased malondialdehyde and reduced glutathione levels. Moreover, the decrease in the activities of superoxide dismutase, catalase, and glutathione peroxidase and the concentration of selenium, zinc, and copper ions were significantly attenuated in renal tissue. In conclusion, epigallocatechin gallate and coenzyme Q10 are equally effective against cisplatin‐induced nephrotoxicity, whereas the intervention by combining these two antioxidants was found to be highly effective at low doses in attenuating oxidative stress in rat kidney.