bluuebunny/crossref_metadata_2025 huggingface dataset:
Crystal structures of two novel sulfonylurea herbicides in complex with Arabidopsis thaliana acetohydroxyacid synthase
Authors: Wang Jian‐Guo , Lee Patrick K.‐M. , Dong Yu‐Hui , Pang Siew Siew , Duggleby Ronald G. , Li Zheng‐Ming , Guddat Luke W.
Published: January 2009

Acetohydroxyacid synthase (AHAS; EC 2.2.1.6) is the first enzyme in the biosynthetic pathway of the branched‐chain amino acids. It catalyzes the conversion of two molecules of pyruvate into 2‐acetolactate or one molecule of pyruvate and one molecule of 2‐ketobutyrate into 2‐aceto‐2‐hydroxybutyrate. AHAS requires the cofactors thiamine diphosphate (ThDP), Mg2+ and FAD for activity. The herbicides that target this enzyme are effective in protecting a broad range of crops from weed species. However, resistance in the field is now a serious problem worldwide. To address this, two new sulfonylureas, monosulfuron and monosulfuron ester, have been developed as commercial herbicides in China. These molecules differ from the traditional sulfonylureas in that the heterocyclic ring attached to the nitrogen atom of the sulfonylurea bridge is monosubstituted rather than disubstituted. The structures of these compounds in complex with the catalytic subunit of Arabidopsis thaliana AHAS have been determined to 3.0 and 2.8 Å, respectively. In both complexes, these molecules are bound in the tunnel leading to the active site, such that the sole substituent of the heterocyclic ring is buried deepest and oriented towards the ThDP. Unlike the structures of Arabidopsis thaliana AHAS in complex with the classic disubstituted sulfonylureas, where ThDP is broken, this cofactor is intact and present most likely as the hydroxylethyl intermediate.
Amino acid discrimination by arginyl‐tRNA synthetases as revealed by an examination of natural specificity variants
Authors: Igloi Gabor L. , Schiefermayr Elfriede
Published: January 2009

l‐Canavanine occurs as a toxic non‐protein amino acid in more than 1500 leguminous plants. One mechanism of its toxicity is its incorporation into proteins, replacing l‐arginine and giving rise to functionally aberrant polypeptides. A comparison between the recombinant arginyl‐tRNA synthetases from a canavanine producer (jack bean) and from a related non‐producer (soybean) provided an opportunity to study the mechanism that has evolved to discriminate successfully between the proteinogenic amino acid and its non‐protein analogue. In contrast to the enzyme from jack bean, the soybean enzyme effectively produced canavanyl‐tRNAArg when using RNA transcribed from the jack bean tRNAACG gene. The corresponding kcat/KM values gave a discrimination factor of 485 for the jack bean enzyme. The arginyl‐tRNA synthetase does not possess hydrolytic post‐transfer editing activity. In a heterologous system containing either native Escherichia coli tRNAArg or the modification‐lacking E. coli transcript RNA, efficient discrimination between l‐arginine and l‐canavanine by both plant enzymes (but not by the E. coli arginyl‐tRNA synthetase) occurred. Thus, interaction of structural features of the tRNA with the enzyme plays a significant role in determining the accuracy of tRNA arginylation. Of the potential amino acid substrates tested, apart from l‐canavanine, only l‐thioarginine was active in aminoacylation. As it is an equally good substrate for the arginyl‐tRNA synthetase from both plants, it is concluded that the higher discriminatory power of the jack bean enzyme towards l‐canavanine does not necessarily provide increased protection against analogues in general, but appears to have evolved specifically to avoid auto‐toxicity.
Anatomical Radical Retropubic Prostatectomy in Patients with a Preexisting Three-Piece Inflatable Prosthesis: A Series of Case Reports
Authors: Deho’ Federico , Salonia Andrea , Briganti Alberto , Zanni Giuseppe , Gallina Andrea , Rokkas Konstantinos , Guazzoni Giorgio , Rigatti Patrizio , Montorsi Francesco
Published: January 2009

Introduction

Only few reports addressed the outcome of patients submitted to anatomical radical retropubic prostatectomy (RRP) with an indwelling inflatable penile prosthesis (IPP).

Aim

To assess the feasibility and safety of RRP in patients with clinically localized prostate cancer and a previously implanted with an IPP.

Main Outcome Measures

We evaluated the surgical parameters and the follow-up functional results in this particular patient population.

Methods

Four patients previously submitted to IPP implant for severe erectile dysfunction underwent RRP for organ-confined prostate cancer. Patients’ charts were carefully reviewed to investigate pre- and perioperative details. Patients were evaluated by the International Index of Erectile Function (IIEF) preoperatively and at 6 months postoperatively. Patients were then contacted to assess long-term functional and oncological outcome.

Results

The outcome of the procedures was comparable to a normal population in terms of operating time, estimated blood loss, hospitalization time, and pathological outcome. No injury to the preexisting penile implant was reported. Continence was obtained in 3 (75%) patients at catheter removal, and in 1 (25%) patient at the 1-month follow-up. No major intra- and postoperative complications were reported. All patients were able to use their prosthesis after RRP. No statistical difference in pre- and post-RRP EF domain scores was found.

Conclusion

The presence of an IPP in patients with prostate cancer is not a contraindication to perform an anatomical RRP. Surgery can be performed safely without injuring the implant and the clinical outcome in these patients is satisfactory. Postoperative implant use is not affected by RRP.
Screening for Erectile Dysfunction in Men with Lifelong Premature Ejaculation—Is the Sexual Health Inventory for Men (SHIM) Reliable?
Authors: McMahon Chris G.
Published: January 2009

Introduction

Some men with premature ejaculation (PE) and normal erectile function record contradictory response/s to The Sexual Health Inventory for Men (SHIM) and may be incorrectly categorized as suffering from erectile dysfunction (ED).

Aims

The aim of this study was to evaluate the frequency of false positive SHIM diagnosis of ED in men with lifelong PE.

Main Outcome Measures

SHIM, stopwatch intravaginal ejaculation latency time (IELT).

Methods

A prospective observational study of men with normal erectile function and lifelong PE, diagnosed using the ISSM definition of lifelong PE, was conducted. The SHIM was self-administered at Visit 1. Mean per subject stopwatch IELT was determined from four subsequent intercourse attempts.

Results

Seventy-eight subjects with a mean age of 33.2 ± 8.3 years and a geometric mean IELT of 15.9 ± 2.3 seconds were enrolled. The mean SHIM score for all subjects was 20.4 ± 6.0. Fifty-two subjects (66.7%) have SHIM scores of >21 (mean 24.3 ± 1.1), consistent with normal erectile function, and a geometric mean IELT of 18.3 ± 2.2 seconds. Twenty-six subjects (33.3%) had SHIM scores <22 (mean 12.7 ± 3.7), consistent with a false positive diagnosis of ED, and a geometric mean IELT of 10.5 ± 2.3 seconds. The incidence of false positive SHIM diagnosis of ED (SHIM < 22) was inversely related to the IELT. Although the geometric mean IELT for subjects with SHIM scores <22 was significantly less than that of all subjects and subjects with SHIM scores >21, there were no significant differences between the geometric mean IELT or the IELT distribution of all subjects vs. the normal erectile function IELT (SHIM > 21) cohort.

Conclusion

This study demonstrates a 33.3% false positive SHIM diagnosis of ED in men with PE. This is likely to limit subject recruitment in clinical trials by exclusion of subjects with low-range IELTs but is unlikely to result in significantly different baseline IELTs or IELT distributions.
Super Chilling Enhances Preservation of the Freshness of Salted Egg Yolk During Long‐Term Storage
Authors: Yanagisawa T. , Watanuki C. , Ariizumi M. , Shigematsu Y. , Kobayashi H. , Hasegawa M. , Watanabe K.
Published: January 2009

ABSTRACT:  Pasteurized egg yolk with 10% (w/w) salt was stored at 5, –5, –15, –20, and –30 °C for 1 to 6 mo, respectively. Changes in generation of volatiles of the stored samples (5 and −5 °C for 6 mo) were analyzed by SPME‐GC‐MS. Emulsifying properties of egg yolk stored at −5, −15, −20, and −30 °C for 1 mo, respectively, were also evaluated by measurement of emulsion particle diameters in model emulsions prepared with the yolk samples. In addition, structural changes in low‐density lipoprotein (LDL) in the egg yolks dependent on storage conditions for 6 mo were evaluated by 31P–NMR. Volatile compounds such as hexanal, 2‐methylbutanal, and 3‐methylbutanal increased in egg yolk during storage at 5 °C; however, volatile compounds hardly increased in any samples stored at −5 °C (super chilling). The mean emulsion particle diameter in super chilled egg yolk was significantly smaller than that in egg yolk stored at the other lower temperatures. In addition, the results of 31P–NMR evaluation suggested that prevention of structural changes of LDL resulted in maintenance of emulsifying properties of egg yolk. Thus, these results indicate that super chilling is an effective means of preserving salted egg yolk during long‐term storage.
Amino Acid Composition and Antioxidative Peptides from Protein Hydrolysates of Yellow Stripe Trevally (Selaroides leptolepis)
Authors: Klompong V. , Benjakul S. , Yachai M. , Visessanguan W. , Shahidi F. , Hayes K.D.
Published: January 2009

ABSTRACT:  Hydrolysates from yellow stripe trevally meat with 15% degree of hydrolysis (DH) obtained using Alcalase (HA) and Flavourzyme (HF) following pH‐stat method were characterized. Both hydrolysates, HA and HF, contained glutamic acid and glutamine as the major amino acids, while glycine was the dominant amino acid in fish flesh. Hydrolysates were also rich in aspartic acid, asparagine, alanine, lysine, and leucine. Essential amino acid/nonessential amino acid ratios were 0.55, 0.63, and 0.62 for flesh, HA, and HF, respectively. After separation on a Sephadex G‐50 column, antioxidative activity of hydrolysate fractions was determined as Trolox equivalent antioxidant capacity. The fraction of HF with molecular weight (MW) of 1.77 kDa exhibited the strongest antioxidative activity, compared with other fractions. Among all fractions of HA, the one having a MW of 2.44 kDa showed the highest antioxidative activity. Thereafter, the selected Sephadex G‐50 fractions from both HA and HF were further chromatographed using a Sephadex C‐25 column, followed by HPLC. MW of antioxidative peptides from HA and HF determined by Maldi TOF/TOF was 656 and 617 Da, respectively. However, peptides isolated from both HA and HF possessed a lower antioxidative activity than Trolox at the same concentration (P < 0.05). HA and HF prevented DNA oxidative damage in Fenton reaction system tested by in vitro plasmid DNA relaxation assay. These results indicate that hydrolysates from yellow stripe trevally can be used as an important source of amino acids and serve as alternative natural antioxidants.
Association of Triclosan to Casein Proteins Through Solvent‐Mediated High‐Pressure Homogenization
Authors: Roach A. , Dunlap J. , Harte F.
Published: January 2009

ABSTRACT:  The association of triclosan (TCS), a widely used hydrophobic compound, to the bovine casein micelle is investigated in this study. The use of high‐pressure homogenization (HPH) at 0, 100, 200, and 300 MPa was introduced as a method for the dissociation of casein micelles in a skim milk/ethanol solution (1: 1, v/v) in the presence of TCS at 20, 80, and 160 mg/L where ethanol evaporation served as the final step for TCS association to caseins. The majority of TCS (over 80%) was associated with the caseins regardless of initial TCS concentration or applied pressure. TCS association to caseins was enhanced by 30% with continued pressurization to 300 MPa. Micellar dissociation and reassociation was found to be an irreversible process as evidenced by microscopy images. Pressurization to 300 MPa resulted in the formation of an integrated protein network of casein proteins and noncovalently linked whey proteins where the solubility of TCS was enhanced up to 40 times its reported water solubility at the highest initial TCS level of 160 mg/L. Reformed micelles exhibited Newtonian flow behavior at all pressure levels. This study provides evidence for the solubility enhancing quality of TCS through the solvent‐mediated pressure/shear‐induced dissociation of casein proteins.
Structural Identification and Antioxidant Properties of Major Anthocyanin Extracted from Omija (Schizandra chinensis) Fruit
Authors: Kim S.‐H. , Joo M. H. , Yoo S.‐H.
Published: January 2009

ABSTRACT:  Omija (Schizandra chinensis) is used as an ingredient in traditional medicine in East Asia. It is consumed as tea and wine and display pinkish‐red color and beneficial physiological activity. However, the origin of Omija's unique color and bioactivity has not been studied extensively and its application is very limited. Thus, it was required to determine the chemical structure of major phenolic compounds of Omija fruit and evaluate their antioxidant activity. The colorants extracted from a domestic Omija cultivar were concentrated by a Sep‐pak® Plus C18 cartridge. A major high‐performance liquid chromatography (HPLC) peak of anthocyan represented 94.1% of total absorbable compounds at 520 nm, which was further identified by LC‐ESI‐MS. The mass‐to‐charge ratio (m/z) of the major anthocyan was determined to be 727. Highly pure anthocyan fraction with a semipreparative HPLC was acid‐hydrolyzed, and the sugar moieties linked to anthocyan (cyanidin) were characterized by thin layer chromatography (TLC) and high‐performance anion exchange chromatography (HPAEC) analyses. The linkage patterns of sugars and core cyanidin structure were determined by 1H‐ and 13C‐NMR analyses. Antioxidant activity of the extract and the purified anthocyanin was evaluated by 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH) and 2,2′‐azino‐bis(3‐ethylbenzthiazoline‐6‐sulphonic acid) (ABTS) methods. As a result, the structure of the purified colorant was identified as Cya‐3‐O‐xylrut. At the same molar level of the samples tested, the purified Cya‐3‐O‐xylrut (31.2% and 39.2%) had substantially greater antioxidant activity than l‐ascorbic acid (17.1% and 10.1%) from DPPH and ABTS methods, respectively. In this study, Omija colorant mostly consisted of Cya‐3‐O‐xylrut explained 86% (DPPH) and 98% (ABTS) of total antioxidant activity derived from water extract from Omija.
Treating Heart Failure With Sildenafil
Authors: Blum Arnon
Published: January 2009

Sildenafil is a selective inhibitor of type 5 phosphodiesterase, the main phosphodiesterase isoform responsible for hydrolysis of intracellular cyclic guanosine monophosphate in the pulmonary vasculature. It improves exercise capacity and quality of life in patients with systolic heart failure, especially in those who develop secondary pulmonary hypertension. It improves peak oxygen consumption, reduces minute ventilation/carbon dioxide output slope, and acts as a selective pulmonary vasodilator during rest and exercise in patients with heart failure and pulmonary hypertension. It improves flow‐mediated maximal dilatation, ergoreflex on ventilation, and breathlessness both after 3 and 6 months of treatment. Sildenafil, by improving endothelial activity and muscle perfusion, improves signaling and ventilatory efficiencies, potentially indicating a novel approach in the therapeutic management of heart failure.
Sudden Cardiac Arrest in Patients With Severe Nonischemic Heart Failure: Risk Stratification With the Heart Failure Survival Score
Authors: Castel Maria A. , Nägele Herbert
Published: January 2009

The authors wanted to investigate whether the heart failure survival score (HFSS) is useful for sudden cardiac arrest (SCA) risk stratification and whether there is a difference with regard to congestive heart failure (CHF) etiology. Data of 712 severe CHF patients (New York Heart Association III/IV 58%/42%, mean age 62±8 years, mean left ventricular ejection fraction 26%±11%) during the period from 1993–2003 were analyzed. The HFSS was calculated using the Aaronson formula. SCA‐free survival was calculated using Kaplan–Meier analysis according to the etiology of CHF: coronary artery disease (CAD) (n=317) vs no CAD (n=395). In regard to SCA risk, the authors found no significant overall difference between patients with or without CAD. Non‐CAD HFSS high‐risk patients had a significantly higher risk for SCA than all the other groups ( P<.001). The HFSS is useful for the detection of a subgroup of non‐CAD severe CHF patients at very high risk for SCA.
The Impact of Anemia on the Prognosis of Chronic Heart Failure: A Meta‐Analysis and Systemic Review
Authors: He Sheng‐Wen , Wang Le‐Xin
Published: January 2009

The aim of this study was to assess the impact of anemia on the clinical outcomes of chronic heart failure (CHF) by a meta‐analysis and systemic review of published literatures. Twenty published English‐language articles were selected from Medline, PubMed, and ISI Database. Clinical data were extracted, pooled, and analyzed with a fixed‐ or random‐effects model. A total of 97,699 patients with CHF were identified from the published studies. Meta‐analysis of these studies indicated that anemia is associated with a higher risk for death (relative risk [RR], 1.66; P<.0001). In addition, anemic patients had more advanced New York Heart Association class (III or IV; RR, 1.35; P<.0001) and lower left ventricular ejection fraction (weight mean difference, −0.53; P<.0001) than nonanemic patients. Systemic review also revealed that the severity of anemia is closely related to the rate of mortality and hospitalization for heart failure. Anemia is associated with an increased risk of mortality and rate of hospitalization for heart failure. Anemia is an independent risk factor for adverse outcomes in patients with CHF.
Dystrophic Calcification of the Aneurysmatic Left Ventricular Apex
Authors: Karaahmet Tansu , Tigen Kursat , Gurel Emre , Tanalp Ali Cevat , Basaran Yelda
Published: January 2009

Pathologic calcium deposition may be observed in the valve leaflets, valvular annulus, pericardial scar areas in chronic constructive pericarditis, and myocardial tissue. A direct x‐ray may reveal the area of calcification in any of these tissues. The most common cause of myocardial calcification is myocardial infarction (MI) in which calcium accumulates in the infarcted tissue during myocardial healing process. The authors present a case of diffuse myocardial calcification located in the left ventricular apical aneurysm in a patient who had an MI 24 years ago, together with a diagnostic and therapeutic approach.
Effusive Constrictive Pericarditis
Authors: Garg Rajeev , Singh Avneet , Chockalingam Anand
Published: January 2009

Effusive constrictive pericarditis (ECP) is a relatively infrequent pericardial condition. The diagnosis is typically made when symptoms and right heart pressure elevation persist despite drainage of pericardial effusion. Visceral and parietal pericardial stripping is an extensive procedure with significant morbidity and mortality but is widely considered the only effective treatment. Recent studies suggest that up to 10% of constriction may be reversible, and a newer series has reported spontaneous complete resolution of symptoms in a subset of ECP patients. In this review, the authors describe 2 patients with ECP who were managed successfully with steroids and colchicine, respectively, thus obviating the need for surgery. The authors also review the current understanding of this reversible pericardial pathology and explore the possible role for colchicine in treating this condition.
How Green is Too Green? Public Opinion of What Constitutes Undesirable Algae Levels in Streams1
Authors: Suplee Michael W. , Watson Vicki , Teply Mark , McKee Heather
Published: January 2009

Abstract:  A public opinion survey was carried out in Montana to ascertain if the public identifies a level of benthic (bottom‐attached) river and stream algae that is undesirable for recreation. The survey had two parts; an On‐River survey and a By‐Mail survey. The On‐River survey was conducted via 44 trips randomly scheduled throughout the state during which recreators were interviewed in‐person at the stream. Selection of stream segments and survey dates/times was based on known, statewide recreational use patterns. By‐Mail survey forms were sent to 2,000 individuals randomly selected from Montana’s Centralized Voter File (CVF) available from the Montana Secretary of State. The CVF was current through 2004 and represented over 85% of the state’s eligible voting population. In both surveys, eight randomly ordered photographs depicting varying levels of stream benthic algae were presented, and participants were asked if the algae level shown was desirable or undesirable for recreation. Survey form design, selection of photographs, and pretesting followed acceptable protocols that limited unintentional bias through survey execution. There were 433 returned forms (389 complete) for the By‐Mail survey, while the On‐River survey documented 563 interviews. In both surveys, as benthic algal chlorophyll a (Chl a) levels increased, desirability for recreation decreased. (Other measures of benthic algae biomass are presented as well.) For the public majority, mean benthic Chl a levels ≥200 mg/m2 were determined to be undesirable for recreation, whereas mean levels ≤150 mg Chl a/m2 were found to be desirable. Error rates were within the survey’s statistical design criteria (≤5%). The largest potential error source was nonresponse in the By‐Mail survey; however, the population represented by nonrespondents would have to exhibit profoundly different perceptions of river and stream algae to meaningfully alter the results. Results support earlier work in the literature suggesting 150 mg Chl a/m2 represents a benthic algae nuisance threshold.
Environmental Exposure of Aquatic and Terrestrial Biota to Triclosan and Triclocarban1
Authors: Chalew Talia E. A. , Halden Rolf U.
Published: January 2009

Abstract:  The synthetic biocides triclosan (5‐chloro‐2‐(2,4‐dichlorophenoxy)phenol) and triclocarban (3,4,4′‐trichlorocarbanilide) are routinely added to a wide array of antimicrobial personal care products and consumer articles. Both compounds can persist in the environment and exhibit toxicity toward a number of biological receptors. Recent reports of toxicological effects in wildlife, human cell cultures, and laboratory animals have heightened the interest in the occurrence of these biocide and related toxic effects. The present study aimed to summarize published environmental concentrations of biocides and contrast them with toxicity threshold values of susceptible organisms. Environmental occurrences and toxicity threshold values span more than six orders of magnitude in concentration. The highest biocide levels, measured in the mid parts‐per‐million range, were determined to occur in aquatic sediments and in municipal biosolids destined for land application. Crustacea and algae were identified as the most sensitive species, susceptible to adverse effects from biocide exposures in the parts‐per‐trillion range. An overlap of environmental concentrations and toxicity threshold values was noted for these more sensitive organisms, suggesting potential adverse ecological effects in aquatic environments. Affirmative evidence for this is lacking, however, since studies examining environmental occurrences of biocides vis‐à‐vis the health and diversity of aquatic species have not yet been conducted.
The Effect of Estrogens, River Water, and Treated Wastewater on Vitellogenin Induction of Japanese Medaka1
Authors: Kitamura Kiyoaki , Miyajima Kiyoshi , Higashitani Tadashi , Nakada Norihide , Komori Koya , Suzuki Yutaka
Published: January 2009

Abstract:  The objective of this study is to evaluate the effect of estrogens on fish endocrine disruption in river water and treated wastewater. Endogenous estrogen estrone (E1), 17β‐estradiol (E2), river water, and treated wastewater were used for exposure tests on male Japanese medaka. Vitellogenin induction in male medaka was regarded as the endpoint of endocrine disruption. The effective concentrations of E1 and E2 on vitellogenin induction in medaka were evaluated by breeding medaka for 14 days in tanks with various concentrations of E1 or E2. Vitellogenin induction increased with elapse of time during exposure, with higher estrogen concentrations causing greater vitellogenin induction. According to the test results, the lowest observed effect concentrations (LOECs) of E1 and E2 were estimated to be 31.6 and 5.0 ng/l, respectively; and the E2 equivalent (EEQ) LOEC value of E1 was 5.2 ng‐E2/l, derived by multiplying the relative potency of E1 by that of E2 as estimated in this study. In continuous exposure tests using river water or treated wastewater, the estrogenic activity, an index of total estrogenic potential measured by yeast screen assay and expressed as EEQ, varied widely during the exposure tests, and significant vitellogenin induction was observed after several days of high levels of estrogenic activity in water. Vitellogenin concentration tended to significantly increase if EEQ exceeded the level of 5 ng‐E2/l. The threshold value was substantially the same as the results for E1 and E2 exposure tests of medaka. Consequently, EEQ over 5 ng‐E2/l was revealed to have the potential to cause endocrine disruption of male medaka. As estrogenic activity exceeding 5 ng‐E2/l was observed in some rivers in Japan, total estrogenic potential needs to be further decreased at wastewater treatment plants to prevent fish endocrine disruption.
Fate and Transport Modeling of Potential Pathogens: The Contribution From Sediments1
Authors: Wu Jianyong , Rees Paula , Storrer Sara , Alderisio Kerri , Dorner Sarah
Published: January 2009

Abstract:  Escherichia coli was used as a bacterial tracer for the development, calibration, and validation of a watershed scale fate and transport model to be extended to a suite of reference pathogens (Cryptosporidium, Giardia, Campylobacter, E. coli O157:H7). E. coli densities in water and sediments from the Blackstone River Watershed, Massachusetts, were measured at three sites for a total of five wet weather events and three dry weather events covering three seasons. The confirmed E. coli strains were identified by ribotyping for tracking the sources of E. coli and for determining the association of downstream E. coli isolates with isolates from upstream sediments. A large number of downstream samples were associated with upstream sediment sources of E. coli. E. coli densities ranged from 71 to 6,401 MPN/100 ml in water samples and from 2 to 335 MPN/g in sediments. Pearson correlation analysis revealed significant correlations between E. coli and total coliforms in water (r = 0.777, p < 0.01) and sediments (r = 0.728, p < 0.01). In addition, E. coli concentrations in water were weakly correlated with sediment particle size and sediment concentrations (r = 0.298, p < 0.01). A hydrologic model, WATFLOOD/SPL9, was used to predict the temporal and spatial variation of E. coli in the Blackstone River. The rapid rise of stream E. coli densities was more accurately predicted by the model with the inclusion of sediment resuspension, thus demonstrating the importance of the process.
Occurrence of Primidone, Carbamazepine, Caffeine, and Precursors for N‐Nitrosodimethylamine in Drinking Water Sources Impacted by Wastewater1
Authors: Guo Y. Carrie , Krasner Stuart W.
Published: January 2009

Abstract:  Wastewater impact on drinking water sources was assessed using several approaches, including analysis of three pharmaceuticals and personal care products (PPCPs) – primidone, carbamazepine, and caffeine – as indicators, and determination of precursor concentrations for the disinfection byproduct N‐nitrosodimethylamine (NDMA) using formation potential (FP) tests. Samples were collected in 2006 and 2007 in rivers impacted by wastewater treatment plant (WWTP) discharges, at drinking water treatment plant (DWTP) intakes upstream or downstream from these discharges, and from two WWTP effluents in two watersheds. The levels [10th percentile − maximum (median)] of primidone, carbamazepine, caffeine, and NDMAFP were 2‐95 (7) ng/l, 2‐207 (18) ng/l, 7‐687 (78) ng/l, and 12‐321 (35) ng/l, respectively. The highest concentrations of primidone, carbamazepine, and NDMA precursors were from one of the WWTP effluents, whereas the highest concentration of caffeine was detected in a river heavily impacted by treated wastewater discharges. The lowest concentrations of the three PPCPs were from a DWTP influent upstream of a metropolitan urban area with minimum wastewater impact. Temporal variations in PPCP and NDMAFP concentrations and streamflows in two selected watersheds were also observed. Furthermore, correlation analysis between caffeine or carbamazepine and primidone was evaluated. The results show that measurement of the two pharmaceuticals and NDMAFP tests can be used to evaluate wastewater impact in different watersheds, whereas caffeine results were more variable.
Ecotoxicogenomics: Emerging Technologies for Emerging Contaminants1
Authors: Poynton Helen C. , Vulpe Chris D.
Published: January 2009

Abstract:  In recent years, new classes of aquatic pollutants have received attention from environmentalists, scientists, and regulators due to their introduction into the environment, unforeseen effects associated with the pollutants, or enhanced analytical techniques presently capable of detecting them. Many of these emerging contaminants are not well studied, making predictions regarding their toxicity to aquatic organisms or environmental fate difficult. Genomic technologies, including DNA microarrays, have been employed in many areas of biology to study disease states and the interaction of chemicals and nutrients with organisms. Here, we present the potential utility of DNA microarrays to address the challenges of emerging contaminants. DNA microarrays produce gene expression profiles creating an illustration of how a pollutant is acting within an exposed organism. Homology searches and online tools such as Gene Ontology can aid in the inferring a Mode of Toxicity, which may guide toxicity testing and risk characterization. Signature gene expression profiles offer the potential to uncover novel biomarkers of exposure and predict the presence of these contaminants in aquatic organisms. The No Observed Transcriptional Effect Level may play a role in determining if a predicted environmental concentration poses a risk to a sensitive species within an ecosystem. Additionally, DNA microarrays may add a complementary approach to Toxicity Identification Evaluations and help characterize causal agents in complex effluents.
PERSPECTIVE: Infection and inflammation in somatic maintenance, growth and longevity
Authors: Kopp Elizabeth B. , Medzhitov Ruslan
Published: January 2009

All organisms must display a certain degree of environmental adaptability to survive and reproduce. Growth and reproduction are metabolically expensive and carry other costs that contribute to aging. Therefore, animals have developed physiologic strategies to assess the harshness of the environment before devoting resources to reproduction. Presumably, these strategies maximize the possibility for offspring survival. Current views of aging reflect a trade‐off between reproductive fitness and somatic maintenance whereby environmental stress induces an adaptive metabolic response aimed at preserving cellular integrity while inhibiting growth, whereas favorable environmental conditions (abundance of food and water, and optimal temperature, etc.) promote growth and reproductive maturity but simultaneously increase cellular damage and aging. Here we propose that the prevalence of infectious pathogens in a given niche represents an additional environmental factor that, via innate immune pathways, actively shifts this balance in favor of somatic maintenance at the expense of reproduction and growth. We additionally propose the construction of a genetic model system with which to test this hypothesis.
ORIGINAL ARTICLE: Probability of emergence of antimalarial resistance in different stages of the parasite life cycle
Authors: Pongtavornpinyo Wirichada , Hastings Ian M. , Dondorp Arjen , White Lisa J. , Maude Richard J. , Saralamba Sompob , Day Nicholas P. , White Nicholas J. , Boni Maciej F.
Published: January 2009

Understanding the evolution of drug resistance in malaria is a central area of study at the intersection of evolution and medicine. Antimalarial drug resistance is a major threat to malaria control and directly related to trends in malaria attributable mortality. Artemisinin combination therapies (ACT) are now recommended worldwide as first line treatment for uncomplicated malaria, and losing them to resistance would be a disaster for malaria control. Understanding the emergence and spread of antimalarial drug resistance in the context of different scenarios of antimalarial drug use is essential for the development of strategies protecting ACTs. In this study, we review the basic mechanisms of resistance emergence and describe several simple equations that can be used to estimate the probabilities of de novo resistance mutations at three stages of the parasite life cycle: sporozoite, hepatic merozoite and asexual blood stages; we discuss the factors that affect parasite survival in a single host in the context of different levels of antimalarial drug use, immunity and parasitaemia. We show that in the absence of drug effects, and despite very different parasite numbers, the probability of resistance emerging at each stage is very low and similar in all stages (for example per‐infection probability of 10−10–10−9 if the per‐parasite chance of mutation is 10−10 per asexual division). However, under the selective pressure provided by antimalarial treatment and particularly in the presence of hyperparasitaemia, the probability of resistance emerging in the blood stage of the parasite can be approximately five orders of magnitude higher than in the absence of drugs. Detailed models built upon these basic methods should allow us to assess the relative probabilities of resistance emergence in the different phases of the parasite life cycle.
Review of hemoglobin A1c in the management of diabetes
Authors: GALLAGHER Emily Jane , LE ROITH Derek , BLOOMGARDEN Zachary
Published: January 2009

Hemoglobin HbA1c (A1c) has been used clinically since the 1980s as a test of glycemic control in individuals with diabetes. The Diabetes Control and Complications Trial (DCCT) demonstrated that tight glycemic control, quantified by lower blood glucose and A1c levels, reduced the risk of the development of complications from diabetes. Subsequently, standardization of A1c measurement was introduced in different countries to ensure accuracy in A1c results. Recently, the International Federation of Clinical Chemists (IFCC) introduced a more precise measurement of A1c, which has gained international acceptance. However, if the IFCC A1c result is expressed as a percentage, it is lower than the current DCCT‐aligned A1c result, which may lead to confusion and deterioration in diabetic control. Alternative methods of reporting have been proposed, including A1c‐derived average glucose (ADAG), which derives an average glucose from the A1c result. Herein, we review A1c, the components involved in A1c formation, and the interindividual and assay variations that can lead to differences in A1c results, despite comparable glycemic control. We discuss the proposed introduction of ADAG as a surrogate for A1c reporting, review imprecisions that may result, and suggest alternative clinical approaches.
Do plant sterol concentrations correlate with coronary artery disease in type 1 diabetes? A report from the Pittsburgh Epidemiology of Diabetes Complications Study
Authors: SHAY Christina Marie , EVANS Rhobert Wyn , ORCHARD Trevor John
Published: January 2009

Background:  It has been suggested that plant sterol absorption is increased in type 1 diabetes mellitus (T1DM) and that this may relate to the increased cardiovascular risk seen in T1DM. The cardiovascular benefit of lowering low‐density lipoprotein–cholesterol with statin medication has also been shown to be influenced by plant sterol absorption.

Methods:  The relationship between sterol concentrations, coronary artery disease (CAD), and the use of statin medications in T1DM was compared between participants with CAD (Minnesota codes 1.1, 1.2, 1.3, 4.1–4.3, 5.1–5.3, and 7.1; n = 82), from the Pittsburgh Epidemiology of Diabetes Complications (EDC) study, and those without (n = 213). Serum sterol concentrations reflecting cholesterol absorption (β‐sitosterol and campesterol) and synthesis (desmosterol and lathosterol) were assayed and analyzed by gas chromatography and were expressed as a ratio of total cholesterol (×103).

Results:  No differences were observed in markers of cholesterol absorption between individuals with and without CAD. In patients with CAD, significantly lower levels were observed for both sterol markers reflecting cholesterol synthesis compared with individuals without CAD [desmosterol: 0.34 vs 0.42, respectively (P = 0.003); lathosterol 0.47 vs 0.54, respectively (P = 0.019)]. Further stratification by statin medication use revealed significantly lower levels of synthesis‐reflecting sterols in individuals taking statin medication, particularly those with CAD.

Conclusions:  Although previous reports suggest that higher levels of cholesterol absorption in T1DM potentially increase cardiovascular risk in this population, the present data suggest no differences in cholesterol absorption between T1DM individuals with and without CAD.
Cardiovascular and thermal responses evoked from the periaqueductal grey require neuronal activity in the hypothalamus
Authors: De Menezes Rodrigo C. A. , Zaretsky Dmitry V. , Fontes Marco A. P. , DiMicco Joseph A.
Published: January 2009

Stimulation of neurons in the lateral/dorsolateral periaqueductal grey (l/dlPAG) produces increases in heart rate (HR) and mean arterial pressure (MAP) that are, according to traditional views, mediated through projections to medullary autonomic centres and independent of forebrain mechanisms. Recent studies in rats suggest that neurons in the l/dlPAG are downstream effectors responsible for responses evoked from the dorsomedial hypothalamus (DMH) from which similar cardiovascular changes and increase in core body temperature (Tco) can be elicited. We hypothesized that, instead, autonomic effects evoked from the l/dlPAG depend on neuronal activity in the DMH. Thus, we examined the effect of microinjection of the neuronal inhibitor muscimol into the DMH on increases in HR, MAP and Tco produced by microinjection of N‐methyl‐d‐aspartate (NMDA) into the l/dlPAG in conscious rats. Microinjection of muscimol alone modestly decreased baseline HR and MAP but failed to alter Tco. Microinjection of NMDA into the l/dlPAG caused marked increases in all three variables, and these were virtually abolished by prior injection of muscimol into the DMH. Similar microinjection of glutamate receptor antagonists into the DMH also suppressed increases in HR and abolished increases in Tco evoked from the PAG. In contrast, microinjection of muscimol into the hypothalamic paraventricular nucleus failed to reduce changes evoked from the PAG and actually enhanced the increase in Tco. Thus, our data suggest that increases in HR, MAP and Tco evoked from the l/dlPAG require neuronal activity in the DMH, challenging traditional views of the place of the PAG in central autonomic neural circuitry.
Asymmetric control of inspiratory and expiratory phases by excitability in the respiratory network of neonatal mice in vitro
Authors: Del Negro Christopher A. , Kam Kaiwen , Hayes John A. , Feldman Jack L.
Published: January 2009

Rhythmic motor behaviours consist of alternating movements, e.g. swing‐stance in stepping, jaw opening and closing during chewing, and inspiration–expiration in breathing, which must be labile in frequency, and in some cases, in the duration of individual phases, to adjust to physiological demands. These movements are the expression of underlying neural circuits whose organization governs the properties of the motor behaviour. To determine if the ability to operate over a broad range of frequencies in respiration is expressed in the rhythm generator, we isolated the kernel of essential respiratory circuits using rhythmically active in vitro slices from neonatal mice. We show respiratory motor output in these slices at very low frequencies (0.008 Hz), well below the typical frequency in vitro (∼0.2 Hz) and in most intact normothermic mammals. Across this broad range of frequencies, inspiratory motor output bursts remained remarkably constant in pattern, i.e. duration, peak amplitude and area. The change in frequency was instead attributable to increased interburst interval, and was largely unaffected by removal of fast inhibitory transmission. Modulation of the frequency was primarily achieved by manipulating extracellular potassium, which significantly affects neuronal excitability. When excitability was lowered to slow down, or in some cases stop, spontaneous rhythm, brief stimulation of the respiratory network with a glutamatergic agonist could evoke (rhythmic) motor output. In slices with slow (<0.02 Hz) spontaneous rhythms, evoked motor output could follow a spontaneous burst at short (≤1 s) or long (∼60 s) intervals. The intensity or timing of stimulation determined the latency to the first evoked burst, with no evidence for a refractory period greater than ∼1 s, even with interburst intervals >60 s. We observed during inspiration a large magnitude (∼0.6 nA) outward current generated by Na+/K+ ATPase that deactivated in 25–100 ms and thus could contribute to burst termination and the latency of evoked bursts but is unlikely to control the interburst interval. We propose that the respiratory network functions over a broad range of frequencies by engaging distinct mechanisms from those controlling inspiratory duration and pattern that specifically govern the interburst interval.
Phenomics of cardiac chloride channels: the systematic study of chloride channel function in the heart
Authors: Duan Dayue
Published: January 2009

Recent studies have identified several chloride (Cl−) channel genes in the heart, includingCFTR,ClC‐2,ClC‐3, CLCA,Bestrophin,andTMEM16A. Gene targeting and transgenic techniques have been used to delineate the functional role of cardiac Cl−channels in the context of health and disease. It has been shown that Cl−channels may contribute to cardiac arrhythmogenesis, myocardial hypertrophy and heart failure, and cardioprotection against ischaemia–reperfusion. The study of physiological or pathophysiological phenotypes of cardiac Cl−channels, however, may be complicated by the compensatory changes in the animals in response to the targeted genetic manipulation. Alternatively, tissue‐specific conditional or inducible knockout or knockin animal models may be more valuable in the phenotypic studies of specific Cl−channels by limiting the effect of compensation on the phenotype. The integrated function of Cl−channels may involve multi‐protein complexes of the Cl−channel subproteome and similar phenotypes can be attained from alternative protein pathways within cellular networks, which are influenced by genetic and environmental factors. Therefore, the phenomics approach, which characterizes phenotypes as a whole phenome and systematically studies the molecular changes that give rise to particular phenotypes achieved by modifying the genotype (such as gene knockouts or knockins) under the scope of genome/proteome/phenome, may provide a more complete understanding of the integrated function of each cardiac Cl−channel in the context of health and disease.
Visual control of stable and unstable loads: what is the feedback delay and extent of linear time‐invariant control?
Authors: Loram Ian D. , Lakie Martin , Gawthrop Peter J.
Published: January 2009

Human balance is commonly described using linear‐time‐invariant (LTI) models. The feedback time delay determines the position of balance in the motor‐control hierarchy. The extent of LTI control illuminates the automaticity of the control process. Using non‐parametric analysis, we measured the feedback delay, extent of LTI control and visuo‐motor transfer function in six randomly disturbed, visuo‐manual compensatory tracking tasks analogous to standing with small mechanical perturbations and purely visual information. The delay depended primarily on load order (2nd: 220 ± 30 ms, 1st: 124 ± 20 ms), and secondarily on visual magnification (extent 2nd: 34 ms, 1st: 8 ms) and was unaffected by load stability. LTI control explained 1st order and stable loads relatively well. For unstable (85% passive stabilisation) 2nd order loads, LTI control accounted for 40% of manual output at 0.1 Hz decreasing below 10% as frequency increased through the important 1–3 Hz region where manual power and visuo‐motor gain are high. Visual control of unstable 2nd order loads incurs substantial feedback delays and the control process will not be LTI. These features do not result from exclusive use of visual inputs because we found much shorter delays and a greater degree of LTI control when subjects visually controlled a 1st order load. Rather, these results suggest that delay and variability are inevitable when more flexible, intentional mechanisms are required to control 2nd order unstable loads. The high variability of quiet standing, and movement generally, may be indicative of flexible, variable delay, intentional mechanisms rather than the automatic LTI responses usually reported in response to large perturbations.
Activity‐dependent depression of the spike after‐depolarization generates long‐lasting intrinsic plasticity in hippocampal CA3 pyramidal neurons
Authors: Brown Jon T. , Randall Andrew D.
Published: January 2009

Persistent plastic changes to the intrinsic excitability of neurons have substantial implications for computational processing within the CNS. We have identified and characterized a novel long‐lasting form of intrinsic plasticity in hippocampal CA3 pyramidal cells. Although the patterns of action potential firing elicited in this cell population by depolarizing current injections exhibited considerable diversity, practically all cells produced an initial high frequency (>100 Hz) burst of two to five spikes. This burst involved conductances that were responsible for the prominent spike afterdepolarization of CA3 pyramids. Long‐lasting changes in the firing behaviour of CA3 cells were produced by conditioning stimuli (CS) consisting of either periods of depolarization in voltage clamp or periods of short (2 or 4 spikes) high frequency (circa 100 Hz) burst firing at 5 or 10 Hz. CS‐induced changes included substantial prolongation of the first inter‐spike interval and increased spike jitter. Similar CS‐induced changes were seen when the test stimulus used to elicit firing resembled a glutamatergic EPSC. In line with this, a long‐lasting depression of the ADP was elicited by the same CS that altered firing patterns of CA3 cells. Conditioning‐induced changes in both spiking patterns and ADP amplitude were blocked by buffering intracellular Ca2+with BAPTA. Furthermore, the Kv7 channel blocker XE991, a cognitive enhancer, both enhanced the ADP and completely eliminated its conditioning‐induced depression. These findings indicate that a persistent enhancement of Kv7 channels, following a transient increase in cytoplasmic Ca2+, results in a prolonged depression of the ADP in CA3 pyramidal neurones.