Supplementation with rumen-protected methionine or choline during the transition period influences whole-blood immune response in periparturient dairy cows

Publication date: Available online 17 March 2017
Source:Journal of Dairy Science
Author(s): M. Vailati-Riboni, Z. Zhou, C.B. Jacometo, A. Minuti, E. Trevisi, D.N. Luchini, J.J. Loor
Methionine, together with Lys, is the most limiting AA for milk production in dairy cows. Besides its crucial role in milk production, Met and its derivate metabolites (e.g., glutathione, taurine, polyamines) are well-known immunonutrients in nonruminants, helping support and boost immune function and activity. In the present study, the effects of Met or choline, as its precursor, were investigated using an ex vivo whole blood challenge. The study involved 33 multiparous Holstein cows (from a larger cohort with a factorial arrangement of treatments) assigned from d −21 to +30 relative to parturition to a basal control (CON) diet, CON plus rumen-protected Met (MET, Smartamine M, Adisseo NA, Alpharetta, GA) at a rate of 0.08% of dry matter, or CON plus rumen-protected choline (CHOL, ReaShure, Balchem Inc., New Hampton, NY) at 60 g/d. Blood was sampled on d −15, −7, 2, 7, and 20 for ex vivo lipopolysaccharide (LPS) challenge, and on d 1, 4, 14, and 28 relative to parturition for phagocytosis and oxidative burst assays. The MET cows had greater energy-corrected milk production and milk protein content. Overall, IL-6 response to LPS increased around parturition, whereas IL-1β remained constant, casting doubt on the existence of systemic immunosuppression in the peripartal period. Supplementation with MET dampened the postpartal blood response to LPS (lower IL-1β), while improving postpartum neutrophil and monocyte phagocytosis capacity and oxidative burst activity. In contrast, CHOL supplementation increased monocyte phagocytosis capacity. Overall, the data revealed a peripartal immune hyper-response, which appeared to have been mitigated by MET supplementation. Both MET and CHOL effectively improved immune function; however, MET affected the immune and antioxidant status before parturition, which might have been beneficial to prepare the cow to respond to metabolic challenges after parturition. These results provide insights on potential differences in the immunomodulatory action of methionine and choline in dairy cows. As such, the effects observed could have implications for ration formulation and dietary strategies.



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Comparative composition, diversity, and abundance of oligosaccharides in early lactation milk from commercial dairy and beef cows

Publication date: Available online 17 March 2017
Source:Journal of Dairy Science
Author(s): William M. Sischo, Diana M. Short, Mareen Geissler, Apichaya Bunyatratchata, Daniela Barile
Prebiotics are nondigestible dietary ingredients, usually oligosaccharides (OS), that provide a health benefit to the host by directly modulating the gut microbiota. Although there is some information describing OS content in dairy-source milk, no information is available to describe the OS content of beef-source milk. Given the different trait emphasis between dairy and beef for milk production and calf survivability, it is plausible that OS composition, diversity, and abundance differ between production types. The goal of this study was to compare OS in milk from commercial dairy and beef cows in early lactation. Early-lactation multiparous cows (5–12 d in milk) from 5 commercial Holstein dairy herds and 5 Angus or Angus hybrid beef herds were sampled once. Milk was obtained from each enrolled cow and frozen on the farm. Subsequently, each milk sample was assessed for total solids, pH, and OS content and relative abundance. Oligosaccharide diversity and abundance within and between samples was transformed through principal component analysis to reduce data complexity. Factors from principal component analysis were used to create similarity clusters, which were subsequently used in a multivariate logistic regression. In total, 30 OS were identified in early-lactation cow milk, including 21 distinct OS and 9 isomers with unique retention times. The majority of OS detected in the milk samples were present in all individual samples regardless of production type. Two clusters described distribution patterns of OS for the study sample; when median OS abundance was compared between the 2 clusters, we found that overall OS relative abundance was consistently greater in the cluster dominated by beef cows. For several of the structures, including those with known prebiotic effect, the difference in abundance was 2- to 4-fold greater in the beef-dominated cluster. Assuming that beef OS content in milk is the gold standard for cattle, it is likely that preweaning dairy calves are deprived of dietary-source OS. Although supplementing rations with OS is an approach to rectify this deficiency, understanding the health and productivity effects of improving OS abundance being fed to preweaning calves is a necessary next step before recommending supplementation. These studies should account for the observation that OS products are variable for both OS diversity and structural complexity, and some products may not be suitable as prebiotics.



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Caprine and ovine Greek dairy products: The official German method generates false-positive results due to κ-casein gene polymorphism

Publication date: Available online 16 March 2017
Source:Journal of Dairy Science
Author(s): V. Tsartsianidou, D. Triantafillidou, N. Karaiskou, P. Tarantili, G. Triantafillidis, E. Georgakis, A. Triantafyllidis
Caseins are widely used for species identification of dairy products. Isoelectric focusing (IEF) of para-κ-casein peptide is used as the official German method for the differentiation between caprine (isoform A) and ovine (isoform B) dairy products, based on their different isoelectric points. The discrimination between Greek goat and ewe dairy products using IEF has, however, been shown to be problematic because of the existence of the ewe isoform in milk from Greek indigenous dairy goats. This could be due to nucleotide polymorphisms within the goat κ-casein gene of Greek indigenous breeds, which alter the isoelectric point of the para-κ-casein peptide and lead to false positive results. Previous DNA analysis of the goat κ-casein gene has shown high levels of polymorphism; however, no such information is available for Greek indigenous dairy goats. Therefore, 87 indigenous dairy goats were sequenced at exon IV of κ-casein gene. In total, 9 polymorphic sites were detected. Three nonsynonymous point mutations were identified, which change the isoelectric point of the goat para-κ-casein peptide so that it appears identical to that of the ewe peptide. Ten composite genotypes were reconstructed and 6 of them included the problematic point mutations. For the verification of genetic results, IEF was carried out. Both goat and ewe patterns appeared in the problematic genotypes. The frequency of these genotypes could be characterized as moderate (0.23) to high (0.60) within Greek indigenous breeds. However, this is not an issue restricted to Greece, as such genotypes have been detected in various non-Greek goat breeds. In conclusion, IEF based on the official German method is certainly inappropriate for ovine and caprine discrimination concerning Greek dairy goat products, and consequently a new method should be established.



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Risk factors associated with postpartum subclinical hypocalcemia in dairy cows

Publication date: Available online 16 March 2017
Source:Journal of Dairy Science
Author(s): R.C. Neves, B.M. Leno, T. Stokol, T.R. Overton, J.A.A. McArt
Our study objectives were to evaluate the association of prepartum plasma Mg concentrations with subclinical hypocalcemia (SCH) classification at parturition and to evaluate the association of other cow-level risk factors with SCH classification at calving or at 2 d in milk (DIM). A total of 301 animals from 2 dairy herds located in New York were enrolled in a cohort study. Blood samples were collected at approximately 1 wk before the expected calving date, within 4 h of calving, and at 2 DIM. Prepartum samples had plasma macromineral concentrations (Ca, K, Mg, P), albumin, and β-hydroxybutyrate analyzed. Samples collected at calving were analyzed for Ca only, and samples from 2 DIM had macromineral and albumin concentrations determined. Postpartum SCH was defined as Ca concentrations ≤2.1 mmol/L. The prevalence of SCH at calving was 2, 40, and 66% for first, second, and third or greater parities, respectively. Only 4% of cows could be classified with prepartum subclinical hypomagnesemia (Mg concentrations <0.8 mmol/L), which did not provide enough power to appropriately determine the association of plasma Mg with postpartum Ca concentrations and its effect on SCH classification. Multiparous cows with Ca concentrations ≤2.4 mmol/L in the prepartum period and third or greater parity cows had a higher risk of being categorized as SCH at calving [relative risk (RR) = 1.4 and 1.7, respectively]. The risk of SCH at 2 DIM was associated with the interaction of Ca status at calving and lameness score. Nonlame cows with Ca concentrations ≤2.1 mmol/L (RR = 3.2) and normocalcemic lame cows at parturition (RR = 3.4) were more likely to be SCH at 2 DIM compared with nonlame normocalcemic cows. In conclusion, we identified a prepartum Ca cut-point for identification of cows that are more likely to be classified as SCH at calving. Different risk factors were associated with SCH depending on the timing of diagnosis relative to parturition.



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Characterization of the chemical structures and physical properties of exopolysaccharides produced by various Streptococcus thermophilus strains

Publication date: Available online 16 March 2017
Source:Journal of Dairy Science
Author(s): U. Pachekrepapol, J.A. Lucey, Y. Gong, R. Naran, P. Azadi
Exopolysaccharides (EPS) produced by some lactic acid bacteria are often used by the dairy industry to improve the rheological and physical properties of yogurt, but the relationship between their structure and functional effect is still unclear. The EPS from different species, or different strains from the same species, may differ in terms of molar mass, repeating unit structure, and EPS yield during fermentation of milk. This study aimed to characterize the detailed properties of EPS produced from 7 strains of Streptococcus thermophilus, which is one of the key cultures used for yogurt manufacture. Milk was fermented with strains DGCC 7698, DGCC 7710, DGCC 7785, ST-10255y, St-143, STCth-9204, and ST4239. These strains were selected because they have been used in previous studies on yogurt texture, but a complete description of their EPS structural properties has not yet been reported. All strains were fermented under a similar acidification rate by adjusting the level of supplementation with peptone or the inoculation level, which allowed for a comparison of EPS yields under similar growth conditions (reconstituted skim milk at 40°C). The EPS from each strain was isolated and the weight-average molar mass and z-average root mean square radius determined using size-exclusion chromatography multiangle laser light scattering. The monosaccharide composition of EPS was determined using gas chromatography-mass spectrometry, and repeating unit structure was determined using nuclear magnetic resonance spectroscopy. The weight-average molar mass values of EPS ranged from 0.14 to 1.61 × 10⁶ g/mol. All 7 EPS samples were uncharged. The strains ST-10255y and ST4239 had EPS with the same repeating unit structure. The monosaccharide compositions of the various EPS were mainly composed of glucose and galactose, with low levels of rhamnose in the EPS isolated from DGCC 7698, and N-acetylgalactosamine in the EPS from DGCC 7785, ST-10255y, and ST4239. The yields of EPS (measured when fermented milks reached pH 4.6) ranged from 8.0 to 76.4 mg of glucose equivalents/kg. In addition to (free) EPS, some strains were also able to produce capsular polysaccharide (associated with the bacterial cells) when observed with negative staining technique. The results of our study will help the dairy industry to better understand the mechanism by which different strains of Streptococcus thermophilus affect yogurt texture.



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Antimicrobial susceptibility and characterization of extended spectrum β-lactamases in Escherichia coli isolated from bovine mastitic milk in South Korea from 2012 to 2015

Publication date: Available online 16 March 2017
Source:Journal of Dairy Science
Author(s): Dong-Seob Tark, Dong Chan Moon, Hee Young Kang, Su-Ran Kim, Hyang-Mi Nam, Hee-Soo Lee, Suk-Chan Jung, Suk-Kyung Lim
In this study, we aimed to assess trends in antimicrobial resistance and to investigate the characteristics of extended-spectrum β-lactamase (ESBL)-producing isolates from bovine mastitic milk from 2012 to 2015. A total of 374 Escherichia coli isolates were analyzed (154 in 2012, 113 in 2013, 76 in 2014, and 31 in 2015). No consistent trends in antimicrobial resistance of E. coli isolates occurred during the 4-yr period. The most frequently observed resistance was tetracycline (23.3%), followed by streptomycin (17.1%), ampicillin (16.6%), neomycin (11.8%), and trimethoprim/sulfamethoxazole (11.2%). Multidrug resistance was observed in 15.5% of isolates. Among these isolates, 15 (4.0%) carried one or more blaCTX-M and AmpC ESBL genes from 11 different farms, including blaCTX-M-15 at 4 farms, blaCTX-M-3 at 2 farms, blaCTX-M-1 at 3 farms, and blaCMY-2 at 3 farms. This study is the first report of blaCTX-M-3-producing E. coli in dairy milk. Transfer of ESBL was observed in 3 blaCTX-M-3-producing isolates, 1 blaCTX-M-1-producing isolate, and all 3 blaCMY-2-producing isolates. Almost all blaCTX-M-15 and blaCTX-M-1 genes possessed an insertion sequence, ISECP1, upstream of the blaCTX-M gene. Identical pulsed-field gel electrophoresis profiles were also observed in blaCTX-M-producing E. coli from the same farm. These results suggested that ESBL might spread by both clonal and horizontal spread in dairy farms in South Korea. Although no significant changes occurred in the antimicrobial resistance of E. coli during the 4-yr study period, the resistance rates and presence of ESBL were high compared with those in other countries. Thus, these findings suggest the importance of control measures for E. coli, particularly ESBL-producing bacteria, on dairy farms to reduce treatment failure and transmission to humans.



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Purulent vaginal discharge in grazing dairy cows: Risk factors, reproductive performance, and prostaglandin F2α treatment

Publication date: Available online 16 March 2017
Source:Journal of Dairy Science
Author(s): M.J. Giuliodori, M. Magnasco, R.P. Magnasco, I.M. Lacau-Mengido, R.L. de la Sota
The objectives of this study were to assess the association of a 4-point scale of vaginal discharge score (VDS) with time to pregnancy to define criteria for a practical case of purulent vaginal discharge (PVD) in dairy cows, to test the risk factors for PVD, and, finally, the effect of a dose of PGF2α on cure and reproductive performance. In experiment 1, grazing Holstein cows (n = 2,414) had their vaginal discharge scored at ∼32 d in milk (DIM) on a 4-point scale, the effect of VDS on the hazard of pregnancy by 300 DIM was then assessed to derive a case definition of PVD. Risk factors for PVD and self-cure were also assessed. In experiment 2, grazing Holstein cows (n = 6,326) from 5 herds were checked for PVD at ∼30 DIM. Cows with PVD were assigned to receive one dose of 500 μg of PGF2α analog (Cloprostenol; Ciclase, Syntex SA, Buenos Aires, Argentina) per cow (odd ear tag number) or to remain untreated (even tag number). Cure was declared if cows presented clear normal vaginal discharge (VDS-0) at visit 2 (∼62 DIM). Data were analyzed with Cox's regression and mixed logistic models. In experiment 1, cows with VDS ≥1 had lower hazard of pregnancy and longer calving to pregnancy interval than cows with VDS-0. This finding was not affected by the time at which the diagnosis was performed. Therefore, a cow ≥21 DIM and having VDS ≥1 was used to define a case of PVD. The odds of PVD were greater in primiparous cows compared with multiparous, in cows with abnormal calving compared with those with normal calving, and in those losing BCS peripartum. In experiment 2, PGF2α treatment tended to slightly increase the hazard of pregnancy (adjusted hazard ratio = 1.13). Conversely, PGF2α had no effect on the odds of cure of PVD [adjusted odds ratio (AOR) = 1.19], pregnancy at first service (AOR = 1.03, P = 0.86), or pregnancy by 100 DIM (AOR = 0.89, P = 0.51) or 200 DIM (AOR = 1.27, P = 0.17). In conclusion, cows with VDS ≥1 can be considered to have PVD because of their lower hazard of pregnancy and longer calving to pregnancy interval (up to 48 d). Important risk factors are parity, calving, and body condition score loss peripartum. Optimal time of diagnosis is ≥28 to 35 DIM because cows experience a high self-cure rate. Self-cure is also affected by parity, prepartum BCS, and VDS. Finally, as treatment with one dose of PGF2α had a small effect on the hazard of pregnancy and no effect on clinical cure, its therapeutic use in grazing dairy cows with PVD is not recommended.



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Relationships between body condition score change, prior mid-lactation phenotypic residual feed intake, and hyperketonemia onset in transition dairy cows

Publication date: Available online 16 March 2017
Source:Journal of Dairy Science
Author(s): Francesca M. Rathbun, Ryan S. Pralle, Sandra J. Bertics, Louis E. Armentano, K. Cho, C. Do, Kent A. Weigel, Heather M. White
Extensive efforts have been made to identify more feed-efficient dairy cows, yet it is unclear how selection for feed efficiency will influence metabolic health. The objectives of this research were to determine the relationships between residual feed intake (RFI), a measure of feed efficiency, body condition score (BCS) change, and hyperketonemia (HYK) incidence. Blood and milk samples were collected twice weekly from cows 5 to 18 d postcalving for a total of 4 samples. Hyperketonemia was diagnosed at a blood β-hydroxybutyrate (BHB) ≥1.2 mmol/L and cows were treated upon diagnosis. Dry period, calving, and final blood sampling BCS was recorded. Prior mid-lactation production, body weight, body weight change, and dry matter intake (DMI) data were used to determine RFI phenotype, calculated as the difference between observed DMI and predicted DMI. The maximum BHB concentration (BHBmax) for each cow was used to group cows into HYK or not hyperketonemic. Lactation number, BCS, and RFI data were analyzed with linear and quadratic orthogonal contrasts. Of the 570 cows sampled, 19.7% were diagnosed with HYK. The first positive HYK test occurred at 9 ± 0.9 d postpartum and the average BHB concentration at the first positive HYK test was 1.53 ± 0.14 mmol/L. In the first 30 d postpartum, HYK-positive cows had increased milk yield and fat concentration, decreased milk protein concentration, and decreased somatic cell count. Cows with a dry BCS ≥4.0, or that lost 1 or more BCS unit across the transition to lactation period, had greater BHBmax than cows with lower BCS. Prior-lactation RFI did not alter BHBmax. Avoiding over conditioning of dry cows and subsequent excessive fat mobilization during the transition period may decrease HYK incidence; however, RFI during a prior lactation does not appear to be associated with HYK onset.



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The Canadian National Dairy Study 2015—Adoption of milking practices in Canadian dairy herds

Publication date: Available online 16 March 2017
Source:Journal of Dairy Science
Author(s): E. Belage, S. Dufour, C. Bauman, A. Jones-Bitton, D.F. Kelton
Several studies have investigated which management practices have the greatest effect on udder health, but little information is available on how broadly the recommended milking practices are adopted across Canada. The National Dairy Study 2015 was designed to gather dairy cattle health and management data on dairy farms across Canada. The objectives of the present study were to describe the current proportions of adoption of milking practices on Canadian dairy farms, and identify factors associated with their use on farms. A bilingual questionnaire measuring use of various practices, including an udder health-specific section, was developed and sent to all Canadian dairy farms. The questions in the udder health section of the questionnaire were adapted from a bilingual questionnaire previously validated and containing questions regarding general milking hygiene and routine, and on-farm mastitis management. Chi-squared tests were used to investigate simple associations between adoption of practices and various explanatory variables including region, milking system, herd size, and bulk tank somatic cell count. In total, 1,373 dairy producers completed the survey. The regional distribution of the participants was representative of the Canadian dairy farm population, and milk quality was, on average, similar to nonparticipants. Overall, Canadian dairy producers followed the recommendations for milking procedures, but some were more extensively used than others. Fore-stripping, cleaning teats, wiping teats dry, using single-cow towels, and use of postmilking teat disinfectant were widely adopted. Use of gloves and glove hygiene, use of a premilking teat disinfectant, and use of automatic takeoffs were not as extensively implemented. Adoption percentages for several practices, including use of gloves, use of a premilking teat disinfectant, teat drying methods, and use of automatic takeoffs were significantly associated with milking system, herd size, and region. It would be helpful to explore the reasons why producers choose to adopt or ignore recommended milking practices as most are easy to include in the routine and are fairly inexpensive.



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Lactoferrin reduces mortality in preweaned calves with diarrhea

Publication date: Available online 16 March 2017
Source:Journal of Dairy Science
Author(s): G. Habing, K. Harris, G.M. Schuenemann, J.M. Piñeiro, J. Lakritz, X. Alcaraz Clavijo
Calf diarrhea is the most common reason for mortality and antimicrobial therapy in preweaned calves on dairy farms in the United States. Conventional and organic livestock producers require alternative therapies for calf diarrhea to reduce the necessity of conventional antimicrobials. Alternatives administered for mild cases or early in the disease course may be useful to mitigate disease progression and reduce the likelihood of septicemia and negative sequelae. Lactoferrin is a bioactive protein naturally found in colostrum that has been shown to prevent septicemia in high-risk infants. Among organic producers, garlic extract is widely used for the treatment of disease and perceived to be efficacious. The objectives of the study were to determine the effectiveness of lactoferrin and garlic extract to reduce mortality and culling, improve weight gain, and reduce the duration of disease in preweaned calves with the first diagnosis of diarrhea. In total, 628 calves with diarrhea from a single commercial dairy were enrolled in a blinded, randomized field trial. Calves diagnosed with diarrhea (fecal score ≥3), were randomized to 3 consecutive days of oral garlic extract, lactoferrin, or water (control). Calves were clinically evaluated for up to 10 d. Body weight was measured at enrollment and 10 d later. For calves receiving garlic extract, the risk of death or culling was not significantly different than calves in the control group; however, calves that received lactoferrin had approximately half the risk of death or culling in the 120 d following diagnosis. Additionally, the relative risk of death or culling in the 60 d following diagnosis was significantly lower for the subset of calves with severe diarrhea at enrollment. Neither garlic nor lactoferrin had a significant effect on disease duration or average weight gain during the 10-d period. Lactoferrin significantly reduced mortality and culling when administered to preweaned calves with the first diagnosis of diarrhea; however, additional studies conducted across multiple farms are necessary to corroborate the observed reduction in mortality and culling. If the results are confirmed, lactoferrin may become an important tool to improve treatment outcomes and reduce the necessity of antimicrobials.



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Effects of feeding hull-less barley on production performance, milk fatty acid composition, and nutrient digestibility of lactating dairy cows

Publication date: Available online 16 March 2017
Source:Journal of Dairy Science
Author(s): Y. Yang, G. Ferreira, C.L. Teets, B.A. Corl, W.E. Thomason, C.A. Griffey
The objectives of this study were to evaluate production performance, milk fatty acid composition, and nutrient digestibility in high-producing dairy cows consuming diets containing corn and hull-less barley (cultivar Amaze 10) in different proportions as the grain source. Eight primiparous and 16 multiparous Holstein cows were assigned to 1 of 4 diets in a replicated 4 × 4 Latin square design with 21-d periods. Cows were fed once daily (1200 h) by means of a Calan gate system (American Calan Inc., Northwood, NH). All diets contained ∼20% grain (dry matter basis). Treatments consisted of 100% corn (0B), 67% corn and 33% hull-less barley (33B), 33% corn and 67% hull-less barley (67B), and 100% hull-less barley (100B) as the grain sources. Total-tract nutrient digestibility was estimated using lanthanum chloride (LaCl3) as an external marker. Dry matter intake differed quadratically among treatments, being lowest for 67B and highest for 0B and 100B. Feeding hull-less barley did not affect milk yield, and milk fat concentration differed cubically among treatments. The cubic response was attributed to the higher milk fat concentration observed for the diet containing 67B. Neither the concentrations in milk of protein and lactose nor the yields of protein and lactose differed among treatments. The proportion of de novo synthesized fatty acids in milk did not differ among treatments. The apparent total-tract digestibility of dry matter, crude protein, and neutral detergent fiber did not differ among treatments. Although a quadratic effect was observed, starch digestibility was minimally affected by treatments. In conclusion, this study indicates that hull-less barley grain is as good as corn grain as an energy source when formulating diets for high-producing dairy cows.



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Effect of dietary mineral phosphorus and phytate on in situ ruminal phytate disappearance from different concentrates in dairy cows

Publication date: Available online 16 March 2017
Source:Journal of Dairy Science
Author(s): E. Haese, J. Möhring, H. Steingass, M. Schollenberger, M. Rodehutscord
The first objective of this study was to determine the influence of dietary composition on the in situ disappearance of phytate (InsP6) from wheat, corn, soybean meal, and rapeseed meal [solvent-extracted, without (RSM) or with (hRSM) heat treatment] in the rumen of dairy cows. The second objective was to assess the primary degradation products of InsP6 in the rumen. Three diets differing in phosphorus and InsP6 concentration (basal diet = 0.38% P in dry matter; high-P diet = 0.56% P; high-InsP6 diet = 0.39% P) were fed to 3 ruminally fistulated lactating Jersey cows in a 3 × 3 Latin square. Ground concentrates (sieve size = 2 mm) were incubated in polyester bags in the rumen for 2, 4, 8, 16, and 24 h. The bag residues were analyzed for P, InsP6, isomers of lower inositol phosphates (InsP5, InsP4, InsP3), and crude protein. The InsP6 disappeared more rapidly from cereal grains than from oilseed meals; however, after 24 h of incubation ≥95% InsP6 had disappeared from all concentrates except hRSM (57%; diet average). Feeding the high-InsP6 diet increased InsP6 disappearance for oilseed meals, but not for corn and wheat. The predominant InsP5 isomer in all bag residues was Ins(1,2,4,5,6)P5 followed by Ins(1,2,3,4,5)P5 and Ins(1,2,3,4,6)P5. A further InsP5 isomer [Ins(1,3,4,5,6)P5] was detected in both rapeseed meal bag residues. Feeding the high-InsP6 diet led to lower concentrations of Ins(1,2,4,5,6)P5 and Ins(1,2,3,4,5)P5, whereas an interaction between diet, concentrate, and time occurred for Ins(1,2,3,4,6)P5 and Ins(1,3,4,5,6)P5. The results confirm the high potential of rumen microorganisms to hydrolyze InsP6; however, increasing the amount of InsP6 in the diet can further enhance InsP6 hydrolysis, which may be relevant when concentrates with slowly degradable InsP6, such as RSM or heat-treated concentrates, are fed to dairy cows. Based on the concentrations of InsP5 isomers, 3 and 6 phytases appear to play a major role in the rumen. Conversely, intrinsic plant phytase activity appears to be less relevant as the percentage of its primary hydrolysis product, Ins(1,2,3,4,5)P5, changed only slightly upon using wheat known for high intrinsic phytase activity instead of the other concentrates. Additional information regarding the factors influencing the extent of ruminal InsP6 disappearance will require further studies to determine the phytase activity of rumen microorganisms and the characteristics of their respective phytases.



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Heritabilities of measured and mid-infrared predicted milk fat globule size, milk fat and protein percentages, and their genetic correlations

Publication date: Available online 16 March 2017
Source:Journal of Dairy Science
Author(s): A. Fleming, F.S. Schenkel, A. Koeck, F. Malchiodi, R.A. Ali, M. Corredig, B. Mallard, M. Sargolzaei, F. Miglior
The objective of this study was to estimate the heritability of milk fat globule (MFG) size and mid-infrared (MIR) predicted MFG size in Holstein cattle. The genetic correlations between measured and predicted MFG size with milk fat and protein percentage were also investigated. Average MFG size was measured in 1,583 milk samples taken from 254 Holstein cows from 29 herds across Canada. Size was expressed as volume moment mean (D[4,3]) and surface moment mean (D[3,2]). Analyzed milk samples also had average MFG size predicted from their MIR spectral records. Fat and protein percentages were obtained for all test-day milk samples in the cow's lactation. Univariate and bivariate repeatability animal models were used to estimate heritability and genetic correlations. Moderate heritabilities of 0.364 and 0.466 were found for D[4,3] and D[3,2], respectively, and a strong genetic correlation was found between the 2 traits (0.98). The heritabilities for the MIR-predicted MFG size were lower than those estimated for the measured MFG size at 0.300 for predicted D[4,3] and 0.239 for predicted D[3,2]. The genetic correlation between measured and predicted D[4,3] was 0.685; the correlation was slightly higher between measured and predicted D[3,2] at 0.764, likely due to the better prediction accuracy of D[3,2]. Milk fat percentage had moderate genetic correlations with both D[4,3] and D[3,2] (0.538 and 0.681, respectively). The genetic correlation between predicted MFG size and fat percentage was much stronger (greater than 0.97 for both predicted D[4,3] and D[3,2]). The stronger correlation suggests a limitation for the use of the predicted values of MFG size as indicator traits for true average MFG size in milk in selection programs. Larger samples sizes are required to provide better evidence of the estimated genetic parameters. A genetic component appears to exist for the average MFG size in bovine milk, and the variation could be exploited in selection programs.



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Prediction and repeatability of milk coagulation properties and curd-firming modeling parameters of ovine milk using Fourier-transform-infrared spectroscopy and Bayesian models

Publication date: Available online 16 March 2017
Source:Journal of Dairy Science
Author(s): A. Ferragina, C. Cipolat-Gotet, A. Cecchinato, M. Pazzola, M.L. Dettori, G.M. Vacca, G. Bittante
The aim of this study was to apply Bayesian models to the Fourier-transform infrared spectroscopy spectra of individual sheep milk samples to derive calibration equations to predict traditional and modeled milk coagulation properties (MCP), and to assess the repeatability of MCP measures and their predictions. Data consisted of 1,002 individual milk samples collected from Sarda ewes reared in 22 farms in the region of Sardinia (Italy) for which MCP and modeled curd-firming parameters were available. Two milk samples were taken from 87 ewes and analyzed with the aim of estimating repeatability, whereas a single sample was taken from the other 915 ewes. Therefore, a total of 1,089 analyses were performed. For each sample, 2 spectra in the infrared region 5,011 to 925 cm⁻¹ were available and averaged before data analysis. BayesB models were used to calibrate equations for each of the traits. Prediction accuracy was estimated for each trait and model using 20 replicates of a training-testing validation procedure. The repeatability of MCP measures and their predictions were also compared. The correlations between measured and predicted traits, in the external validation, were always higher than 0.5 (0.88 for rennet coagulation time). We confirmed that the most important element for finding the prediction accuracy is the repeatability of the gold standard analyses used for building calibration equations. Repeatability measures of the predicted traits were generally high (≥95%), even for those traits with moderate analytical repeatability. Our results show that Bayesian models applied to Fourier-transform infrared spectra are powerful tools for cheap and rapid prediction of important traits in ovine milk and, compared with other methods, could help in the interpretation of results.



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Alzheimer's Disease and other Neurodegenerative Diseases may be due to Nutritional Deficiencies Secondary to Unrecognized Exocrine Pancreatic Insufficiency

Publication date: Available online 15 March 2017
Source:Medical Hypotheses
Author(s): Steven R Brenner
Alzheimer's Disease (AD) may be related to nutritional deficiencies from exocrine pancreatic insufficiency (EPI) with mal-absorption of essential nutrients, vitamins and minerals. EPI occurs in about twenty percent of the elderly population, sometimes without obvious symptoms, a number similar to the incidence of AD.Other Neurological degenerative diseases with potential nutritional components such as Parkinson's disease, Frailty of Age and Multiple Sclerosis, a disease with increased activity from vitamin D deficiency, may also be related to untreated exocrine pancreatic insufficiency causing impaired absorption of essential dietary elements.Testing of patients with Neurological degenerative diseases for EPI may enable correction of underlying nutritional deficiencies with enzyme replacement as necessary, possibly resulting in improvement of the underlying Neurological condition.



http://ift.tt/2nM2IJV

Approaches to Optimize Gene Therapy for the Treatment of Hematologic Malignancies: Overcoming the Obstacles

Gene transfer and oncolytic viruses provide new therapeutic approaches for the treatment of hematologic malignancies. However, it is still too early to introduce gene delivery or oncolytic viruses into standard clinical protocol. It is very important to discuss the obstacles that gene transfer and oncolytic virotherapy face for the further clinical application for the treatment of hematologic malignancies, and updating the advances made to overcome them. The major concerns in this review include the approaches of the development of immuno-stimulatory gene transfer mediated-vaccination for leukemia therapy, RNAi-based therapy for leukemia and enhancement of sensitivity of target malignant cells to virotherapy and alteration of host immune response to favor oncolytic viruses. We conclude with a perspective on the future of the gene therapy and virotherapy for the treatment of hematologic malignancies, emphasizing the problems we should solve and the technological requirements for further clinical applications.

http://ift.tt/2ncyL9j

Near-field investigation of the explosive dispersal of radioactive material based on a reconstructed spherical blast-wave flow

Publication date: June 2017
Source:Journal of Environmental Radioactivity, Volume 172
Author(s): David Hummel, Lucian Ivan
A "dirty bomb" is a type of radiological dispersal device (RDD) that has been the subject of significant safety and security concerns given the disruption that would result from a postulated terrorist attack. Assessing the risks of radioactive dose in a hypothetical scenario requires models that can accurately predict dispersion in a realistic environment. Modelling a RDD is complicated by the fact that the most important phenomena occur over vastly disparate spatial and temporal length scales. Particulate dispersion in the air is generally considered on scales of hundreds to thousands of meters, and over periods of minutes and hours. Dispersion models are extremely sensitive, however, to the particle size and source characterization, which are determined in distances measured in micrometers to meters, over milliseconds or less.This study examines the extent to which the explosive blast determines the transport of contaminant particles relative to the atmospheric wind over distances relevant to "near-field" dispersion problems (i.e., hundreds of meters), which are relevant to urban environments. Our results indicate that whether or not the effect of the blast should be included in a near-field dispersion model is largely dependent on the size of the contaminant particle. Relatively large particles (i.e., >40 μm in diameter), which are most likely to be produced by a RDD, penetrate the leading shock front, thereby avoiding the reverse blast wind. Consequently, they travel much farther than suspended aerosols (<10 μm) before approaching the ambient wind velocity. This suggests that, for these "near-field" dispersion problems in urban environments, the transport of contaminants from the blast wave may be integral to accurately predicting their dispersion.



http://ift.tt/2mzgEGd

Monitoring and descriptive analysis of radon in relation to seismic activity of Northern Pakistan

Publication date: June 2017
Source:Journal of Environmental Radioactivity, Volume 172
Author(s): Zeeshan Jilani, Tahir Mehmood, Aftab Alam, Muhammad Awais, Talat Iqbal
Earthquakes are one of the major causes of natural disasters and its forecasting is challenging task. Some precursory phenomenon exists in theory in relation to earthquakes occurrence. The emission of radioactive gas named 'radon' before the earthquakes is a potential earthquake precursory candidate. The study aims to monitor and to analyze the radon in relation to seismic activity in Northern Pakistan. For this purpose RTM-2200 has been used to monitor the changes in radon concentration from August 01, 2014 to January 31, 2015 in Northern Pakistan. Significant temporal variations has been observed in radon concentration. The bivariate analysis of radon with other variables manifests its positive relationship with air pressure and relative humidity and negative relationship with temperature. 2σ upper control limit on monthly basis are computed for detection of anomalous trends in the data. Overall increasing trend is detected in radon concentration. Five earthquakes from August 01, 2014 to January 31, 2015 have been selected from earthquake catalogue, depending upon their magnitude and distance from monitoring station and out of which radon concentration can be associated with only two earthquakes correlated with tectonic effect of radon concentration. Both of events have same magnitude 5.5 and occurred on September 13 and October 14, 2014 respectively. Very large variations have been observed in radon for the last two months of the study period, which may be occurred due to some other geological and environmental changes, but are not related to the earthquake activity.



http://ift.tt/2m8ZyDz

Organic aerosols over Indo-Gangetic Plain: Sources, distributions and climatic implications

Publication date: May 2017
Source:Atmospheric Environment, Volume 157
Author(s): Nandita Singh, Alaa Mhawish, Karine Deboudt, R.S. Singh, Tirthankar Banerjee
Organic aerosol (OA) constitutes a dominant fraction of airborne particulates over Indo-Gangetic Plain (IGP) especially during post-monsoon and winter. Its exposure has been associated with adverse health effects while there are evidences of its interference with Earth's radiation balance and cloud condensation (CC), resulting possible alteration of hydrological cycle. Therefore, presence and effects of OA directly link it with food security and thereby, sustainability issues. In these contexts, atmospheric chemistry involving formation, volatility and aging of primary OA (POA) and secondary OA (SOA) have been reviewed with specific reference to IGP. Systematic reviews on science of OA sources, evolution and climate perturbations are presented with databases collected from 82 publications available throughout IGP till 2016. Both gaseous and aqueous phase chemical reactions were studied in terms of their potential to form SOA. Efforts were made to recognize the regional variation of OA, its chemical constituents and sources throughout IGP and inferences were made on its possible impacts on regional air quality. Mass fractions of OA to airborne particulate showed spatial variation likewise in Lahore (37 and 44% in fine and coarse fractions, respectively), Patiala (28 and 37%), Delhi (25 and 38%), Kanpur (24 and 30%), Kolkata (11 and 21%) and Dhaka. Source apportionment studies indicate biomass burning, coal combustion and vehicular emissions as predominant OA sources. However, sources represent considerable seasonal variations with dominance of gasoline and diesel emissions during summer and coal and biomass based emissions during winter and post-monsoon. Crop residue burning over upper-IGP was also frequently held responsible for massive OA emission, mostly characterized by its hygroscopic nature, thus having potential to act as CC nuclei. Conclusively, climatic implication of particulate bound OA has been discussed in terms of its interaction with radiation balance.

Graphical abstract

Teaser

Large heterogeneities of organic aerosol were reported throughout IGP with characteristic variations in compositions and climate implications.


http://ift.tt/2mPFcMx

Locating hazardous gas leaks in the atmosphere via modified genetic, MCMC and particle swarm optimization algorithms

Publication date: May 2017
Source:Atmospheric Environment, Volume 157
Author(s): Ji Wang, Ru Zhang, Yuting Yan, Xiaoqiang Dong, Jun Ming Li
Hazardous gas leaks in the atmosphere can cause significant economic losses in addition to environmental hazards, such as fires and explosions. A three-stage hazardous gas leak source localization method was developed that uses movable and stationary gas concentration sensors. The method calculates a preliminary source inversion with a modified genetic algorithm (MGA) and has the potential to crossover with eliminated individuals from the population, following the selection of the best candidate. The method then determines a search zone using Markov Chain Monte Carlo (MCMC) sampling, utilizing a partial evaluation strategy. The leak source is then accurately localized using a modified guaranteed convergence particle swarm optimization algorithm with several bad-performing individuals, following selection of the most successful individual with dynamic updates. The first two stages are based on data collected by motionless sensors, and the last stage is based on data from movable robots with sensors. The measurement error adaptability and the effect of the leak source location were analyzed. The test results showed that this three-stage localization process can localize a leak source within 1.0 m of the source for different leak source locations, with measurement error standard deviation smaller than 2.0.



http://ift.tt/2mPuHZR

Photochemical reaction between triclosan and nitrous acid in the atmospheric aqueous environment

Publication date: May 2017
Source:Atmospheric Environment, Volume 157
Author(s): Jianzhong Ma, Chengzhu Zhu, Jun Lu, Yu Lei, Jizhong Wang, Tianhu Chen
Nitrous acid (HONO) is an important tropospheric pollutant and a major source of hydroxyl radical in the atmospheric gas phase. However, studies on the role of HONO in atmospheric aqueous phase chemistry processes are relatively few. The present work investigated the photochemical reaction of HONO with triclosan (TCS), which is an emerging contaminant, using a combination of laser flash photolysis spectrometry and gas chromatography mass spectrometry. With these techniques, the reaction pathway of HONO with TCS was proposed by directly monitoring the transient species and detecting the stable products. ·OH was generated from the photodissociation of the HONO aqueous solution and attacked TCS molecules on different sites to produce the TCS-OH adducts with a second-order rate constant of 1.11 × 10⁹ L mol⁻¹ s⁻¹. The ·OH added a C atom adjacent to the ether bond in the aromatic ring of TCS and self-decayed when the ether bond broke. The intermediates generated from the addition of ·OH to the benzene ring of the TCS molecular structure were immediately nitrated by HONO, which played a key role in the formation process of nitrocompounds. An atmospheric model suggests that the aqueous oxidation of TCS by ·OH is a major reaction at high liquid water concentrations, and the photolysis of TCS dominates under low-humidity conditions.

Graphical abstract

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Particulate and gaseous emissions from different wood fuels during combustion in a small-scale biomass heating system

Publication date: May 2017
Source:Atmospheric Environment, Volume 157
Author(s): R.J. Olave, E.G.A. Forbes, C.R. Johnston, J. Relf
Woodchip is widely used as fuel in dedicated biomass and, even in some conventional energy generation plants. However, there are concerns about atmospheric air pollution from flue gases emitted during wood biomass combustion, particularly oxides of nitrogen (NOx) and particulates <10 μm diameter (PM10). In the United Kingdom (UK) a small scale biomass heat generation support scheme, the Renewable Heat Incentive (RHI), has been introduced. Qualifying criteria for this scheme have included limits for flue gas emissions of NOX and PM10 of 150 and 30 g per gigajoule (g/GJ) of energy input, respectively. In an experiment, three locally available types of Willow (Salix spp) and one of Sitka spruce (Picea sitchensis) woodchips, showed significant differences in physical and chemical constituents, gaseous and particulate emissions. During combustion in a 120 kW biomass system, air flows, flue gas temperatures and energy output correlated with gaseous emissions, NOx with raw fuel ash, nitrogen, phosphorus and potassium content, as did all flue gas particulate fractions. PM10 ranged from 30.3 to 105.7 g/GJ and NOx from 91.2 to 174.3 g/GJ. Sitka spruce produced significantly lower emissions of PM10 and NOx (27.5 and 52.6% less, respectively) than the three willow fuels, from which emissions were above the RHI emissions limits.



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Motor Unit Number Estimation in the Quantitative Assessment of Severity and Progression of Motor Unit Loss in Hirayama Disease

Publication date: Available online 16 March 2017
Source:Clinical Neurophysiology
Author(s): Chaojun Zheng, Yu Zhu, Dongqing Zhu, Feizhou Lu, Xinlei Xia, Jianyuan Jiang, Xiaosheng Ma
ObjectiveTo investigate motor unit number estimation (MUNE) as a method to quantitatively evaluate severity and progression of motor unit loss in Hirayama Disease (HD).MethodsMultipoint Incremental MUNE was performed bilaterally on both abductor digiti minimi and abductor pollicis brevis muscles in 46 HD patients and 32 controls, along with handgrip strength examination. MUNE was reevaluated approximately 1 year after initial examination in 17 HD patients.ResultsThe MUNE values were significantly lower in all tested muscles in the HD group (P<0.05). Despite abnormally low MUNE values, 54.3% (25/46) HD patients had normal ipsilateral grip power. There was a significant inverse correlation between MUNE values and disease duration (P<0.05). A longitudinal follow-up MUNE analysis demonstrated slow progression of motor unit loss in HD patients within approximately 1 year (P<0.05), even in patients with an illness duration greater than four years.ConclusionsA reduction in the functioning motor units was found in HD patients compared with controls, even in the early asymptomatic stages. Moreover, the motor unit loss in HD progresses gradually as the disease advances.SignificanceThese results have providedevidenceforapplication of MUNE in estimating the reduction of motor unit in HD and confirm the validity of MUNE for tracking the progression of HD in a clinical setting.



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Parietomotor connectivity in the contralesional hemisphere after stroke: A paired-pulse TMS study

Publication date: May 2017
Source:Clinical Neurophysiology, Volume 128, Issue 5
Author(s): Etienne Allart, Arnaud Delval, Alexandre Caux-Dedeystere, Julien Labreuche, Romain Viard, Renaud Lopes, Hervé Devanne
ObjectivesTo assess the contralesional connectivity between the posterior parietal cortex (PPC) and the motor cortex (M1) in stroke patients, and to probe putative relationships with spatial neglect and motor impairment.MethodsIn 12 right-side stroke patients and 12 age-matched healthy controls, we used paired-pulse transcranial magnetic stimulation to assess the contralesional connectivity between three left-side PPC sites (the anterior intraparietal sulcus (aIPS), the posterior intraparietal sulcus and the superior parieto-occipital cortex (SPOC)) and M1. The interstimulus interval (ISI) was set to 4 or 6ms.ResultsAlthough there were no differences between the stroke patient group and the controls, a subgroup analysis showed that stimulation over the SPOC with an ISI of 6ms facilitated motor-evoked potential responses in patients with neglect (and especially those with severe peripersonal neglect), relative to non-neglect patients. With an ISI of 4ms, the aIPS exerted an inhibitory influence on M1 in all subjects. The severity of motor impairment was not associated with PPC-M1 connectivity.ConclusionsaIPS-M1 connectivity seems to be unaffected in stroke patients, whereas connectivity from the most posterior parts of the parietal cortex depends on the patient's neglect status.SignificanceThese results provide insight into post-stroke changes in contralesional PPC-M1 connectivity.



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Repetitive transcranial magnetic stimulation for treating the symptoms of schizophrenia: A PRISMA compliant meta-analysis

Publication date: May 2017
Source:Clinical Neurophysiology, Volume 128, Issue 5
Author(s): Hairong He, Jun Lu, Lihong Yang, Jie Zheng, Fan Gao, Yajing Zhai, Junqin Feng, Yajuan Fan, Xiancang Ma
ObjectiveTo explore the efficacies of 1-Hz (low frequency) and 10-Hz (high frequency) repetitive transcranial magnetic stimulation (rTMS) in treating auditory hallucinations and negative symptoms of schizophrenia, respectively.MethodsElectronic databases were searched to identify relevant literature. Standard mean difference (SMD) and 95% confidence interval (CI) values were used to evaluate the effects of rTMS. The stability and sensitivity of the results, the source of heterogeneity, and the recommended grade of the evidence were also analyzed.ResultsThirteen studies of 1-Hz rTMS were included. The auditory hallucinations improved more in the rTMS group than in the sham group (SMD=−0.29, 95%CI=−0.57 to −0.01). However, this result was not stable after sensitivity analysis, and publication bias had a substantial impact on the results. Meta-analysis performed for seven studies of 10-Hz rTMS found that improvement of negative symptoms did not differ significantly between the real rTMS and sham groups. Finally, the grade of evidence for this meta-analysis was found to be low.ConclusionAlthough there may appear to be a therapeutic effect for 1-Hz rTMS on auditory hallucinations of schizophrenia, this needs to be confirmed by large-scale randomized controlled trials before this finding can be recommended in clinical practice.Significance1-Hz rTMS might have an effect on auditory hallucinations of schizophrenia.



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Ultrasound assessment of peripheral nerve pathology in neurofibromatosis type 1 and 2

Publication date: May 2017
Source:Clinical Neurophysiology, Volume 128, Issue 5
Author(s): Natalie Winter, Tim W. Rattay, Hubertus Axer, Eva Schäffer, Bernhard F. Décard, Isabel Gugel, Martin Schuhmann, Alexander Grimm
ObjectiveThe neurofibromatoses (NF) type 1 and 2 are hereditary tumor predisposition syndromes caused by germline mutations in the NF1 and NF2 tumor suppressor genes. In NF1 and 2, peripheral nerve tumors occur regularly. For further characterizing nerve ultrasound was performed in patients with NF1 and 2.MethodsPatients with established diagnosis of NF1 (n=27) and NF2 (n=10) were included. Ultrasound of peripheral nerves and cervical roots was performed during routine follow-up visits. Healthy volunteers were studied for comparison.ResultsIn patients with NF1, median cross-sectional area (CSA) of most nerves was significantly increased compared to controls and to NF2 due to generalized plexiform tumors, which arose out of multiple fascicles in 23 of 27 patients (85%). These were often accompanied by cutaneous or subcutaneous neurofibromas. In NF2, the overall aspect of peripheral nerves consisted of localized schwannomas (80%) and, apart from that, normal nerve segments.ConclusionNerve ultrasound is able to visualize different nerve pathologies in NF1 and NF2. It is a precise and inexpensive screening method for peripheral nerve manifestation in neurofibromatosis and should be considered as the first choice screening imaging modality for all peripheral nerves within reach of non-invasive ultrasound techniques.SignificanceUltrasound patterns of peripheral nerve pathologies are described for the first time in a large cohort of patients with NF1 and NF2. It is a suitable screening tool and enables targeted MRI analysis.



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What It Should Mean for an Algorithm to Pass a Statistical Turing Test for Detection of Epileptiform Discharges

Publication date: Available online 16 March 2017
Source:Clinical Neurophysiology
Author(s): M. Brandon Westover, Jonathan J. Halford, Matt T. Bianchi




http://ift.tt/2mBpsMp

Quantifying Neuromuscular Ultrasound in Amyotrophic Lateral Sclerosis

Publication date: Available online 16 March 2017
Source:Clinical Neurophysiology
Author(s): Lisa D. Hobson-Webb, Alexander Grimm




http://ift.tt/2m972GK

Sleep Architecture in Insomniacs with severe Benzodiazepine Abuse

Publication date: Available online 16 March 2017
Source:Clinical Neurophysiology
Author(s): Mauro Manconi, Raffaele Ferri, Silvia Miano, Michelangelo Maestri, Valentina Bottasini, Marco Zucconi, Luigi Ferini-Strambi
ObjectiveBenzodiazepines (BZDs) are the most commonly prescribed compounds in insomnia. A long-term of BZDs use may cause dependence and abuse. The aim of this study was to evaluate sleep architecture and microstructure (in terms of cyclic alternating pattern -CAP- analysis and of sleep EEG power spectral analysis) in a group of long-term users of high doses of BZDs for their primary chronic insomnia.MethodsTwenty patients consecutively admitted at the Sleep Centre for drug discontinuation and 13 matched healthy controls underwent a full nocturnal video-polysomnographic recording, after one adaptation night.ResultsSignificant differences were found in time in bed, REM sleep latency and sleep stage 1 percentage which were increased in patients compared to controls, while CAP rate was dramatically decreased. During NREM sleep, patients showed a clear decrease in the relative power of delta band.ConclusionsOur data demonstrate that in adults with chronic insomnia, long-term use of high doses of BZDs induces a severe disruption of sleep microstructure, while sleep architecture seems to be much less affected.SignificanceThe long term use of high doses of BZDs for chronic insomnia induces a marked depression of slow wave activity and of its physiological instability.



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Reply to “What It Should Mean for an Algorithm to Pass a Statistical Turing Test for Detection of Epileptiform Discharges”

Publication date: Available online 16 March 2017
Source:Clinical Neurophysiology
Author(s): Mark L. Scheuer, Anto Bagic, Scott B. Wilson




http://ift.tt/2mBn3Br

Structural Biology of the Zika Virus

Publication date: Available online 16 March 2017
Source:Trends in Biochemical Sciences
Author(s): Yi Shi, George F. Gao
Zika virus (ZIKV), a Flaviviridae family member transmitted to humans by mosquitoes, has emerged as a major health concern. ZIKV infections can cause serious neurological complications in adults, and infection in pregnant women can cause congenital malformations, including fetal and newborn microcephaly. In response to this emerging concern, the structural virology field was quick to explore the features of ZIKV. These efforts have provided significant insights into ZIKV pathogenesis, and have identified targets for drug design. Here, we review the remarkable progress in structure-based ZIKV research and discuss the current challenges and future opportunities.



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Involvement of phenazine-1-carboxylic acid in the interaction between Pseudomonas chlororaphis subsp. aureofaciens strain M71 and Seiridium cardinale in vivo

Publication date: Available online 16 March 2017
Source:Microbiological Research
Author(s): Aida Raio, Pierluigi Reveglia, Gerardo Puopolo, Alessio Cimmino, Roberto Danti, Antonio Evidente
Pseudomonas chlororaphis subsp. aureofaciens encompasses bacterial strains that effectively control phytopathogenic fungi through the production of the natural antibiotics named phenazines. In this work, the involvement of phenazine production in the interaction between the biological control agent P. chlororaphis subsp. aureofaciens M71 and the fungus Seiridium cardinale, a serious cypress pathogen, was investigated.Field trials were carried out to assess the role of phenazines in the control of S. cardinale in vivo. Results showed that P. chlororaphis subsp. aureofaciens M71 and 30-84, both able to produce phenazine-1-carboxylic acid (PCA), drastically reduced the canker development incited by S. cardinale. Conversely, strain M71b, a natural gacA mutant of P. chlororaphis subsp. aureofaciens M71, showed a decrease in PCA production and a reduction in controlling S. cardinale. These results were enforced by the reduction of canker size higher than 94% registered when 6μg of pure PCA was directly applied on each cypress wound. Furthermore, PCA was detected in cypress plant tissues only when P. chlororaphis subsp. aureofaciens M71 was interacting with S. cardinale for 30 days. All these data support that the biological control of S. cardinale achieved by the application of P. chlororaphis subsp. aureofaciens M71 relies mainly on the ability of the bacterial strain to produce PCA in planta.



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Transcriptome-based analysis of the saprophytic fungus Abortiporus biennis – Response to oxalic acid

Publication date: Available online 16 March 2017
Source:Microbiological Research
Author(s): Marcin Grąz, Anna Jarosz-Wilkołazka, Grzegorz Janusz, Andrzej Mazur, Jerzy Wielbo, Piotr Koper, Kamil Żebracki, A. Kubik-Komar
In this study, the transcriptomic-based response of the white rot fungus Abortiporus biennis to oxalic acid induction was reported. The whole transcriptome of A. biennis was analysed using the RNA-based sequencing technology and Solid 5500 platform. De novo assembly of reads generated 37,719 contigs. A molecular function for 26,280 unique transcripts was assigned. The analysis of the A. biennis transcriptome predicted 635 hypothetical open reading frames encoding carbohydrate active enzymes distributed in 122 families. 82 genes were identified, whose expression level was significantly changed after oxalic acid addition. Among them, 18 genes were up-regulated and 64 genes were down-regulated. Genes coding for putative cellulose and hemicellulose degrading enzymes were predominantly up-regulated in the mycelium induced with oxalic acid; it was in the case of cellulases and xylanases (hemicellulases), in particular, β-glucosidase and endo-1,4-β-xylanases. On the contrary, several genes coding for lignolytic enzymes were down-regulated, with the significant repression level in the case of versatile peroxidase.Finally, we identified putative genes involved in oxalate metabolism. Among the transcripts detected in the A. biennis transcriptome, one was annotated as coding for putative oxalate decarboxylase (ODC) and nine transcripts were annotated as formate dehydrogenases (FDH). The addition of oxalic acid to the culture caused upregulation of the gene coding for ODC and three genes for FDH. Amongst the transcripts of putative FDH genes, one designated as NODE_36057, demonstrated the highest induction level recorded in this study after the oxalic acid addition.



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Mutation Matters in Precision Medicine: A Future to Believe In

Publication date: Available online 16 March 2017
Source:Cancer Treatment Reviews
Author(s): Dey Nandini, Williams Casey, Leyland-Jones Brian, De Pradip
As a genetic disease [1] cancer dysregulates key oncogenic pathways that influence cell growth, proliferation, survival, angiogenesis, and metastasis. Among the major determinants that enable cancer cells to acquire malignant traits are genomic diversity and instability. In the post human genome project era, cancer-specific genomic maps are redesigning tumor taxonomy. The treatment modalities, as well as the overall management of cancer as a disease in today's clinic, have started depending heavily on the molecular pathology of the individual tumor(s) in addition to the fundamental classification of cancers by histopathology. The enrichment tumor taxonomy by genomic morphology has also opened up the possibilities for genomics-driven drug development. The success of a cancer drug today is fundamentally based on the success in identifying target genes that control tumorigenic pathways. One primary goal of precision cancer medicine is to make clinical decisions based on genomic/proteomic data, which can identify a target or targets for therapy, and subsequent inevitable development of therapeutic resistance to the drug. The ability to exploit tumor genetic information for its full clinical potential has only recently become evident. Over the last decade, the convergence of discovery, technology, and therapeutic development has created an unparalleled opportunity to test the hypothesis that systematic knowledge of genomic and proteomic information from individual tumor(s) may significantly improve clinical outcomes for many patients with unmanageable tumor burden. This review presents the signaling logic behind the ground rules for the rational approach to the genomics-driven precision medicine.

Graphical abstract

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2-picolylamine derivatization for high sensitivity detection of abscisic acid in apicomplexan blood-infecting parasites

Publication date: 1 June 2017
Source:Talanta, Volume 168
Author(s): Ernest Moles, Josep Marcos, Santiago Imperial, Oscar J. Pozo, Xavier Fernàndez-Busquets
We have developed a new liquid chromatography-electrospray ionization tandem mass spectrometry methodology based on 2-picolylamine derivatization and positive ion mode detection for abscisic acid (ABA) identification. The selected reaction leads to the formation of an amide derivative which contains a highly active pyridyl group. The enhanced ionization allows for a 700-fold increase over commonly monitored unmodified ABA, which in turn leads to excellent limits of detection and quantification values of 0.03 and 0.15ngmL^-1, respectively. This method has been validated in the highly complex matrix of a red blood cell extract. In spite of the high sensitivity achieved, ABA could not be detected in Plasmodium falciparum-infected red blood cells, suggesting that, if present, it will be found either in ultratrace amounts or as brief bursts at defined time points within the intraerythrocytic cycle and/or in the form of a biosynthetic analogue.

Graphical abstract

http://ift.tt/2mB9GRA

PAMAM dendrimers: A multifunctional nanomaterial for ECL biosensors

Publication date: 1 June 2017
Source:Talanta, Volume 168
Author(s): Sudeshna Chandra, Michael Mayer, Antje J. Baeumner
Polyamido amine (PAMAM) dendrimers have been shown to function as electrochemiluminescence (ECL) co-reactant and have the inherent capability of improving immobilization of molecules on surfaces due to their dendritic structure. Here, we investigated the combination of both of these properties as the basis for biosensor development. Dendrimers with 5, 8, 10 and 16 terminal amine groups, respectively, were used. These were covalently coupled to biotin as model recognition site, and tagged with Ru(bpy)3²⁺ via adsorption. Due to their hydrophilicity, Ru-dendrimers showed significantly improved electrochemical activity in comparison to the standard tripropylamine (TPA) assisted ECL and similar luminescence yields even though 10 fold less dendrimer concentration was required in comparison to TPA. Best signals were obtained for D8 and D10 dendrimers. These Ru-dendrimers were subsequently used for the quantification of streptavidin, as its binding to the biotin-tag caused a proportional decrease in ECL signal with a dynamic range of 5nM to 1μM. These preliminary studies demonstrate that PAMAM dendrimers can function as responsive signal generators in solution-based ECL-bioassays with an assumed even higher impact when being immobilized directly on the electrode-surface.

Graphical abstract

http://ift.tt/2mB64iC

Alternative method to quantify biodiesel and vegetable oil in diesel-biodiesel blends through 1H NMR spectroscopy

Publication date: 1 June 2017
Source:Talanta, Volume 168
Author(s): Gustavo G. Shimamoto, Luis F. Bianchessi, Matthieu Tubino
An alternative method is proposed for the quantitative analysis of biodiesel in diesel-biodiesel blends. It is based on hydrogen nuclear magnetic resonance (¹H NMR) spectroscopy and applies univariate calibration, in which the integrals of the spectra are considered. Statistical comparisons between the results obtained from the method proposed here and from the infrared (IR) spectrometry method, which is recommended by the European Standard EN 14078, show that the ¹H NMR method offers equivalent results compared with standard ones. Furthermore, the proposed ¹H NMR method recognizes the difference between biodiesel and vegetable oil, whereas the IR method cannot. Therefore, the ¹H NMR method developed to quantify biodiesel in diesel-biodiesel blends is proposed here as a more practical and efficient alternative to the official method, because besides quantifying biodiesel in blends, it indicates adulteration with vegetable oil, either as the intentional and illegal addition of this raw material or because of a low degree of transesterification conversion during biodiesel synthesis.

Graphical abstract

http://ift.tt/2mB4PzP

Local co-administration of gene-silencing RNA and drugs in cancer therapy: State-of-the art and therapeutic potential

Publication date: Available online 16 March 2017
Source:Cancer Treatment Reviews
Author(s): Mikael Larsson, Wei-Ting Huang, Dean-Mo Liu, Dusan Losic
Gene-silencing miRNA and siRNA are emerging as attractive therapeutics with potential to suppress any genes, which could be especially useful in combination cancer therapy to overcome multidrug resistant (MDR) cancer. Nanomedicine aims to advance cancer treatment through functional nanocarriers that delivers one or more therapeutics to cancer tissue and cells with minimal off-target effects and suitable release kinetics and dosages. Although much effort has gone into developing circulating nanocarriers with targeting functionality for systemic administration, another alternative and straightforward approach is to utilize formulations to be administered directly to the site of action, such as pulmonary and intratumoral delivery. The combination of gene-silencing RNA with drugs in nanocarriers for localized delivery is emerging with promising results.In this review, the current progress and strategies for local co-administration of RNA and drug for synergistic effects and future potential in cancer treatment are presented and discussed. Key advances in RNA-drug anticancer synergy and localized delivery systems were combined with a review of the available literature on local co-administration of RNA and drug for cancer treatment. It is concluded that advanced delivery systems for local administration of gene-silencing RNA and drug hold potential in treatment of cancer, depending on indication. In particular, there are promising developments using pulmonary delivery and intratumoral delivery in murine models, but further research should be conducted on other local administration strategies, designs that achieve effective intracellular delivery and maximize synergy and feasibility for clinical use.

Graphical abstract

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Selective determination of aromatic acids by new magnetic hydroxylated MWCNTs and MOFs based composite

Publication date: 1 June 2017
Source:Talanta, Volume 168
Author(s): Wen-kui Li, Juan Chen, Hai-xia Zhang, Yan-ping Shi
A novel, efficient, and high-selectivity magnetic solid-phase extraction (MSPE) adsorbent based on Fe3O4 nanoparticles, hydroxylated multi-walled carbon nanotubes (MWCNTs-OH) and metal-organic frameworks (MOFs) was prepared and applied for trace aromatic acids determination in solid samples by applying a template-free in situ strategy. The morphology, configuration and magnetic behavior of the adsorbent were characterized by scanning electron microscopy (SEM), transmission electron microscope (TEM), X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectra, and vibrating sample magnetometer (VSM). The adsorbent can achieve the selective extraction of aromatic acids from the aromatic mixture in apple samples, which was mainly promoted by intermolecular hydrogen bonding and π-π electron-donor-acceptor (EDA) interaction. The potential application of the adsorbent was evaluated by MSPE of trace 1-naphthylacetic acid (NAA), cinnamic acid (CA) and terephthalic acid (TPA) from apple samples under the optimal conditions which were investigated. Satisfactory linearities were obtained in a range of 5–500ng/g and the recoveries of three aromatic acids at three spiked levels ranged from 91.2% to 98.0% with the relative standard deviations (RSD) of less than 5.5%. The limits of detection (LODs) for CA, TPA and NAA were 0.17, 0.61, and 0.86ng/g. The satisfactory results confirmed the great potential of the novel adsorbent for the selective extraction of aromatic acids from complex sample matrices.

Graphical abstract

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Electrochemical behavior and voltammetric detection of fenitrothion based on a pencil graphite electrode modified with reduced graphene oxide (RGO)/poly(E)-1-(4-((4-(phenylamino)phenyl)diazenyl)phenyl)ethanone (DPA) composite film

Publication date: 1 June 2017
Source:Talanta, Volume 168
Author(s): Ozge Surucu, Gulcin Bolat, Serdar Abaci
A combination of a novel synthesized azo dye (E)-1-(4-((4-(phenylamino)phenyl)diazenyl) phenyl)ethanone and reduced graphene oxide was used to electrochemically modify the surface of a pencil graphite electrode. The surfaces of the modified electrodes were characterized using electrochemical techniques (cyclic voltammetry and electrochemical impedance spectroscopy) and spectroscopic techniques (scanning electron microscopy and attenuated total reflectance). This azo dye/reduced graphene oxide modified electrode was applied first time for the electrochemical detection of an organophosphorus pesticide, fenitrothion. The modified pencil graphite electrode displayed excellent performance for the detection of fenitrothion. Cyclic voltammetry was used to study the dependence of the scan rate on the peak current and peak potential and to determine the kinetic parameters for fenitrothion. Square wave voltammetry was used to determine the effect of pH on the peak potential and for the sensitive and selective detection of fenitrothion using the modified electrode. Satisfactory results were obtained with the proposed sensor for the analysis of FT in tomato samples.

Graphical abstract

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Electrochemical behavior of amaranth and its sensitive determination based on Pd-doped polyelectrolyte functionalized graphene modified electrode

Publication date: 1 June 2017
Source:Talanta, Volume 168
Author(s): Yudong Gao, Lu Wang, Yulong Zhang, Lina Zou, Gaiping Li, Baoxian Ye
In this work, poly(sodium p-styrenesulfonate) (PSS)-functionalized graphene supported palladium nanoparticles (Pd) composites were fabricated with simple ultrasonic bath method. The morphology and structure of PSS-GR-Pd composites were characterized using UV–vis absorption spectra, X-ray diffraction and Transmission Electron Microscopy. By combining the merits of the PSS-GR and Pd NPs, a new electrochemical sensor was erected to detect amaranth based on the PSS-GR-Pd nanocomposites. The electrochemical behavior of amaranth was investigated systematically in 0.1molL⁻¹ phosphate buffer solution (PBS 2.0). At the optimum parameter, Ipa was found to be linearly dependent on the concentrations of amaranth (1×10⁻⁷–9×10⁻⁶molL⁻¹). The detection limit was 7nM (S/N=3) and sensitivity was 5.85μAμM⁻¹. Finally, this system was utilized for determining amaranth in soft drink using the standard addition method.

Graphical abstract

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Mercury fractionation in soil and sediment samples using thermo-desorption method

Publication date: 1 June 2017
Source:Talanta, Volume 168
Author(s): Dominika Saniewska, M. Bełdowska
Mercury is one of the most hazardous elements. Its transformation and transport in the environment strongly depend on its chemical form. The information about Hg form is also important for understanding the bioavailability as well as toxicity of this element. There are many methods for Hg speciation but most of them are expensive and time consuming. Therefore the aim of this research was to develop a simple thermo-desorption method for mercury fractionation in soil and sediment samples using a direct mercury analyser. The DMA-80 direct mercury analyser (Milestone, Italy) was chosen for this purpose and Hg species were characterised by the temperature range at which they were released. Thirteen synthetic standard materials as well as "natural" standards for a humus-like substance and methyl mercury were used in this work. The method was tested on a certified reference material as well as on natural samples: soil, beach sand and marine sediment. The obtained results show that the temperature fractionation, in spite of some limitations, could be considered as a screening method for the evaluation of the percentage contribution of certain groups of Hg compounds with similar properties in solid samples. This method could be applied for solid samples with low, environmental Hg concentration. The result obtained by this four-step fractionation could be comparable with different research, conducted using other mercury analysers.

Graphical abstract

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Authorship selection in industry sponsored publications of dermatology clinical trials

Abstract

The issue of conflict of interest management and authorship has been the subject of debates and recommendations over the past 15 years^1–7. Some grey areas persist concerning the definition of authorship in industry-sponsored clinical trials (IRCT)⁸. The objective of the present study was to better understand this process.

This article is protected by copyright. All rights reserved.

http://ift.tt/2m8tIa4

Longitudinal whole brain atrophy and ventricular enlargement in non-demented parkinson’s disease

Publication date: Available online 16 March 2017
Source:Neurobiology of Aging
Author(s): Elijah Mak, Li Su, Guy B. Williams, Michael J. Firbank, Rachael A. Lawson, Alison J. Yarnall, Gordon W. Duncan, Brit Mollenhauer, Adrian M. Owen, Tien K. Khoo, David J. Brooks, James B. Rowe, Roger A. Barker, David J. Burn, John T. O'Brien
We investigated whole brain atrophy and ventricular enlargement over 18 months in non-demented PD, and examined their associations with clinical measures and baseline CSF markers. PD subjects (n=100) were classified at baseline into those with MCI (PD-MCI, n=36) and no cognitive impairment (PD-NC, n=64). Percentage of whole brain volume change (PBVC) and ventricular expansion over 18 months were assessed with FSL-SIENA and VIENA respectively. PD-MCI showed increased global atrophy (-1.1% ± 0.8) and ventricular enlargement (6.9 % ± 5.2) compared to both PD-NC (PBVC: -0.4 ± 0.5, p<0.01; VIENA: 2.1% ± 4.3, p<0.01) and healthy controls. In a subset of 35 PD subjects, CSF levels of tau and Aβ42/Aβ40 ratio were correlated with PBVC and ventricular enlargement respectively. The sample size required to demonstrate a 20% reduction in PBVC and VIENA was approximately 1/15^th of that required to detect equivalent changes in cognitive decline. These findings suggest that longitudinal MRI measurements have potential to serve as surrogate markers to complement clinical assessments for future disease-modifying trials in PD.



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Is there a role of magnetic resonance imaging in deciding to stop anti-tumor necrosis factor treatment in ileal Crohn's disease?

Publication date: Available online 16 March 2017
Source:Clinical Imaging
Author(s): Jose C. Gallego, Ana Echarri
PurposeThis study was performed to assess the ability of magnetic resonance enterography to predict the evolution of patients in whom anti-tumor necrosis factor-α therapy was suspended.MethodsA prospective study of patients with ileal Crohn's disease was performed.ResultsTwenty-nine patients were included. Patients who later relapsed showed higher magnetic resonance scores than those who did not relapse (4.2 vs. 2.5, respectively; p<0.02). The area under the receiving-operating characteristics curve was 0.755 when discriminating patients who relapsed.ConclusionsMagnetic resonance enterography should be taken into account when deciding the withdrawal of anti-tumor necrosis factor-α in patients with Crohn's disease.



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Association between nephrolithiasis and fatty liver detected on non-enhanced CT for clinically suspected renal colic

Publication date: Available online 16 March 2017
Source:Clinical Imaging
Author(s): Abdel-Rauf Zeina, Limor Goldenberg, Alicia Nachtigal, Rabea Hasadia, Walid Saliba
PurposeTo estimate a direct association between nephrolithiasis and hepatosteatosis in patients referred to CT due to clinical suspicion of renal colic.MethodsA 508 non-contrast CT scans were examined for calculi in the kidneys or urinary tract, including measurements of liver attenuation, spleen attenuation, thickness of visceral and subcutaneous fat. Logistic regression examined the association of nephrolithiasis and hepatosteatosis findings.ResultsNephrolithiasis was found in 421 (83.9%) and hepatosteatosis in 80 (15.7%) cases. Univariate analysis showed a statistically significant association between nephrolithiasis and hepatosteatosis OR=3.24 (95% CI 1.36–7.68), p=0.008.ConclusionsA significant association was determined between nephrolithiasis and hepatosteatosis.



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Biomarkers for the diagnosis of Alzheimer's disease in clinical practice: an Italian intersocietal roadmap

Publication date: April 2017
Source:Neurobiology of Aging, Volume 52
Author(s): Giovanni B. Frisoni, Daniela Perani, Stefano Bastianello, Gaetano Bernardi, Corinna Porteri, Marina Boccardi, Stefano F. Cappa, Marco Trabucchi, Alessandro Padovani
Biomarkers of brain amyloidosis and neurodegeneration/synaptic dysfunction are featured in recent diagnostic criteria for Alzheimer's disease. Several gaps in our knowledge, however, need to be filled before they can be adopted clinically. The aim of this article is to describe a roadmap, developed by a multidisciplinary task force, to rationally implement biomarkers for Italian Memory Clinics. This roadmap is based on a framework comprising 5 sequential phases: identification of leads for potentially useful biomarkers; development of clinical assays for clinical disease; evaluation of detection of early stages; definition of operating characteristics in relevant populations; and estimation of reducing disease-associated mortality, morbidity, and disability. The roadmap was devised by identifying current evidence of validity, still missing evidence, and action needed to collect this missing evidence. With appropriate adaptation to local, country-specific circumstances, the roadmap can be translated to other countries.



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Clinical validity of presynaptic dopaminergic imaging with 123I-ioflupane and noradrenergic imaging with 123I-MIBG in the differential diagnosis between Alzheimer's disease and dementia with Lewy bodies in the context of a structured 5-phase development framework

Publication date: April 2017
Source:Neurobiology of Aging, Volume 52
Author(s): Ida Sonni, Osman Ratib, Marina Boccardi, Agnese Picco, Karl Herholz, Flavio Nobili, Andrea Varrone
The use of biomarkers (BMs) for accurate diagnosis of Alzheimer's disease (AD) has been proposed by recent diagnostic criteria; however, their maturity is not sufficient to grant implementation in the clinical routine. A proper diagnostic process requires not only confirmation of the disease but also the exclusion of similar disorders entering differential diagnosis, like dementia with Lewy bodies (DLB). This review is aimed at evaluating the clinical validity of ¹²³I-ioflupane brain single photon emission tomography and ¹²³I-MIBG cardiac scintigraphy as imaging BMs for DLB. For this purpose, we used an adapted version of the 5-phase oncology framework for BMs development. A review of the literature was conducted using homogenous search criteria with other BMs addressed in parallel reviews. Results of our literature search showed that the rationale for the use of both BMs in the differential diagnosis of DLB and AD is strong (phase 1) and that they allow a good discrimination ability (phase 2), but studies investigating BMs distribution antemortem and postmortem on pathology are lacking. Moreover, thresholds for test positivity have not been defined for ¹²³I-MIBG. The 2 BMs have not been yet assessed in early phases of DLB and AD (phase 3). No phase 4 and phase 5 studies have so far been carried out. This review highlights the priorities to address in future investigations to enable the proper use of ¹²³I-ioflupane and ¹²³I-MIBG for the differential diagnosis of dementia.

Graphical abstract

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Clinical validity of medial temporal atrophy as a biomarker for Alzheimer's disease in the context of a structured 5-phase development framework

Publication date: April 2017
Source:Neurobiology of Aging, Volume 52
Author(s): Mara ten Kate, Frederik Barkhof, Marina Boccardi, Pieter Jelle Visser, Clifford R. Jack, Karl-Olof Lovblad, Giovanni B. Frisoni, Philip Scheltens
Research criteria for Alzheimer's disease recommend the use of biomarkers for diagnosis, but whether biomarkers improve the diagnosis in clinical routine has not been systematically assessed. The aim is to evaluate the evidence for use of medial temporal lobe atrophy (MTA) as a biomarker for Alzheimer's disease at the mild cognitive impairment stage in routine clinical practice, with an adapted version of the 5-phase oncology framework for biomarker development. A literature review on visual assessment of MTA and hippocampal volumetry was conducted with other biomarkers addressed in parallel reviews. Ample evidence is available for phase 1 (rationale for use) and phase 2 (discriminative ability between diseased and control subjects). Phase 3 (early detection ability) is partly achieved: most evidence is derived from research cohorts or clinical populations with short follow-up, but validation in clinical mild cognitive impairment cohorts is required. In phase 4, only the practical feasibility has been addressed for visual rating of MTA. The rest of phase 4 and phase 5 have not yet been addressed.

Graphical abstract

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The Expression and Activity of KV3.4 Channel Subunits Are Precociously upregulated in Astrocytes Exposed to Aβ oligomers and in Astrocytes of Alzheimer's Disease Tg2576 Mice

Publication date: Available online 16 March 2017
Source:Neurobiology of Aging
Author(s): Francesca Boscia, Anna Pannaccione, Roselia Ciccone, Antonella Casamassa, Cristina Franco, Ilaria Piccialli, Valeria de Rosa, Antonio Vinciguerra, Gianfranco Di Renzo, Lucio Annunziato
Astrocyte dysfunction emerges early in Alzheimer's disease (AD) and may contribute to its pathology and progression. Recently, the voltage gated potassium channel KV3.4 subunit, which underlies the fast-inactivating K⁺ currents (IA), has been recognized to be relevant for AD pathogenesis and is emerging as a new target candidate for AD. In the present study, we investigated both in in vitro and in vivo models of AD the expression and functional activity of KV3.4 potassium channel subunits in astrocytes. In primary astrocytes our biochemical, immunohistochemical, and electrophysiological studies demonstrated a time-dependent upregulation of KV3.4 expression and functional activity after exposure to amyloid-β (Aβ) oligomers. Consistently, astrocytic KV3.4 expression was upregulated in the cerebral cortex, hippocampus, and cerebellum of 6-month-old Tg2576 mice. Further, confocal triple labeling studies revealed that in 6-month-old Tg2576 mice, KV3.4 was intensely coexpressed with Aβ in non-plaque associated astrocytes. Interestingly, in the cortical and hippocampal regions of 12-month-old Tg2576 mice, plaque-associated astrocytes much more intensely expressed KV3.4 subunits, but not Aβ. More important, we evidenced that the selective knockdown of KV3.4 expression significantly downregulated both glial fibrillary acidic protein levels and Aβ trimers in the brain of 6-month-old Tg2576 mice. Collectively, our results demonstrate that the expression and function of KV3.4 channel subunits are precociously upregulated in cultured astrocytes exposed to Aβ oligomers and in reactive astrocytes of AD Tg2576 mice.



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The biomarker-based diagnosis of Alzheimer's disease. 2—lessons from oncology

Publication date: April 2017
Source:Neurobiology of Aging, Volume 52
Author(s): Marina Boccardi, Valentina Gallo, Yutaka Yasui, Paolo Vineis, Alessandro Padovani, Urs Mosimann, Panteleimon Giannakopoulos, Gabriel Gold, Bruno Dubois, Clifford R. Jack, Bengt Winblad, Giovanni B. Frisoni, Emiliano Albanese
Biomarkers for the diagnosis of Alzheimer's disease (AD) are not yet validated for use in clinical settings. We aim to provide a methodological framework for their systematic validation, by reference to that developed for oncology biomarkers. As for this discipline, the steps for the systematic validation of AD biomarkers need to target analytical validity, clinical validity, and clinical utility. However, the premises are different from oncology: the nature of disease (neurodegeneration vs. cancer), the purpose (improve diagnosis in clinically affected vs. screening preclinical individuals), and the target population (mild cognitive impairment patients referring to memory clinics vs. general population) lead to important differences, influencing both the design of validation studies and the use of selected biomarkers. This framework is applied within a wider initiative to assess the current available evidence on the clinical validity of biomarkers for AD, for the final aim to identify gaps and research priorities, and to inform coordinated research efforts boosting AD biomarkers research.

Graphical abstract

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Clinical validity of cerebrospinal fluid Aβ42, tau, and phospho-tau as biomarkers for Alzheimer's disease in the context of a structured 5-phase development framework

Publication date: April 2017
Source:Neurobiology of Aging, Volume 52
Author(s): Niklas Mattsson, Anders Lönneborg, Marina Boccardi, Kaj Blennow, Oskar Hansson
Novel diagnostic criteria for Alzheimer's disease (AD) incorporate biomarkers, but their maturity for implementation in clinical practice at the prodromal stage (mild cognitive impairment [MCI]) is unclear. Here, we evaluate cerebrospinal fluid (CSF) β-amyloid42 (Aβ42), total tau, and phosphorylated tau in the light of a 5-phase framework for biomarker development. Ample evidence is available for phase 1 (identifying useful leads) and phase 2 (assessing the accuracy for AD dementia versus controls) for CSF biomarkers. Phase 3 (utility in MCI) is partially achieved. In cohorts with long follow-up time, CSF Aβ42, total tau, and phosphorylated tau have high diagnostic accuracy for MCI due to AD. Phase 4 (performance in real world) is ongoing, and phase 5 studies (quantify impact and costs) are to come. Our results highlight priorities to pursue and to enable the proper use of CSF biomarkers in the clinic. Priorities are to reduce measurement variability by introduction of fully automated assay systems; to increase diagnostic specificity toward non-AD neurocognitive diseases at the MCI stage; and to clarify the role of CSF biomarkers versus other biomarker modalities in clinical practice and in design of clinical trials. These efforts are currently ongoing.

Graphical abstract

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Contents

Publication date: April 2017
Source:Neurobiology of Aging, Volume 52





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Anticholinergic drug use is associated with episodic memory decline in older adults without dementia

Publication date: Available online 16 March 2017
Source:Neurobiology of Aging
Author(s): Goran Papenberg, Lars Bäckman, Laura Fratiglioni, Erika J. Laukka, Johan Fastbom, Kristina Johnell
Anticholinergic drug use is common in older adults and has been related to increased dementia risk. This suggests that users of these drugs may experience accelerated cognitive decline. So far, however, longitudinal data on this topic are absent and the available evidence is inconclusive with respect to effects on specific cognitive domains due to suboptimal control of confounding variables.We investigated whether anticholinergic medication use is associated with cognitive decline over 6 years in a population-based study of older adults (aged 60 to 90; n = 1473) without dementia. We found that users (n=29) declined more on episodic memory over 6 years compared to non-users (n=1418). These results were independent of age, sex, education, overall drug intake, physical activity, depression, cardiovascular risk burden, and cardiovascular disease. By contrast, anticholinergic drug use was unrelated to performance in processing speed, semantic memory, short-term memory, verbal fluency, and global cognition (the Mini-Mental-State Examination).Our results suggest that effects of anticholinergics may be particularly detrimental to episodic memory in older adults, which supports the assertion that the cholinergic system plays an important role in episodic memory formation.



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Alzheimer's disease biomarker development: a call to funding bodies

Publication date: April 2017
Source:Neurobiology of Aging, Volume 52
Author(s): Giovanni B. Frisoni, Clifford R. Jack, Bengt Winblad




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The biomarker-based diagnosis of Alzheimer's disease. 1—ethical and societal issues

Publication date: April 2017
Source:Neurobiology of Aging, Volume 52
Author(s): Corinna Porteri, Emiliano Albanese, Charles Scerri, Maria C. Carrillo, Heather M. Snyder, Birgitta Martensson, Mark Baker, Ezio Giacobini, Marina Boccardi, Bengt Winblad, Giovanni B. Frisoni, Samia Hurst
There is great interest in the use of biomarkers to assist in the timely identification of Alzheimer's disease (AD) in individuals with mild symptoms. However, the inclusion of AD biomarkers in clinical criteria poses socioethical challenges. The Geneva Task Force for the Roadmap of Alzheimer's Biomarkers was established to deliver a systematic strategic research agenda (aka roadmap) to promote efficient and effective validation of AD biomarkers and to foster their uptake in clinical practice. In this article, we summarize the workshop discussion of the Geneva Task Force "ethical and societal issues" working group, which comprised bioethicists, clinicians, health economists, and representatives of those affected by AD. The working group identified the following key issues that need to be included in the roadmap: improving access to services through timely diagnosis, the need for a diagnostic research protocol before moving to clinical routine, recruitment in diagnostic research protocols in the absence of effective therapy, respect for the autonomy of the individual with mild cognitive impairment in information and consent process and the right not to know biomarkers results, need for counseling programs, disclosure of the diagnosis in a structured environment and the involvement of family members, health policies including the individuals' views and the protection of their interests, and the economic costs for society.



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Editorial Advisory Board

Publication date: April 2017
Source:Neurobiology of Aging, Volume 52





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Clinical validity of delayed recall tests as a gateway biomarker for Alzheimer's disease in the context of a structured 5-phase development framework

Publication date: April 2017
Source:Neurobiology of Aging, Volume 52
Author(s): Chiara Cerami, Bruno Dubois, Marina Boccardi, Andreas U. Monsch, Jean Francois Demonet, Stefano F. Cappa
Although Alzheimer's disease criteria promote the use of biomarkers, their maturity in clinical routine still needs to be assessed. In the light of the oncology framework, we conducted a literature review on measures used to assess delayed recall impairment due to medial temporal lobe dysfunction (i.e., free and cued word list recall tests). Ample evidence is available for phases 1 (rationale for use), 2 (discriminative ability), and 3 (early detection ability) for many of the tests in routine use. Evidence about phase 4 (performance in real world) and phase 5 (quantify impact and costs) is yet to come. Administration procedures have been standardized and cutoff scores are well validated in large Alzheimer's disease and mild cognitive impaired series. Some aspects (e.g., different task formats), however, hamper the comparability of results among different populations and the reproducibility between laboratories. No definite guideline for their use can thus be proposed at the moment. Accordingly, the maturity of such markers is not yet sufficient and requires future investigation to promote the proper use of memory measures in clinical settings.

Graphical abstract

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Clinical validity of brain fluorodeoxyglucose positron emission tomography as a biomarker for Alzheimer's disease in the context of a structured 5-phase development framework

Publication date: April 2017
Source:Neurobiology of Aging, Volume 52
Author(s): Valentina Garibotto, Karl Herholz, Marina Boccardi, Agnese Picco, Andrea Varrone, Agneta Nordberg, Flavio Nobili, Osman Ratib
The use of Alzheimer's disease (AD) biomarkers is supported in diagnostic criteria, but their maturity for clinical routine is still debated. Here, we evaluate brain fluorodeoxyglucose positron emission tomography (FDG PET), a measure of cerebral glucose metabolism, as a biomarker to identify clinical and prodromal AD according to the framework suggested for biomarkers in oncology, using homogenous criteria with other biomarkers addressed in parallel reviews. FDG PET has fully achieved phase 1 (rational for use) and most of phase 2 (ability to discriminate AD subjects from healthy controls or other forms of dementia) aims. Phase 3 aims (early detection ability) are partly achieved. Phase 4 studies (routine use in prodromal patients) are ongoing, and only preliminary results can be extrapolated from retrospective observations. Phase 5 studies (quantify impact and costs) have not been performed. The results of this study show that specific efforts are needed to complete phase 3 evidence, in particular comparing and combining FDG PET with other biomarkers, and to properly design phase 4 prospective studies as a basis for phase 5 evaluations.

Graphical abstract

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Transcriptional profiling reveals protective mechanisms in brains of long-lived mice

Publication date: April 2017
Source:Neurobiology of Aging, Volume 52
Author(s): Christiane Frahm, Akash Srivastava, Silvio Schmidt, Jule Mueller, Marco Groth, Madlen Guenther, Yuanyuan Ji, Steffen Priebe, Matthias Platzer, Otto W. Witte
The brain plays a central role in organismal aging but is itself most sensitive to aging-related functional impairments and pathologies. Insights into processes underlying brain aging are the basis to positively impact brain health. Using high-throughput RNA sequencing and quantitative polymerase chain reaction (PCR), we monitored cerebral gene expression in mice throughout their whole lifespan (2, 9, 15, 24, and 30 months). Differentially expressed genes were clustered in 6 characteristic temporal expression profiles, 3 of which revealed a distinct change between 24 and 30 months, the period when most mice die. Functional annotation of these genes indicated a participation in protection against cancer and oxidative stress. Specifically, the most enriched pathways for the differentially expressed genes with higher expression at 30 versus 24 months were found to be glutathione metabolism and chemokine signaling pathway, whereas those lower expressed were enriched in focal adhesion and pathways in cancer. We therefore conclude that brains of very old mice are protected from certain aspects of aging, in particular cancer, which might have an impact on organismal health and lifespan.



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Clinical validity of increased cortical uptake of amyloid ligands on PET as a biomarker for Alzheimer's disease in the context of a structured 5-phase development framework

Publication date: April 2017
Source:Neurobiology of Aging, Volume 52
Author(s): Konstantinos Chiotis, Laure Saint-Aubert, Marina Boccardi, Anton Gietl, Agnese Picco, Andrea Varrone, Valentina Garibotto, Karl Herholz, Flavio Nobili, Agneta Nordberg
The use of biomarkers has been proposed for diagnosing Alzheimer's disease in recent criteria, but some biomarkers have not been sufficiently investigated to justify their routine clinical use. Here, we evaluate in a literature review the clinical validity of amyloid positron emission tomography (PET) imaging using a structured framework developed for the assessment of oncological biomarkers. Homogenous criteria have been addressed in reviews of other Alzheimer's disease biomarkers. There is adequate evidence that the main aims of phases 1 (rationale for use) and 2 (discriminative ability) have been achieved. The aims of phase 3 (early detection ability) have been partly achieved, while phase 4 studies (performance in representative mild cognitive impairment patients) are currently ongoing. Phase 5 studies (quantification of impact and costs) are still to come. This review highlights the priorities to be pursued to enable the proper use of amyloid PET imaging in a clinical setting. Future investigations will primarily be large, phase 4 studies that will assess the utility of amyloid PET imaging in routine clinical practice.

Graphical abstract

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Contents continued

Publication date: April 2017
Source:Neurobiology of Aging, Volume 52





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TMEM230 In Parkinson’s Disease

Publication date: Available online 16 March 2017
Source:Neurobiology of Aging
Author(s): Laura Ibanez, Umber Dube, John Budde, Kathleen Black, Alexandra Medvedeva, Albert A. Davis, Joel S. Perlmutter, Bruno A. Benitez, Carlos Cruchaga
A study on familial Parkinson disease (PD) described four variants in the gene TMEM230 (Chr. 20p13) as cause of PD (1). The aim of this study was to test if variants in the TEMEM230 gene are associated with PD in two independent American European datasets. No variants in the TMEM230 region were found associated with PD, age at onset or cerebrospinal fluid α-synuclein levels.



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