Altered Hippocampal Glutamatergic Neurotransmission and Cognitive Impairment in APP Knock-In Mice.

It is well established that glutamatergic neurotransmission plays an essential role in learning and memory. Previous studies indicate that glutamate dynamics shift with Alzheimer's disease (AD) progression, contributing to negative cognitive outcomes. In this study, we characterized hippocampal glutamatergic signaling with age and disease progression in a knock-in mouse model of AD (APPNL-F/NL-F). At 2-4 and 18+ months old, male and female APPNL/NL, APPNL-F/NL-F, and C57BL/6 mice underwent cognitive assessment using Morris water maze (MWM) and Novel Object Recognition (NOR). Then, basal and 70 mM KCl stimulus-evoked glutamate release was measured in the dentate gyrus (DG), CA3, and CA1 regions of the hippocampus using a glutamate-selective microelectrode in anesthetized mice. Glutamate recordings support elevated stimulus-evoked glutamate release in the DG and CA3 of young APPNL-F/NL-F male mice that declined with age compared to age-matched control mice. Young female APPNL-F/NL-F mice exhibited increased glutamate clearance in the CA1 that slowed with age compared to age-matched control mice. Male and female APPNL-F/NL-F mice exhibited decreased CA1 basal glutamate levels, while males also showed depletion in the CA3. Cognitive assessment demonstrated impaired spatial cognition in aged male and female APPNL-F/NL-F mice, but only aged females displayed recognition memory deficits compared to age-matched control mice. These findings confirm a sex-dependent hyper-to-hypoactivation glutamatergic paradigm in APPNL-F/NL-F mice. Further, data illustrate a sexually dimorphic biological aging process resulting in a more severe cognitive phenotype for female APPNL-F/NL-F mice than their male counterparts. Research outcomes mirror that of human AD pathology and provide further evidence of divergent AD pathogenesis between sexes.

A compilation of tri-allelic SNPs from 1000 Genomes and use of the most polymorphic loci for a large-scale human identification panel.

In a directed search of 1000 Genomes Phase III variation data, 271,934 tri-allelic single nucleotide polymorphisms (SNPs) were identified amongst the genotypes of 2,504 individuals from 26 populations. The majority of tri-allelic SNPs have three nucleotide substitution-based alleles at the same position, while a much smaller proportion, which we did not compile, have a nucleotide insertion/deletion plus substitution alleles. SNPs with three alleles have higher discrimination power than binary loci but keep the same characteristic of optimum amplification of the fragmented DNA found in highly degraded forensic samples. Although most of the tri-allelic SNPs identified had one or two alleles at low frequencies, often single observations, we present a full compilation of the genome positions, rs-numbers and genotypes of all tri-allelic SNPs detected by the 1000 Genomes project from the more detailed analyses it applied to Phase III sequence data. A total of 8,705 tri-allelic SNPs had overall heterozygosities (averaged across all 1000 Genomes populations) higher than the binary SNP maximum value of 0.5. Of these, 1,637 displayed the highest average heterozygosity values of 0.6-0.666. The most informative tri-allelic SNPs we identified were used to construct a large-scale human identification panel for massively parallel sequencing, designed for the identification of missing persons. The large-scale MPS identification panel comprised: 1,241 autosomal tri-allelic SNPs and 29 X tri-allelic SNPs (plus 46 microhaplotypes adapted for genotyping from reduced length sequences). Allele frequency estimates are detailed for African, European, South Asian and East Asian population groups plus the Peruvian population sampled by 1000 Genomes for the 1,270 tri-allelic SNPs of the final MPS panel. We describe the selection criteria, kinship simulation experiments and genomic analyses used to select the tri-allelic SNP components of the panel. Approximately 5 % of the tri-allelic SNPs selected for the large-scale MPS identification panel gave three-genotype patterns in single individual samples or discordant genotypes for genomic control DNAs. A likely explanation for some of these unreliably genotyped loci is that they map to multiple sites in the genome - highlighting the need for caution and detailed scrutiny of multiple-allele variant data when designing future forensic SNP panels, as such patterns can arise from common structural variation in the genome, such as segmental duplications.

Electron-density distributions in selected ferrocenyl-pyrazolyl late transition-metal complexes.

57Fe Mössbauer spectroscopy has been used to study electronic dispersions in complexes of Fe, Co, Ni and Pd anchored onto 3-ferrocenyl-5-methylpyrazolylmethylenepyridine and 3-ferrocenylpyrazolylmethylenepyridine ligands. Mössbauer spectroscopy shows that pyrazolyl-derivatizing of ferrocene increases the electron-density at the Fe-centre as well as facilitating the Fe to cyclopentadienyl ring back-donation of electron-density. The coordination of the ferrocenyl-pyrazolyl ligand to transition metals such as Fe, Co, Ni and Pd reduces the electron-density at the Fe-centre of the ferrocenyl moiety while increasing the electron-density at the coordinated metal centre, especially in the Fe complexes. The electron-density change at the coordination metal centre is inversely proportional to the electronegativity of the halide substituent. Furthermore, the type of substituent (Me or H) at position 5 on the pyrazolyl moiety has an influence on the electron density at the ferrocenyl-Fe and the coordinated metal centre. The methyl group as a substituent reduces the π-acceptor ability of the pyrazolyl and therefore increases the electron-density at the ferrocenyl-Fe centre. However, when the substituent is hydrogen, the electron-density at the coordination metal centre increases. Similarly, for other metals (i.e., Co, Ni and Pd) the electron density at the ferrocenyl-Fe is also significantly reduced upon coordination of the ligand to the metal. Additionally, Mössbauer experiments reveal a trivalent Fe species in the synthesized complexes which is not discerned by X-ray and elemental analysis. The species has been identified as the oxidative product [Fe(iii)X4]- where X = Cl or Br. The study also highlights and cautions on the possibility of photo-oxidation processes involving both ferrocene and the coordinating Fe-halides under standard lighting conditions with possible contributions from aerated solvents.

Seroprevalence of brucellosis in goats and sheep in Thailand: Results from the Thai National Brucellosis Surveillance System from 2013 to 2015.

In Thailand, brucellosis re-emerged in humans in 2003 and is considered a public health risk to goat farmers as the disease is endemic in small ruminants. The Thai Department of Livestock Development (DLD) established a nationwide surveillance system for brucellosis in goats and sheep in 1997. Using data from this surveillance system, we describe the seroprevalence of brucellosis from 2013 to 2015 in small ruminants and the spatial distribution of the disease throughout Thailand. Surveillance data collected included the number of animals and herds tested, the province of the animal and herd and the laboratory results. Seroprevalence was estimated at both the animal and herd levels. During the 3-year period, 443,561 goats and sheep were tested for brucellosis by the DLD throughout Thailand using the Rose Bengal Plate Test (RBPT) and the enzyme-linked immunosorbent assay test for Brucella. Among the 3 years, 2013 had the highest proportion of herds that tested positive for brucellosis at 13.80% (95% CI, 12.52, 15.16). Overall, this study found that brucellosis seroprevalence in small ruminants is decreasing throughout Thailand. However, there is variability in the spread of the disease with provinces in the eastern and western regions of Thailand having higher proportions of animals and herds testing positive. Overall provinces in the south had the lowest proportion of animals and herds testing positive for brucellosis. Periodic review of surveillance data documents the impact of the current brucellosis control programme and supports a targeted response in higher prevalence regions when there are limited financial resources for control measures.

Diagnostic yield of active case finding for tuberculosis and HIV at the household level in slums in Haiti.

SETTING: Haiti has the highest burden of tuberculosis (TB) in the Americas, with an estimated prevalence of 254 per 100 000 population. The Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections (Groupe Haïtien d'Etude du Sarcome de Kaposi et des Infections Opportunistes, GHESKIO) conducted active case finding (ACF) for TB at the household level in nine slums in Port-au-Prince. OBJECTIVE: We report on the prevalence of undiagnosed TB detected through GHESKIO's ACF campaign. DESIGN: From 1 August 2014 to 31 July 2015, we conducted a retrospective cohort analysis using GHESKIO's ACF campaign data. All individuals who reported chronic cough (cough 2 weeks) were tested for TB at GHESKIO, and those aged 10 years were included in the analyses. RESULTS: Of 104 097 individuals screened in the community, 5598 (5%) reported chronic cough and satisfied the study inclusion criteria. A total of 1110 (20%) were diagnosed with active TB disease (prevalence of 1066/100 000). Of the 5472 (98%) patients tested for human immunodeficiency virus (HIV), 528 (10%) were HIV-positive; 143 (3%) patients were diagnosed with both diseases. CONCLUSION: Household-level screening for cough with TB and HIV testing for symptomatic patients was a high-yield strategy, leading to the detection of a prevalence of undiagnosed disease exceeding national estimates by more than four-fold for TB, and by five-fold for HIV.

Measuring respiration rates in marine fish larvae: challenges and advances.

Metabolic costs can be extremely high in marine fish larvae and gaining reliable estimates of the effects of intrinsic and extrinsic factors on those costs is important to understand environmental constraints on early growth and survival. This review provides an historical perspective of measurements of larval marine fish respiration (O2 consumption) including the methods (Winkler, manometric, polarographic, paramagnetic and optodes) and systems (closed system to intermittent-flow) used. This study compares and systematically reviews the results (metabolic rates, ontogenetic changes and taxonomic differences) obtained from 59 studies examining 53 species from 30 families. Standard (anaesthetized or darkness), routine and active respiration rates were reported in 14, 94 and 8% of the studies and much more work has been performed on larvae of temperate (88%) compared with tropical (9%) and polar (3%) species. More than 35% of the studies have been published since 2000 owing to both advances in oxygen sensors and the growing emphasis on understanding physiological effects of environmental change. Common protocols are needed to facilitate cross-taxa comparisons such as the effect of temperature (Q10 : 1·47-3·47), body mass (slope of allometric changes in O2 consumption rate from 0·5 to 1·3) and activity level on metabolic costs as measured via respiration rate. A set of recommendations is provided that will make it easier for researchers to design measurement systems, to judge the reliability of measurements and to make inter-comparisons among studies and species.

Born small, die young: Intrinsic, size-selective mortality in marine larval fish.

Mortality during the early stages is a major cause of the natural variations in the size and recruitment strength of marine fish populations. In this study, the relation between the size-at-hatch and early survival was assessed using laboratory experiments and on field-caught larvae of the European sardine (Sardina pilchardus). Larval size-at-hatch was not related to the egg size but was significantly, positively related to the diameter of the otolith-at-hatch. Otolith diameter-at-hatch was also significantly correlated with survival-at-age in fed and unfed larvae in the laboratory. For sardine larvae collected in the Bay of Biscay during the spring of 2008, otolith radius-at-hatch was also significantly related to viability. Larval mortality has frequently been related to adverse environmental conditions and intrinsic factors affecting feeding ability and vulnerability to predators. Our study offers evidence indicating that a significant portion of fish mortality occurs during the endogenous (yolk) and mixed (yolk /prey) feeding period in the absence of predators, revealing that marine fish with high fecundity, such as small pelagics, can spawn a relatively large amount of eggs resulting in small larvae with no chances to survive. Our findings help to better understand the mass mortalities occurring at early stages of marine fish.

Applications of PET imaging with the proliferation marker [18F]-FLT.

[18F]-3'-fluoro-3'-deoxythymidine (FLT) is a nucleoside-analog imaging agent for quantifying cellular proliferation that was first reported in 1998. It accumulates during the S-phase of the cell cycle through the action of cytosolic thymidine kinase, TK1. Since TK1 is primarily expressed in dividing cells, FLT uptake is essentially limited to dividing cells. Thus FLT is an effective measure of cell proliferation. FLT uptake has been shown to correlate with the more classic proliferation marker, the monoclonal antibody to Ki-67. Increased cellular proliferation is known to correlate with worse outcome in many cancers. However, the Ki-67 binding assay is performed on a sampled preparation, ex vivo, whereas FLT can be quantitatively measured in vivo using positron emission tomography (PET). FLT is an effective and quantitative marker of cell proliferation, and therefore a useful prognostic predictor in the setting of neoplastic disease. This review summarizes clinical studies from 2011 forward that used FLT-PET to assess tumor response to therapy. The paper focuses on our recommendations for a standardized clinical trial protocol and components of a report so multi center studies can be effectively conducted, and different studies can be compared. For example, since FLT is glucuronidated by the liver, and the metabolite is not transported into the cell, the plasma fraction of FLT can be significantly changed by treatment with particular drugs that deplete this enzyme, including some chemotherapy agents and pain medications. Therefore, the plasma level of metabolites should be measured to assure FLT uptake kinetics can be accurately calculated. This is important because the flux constant (KFLT) is a more accurate measure of proliferation and, by inference, a better discriminator of tumor recurrence than standardized uptake value (SUVFLT). This will allow FLT imaging to be a specific and clinically relevant prognostic predictor in the treatment of neoplastic disease.

Standard metabolism and growth dynamics of laboratory-reared larvae of Sardina pilchardus.

This study provides the first measurements of the standard respiration rate (R(S)) and growth dynamics of European sardine Sardina pilchardus larvae reared in the laboratory. At 15° C, the relationship between RS (µl O(2) individual(-1) h(-1)) and larval dry mass (M(D), µg) was equal to: R(S) = 0·0057(±0·0007, ± s.e.)·M(D) (0·8835(±0·0268)), (8-11% M(D) day(-1)). Interindividual differences in RS were not related to interindividual differences in growth rate or somatic (Fulton's condition factor) or biochemical-based condition (RNA:DNA).

The McGrath® Series 5 videolaryngoscope vs the Macintosh laryngoscope: a randomised, controlled trial in patients with a simulated difficult airway.

We compared the McGrath® Series 5 videolaryngoscope with the Macintosh laryngoscope in a simulated difficult airway, using manual in-line stabilisation in 88 anaesthestised patients of ASA physical status 1-2. The primary outcome was laryngoscopic view. Secondary outcomes included rates of successful tracheal intubation and complications. A Cormack and Lehane grade-1 or -2 view was found in all patients when using the McGrath compared with 45 (51%, p < 0.0001) using the Macintosh laryngoscopes. The mean (SD) percentage of glottic opening was 82 (23)% using the McGrath compared with 13 (23)% using the Macintosh (p < 0.0001). In 66 out of 88 patients (75%), the McGrath improved the glottic view by one to three grades compared with the Macintosh (p < 0.001). Intubation of the trachea was successful in all patients using the McGrath, while the Macintosh was successful in 26 (59%, p < 0.001). There was no significant difference in the complication rates between the devices.

The use of leukocyte- and platelet-rich fibrin (L-PRF) to facilitate implant placement in bone-deficient sites: a report of two cases.

Successful dental implant treatment usually requires that the implant be placed in the ideal anatomic position, so that it will readily facilitate the placement of a functional and aesthetically acceptable restoration. However, this is not always possible, and in many cases augmentation procedures may be required to compensate for lost tissue structures. These interventions often require more complex surgery, as well as the use of graft material derived from animal sources. Leukocyte- and patelet-rich fibrin (LPRF) is a newly developed platelet concentrate that has successfully been used in a number of surgical procedures to optimise wound healing. Several studies indicate that it may also have the ability to stimulate bone formation. In this article we present two cases where L-PRF was used to stimulate bone formation to facilitate ideal placement of implants.

Genomic impact of cigarette smoke, with application to three smoking-related diseases.

There is considerable evidence that inhaled toxicants such as cigarette smoke can cause both irreversible changes to the genetic material (DNA mutations) and putatively reversible changes to the epigenetic landscape (changes in the DNA methylation and chromatin modification state). The diseases that are believed to involve genetic and epigenetic perturbations include lung cancer, chronic obstructive pulmonary disease (COPD), and cardiovascular disease (CVD), all of which are strongly linked epidemiologically to cigarette smoking. In this review, we highlight the significance of genomics and epigenomics in these major smoking-related diseases. We also summarize the in vitro and in vivo findings on the specific perturbations that smoke and its constituent compounds can inflict upon the genome, particularly on the pulmonary system. Finally, we review state-of-the-art genomics and new techniques such as high-throughput sequencing and genome-wide chromatin assays, rapidly evolving techniques which have allowed epigenetic changes to be characterized at the genome level. These techniques have the potential to significantly improve our understanding of the specific mechanisms by which exposure to environmental chemicals causes disease. Such mechanistic knowledge provides a variety of opportunities for enhanced product safety assessment and the discovery of novel therapeutic interventions.

Echocardiography and the non-cardiac anaesthetist.

Echocardiography is destined to revolutionize perioperative and intensive care medicine, as it has already in cardiac anaesthesia. This article reviews the evidence underlining why now is the time for general anaesthetists to get involved in this rapidly evolving field.

The domestication of fire: the relationship between biomass fuel, fossil fuel and burns.

Primitive man's discovery and use of fire had a tremendous impact on modern development. It changed lifestyles, and brought with it new fuel sources and cooking methods. It also introduced devastation, injury, pain, disfigurement, and loss of life, and the need to continuously develop management, training and prevention programs.

Spore germination of the psychrotolerant, red meat spoiler, Clostridium frigidicarnis.

AIMS: To determine germination triggers of Clostridium frigidicarnis, an important spoilage bacterium of chilled vacuum-packed meat. METHODS AND RESULTS: Germination of Cl. frigidicarnis spores in the presence of a range of potential nutrient and non-nutrient germinants was tested by monitoring the fall in optical density and by phase-contrast microscopy. The amino acid L-valine induced strong germination when paired with L-lactate in sodium phosphate under anaerobic conditions. Several other amino acids promoted germination when paired with L-lactate in sodium phosphate and the co-germinants NaHCO3 and L-cysteine. Heat activation, while not necessary for germination, increased the rate of germination. Spore germination was not observed when spores were incubated aerobically. CONCLUSIONS: Spores of psychrotolerant Cl. frigidicarnis germinated in the presence of L-valine in combination with L-lactate in sodium phosphate buffer under anaerobic conditions. SIGNIFICANCE AND IMPACT OF THE STUDY: Anaerobic conditions, L-valine and L-lactate, have been identified as triggering germination in Cl. frigidicarnis, and are all present in packs of fresh, vacuum-packaged, red meat. This new information adds to what is known about red meat spoilage by cold tolerant clostridia and can be used to develop intervention strategies to prevent meat spoilage.