Type-2-diabetes alters CSF but not plasma metabolomic and AD risk profiles in vervet monkeys

Epidemiological studies suggest that individuals with type 2 diabetes (T2D) have a twofold to fourfold increased risk for developing Alzheimer's disease (AD), however, the exact mechanisms linking the two diseases are unknown. In both conditions, the majority of pathophysiological changes, including glucose and insulin dysregulation, insulin resistance, and AD-related changes in Aβ and tau, occur decades before the onset of clinical symptoms and diagnosis. In this study, we investigated the relationship between metabolic biomarkers associated with T2D and amyloid pathology including Aβ levels, from cerebrospinal fluid (CSF) and fasting plasma of healthy, pre-diabetic (PreD), and T2D vervet monkeys (Chlorocebus aethiops sabaeus). Consistent with the human disease, T2D monkeys have increased plasma and CSF glucose levels as they transition from normoglycemia to PreD and diabetic states. Although plasma levels of acylcarnitines and amino acids remained largely unchanged, peripheral hyperglycemia correlated with decreased CSF acylcarnitines and CSF amino acids, including branched chain amino acid (BCAA) concentrations, suggesting profound changes in cerebral metabolism coincident with systemic glucose dysregulation. Moreover, CSF Aβ 40 and CSF Aβ 42 levels decreased in T2D monkeys, a phenomenon observed in the human course of AD which coincides with increased amyloid deposition within the brain. In agreement with previous studies in mice, CSF Aβ 40 and CSF Aβ 42 were highly correlated with CSF glucose levels, suggesting that glucose levels in the brain are associated with changes in Aβ metabolism. Interestingly, CSF Aβ 40 and CSF Aβ 42 levels were also highly correlated with plasma but not CSF lactate levels, suggesting that plasma lactate might serve as a potential biomarker of disease progression in AD. Moreover, CSF glucose and plasma lactate levels were correlated with CSF amino acid and acylcarnitine levels, demonstrating alterations in cerebral metabolism occurring with the onset of T2D. Together, these data suggest that peripheral metabolic changes associated with the development of T2D produce alterations in brain metabolism that lead to early changes in the amyloid cascade, similar to those observed in pre-symptomatic AD

An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. RESULTS: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. CONCLUSIONS: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups

Knowledge of Bovine Tuberculosis, Cattle Husbandry and Dairy Practices amongst Pastoralists and Small-Scale Dairy Farmers in Cameroon

BACKGROUND:Control of bovine tuberculosis (bTB) and zoonotic tuberculosis (zTB) has relied upon surveillance and slaughter of infected cattle, milk pasteurisation and public health education. In Cameroon, like many other sub-Saharan African countries, there is limited understanding of current cattle husbandry or milk processing practices or livestock keepers awareness of bTB. This paper describes husbandry and milk processing practices within different Cameroonian cattle keeping communities and bTB awareness in comparison to other infectious diseases. STUDY DESIGN:A population based cross-sectional sample of herdsmen and a questionnaire were used to gather data from pastoralists and dairy farmers in the North West Region and Vina Division of Cameroon. RESULTS:Pastoralists were predominately male Fulanis who had kept cattle for over a decade. Dairy farmers were non-Fulani and nearly half were female. Pastoralists went on transhumance with their cattle and came into contact with other herds and potential wildlife reservoirs of bTB. Dairy farmers housed their cattle and had little contact with other herds or wildlife. Pastoralists were aware of bTB and other infectious diseases such as foot-and-mouth disease and fasciolosis. These pastoralists were also able to identify clinical signs of these diseases. A similar proportion of dairy farmers were aware of bTB but fewer were aware of foot-and-mouth and fasciolosis. In general, dairy farmers were unable to identify any clinical signs for any of these diseases. Importantly most pastoralists and dairy farmers were unaware that bTB could be transmitted to people by consuming milk. CONCLUSIONS:Current cattle husbandry practices make the control of bTB in cattle challenging especially in mobile pastoralist herds. Routine test and slaughter control in dairy herds would be tractable but would have profound impact on dairy farmer livelihoods. Prevention of transmission in milk offers the best approach for human risk mitigation in Cameroon but requires strategies that improved risk awareness amongst producers and consumers

Evolution of the AT-rich mitochondrial DNA of the root knot nematode, Meloidogyne hapla

Mitochondrial DNA of the root knot nematode Meloidogyne hapla was investigated for intraspecific diversity and divergence from other parthenogenetic root knot nematodes. A 1,900-bp fragment containing COII, tRNAHis, 16S rRNA, ND3 and Cyt b genes has been cloned and sequenced from one individual and an 1,188-bp region within this region was sequenced from four other Australian isolates. M. hapla mtDNA is more than 80% AT-rich, like other Meloidogyne spp. Nucleotide diversity within M. hapla is some 10-fold higher than across three other parthenogenetic species of root-knot nematode (M. arenaria, M. javanica, and M. incognita), implying an earlier origin for M. hapla. Nucleotide divergence between M. hapla and its congener M. javanica is as great as that between Ascaris suum and Caenorhabditis elegans, members of different nematode subclasses, while amino acid sequence difference between Meloidogyne is more than twice as great. This is interpreted as an AT-bias-induced acceleration of the amino acid substitution rate, over and above saturation of nucleotide divergence in the strongly AT-biased DNA, on three lines of evidence: (1) in conserved blocks in 16S rDNA congeneric Meloidogyne have no more differences than between A. suum and C. elegans; (2) the Meloidogyne lineage has more amino acid changes relative to the Ascaris/Caenorhabditis lineage with respect to four of five outgroups, the exceptional outgroup being the only species (Apis) as AT-rich as Meloidogyne; and (3) between the two Meloidogyne there are more first and second but fewer third codon position changes than between the other nematode species. M. hapla is also found to contain a 102-bp tandem repeat of at least 40 copies; a size, arrangement, and position the same as in M. javanica, but sequence comparisons did not demonstrate homology between the two repeats

Superconducting sextupole correction coil operating in persistent mode

Error fields in a dipole due to superconductor magnetization and conductor misplacements add unwanted multipole, mainly sextupole and decapole, terms to the desired dipole field. Two persistent mode sextupole correction coils inside the bore of model SSC dipoles have been built and tested. A shorted superconducting sextupole coil has a current induced in it by the error sextupole field such that no sextupole field can penetrate into the proton beam region. The correction sextupole coils are one layer thick and are wound from a single length of insulated composite Nb-Ti and copper wire 0.60 mm in diameter. Each of the six poles has ten turns and is mounted on a 1.75 cm radius stainless steel bore tube. Details of testing and trimming of the correction coils are described. Test results of the measured magnetic field within the model SSC dipoles with the correction coils in and out of persistent mode operation are presented. An electrical heater is used to drive the coil out of the persistent mode. Measurements of joint resistance and coil decay time constants are also given

Tubular heart valves: A new tissue prosthesis design — Preclinical evaluation of the 3F aortic bioprosthesis

Background: It was hypothesized that native heart valves function as if they were simple tubes with sides that collapse when external pressure is applied. Because “form follows function,” this hypothesis could theoretically be confirmed by implanting a simple tube into the anatomic position of any native heart valve and documenting that under the same anatomic constraints and physiologic conditions as the native valve, the tube would assume the form of that native valve. If the hypothesis were thus proved, it would follow that a tissue valve based on a tubular design would have superior flow dynamics and stress distribution and would therefore be expected to outlast currently available tissue valves. Such a tubular tissue valve, the 3F Aortic Bioprosthesis (3F Therapeutics, Inc, Lake Forest, Calif) was designed and tested in vitro against a commercially available stentless aortic bioprosthesis. Methods: With the use of state-of-the-art testing equipment, some of which had to be developed especially to test this truly stentless bioprosthesis in vitro, transvalvular gradients, effective orifice areas, degree of transvalvular laminar flow, finite element analysis of the distribution of leaflet stress, and accelerated wear testing for long-term durability were evaluated for the new 3F Aortic Bioprosthesis in comparison with the St Jude Medical Toronto SPV aortic bioprosthesis (St Jude Medical, Inc, St Paul, Minn). Results: The valve gradients were lower and the effective orifice areas were greater for the 3F Aortic Bioprosthesis at all valve sizes and under all test conditions, including cardiac outputs ranging from 2.0 to 7.0 L/min, mean perfusion pressures from 40 to 200 mm Hg, and aortic compliances of 4% and 16%. The transvalvular flow across the 3F Aortic Bioprosthesis in vitro was qualitatively smooth, with a minimum of surrounding vortices. Maximum stress occurred in the belly of the leaflets of the 3F Aortic Bioprosthesis, with minimum stress at the commissural posts. The 3F Aortic Bioprosthesis was superior to the Toronto SPV valve in accelerated wear tests. Conclusions: These in vitro studies show that a tissue aortic valve designed on the basis of the proved engineering principle that form follows function has better hemodynamics, flow dynamics, stress distribution, and durability when compared under identical in vitro conditions with an excellent commercially available tissue aortic valve