The SPECTRA Collaboration OMERACT Special Interest Group: Current Research and Future Directions

Objective High-resolution peripheral quantitative computed tomography (HR-pQCT) has the potential to improve radiographic progression determination in clinical trials and longitudinal observational studies. The goal of this work was to describe the current state of research presented at Outcome Measures in Rheumatology (OMERACT) 2016 and ensuing future directions outlined during discussion among attendees. Methods At OMERACT 2016, SPECTRA (Study grouP for xtrEme-Computed Tomography in Rheumatoid Arthritis) introduced efforts to (1) validate the HR-pQCT according to OMERACT guidelines, focusing on rheumatoid arthritis (RA), and (2) find alternatives for automated joint space width (JSW) analysis. The Special Interest Group (SIG) was presented to patient research partners, physicians/researchers, and SIG leaders followed by a 40-min discussion on future directions. Results A consensus definition for RA erosion using HR-pQCT was demonstrated through a systematic literature review and a Delphi exercise. Histopathology and perfusion studies were presented that analyzed the true characteristics of cortical breaks in HR-pQCT images, and to provide criterion validity. Results indicate that readers were able to discriminate between erosion and small vascular channels. Moderate reliability (ICC 0.206–0.871) of direct erosion size measures was shown, which improved (> 0.9) only when experienced readers were considered. Quantification of erosion size was presented for scoring, direct measurement, and volumetric approaches, as well as a reliability exercise for direct measurement. Three methods for JSW measurement were compared, all indicating excellent reproducibility with differences at the extremes (i.e., near-zero and joint edge thickness). Conclusion Initial reports on HR-pQCT are promising; however, to consider its use in clinical trials and longitudinal observational studies, it is imperative to assess the responsiveness of erosion measurement quantification

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

The mechanism of inhibition by fluoride of mitochondrial fatty acid oxidation

The following evidence is presented in favour of the old hypothesis that F− inhibition of fatty acid oxidation in intact, coupled rat-liver mitochondria is due to an accumulation of pyrophosphate in the mitochondrial matrix: 1. 1.Addition of fatty acid to mitochondria oxidizing malate in the presence of F− initially causes an increased rate of O2 uptake, followed by a gradual decrease, indicating the accumulation of an inhibitor as a result of fatty acid oxidation. 2. 2. This inhibition is only found when the fatty acid substrate is activated in the mitochondrial matrix. 3. 3. The matrix acyl-CoA synthetase (acid:CoA ligase (AMP), EC 6.2.1.3) is strongly inhibited by pyrophosphate. 4. 4. Mitochondrial pyrophosphatase (pyrophosphate phosphohydrolase, EC 3.6.1.1) is inhibited by F− and is localized mainly in the matrix. 5. 5. The mitochondrial inner membrane is impermeable to pyrophosphate. 6. 6. Pyrophosphate accumulates in mitochondria oxidizing fatty acid in the presence of fluoride. Oxidation of fatty acids by uncoupled mitochondria in the absence of inorganic phosphate also leads to pyrophosphate accumulation when F− is added, showing that under these conditions too, an ATP-dependent acyl-CoA synthetase is active

Glycogen metabolism in Schistosoma mansoni worms after their isolation from the host

Adult Schistosoma mansoni worms rapidly degrade their endogenous glycogen stores immediately after isolation from the host. In NCTC 109 or in a diphasic culture medium the glycogen levels slowly recovered again after the initial decrease. The rapid degradation of glycogen could be prevented, even in a simple salt medium, if 100 mM glucose and 1% bovine serum albumin were present. Incubations with 14C-labelled glucose under different conditions revealed that the degradation of glycogen was induced by the limited catabolism of external glucose. Conditions are described which induce glycogen degradation or resynthesis by S. mansoni. The physiological function of the glycogen stores is probably to provide substrate during periods of insufficient supply of external glucose. It is speculated that such periods occur when the worm pair moves into the small mesenteric veins of the host. This hypothesis explains the remarkable wandering behaviour of the parasite in the mesenteric veins, since the schistosomes would have return to larger vessels when their endogenous glycogen stores are exhausted

Effects of volatile fatty acids, ketone bodies, glucose, and insulin on lipolysis in bovine adipose tissue

Our interest in the aetiology of ketosis in cattle recently led us to investigate possible metabolic control mechanisms of fat mobilization in bovine adipose tissue. Acetic, propionic and butyric acid are the major sources of metabolic energy made available to the adult ruminant by digestion and absorption. No studies have been published on the effects of these volatile fatty acids on the rate of lipolysis in adipose tissue either from monogastric mammals or from ruminants

Overleven zonder zuurstof

Het verhaal over het verband tussen leven en zuurstof kan je op elk moment in de geschiedenis laten beginnen. Zolang er mensen op aarde zijn geweest, zijn er mensen gestikt bij gebrek aan zuurstof. Wat dat betreft is 'overleven' zonder zuurstof' een tijdloos streven. Zoals we straks zullen zien, zouden we het verhaal bij de oude Egyptenaren kunnen beginnen. Maar ik begin liever bij Leonardo da Vinci (1452-1519), want dan zijn we een beetje op bekend terrein. Leonardo was misschien wel de laatste 'uomo universale', een universeel genie, een kunstenaar in vele kunstvormen en een wetenschapper op alle toen bekende terreinen van wetenschap. Hij zag nieuwe verbanden en trok daaruit originele conclusies. Zo zag hij een verband tussen het feit dat een muis, die onder een glazen stolp wordt afgesloten van de lucht, na enige tijd dood gaat en het feit dat een brandende kaars onder diezelfde omstandigheden na enige tijd uitdooft. Uit die twee feiten concludeerde hij dat levende wezens hun voedsel blijkbaar verbranden en dat zij, als die verbranding onmogelijk wordt gemaakt, dood gaan

The energy metabolism of Fasciola hepatica during its development in the final host

Mature liver flukes, Fasciola hepatica, of different ages were isolated from the bile ducts of experimentally infected rats. Their energy metabolism was studied during aerobic incubation with [6-14C]glucose. The results showed that the aerobic potentials of the parenchymal liver flukes are not lost immediately after arrival in the bile ducts, but in a later phase. During the development of the newly excysted juvenile into the mature adult the major part of ATP production in aerobic incubations is successively contributed by three different pathways of glucose breakdown. The Krebs cycle, which is by far the main energy-yielding pathway of the juvenile fluke, is gradually replaced by aerobic acetate formation and, finally, by the anaerobic dismutation reactions of the adult liver fluke. This observed decrease in Krebs-cycle activity per mg protein is not the result of a decrease in activity per individual fluke. The Krebs-cycle activity per fluke actually increases enormously during its whole development. This indicates that the aerobic potential of adult F. hepatica is not just a remnant of earlier aerobic stages but that classical, mammalian type mitochondria are produced during the entire development of the fluke. Calculations are presented which demonstrate that the Krebs-cycle activity of the developing F. hepatica is directly proportional to the surface area of the fluke. This supports our view that Krebs-cycle activity is limited by the diffusion of oxygen and can only occur in the outer layer of the liver fluke during its entire development in the final host

Differences in intermediary energy metabolism between juvenile and adult Fasciola hepatica

A comparison of glucose catabolism by juvenile and adult liver flukes, Fasciola hepatica, showed that in the adult the cytosolic degradation of glucose via phosphoenolpyruvate carboxykinase (PEPCK) was the most important route, whereas in the freshly excysted juvenile a large part was degraded via pyruvate kinase (PK). However, it was also shown that the adult did not exclusively use the PEPCK pathway, nor did the juvenile exclusively use the PK pathway. When the juvenile was forced to anaerobic functioning it produced propionate and acetate just like the adult, but this did not imply that it switched to the pathways of the adult: the pathway via PK remained important. Malic enzyme (NADP(H)-dependent) was demonstrated to be present in the cytosol and in the mitochondria of both juveniles and adults. These enzyme activities enable the parasite to use a mixture of malate and pyruvate in any ratio as substrate for the mitochondrial production of proportionate and acetate. Pyruvate dismutation was important in the anaerobically functioning juvenile, whereas in the adult malate was the major, but not the only mitochondrial substrate. The pH profiles of PK and PEPCK showed that the pathway of PEP metabolism at the PK/PEPCK branchpoint can be regulated by the pH. However, the end products of glucose breakdown were not dependent on the pH. During its development, the liver fluke will gradually be forced to anaerobic functioning. At first, the acidic end product will favour a partitioning of PEP at the PK/PEPCK branchpoint toward malate formation. Later, a lasting predominance of the PEPCK pathway occurs as PK activity almost completely disappears. During the development of F. hepatica also a transition in the mitochondria occurs: at the acetyl-coenzyme A branchpoint a switch from citrate to acetate formation could be demonstrated. The most likely mechanism of this change is discussed