Test–retest repeatability of [18F]Flortaucipir PET in Alzheimer’s disease and cognitively normal individuals

The aim of this study was to investigate the test–retest (TRT) repeatability of various parametric quantification methods for [¹⁸F]Flortaucipir positron emission tomography (PET). We included eight subjects with dementia or mild cognitive impairment due to Alzheimer’s disease and six cognitively normal subjects. All underwent two 130-min dynamic [¹⁸F]Flortaucipir PET scans within 3 ± 1 weeks. Data were analyzed using reference region models receptor parametric mapping (RPM), simplified reference tissue method 2 (SRTM2) and reference logan (RLogan), as well as standardized uptake value ratios (SUVr, time intervals 40–60, 80–100 and 110–130 min post-injection) with cerebellar gray matter as reference region. We obtained distribution volume ratio or SUVr, first for all brain regions and then in three tau-specific regions-of-interest (ROIs). TRT repeatability (%) was defined as |retest–test|/(average (test + retest)) × 100. For all methods and across ROIs, TRT repeatability ranged from (median (IQR)) 0.84% (0.68–2.15) to 6.84% (2.99–11.50). TRT repeatability was good for all reference methods used, although semi-quantitative models (i.e. SUVr) performed marginally worse than quantitative models, for instance TRT repeatability of RPM: 1.98% (0.78–3.58) vs. SUVr_80–100: 3.05% (1.28–5.52), p < 0.001. Furthermore, for SUVr_80–100 and SUVr_110–130, with higher average SUVr, more variation was observed. In conclusion, while TRT repeatability was good for all models used, quantitative methods performed slightly better than semi-quantitative methods.     

Systematic analysis of research underfunding in maternal and perinatal health

Background  Little published evidence supports the widely held contention that research in pregnancy is underfunded compared with other disease areas.
Objectives  To assess absolute and relative government and charitable funding for maternal and perinatal research in the UK and internationally.
Search strategy, selection criteria, data collection, and analysis  Major research funding bodies and alliances were identified from an Internet search and discussions with opinion leaders/senior investigators. Websites and annual reports were reviewed for details of strategy, research spend, grants awarded, and allocation to maternal and/or perinatal disease using generic and disease-specific search terms.
Main results  Within the imprecision in the data sets, ≤1% of health research spend in the UK was on maternal/perinatal health. Other countries fared better with 1–4% investment, although nonexclusive categorisation may render this an overestimate. In low-resource settings, government funders focused on infectious disease but not maternal and perinatal health despite high relative disease burden, while global philanthropy concentrated on service provision rather than research. Although research expenditure has been deemed as appropriate for 'reproductive health' disease burden in the UK, there are no data on the equity of maternal/perinatal research spend against disease burden, which globally may justify a manyfold increase.
Author's conclusions  This systematic review of research expenditure and priorities from national and international funding bodies suggests relative underinvestment in maternal/perinatal health. Contributing factors include the low political priority given to women's health, the challenging nature of clinical research in pregnancy, and research capacity dearth as a consequence of chronic underinvestment.     

The role of acid in the pathogenesis of indomethacin-induced gastric antral ulcers in the rat.

BACKGROUND: The role of acid in the pathogenesis of indomethacin- induced ulcers of the rat gastric antrum was studied by comparing the effects of pretreating animals with both long-acting (loxtidine, AH22216) and short-acting (ranitidine and cimetidine) inhibitors of acid secretion. RESULTS: Ranitidine and cimetidine were much weaker at inhibiting antral damage when compared to their reported potencies as antisecretory agents. In marked contrast, loxtidine and AH22216 inhibited indomethacin-induced antral ulcers at doses similar to their reported potencies as inhibitors of acid secretion. Histological analysis at doses causing near maximal inhibition of macroscopic damage revealed an almost complete absence of ulcers but a large and significant increase in mucosal damage due to superficial erosions. Hourly dosing with hydrochloric acid reversed the protective effect of ranitidine, cimetidine and loxtidine on macroscopic damage and, histologically, this was associated with the widespread appearance of antral ulcers and a reduction in the proportion of mucosal damage caused by superficial erosions. CONCLUSIONS: The results of this study suggest that the pathogenesis of nonsteroidal anti-inflammatory drug (NSAID)-induced antral ulcers involves at least two stages: (1) an initial acid-independent formation of mucosal erosions followed by (2) an acid-dependent conversion of erosions to frank ulcers. Clinically, drugs that suppress acid completely for long periods may be very effective in preventing NSAID-induced gastric antral ulcers.     

Validation and reproducibility of computerised cell-viability analysis of tissue slices

Background

The identification of live cells using membrane integrity dyes has become a frequently used technique, especially with articular cartilage and chondrocytes in situ where tissue slices are used to assess cell recovery as a function of location. The development of a reproducible computerised method of cell evaluation would eliminate many variables associated with manual counting and significantly reduce the amount of time required to evaluate experimental results.

Methods

To validate a custom computerised counting program, intra-person and inter-person cell counts of nine human evaluators (three groups – unskilled, novice, and experienced) were compared with repeated pixel counts of the custom program on 15 digitised images (in triplicate) of chondrocytes in situ stained with fluorescent dyes.

Results

Results indicated increased reproducibility with increased experience within evaluators [Intraclass Correlation Coefficient (ICC) range = 0.67 (unskilled) to 0.99 (experienced)] and between evaluators [ICC = 0.47 (unskilled), 0.85 (novice), 0.93 (experienced)]. The computer program had perfect reproducibility (ICC = 1.0). There was a significant relationship between the average of the experienced evaluators results and the custom program results (ICC = 0.77).

Conclusions

This study demonstrated that increased experience in cell counting resulted in increased reproducibility both within and between human evaluators but confirmed that the computer program was the most reproducible. There was a good correlation between the intact cell recovery determined by the computer program and the experienced human evaluators. The results of this study showed that the computer counting program was a reproducible tool to evaluate intact cell recovery after use of membrane integrity dyes on chondrocytes in situ. This and the significant decrease in the time used to count the cells by the computer program advocate its use in future studies because it has significant advantages.

     

Iron, ascorbate and copper status of Sowetan Blacks with calcific chronic pancreatitis

Vitamin C can be used to overcome oxidative stress and ease pain in chronic pancreatitis. But its use is deprecated in conditions of tissue iron overload, because its bioactive form, ascorbate, can accelerate free-radical reactions that are driven by transition metals. We measured iron, ascorbate and copper in Sowetan Blacks (RSA) with chronic pancreatitis, obtaining serum/plasma from 14 consecutive patients and 15 controls. Compared with data from corresponding groups in Manchester, African samples had less ascorbate (p < 0.0001), but more caeruloplasmin (p < 0.0001). African and British controls had comparable iron and iron-binding capacity. Plasma from African patients had less ascorbate than that from African controls (p < 0.005) and in six samples, ferritin exceeded 300 micrograms/l (677 pmol/l). Low- molecular-mass iron or copper, capable of participating in free radical reactions, was not detected. British patients, had similar caeruloplasmin levels to African patients but higher ascorbate levels. There is no evidence of iron overload in our African samples. Outwardly healthy controls from Soweto have elevated levels of caeruloplasmin, possibly to compensate for dietary deficiency of ascorbate. Persistent oxidative stress is a unifying feature of chronic pancreatitis, but its degree is higher in African than British patients. Supplements of vitamin C should be safe in Blacks of southern Africa.