Anemia of the Belgrade rat: evidence for defective membrane transport of iron

The mechanisms underlying the impaired utilization of transferrin-bound iron by erythroid cells in the anemia of the Belgrade laboratory rat were investigated using reticulocytes from homozygous anemic animals and transferrin labeled with 59Fe and 125I. The results were compared with those obtained using reticulocytes from phenylhydrazine-treated rats and iron-deficient rats. Each step in the iron uptake mechanism was investigated, ie, transferrin-receptor interaction, transferrin endocytosis, iron release from transferrin, and transferrin exocytosis. Although there were quantitative differences, no fundamental difference was found in any of the abovementioned aspects of cellular function when the reticulocytes from Belgrade rats were compared with those from iron-deficient animals. The basic defect in the Belgrade reticulocytes must therefore reside in subsequent steps in iron uptake, after it is released from transferrin within endocytotic vesicles, ie, in the mechanism by which it is transferred across the lining membrane of the vesicles into the cell cytosol. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of reticulocyte ghosts extracts demonstrated a prominent protein band of mol wt 69,000 that was absent or present only in low concentration extracts from the other two types of reticulocytes. This may be a result of the genetic defect.     

Topical sensor metrics for 18F-FDG positron emission tomography dose extravasation

IntroductionExtravasation or partial extravasation of the positron emission tomography (PET) tracer negatively effects image quality in PET and the accuracy of the standard uptake value (SUV). A commercially available topical sensor has been validated using a number of metrics to characterise injection quality. This evaluation explores contributing factors for extravasation and refines metrics to predict extravasation based on the time-activity-curves (TAC) of the topical sensor device.MethodsA multi-site, multi-national pooling of 18F FDG PET/CT data was undertaken with 863 patients from 6 sites in the USA and 2 sites in Australia. A number of dose migration metrics determined with topical application of Lara sensors were retrospectively analysed using conventional statistical analysis. Deeper insights into the complex relationship between variables was further explored using an artificial neural network.ResultsExtravasation was independently predicted by the time taken for the injection sensor counts to reach double the counts of the reference sensor (tc50), the normalised difference between injection and reference sensors counts at 4 min post injection (ndAvgN), or the ratio of injection sensor counts to reference sensor counts at the end of data collection (CEnd ratio). The algorithm developed using the artificial neural network produced 100% sensitivity and 100% specificity against grounded truth for detecting extravasation by weighting and scaling these 3 key metrics; CEnd ratio, ndAvgN and tc50.ConclusionPartial extravasation of a PET dose is readily detected and differentiated using TAC metrics and these metrics could provide deeper insight into the impact of partial extravasation on image quality or quantitation. Further validation of key metrics developed in this study are recommended in a larger and more diverse cohort.Implications for practicePartial extravasation undermines image quality and accuracy of quantitation, impacting efficacy of outcomes for patients. Characterisation of extravasation informs decision making to optimise protocol and procedure, enhancing patient outcomes. Awareness provides the opportunity for education and training to minimise impact. The information can be used to drive policy and regulations to support improved techniques in practice.     

Preferred Functions of Personal Health Records in Rural Primary Health Clinics in Canada: Health Care Team Perspectives

Background  Personal health records (PHR) provide opportunities for improved patient engagement, collection of patient-generated data, and overcome health-system inefficiencies. While PHR use is increasing, uptake in rural populations is lower than in urban areas. Objectives  The study aimed to identify priorities for PHR functionality and gain insights into meaning, value, and use of patient-generated data for rural primary care providers. Methods  We performed PHR preimplementation focus groups with rural providers and their health care teams from five primary care clinics in a sparsely populated mountainous region of British Columbia, Canada to obtain their understanding of PHR functionality, needs, and perceived challenges. Results  Eight general practitioners (GP), five medical office assistants, two nurse practitioners (NP), and two registered nurses (14 females and 3 males) participated in focus groups held at their respective clinics. Providers (GPs, NPs, and RNs) had been practicing for a median of 9.5 (range = 1–38) years and had used an electronic medical record for 7.0 (1–20) years. Participants expressed interest in incorporating functionality around two-way communication and appointment scheduling, previsit data gathering, patient and provider data sharing, virtual care including visits using videoconferencing tools, and postvisit sharing of educational materials. Three further themes emerged from the focus groups: (1) the context in which the providers'' practice matters, (2) the need for providing patients and providers with choice (e.g., which data to share, who gets to initiate/respond in communications, and processes around virtual care visits), and (3) perceived risks of system use (e.g., increased complexity for older patients and workload barriers for the health care team). Conclusion  Rural primary care teams perceived PHR opportunities for increased patient engagement and access to patient-generated data, while worries about changes in workflow were the biggest perceived risk. Recommendations for PHR adoption in a rural primary health network include setting provider-patient expectations about response times, ability to share notes selectively, and automatically augmented note-taking from virtual-care visits.     

Changes in the responsiveness of adrenal cells from foetal goats at different times during pregnancy

To understand the factors responsible for the increased pre-partum output of cortisol from the adrenal glands of the goat foetus, we measured changes in responsiveness to ACTH in vitro of dispersed adrenal cells from foetal goats of various gestational ages and we determined the output of cortisol (F) and corticosterone (B) in the presence of exogenous progesterone (P4) and 17 alpha-hydroxyprogesterone (17 alpha-OHP4). The increment in F output after ACTH increased 5-fold between day 100 and days 147 or 154 (term). This increase was not associated with changes in the ED50 for ACTH stimulation of F output. The basal and ACTH-stimulated output of F was similar to that of B at day 100 but 5-7 times greater than that of B at day 154. There was a significant effect of ACTH on P4 output on days 77, 100 and 147 but net utilization of P4 by the cells at term. The ratio of exogenous P4: 17 alpha-OHP4 converted to F varied with gestation and increased from 0.11 at day 100 to 0.99 at day 154. Exogenous P4 was converted to B at all stages of pregnancy. We conclude that in the goat there is an increase in the responsiveness of foetal adrenal cells to ACTH between day 100 of gestation and term. One factor associated with this change in adrenal responsiveness may be an increase in the activity of the enzyme 17 alpha-hydroxylase.     

The effects of HIV protease inhibitors atazanavir and lopinavir/ritonavir on insulin sensitivity in HIV-seronegative healthy adults

BACKGROUND: Therapy with some HIV protease inhibitors (PI) contributes to insulin resistance and type 2 diabetes mellitus, by inhibition of insulin-sensitive glucose transporters. Atazanavir (ATV) is a new PI with substantially less in vitro effect on glucose transport than observed with other PI, including lopinavir (LPV) or ritonavir (RTV). METHODS: Randomized, double-blind, crossover study of the effect of 5 days of administering ATV, lopinavir/ritonavir (LPV/r) or placebo on insulin-stimulated glucose disposal in 30 healthy HIV-negative subjects. Each subject was studied on two of three possible treatments with a wash-out period between treatments. RESULTS: The mean insulin-stimulated glucose disposal (mg/min per kg body weight) per unit insulin (microU/ml) (M/I) was 9.88, 9.80 and 7.52 for placebo, ATV and LPV/r, respectively (SEM, 0.84 for all). There was no significant difference between ATV and placebo. The M/I for LPV/r was 23% lower than that for ATV (P = 0.010) and 24% lower than that for placebo (P = 0.008). The mean glycogen storage rates were 3.85, 4.00 and 2.54 mg/min per kg for placebo, ATV and LPV/r, respectively (SEM, 0.39 for all). There was no significant difference between ATV and placebo. The glycogen storage rate for LPV/r was 36% lower than ATV (P = 0.003) and 34% lower than placebo (P = 0.006). CONCLUSIONS: ATV given to healthy subjects for 5 days did not affect insulin sensitivity, while LPV/r induced insulin resistance. This observation is consistent with differential in vitro effects of these PI on glucose transport. Further data are needed to assess clinical implications for body composition.