Intracranial circulation: pulse-sequence considerations in three- dimensional (volume) MR angiography

The technique and feasibility of magnetic resonance (MR) angiography of intracranial vessels were studied in 35 healthy volunteers. Variations in image orientation, repetition time (TR), and flip angle were evaluated to determine their effects on flow-related enhancement. Gradient modifications--including echo time (TE), motion compensation, bandwidth, and field of view--were also studied in an effort to reduce motion-induced phase shifts. Results indicated that a FISP (fast imaging with steady precession) sequence with a TR of 50 msec, TE of 15 msec, velocity compensation in the read and section-select directions, acceleration compensation in the read direction, anisotropic volume, and a 1.25-mm partition thickness produced three-dimensional angiographic MR images that were accurate and reproducible in the depiction of the major intracranial vessels. Difficulties with field of view, persistent signal void secondary to higher-order motion, and spatial resolution remain major problems requiring additional study.     

Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone,the murine model of X‐linked hypophosphatemia

X‐linked hypophosphatemia (XLH/HYP)—with renal phosphate wasting, hypophosphatemia, osteomalacia, and tooth abscesses—is caused by mutations in the zinc‐metallopeptidase PHEX gene (phosphate‐regulating gene with homologies to endopeptidase on the X chromosome). PHEX is highly expressed by mineralized tissue cells. Inactivating mutations in PHEX lead to distal renal effects (implying accumulation of a secreted, circulating phosphaturic factor) and accumulation in bone and teeth of mineralization‐inhibiting, acidic serine‐ and aspartate‐rich motif (ASARM)‐containing peptides, which are proteolytically derived from the mineral‐binding matrix proteins of the SIBLING family (small, integrin‐binding ligand N‐linked glycoproteins). Although the latter observation suggests a local, direct matrix effect for PHEX, its physiologically relevant substrate protein(s) have not been identified. Here, we investigated two SIBLING proteins containing the ASARM motif—osteopontin (OPN) and bone sialoprotein (BSP)—as potential substrates for PHEX. Using cleavage assays, gel electrophoresis, and mass spectrometry, we report that OPN is a full‐length protein substrate for PHEX. Degradation of OPN was essentially complete, including hydrolysis of the ASARM motif, resulting in only very small residual fragments. Western blotting of Hyp (the murine homolog of human XLH) mouse bone extracts having no PHEX activity clearly showed accumulation of an ～35 kDa OPN fragment that was not present in wild‐type mouse bone. Immunohistochemistry and immunogold labeling (electron microscopy) for OPN in Hyp bone likewise showed an accumulation of OPN and/or its fragments compared with normal wild‐type bone. Incubation of Hyp mouse bone extracts with PHEX resulted in the complete degradation of these fragments. In conclusion, these results identify full‐length OPN and its fragments as novel, physiologically relevant substrates for PHEX, suggesting that accumulation of mineralization‐inhibiting OPN fragments may contribute to the mineralization defect seen in the osteomalacic bone characteristic of XLH/HYP. © 2013 American Society for Bone and Mineral Research.     

Liver vitamin A reserves of very low birth weight neonates

This study assessed the liver vitamin A concentrations at birth in a group of very low birth weight neonates (n = 25) (less than 1500 g birth weight, less than 32 wk gestation), dying within 24 h of birth, prior to possible changes in vitamin A status induced by postnatal intervention. Serum concentrations of vitamin A and retinol-binding protein were also measured in 16 of these neonates. The mean (+/- SD) liver vitamin A concentration was 30.0 +/- 12.9 micrograms/g (range 2.0-49.0 micrograms/g). The mean (+/- SD) serum vitamin A concentration was 13.0 +/- 4.7 micrograms/dl (range 6.7-22.8 micrograms/dl). The mean (+/- SD) serum retinol-binding protein concentration was 2.2 +/- 0.8 mg/dl (range 1.5-4.8 mg/dl). Liver vitamin A, serum vitamin A, and serum retinol-binding protein concentrations did not correlate significantly with gestational age or birth weight. Linear regression analysis did not show a significant correlation between liver vitamin A, and serum vitamin A or retinol-binding protein concentrations. This study provides reference values for vitamin A concentrations at birth in very low birth weight neonates, which may be helpful in future studies designed to evaluate postnatal changes in the vitamin A status of these high-risk neonates.     

Induction of chromosome-specific aneuploidy and micronuclei in human lymphocytes by metabolites of 1,3-butadiene

1,3-Butadiene is a carcinogen in rodents, but its potential carcinogenicity to humans remains controversial. Numerous studies have shown that butadiene and its metabolites cause sister chromatid exchanges in vitro and in vivo. To test for other types of genotoxicity, the micronucleus assay and fluorescence in situ hybridization (FISH) have been used to detect chromosome damage in human lymphocytes caused by two reactive metabolites of butadiene, diepoxybutane (DEB) and monoepoxybutene (MEB). DEB (0.5-5.0 microM) significantly increased micronucleus formation 4- to 6-fold (P <0.01) and MEB (1-500 microM) by 2- to 4-fold (P <0.01) over control levels. The ability of DEB and MEB to induce aneuploidy of chromosomes 7, 8, 12, and X was examined using dual-color FISH in both interphase and metaphase cells. These chromosomes were chosen because of their involvement in leukemogenesis. Both DEB and MEB caused dose-dependent increases in hyperdiploidy of chromosomes 12 and X, but had no discernible effect on chromosomes 7 and 8. These results suggest that DEB and MEB cause chromosome-specific aneuploidy in human cells. If formed in sufficient amounts, DEB and MEB may produce chromosome damage of the type found in leukemia following exposure to butadiene.      

Growth hormone (GH) profiles in response to continuous subcutaneous infusion of GH-releasing hormone(1— 29)-NH2 in children with GH deficiency

Six children presenting with partial growth hormone (GH) deficiency (mean GH peak in two different tests, 8.0 k1.3 μ g/l ) aged 8–10.3 years (mean, 2.7 ± 0.9 years) were treated for 6 months by continuous subcutaneous infusion of GH-releasing hormone(1–29)-NH, (GHRH(1–29)-NH₂); 24-hour GH profiles and height velocity were measured. A biphasic effect of GHRH(1–29)-NH₂ infusion was observed. After an early substantial increase in the 24-hour integrated concentration of GH, from 1.6 ± 0.1 to 3.5 ± 0.7 μg/l/minute, a subsequent consistent decrease occurred by 3 months, which was more pronounced after 6 months (mean 24-hour integrated concentration of GH, 1.9± 0.9 μg/l/minute). This effect reflects modification of both pulse amplitude and frequency of GH secretion. At the end of the study, one child had complete suppression of GH secretion and two others showed only one peak above 5 μg/1 during a 24-hour period. No correlation was found between these changes and height velocity. Three children did not grow significantly; the other three children who had a growth response to GHRH(1–29)-NH₂ were those with the lowest 24-hour integrated GH concentration at the end of the study. The possible mechanisms involved in this biphasic effect, including GHRH antibodies, changes in somatostatin levels and/or desensitization of pituitary GHRH receptors, have been investigated.     

Community based, effective, low cost approach to the treatment of severe malnutrition in rural Jamaica

Moderate and severe malnutrition are endemic in much of the developing world and in association with pockets of deprivation in the developed world. The cost in terms of individual and social development is high. The principles of effective management are clearly documented. A low cost, community based treatment programme for moderately and severely malnourished children under 3 years of age was established at a health centre in rural Jamaica. Children were followed up monthly and defaulters were rigorously recalled. Management consisted of carefully delivered dietary advice, antibiotics, anthelminthics, and vitamin supplements. All children improved and the response of 36 children, who were treated in the first year, showed an accelerated weight gain, with catch-up growth and the maintenance of length gain. There was a significant increase in the weight for age, at 1.9% per month over six months, which exceeds the rate reported with food supplementation programmes and nutrition rehabilitation centres.