Onset, progression, and plateau of skeletal lesions in fibrous dysplasia and the relationship to functional outcome.

Most lesions in FD and their attendant functional disability occur within the first decade; 90% of lesions are present by 15 years, and the median age when assistive devices are needed is 7 years. These findings have implications for prognosis and determining the timing and type of therapy. INTRODUCTION: Fibrous dysplasia of bone (FD) is an uncommon skeletal disorder in which normal bone is replaced by abnormal fibro-osseous tissue. Variable amounts of skeletal involvement and disability occur. The age at which lesions are established, the pace at which the disease progresses, if (or when) the disease plateaus, and how these parameters relate to the onset of disability are unknown. To answer these questions, we performed a retrospective analysis of a group of subjects with FD. MATERIALS AND METHODS: One hundred nine subjects with a spectrum of FD were studied for up to 32 years. Disease progression was assessed in serial (99)Tc-MDP bone scans by determining the location and extent of FD lesions using a validated bone scan scoring tool. Physical function and the need for ambulatory aids were assessed. RESULTS: Ninety percent of the total body disease skeletal burden was established by age 15. Disease was established in a region-specific pattern; in the craniofacial region, 90% of the lesions were present by 3.4 yr, in the extremities, 90% were present by 13.7 yr, and in the axial skeleton, 90% were present by 15.5 yr. Twenty-five of 103 subjects eventually needed ambulatory aids. The median age at which assistance was needed was 7 yr (range, 1-43 yr). The median bone scan score for subjects needing assistance was 64.3 (range, 18.6-75) compared with 23.1 (range, 0.5-63.5) in the unassisted subjects (p < 0.0001). Among subjects needing assistance with ambulation, 92% showed this need by 17 yr. CONCLUSIONS: The majority of skeletal lesions and the associated functional disability occur within the first decade of life. The implication is that the window of time for preventative therapies is narrow. Likewise, therapeutic interventions must be tailored to where the patient is in the natural history of the disease (i.e., progressive disease [young] versus established disease [older subjects]). These findings have implications for prognosis, the timing and type of therapy, and the development of trials of new therapies and their interpretation.     

Investigations on the possible involvement of the dopaminergic system in the modulation of the growth and steroidogenic capacity of the rat adrenal zona glomerulosa: A coupled morphometric and biochemical study

The effects of metoclopramide (MTC) and bromocriptine (BRC) (two drugs which act as antagonist and agonist of DOPA-receptors, respectively) on the zona glomerulosa of dexamethasone/ACTH-treated rats were investigated by coupled biochemical and morphometric techniques. Short-term (1-h) MTC administration significantly increased the plasma concentration of aldosterone, while long-term (7-day) MTC administration, as well as short- and long-term treatment with BRC did not cause any apparent change. Long-term MTC administration was found to significantly potentiate both the rise in the plasma level of aldosterone and the hypertrophy of the zona glomerulosa and its parenchymal cells induced by a prolonged treatment with angiotensin II (AII), but not those evoked by a chronic sodium deprivation alone or combined with AII infusion. Long-term BRC administration notably counteracted the effects of sodium restriction (coupled or not with AII infusion), but not those induced by the administration of AII alone. Long-term MTC administration partially reversed both the lowering of the plasma concentration of aldosterone and the atrophy of the zona glomerulosa and its parenchymal cells caused by a prolonged sodium-loading (combined or not with captopril infusion), but not those produced by the administration of captopril alone. On the other hand, long-term BRC treatment induced a further significant reduction in the blood level of aldosterone and the volume of zona glomerulosa and its cells only in captopril-treated animals. These findings are consistent with the view that the dopaminergic system exerts a maximal tonic inhibitory effect not only on the secretory activity, but also on the growth and steroidogenic capacity of the rat zona glomerulosa. Furthermore, they suggest that the activity of the dopaminergic system is in turn controlled by the sodium balance, being almost completely suppressed by a prolonged sodium deprivation.     

Osteointegration of bioactive glass-coated zirconia in healthy bone: an in vivo evaluation

Osteointegration of yttria stabilised tetragonal zirconia (YSTZ), either coated with bioactive glass named RKKP bioglaze (RKKP) or uncoated, was evaluated in an animal model. RKKP-coated and uncoated (controls) YSTZ cylinders were implanted in the distal femoral epiphyses of 14 Sprague Dawley rats under general anaesthesia. At the experimental times of 30 and 60 days after sacrifice, histomorphometry and SEM microanalysis were performed on methylmethacrylate-embedded undecalcified sections to determine the osteointegration rate. At 30 days, a significantly higher affinity index was demonstrated in vivo by histomorphometric evaluation in RKKP-coated versus uncoated YSTZ implants p < 0.05); at 60 days, the coated implants behaved better than controls (affinity index of + 32%), but the difference observed lay within the statistical uncertainty. SEM analysis demonstrated better bone adhesion to the material in RKKP-coated YSTZ at both 30 and 60 days. These findings suggest that YSTZ coated with the bioactive glass named RKKP enhances osteointegration of ceramics.     

A morphometric study of the reversal of ACTH-induced hypertrophy of rat adrenocortical cells after cessation of treatment

The effect of a prolonged (7-day) ACTH administration on rat zona fasciculata cells and its reversal after cessation of treatment was investigated by morphometry. ACTH treatment caused a notable cell hypertrophy, which was mainly due to the increase in the volume of the mitochondrial compartment and to smooth endoplasmic reticulum (SER) proliferation, and a conspicuous rise in the basal level of corticosterone. After cessation of ACTH administration, rat zona fasciculata cells underwent a time-dependent atrophy, so that after 5 days they resembled those of control animals, and the blood concentration of corticosterone reverted to the base-line value. The cell atrophy was provoked by the decrease in the volumes of the mitochondrial compartment and SER, and was associated with a striking time-dependent accumulation of dense bodies. Stereology demonstrated that during the first two days after ACTH withdrawal the decrease of SER prevailed over that of the mitochondrial compartment, while the reverse occurred during the remaining three days. The increase in the volume of dense-body compartment, though largely due to the accumulation of residual bodies, was mainly coupled with a rise in the volume of the microautophagic-vacuole compartment during the first two days after ACTH cessation and with an increase in that of the macroautophagic-vacuole compartment during the following three days. The hypothesis is advanced that both micro- and macroautophagy play a role in the reversal of ACTH-induced hypertrophy of rat zona fasciculata cells after cessation of treatment, the first process being mainly involved in the elimination of SER, and the second one in the degradation of mitochondria.     

Ring chromosome 15 and 15qs+ mosaic: Clinical and cytogenetic behaviour spanning 29 years

A phenotypic female with mild mental retardation, minor facial anomalies, and short stature has been evaluated clinically and cytogenetically over 29 years. At age 59, she remains physically well and shows no signs of dementia. Cytogenetic analysis, performed on peripheral blood specimens on 10 occasions between 1961 and 1990, showed mosaicism with one cell line containing a large stable ring (15) chromosome and another cell line without the ring but with a 15qs +. The different cell lines remained constant. The case provides information on the natural history of the ring chromosome 15 syndrome.     

Buffering action of endogenous nitric oxide on the adrenocortical secretagogue effect of endothelins in the rat

The secretagogue effect of endothelins (ETs) on the rat adrenal cortex is mediated by the ETB receptor. ETB receptors are coupled with nitric oxide (NO) synthase (NOS), and NO is known to inhibit steroid-hormone secretion from adrenal cortex. We investigated whether ETB-mediated NO production interferes with the stimulatory action of ETs on rat adrenal cortex. The selective agonist of ETB receptor BQ-3020 concentration-dependently increased aldosterone secretion from dispersed zona glomerulosa (ZG) cells and corticosterone secretion from dispersed zona fasciculata-reticularis (ZF/R) cells, and the NOS inhibitor NG-nitro-L-arginine methylester (L-NAME) potentiated the effect of BQ-3020 in a concentration-dependent manner. The guanylate cyclase inhibitor Ly-83583, at a concentration suppressing guanylin- and L-arginine-induced cyclic-GMP release from dispersed adrenocortical cells, did not affect the secretory response of ZG and ZF/R cells to BQ-3020. ET-1, an agonist of both ETA and ETB receptors, stimulated the release of both aldosterone and corticosterone by in situ perfused rat adrenal gland. This effect was potentiated by L-NAME and unaffected by Ly-83583. Collectively, our findings allow us to suggest that endogenous NO exerts in vivo and in vitro a cyclic-GMP-independent buffering action on the ETB receptor-mediated adrenocortical secretagogue action of ETs.     

Investigations on the turnover of adrenocortical mitochondria. X. A correlated biochemical and stereological study of the effects of Chronic treatment with chloramphenicol on the mitochondria of the rat zona fasciculata

The effects of chloramphenicol (CAP) on rat adrenocortical cells were investigated by biochemical and stereological methods. It was found that administering 50 mg/kg of CAP every 12 hours provoked a persistent inhibition of the incorporation of ³H-leucine into mitochondrial proteins. Chronic treatment (up to 15 consecutive days) with this dose of CAP induced a significant decrease in the volume of the mitochondrial compartment, in the surface area of the outer and inner mitochondrial membranes and in the number of mitochondria per cell. These results confirm the hypothesis that the ACTH-induced maintenance of adrenocortical mitochondrial growth requires continuous mitochondrial DNA-dependent protein synthesis.     

On-line urea kinetics in haemodiafiltration

BACKGROUND.: Calculation of Kt/V and assessment of nutrition have so farbeen dependent upon off-line urea measurements of blood or dialysatesamples. Here we describe a biosensor for on-line urea measurementduring haemodiafiltration. METHODS.: The biosensor consisted of a cartridge containing covalentlylinked urease placed between two conductivity cells. The biosensorwas placed on the outlet line of a haemofilter in series witha dialyser in order to obtain an aliquot of plasma ultrafiltratefor on-line measurement of urea. RESULTS.: Urea nitrogen concentrations were highly correlated to the difference() in conductivity measured by the two conductivity cells bothin aqueous solutions (in-vitro studies, y=–6.676+32.12x,R²=0.998, P<0.0001) and in ultrafiltrates (ex-vivo studies,y=–6.7+32.01x, R²=0.98, P<0.00001). conductivity washighly reproducible (% variation: 0.8–5.3%) and stable(maximal % variation at 150 mg/dl after 180 min: 0.9±0.3vs initial values). The intradialytic plasma water urea profilewas obtained in 10 haemodialysis patients. To study recirculation,the plasma water urea profile was analysed before and 3 minafter stopping the dialysate flow. The pre- and post-stoppedflow ratio (1.21±0.1, mean±1 SD) was superimposableto conventional blood sampling data (opposite arm venous/arterial:1.22±0.11) and allowed correction for recirculation.A novel approach to urea kinetic modelling was described andused to reliably project end-dialysis and post-dialysis reboundurea concentration as early as 90 min. Projected (29.2±10.4g) or measured (29.8±10.5 g) net urea removal was highlycorrelated with the amount of urea collected in the total spentdialysate (29.7±10.6 g) (R²=0.99, R²=0.97 respectively). CONCLUSIONS.: These results indicate that on-line, real-time analysis of ureakinetics may provide information on delivery of adequate dialysisin high-efficiency techniques.