Sickle cell bone disease and response to intravenous bisphosphonates in children.

Children with sickle cell disease (SCD) have the potential for extensive and early-onset bone morbidity. This study reports on the diversity of bone morbidity seen in children with SCD followed at three tertiary centers. IV bisphosphonates were effective for bone pain analgesia and did not trigger sickle cell complications. INTRODUCTION: To evaluate bone morbidity and the response to intravenous (IV) bisphosphonate therapy in children with SCD. METHODS: We conducted a retrospective review of patient records from 2003 to 2019 at three Canadian pediatric tertiary care centers. Radiographs, magnetic resonance images, and computed tomography scans were reviewed for the presence of avascular necrosis (AVN), bone infarcts, and myositis. IV bisphosphonates were offered for bone pain management. Bone mineral density was assessed by dual-energy X-ray absorptiometry (DXA). RESULTS: Forty-six children (20 girls, 43%) had bone morbidity at a mean age of 11.8 years (SD 3.9) including AVN of the femoral (17/46, 37%) and humeral (8/46, 17%) heads, H-shaped vertebral body deformities due to endplate infarcts (35/46, 76%), and non-vertebral body skeletal infarcts (15/46, 32%). Five children (5/26, 19%) had myositis overlying areas of AVN or bone infarcts visualized on magnetic resonance imaging. Twenty-three children (8/23 girls) received IV bisphosphonate therapy. They all reported significant or complete resolution of bone pain. There were no reports of sickle cell hemolytic crises, pain crises, or stroke attributed to IV bisphosphonate therapy. CONCLUSION: Children with SCD have the potential for extensive and early-onset bone morbidity. In this series, IV bisphosphonates were effective for bone pain analgesia and did not trigger sickle cell complications.

Musculoskeletal health in newly diagnosed children with Crohn's disease.

We evaluated the impact of Crohn's disease on muscle and bone strength, mass, density, and geometry in children with newly diagnosed CD and found profound muscle and bone deficits; nevertheless, the prevalence of vertebral fractures at this time point was low. INTRODUCTION: Crohn's disease (CD) is an inflammatory condition of the gastrointestinal tract that can affect the musculoskeletal system. The objective of this study was to determine the prevalence of vertebral fractures and the impact of CD on muscle and bone mass, strength, density, and geometry in children with newly diagnosed CD. METHODS: Seventy-three children (26 girls) aged 7.0 to 17.7 years were examined within 35 days following CD diagnosis by lateral spine radiograph for vertebral fractures and by jumping mechanography for muscle strength. Bone and muscle mass, density, and geometry were assessed by dual-energy x-ray absorptiometry and peripheral quantitative computed tomography (pQCT). RESULTS: Disease activity was moderate to severe in 66 (90%) patients. Mean height (Z-score -0.3, standard deviation (SD) 1.1, p = 0.02), weight (Z-score -0.8, SD 1.3, p < 0.01), body mass index (Z-score -1.0, SD 1.3, p < 0.01), lumbar spine areal bone mineral density (BMD; Z-score -1.1, SD 1.0, p < 0.01), total body bone mineral content (Z-score -1.5, SD 1.0, p < 0.01), and total body lean mass (Z-score -2.5, SD 1.1, p < 0.01) were all low for age and gender. pQCT showed reduced trabecular volumetric BMD at the tibial metaphysis, expansion of the bone marrow cavity and thin cortices at the diaphysis, and low calf muscle cross-sectional area. Jumping mechanography demonstrated low muscle power. Only one patient had a vertebral fracture. CONCLUSIONS: Children with newly diagnosed CD have profound muscle and bone deficits; nevertheless, the prevalence of vertebral fractures at this time point was low.

The time to and determinants of first fractures in boys with Duchenne muscular dystrophy.

Boys with vertebral fractures (VF) identified through routine spine radiographs had milder, less symptomatic, and fewer VF compared to those diagnosed with VF following consultation for back pain. Spontaneous (i.e., medication-unassisted) reshaping of fractured vertebral bodies was absent. Long bone fractures were present even before Duchenne muscular dystrophy (DMD) diagnosis in some boys. INTRODUCTION: The objective of the study was to determine the time to and characteristics of first fractures in Duchenne muscular dystrophy. METHODS: This study was a retrospective longitudinal study of 30 boys with DMD <18 years. Boys were classified into four groups according to their first fracture: those with VF identified on routine lateral spine radiographs, those with VF diagnosed following consultation for back pain, those with long bone fractures, and those without fractures. RESULTS: Compared to boys diagnosed with VF as their initial fracture following consultation for back pain, those with VF surveillance radiographs had shorter durations of glucocorticoid (GC) therapy at the time of VF diagnosis (median 1.6 versus 5.3 years, p < 0.01), higher areal (mean ± standard deviation -1.4 ± 0.7 versus -3.1 ± 0.8, p = 0.01), and volumetric (-0.3 ± 0.5 versus -2.6 ± 0.8, p < 0.01) lumbar spine bone mineral density Z-scores, as well as fewer VF (median 1.4 versus 5.2 per person, p < 0.01) and a lower median spinal deformity index (median 1.5 versus 9.5, p < 0.01). Vertebral body reshaping following VF was not observed. Ten boys sustained a long bone fracture as their first fracture at a mean age of 8.9 ± 4.0 years; four of these boys later sustained a total of 27 incident VF. CONCLUSIONS: Routine lateral spine radiographs led to detection of VF in their earlier stages, vertebral body reshaping following VF was absent, and VF were frequent after the first long bone fracture. These results support the inclusion of a lateral spine radiograph starting at the time of GC initiation as part of routine bone health monitoring in DMD.

The management of osteoporosis in children.

This article reviews the manifestations and risk factors associated with osteoporosis in childhood, the definition of osteoporosis and recommendations for monitoring and prevention. As well, this article discusses when a child should be considered a candidate for osteoporosis therapy, which agents should be prescribed, duration of therapy and side effects. There has been significant progress in our understanding of risk factors and the natural history of osteoporosis in children over the past number of years. This knowledge has fostered the development of logical approaches to the diagnosis, monitoring, and optimal timing of osteoporosis intervention in this setting. Current management strategies are predicated upon monitoring at-risk children to identify and then treat earlier rather than later signs of osteoporosis in those with limited potential for spontaneous recovery. On the other hand, trials addressing the prevention of the first-ever fracture are still needed for children who have both a high likelihood of developing fractures and less potential for recovery. This review focuses on the evidence that shapes the current approach to diagnosis, monitoring, and treatment of osteoporosis in childhood, with emphasis on the key pediatric-specific biological principles that are pivotal to the overall approach and on the main questions with which clinicians struggle on a daily basis. The scope of this article is to review the manifestations of and risk factors for primary and secondary osteoporosis in children, to discuss the definition of pediatric osteoporosis, and to summarize recommendations for monitoring and prevention of bone fragility. As well, this article reviews when a child is a candidate for osteoporosis therapy, which agents and doses should be prescribed, the duration of therapy, how the response to therapy is adjudicated, and the short- and long-term side effects. With this information, the bone health clinician will be poised to diagnose osteoporosis in children and to identify when children need osteoporosis therapy and the clinical outcomes that gauge efficacy and safety of treatment.

Enzymes of glucose and glycerol catabolism in in vitro-propagated Theileria parva schizonts.

Theileria parva schizonts propagated in vitro in peripheral blood lymphocytes were purified and assayed for key enzymes of glucose and glycerol catabolism and the citric acid cycle. The activities of glycolytic enzymes were in the range of 21-100 nmol/min/mg protein. Glycerol kinase and alpha -glycerophosphate dehydrogenase activities were more than 16 times lower than the activities of other enzymes catalysing the oxidation of the triose phosphates to lactate. It was suggested that the catabolism of glycerol is negligible and that glucose is catabolized to lactate via the Embden-Meyerhof pathway. The activities of the enzymes catalysing the section of the citric acid cycle that involves the formation of citrate to succinyl-CoA were consistently very low (less than 2.0 nmol/min/mg protein), indicating that this part of the cycle plays a minor role in this parasite. Enzyme activities of the cycle catalysing the formation of succinate from oxaloacetate were relatively higher than those catalysing other sections of the citric acid cycle, suggesting that this section of the cycle could be important to the parasite. Pyruvate carboxylase activity was more than 10 times that of phosphoenolpyruvate carboxykinase. It was suggested that pyruvate could be carboxylated to oxaloacetate. Taken together, these results suggest that the catabolism of glucose in Theileria parva schizonts is mainly via the Embden-Meyerhof pathway and that the citric acid cycle plays a minor role in energy production.

Thyroid status and adenosine triphosphatase activity in experimental Trypanosoma congolense infection in rabbits.

The effect of trypanosome infection on the plasma levels and ratios of tri-iodothyronine (T3) and thyroxine (T4) as well as the activity of mitochondrial adenosine triphosphatase (ATPase) were investigated. Three groups of sexually mature white New Zealand rabbits were used. Group 1 consisted of the normal non-infected rabbits, group 2 were experimentally infected with Trypanosoma congolense and group 3 were infected but given replacement doses of thyroxine. The infected animals (group 2) showed a rapid decline in both T3 and T4 but an increase in the T3/T4 ratio indicating differential production or clearance rates between the two hormones. The mitochondrial ATPase activity was found to be depressed in the infected group whereas there was no significant difference in the ATPase activity between the non-infected (group 1) and infected-treated animals (group 2). It is postulated that trypanosome induced hypothyroid status may play a role in the impairment of mitochondrial ATPase activity, a key enzyme in energy metabolism.

The effect of L-thyroxine on the anaemia response in Trypanosoma congolense infected rabbits.

The development of anaemia is a major pathological manifestation in chronic trypanosomosis. The anaemia in African trypanosomosis coincides with a marked decrease in plasma concentration of both thyroxine (T4) and 3,5,3' triiodothyronine (T3). To evaluate the effect of trypanosome-induced hypothyroidism on the development of anaemia, sexually mature white New Zealand rabbits were used. Three groups were set up, each of ten rabbits: one group was infected with Trypanosoma congolense; the second group was infected but given replacement doses of thyroxine (treated); the third group was not infected. Small volumes of blood were collected for the determination of parasitaemia and packed cell volume (PCV). The concentrations of T3 and T4 were measured in plasma by radioimmunoassay. The decrease in PCV correlated closely (y = -0.38x + 15.2; r = 0.82, P = 0.001) with the intensity and duration of parasitaemia. The critical PCV value was 0.15 11-1 with a peak parasitaemia of approximately 5 x 10(6) trypanosomes ml-1 of blood. There was a significant correlation between the plasma T3 and PCV (y = 0.049x + 0.57; r = 0.66, P = 0.020). There was also a good positive correlation between T4 and PCV (y = 14.5 + 3.03; r = 0.95, P < 0.001) in the infected untreated group. The PCV levels were significantly different among the three groups of animals (P < 0.05). The infected-treated animals sustained longer periods of infection than the infected and untreated ones. The sustained physiological level of bioactive thyroid hormones T3 and T4 significantly arrested the decline in PCV as the disease progressed.(ABSTRACT TRUNCATED AT 250 WORDS)

Altered 3,5,3'-triiodothyronine thyroxine ratio in experimentally induced kwashiorkor and obesity in rats.

The plasma triiodothyronine (T3) and thyroxine (T4) ratios have been evaluated in kwashiorkor and diet-induced obese weaned rats. The concentrations of T3 and T4 were determined in plasma by radio-immunoassay. A significant decrease in T3 level in the order kwashiorkor < obese < control was observed. However T4 concentration was more elevated (P < 0.01) in the obese than the normal controls, while more significantly depressed (P < 0.001) in the kwashiorkor than in control animals. The T3/T4 ratio decreased in the order obese < kwashiorkor < control. It was concluded from these studies that kwashiorkor and diet-induced obesity not only interfere with the absolute concentration of the thyroid hormones but also alter the T3/T4 ratio. The altered T3 and T4 ratio perhaps contributes to the maintenance of the isoenergetic state rather than to the promotion of negative or positive energy balance in kwashiorkor and obese subjects respectively.

Respiratory activity of isolated liver Mitochondria following Trypanosoma congolense infection in rabbits: the role of thyroxine.

1. The effect of trypanosome infection on rabbit liver mitochondrial oxidative phosphorylation was investigated, with and without thyroxine replacement. 2. State 3 respiration, respiratory control ratio (RCR) and ADP/O ratio were significantly reduced in mitochondria from trypanosome-infected animals whereas there was no change in state 4 respiration. 3. State 3 respiration, RCR and ADP/O ratio were not significantly altered in trypanosome-infected animals given thyroxine replacement therapy. 4. Trypanosome infection leads to impairment of mitochondrial integrity, apparently through lowered thyroxine levels. Replacement of thyroxine therefore sustains optimal mitochondrial respiratory activity.

Defects in resting metabolic rates and mitochondrial respiration in Kwashiorkor and dietary obese rats.

Resting metabolic rates have been measured and compared with hepatic mitochondrial respiration in Kwashiorkor and diet-induced obese weaned rats. In Kwashiorkor, resting metabolic rate was 21% lower than the value of controls, while that of the obese rats was 14% higher than in control animals. The resting metabolic rate for Kwashiorkor animals was 50% of the predicted basal metabolic rate (BMR), whereas that of the obese rats was 23% higher than the predicted BMR. The mitochondrial oxygen consumption patterns, using malate plus glutamate or succinate as respiratory substrates, revealed that the resting respiration (state 4) was 23.9% higher in Kwashiorkor and 29.1% higher in obese animals, while the active (state 3) respiration was 34.8% lower in Kwashiorkor and 43.3% lower in obese rats compared to controls. The respiratory control ratios (RCR) were 51.1% and 43.8% in Kwashiorkor and obese rats, respectively, relative to the values in control rats. It is concluded from these studies that Kwashiorkor disease and diet-induced obesity appear to interfere with oxygen utilization at the level of state 3 mitochondrial respiration, which is markedly decreased when compared to the values for control animals.

Interaction of benzoquinones with mitochondria interferes with oxidative phosphorylation characteristics.

Studies with four benzoquinones, viz. juglone, embelin, maesaquinone and maesanin, on rat liver mitochondria oxidative phosphorylation have been carried out. Three of the benzoquinones are uncouplers in the order juglone greater than maesoquinone greater than embelin, while maesanin is an inhibitor of electron transport and oxidative phosphorylation.

Transport of Ca2+ and Mn2+ by mitochondria from rat liver, heart and brain.

The energy-dependent, respiration-supported uptake and the uncoupler- or Na+-induced release of Ca2+ and Mn2+ by mitochondria from rat liver, heart and brain were investigated, using as indicators radioisotopes (45Ca and 54Mn), proton ejection, oxygen consumption, nicotinamide nucleotide oxidation-reduction and, in the case of Ca2+, the metallochromic dye Arsenazo III. Ca2+ uptake in the presence of Pi was rapid in mitochondria from liver and brain, and less rapid in those from heart. Mn2+ uptake was much slower than that of Ca2+ in liver and heart, but only slightly slower in brain. When added together, Ca2+ accelerated the uptake of Mn2+, and Mn2+ retarded the uptake of Ca2+, by mitochondria from all three tissues. When Mn2+ was present during Ca2+ uptake, its own uptake remained accelerated even after Ca2+ uptake was terminated. Mg2+, which was not taken up, inhibited Ca2+ uptake by mitochondria from all three tissues, and, when present during Ca2+ uptake, accelerated the subsequent uptake of Mn2+. The uncoupler CCCP induced a release of both Ca2+ and Mn2+ from all three sources of mitochondria; yet, release of Mn2+ took place only in the absence of Pi. The release followed the same pattern as the uptake, i.e., Ca2+ accelerated the release of Mn2+ and Mn2+ retarded the release of Ca2+. Na+ induced a release of both Ca2+ and Mn2+ from heart and brain but not from liver mitochondria; again, Mn2+ release occurred only in the absence of Pi. The Na+-induced release of Ca2+ was inhibited by Mn2+, but the Na+-induced release of Mn2+ was not accelerated by Ca2+.(ABSTRACT TRUNCATED AT 250 WORDS)