Chronic daily headaches in pediatric neurology practice.

Using a comprehensive computerized database for a single general pediatric neurology ambulatory practice, the clinical profile, together with the precipitating features and outcomes, in a consecutive series of children with chronic daily headache was ascertained. Chronic daily headache was defined as persistent or daily headaches of at least 3 months' duration. Children with persistent headaches owing to a serious medical condition were specifically excluded from analysis. Of 1669 children (24% of total seen) referred over an 11-year inclusive interval for the evaluation of headaches, 50 (3%) merited a diagnosis of chronic daily headache. The overwhelming majority were female (45/50; 90%), with a mean age at diagnosis of 12.9 years (range 7-16 years). Transformed migraine was determined to be the etiology in the majority (35/50; 70%), with a minority attributable either to postconcussion syndrome (7/50; 14%) or new daily persistent headaches (6/50; 12%). Analgesic abuse was evident in a majority (26/50; 52%). Treatment consisted predominantly of migraine and analgesic education, with a majority of children (42/50; 84%) also receiving daily prophylaxis. Four fifths (41/50; 82%) returned for at least one follow-up. Of these, 56% (23/41) were improved, 32% (13/41) unchanged, and 12% (5/41) worse. Eventually, almost half (20/41) experienced complete resolution of their headache symptoms, with a mean time to resolution of 8 months (range 2-48 months). Children with chronic daily headache are thus a small subset of children with headache seen in general ambulatory practice. They tend to be females in the midteen years experiencing a transformed migraine complicated by analgesic abuse, suggesting potential preventability. Simple measures, which can include the use of prophylactic agents, can be expected to result in improvement and eventual resolution of headache symptoms.

Neurodevelopmental outcome of young pediatric intensive care survivors of serious brain injury.

OBJECTIVES: To determine the number of children with severe brain injury due to closed head injury or hypoxic-ischemic encephalopathy as a proportion of all admissions of children <3 yrs of age in the regional pediatric intensive care unit; to determine the outcome of these children at >6 mos postinjury; and to explore the relationship of outcome measures to predictors of outcome obtained within the first 24 hrs after brain injury. DESIGN: Prospective, descriptive outcome study of an inception cohort. RESULTS: Neonatal and Infant Follow-up Clinic, Glenrose Rehabilitation Hospital, Edmonton, Canada. PATIENTS: Of a cohort of 53 children of <3 yrs of age (4% of pediatric intensive care unit admissions, 1995-1998) admitted for severe acquired brain injury (Glasgow Coma Score, 80% have adverse outcome of death, disability, or mental or motor developmental scores below average. A Glasgow Outcome Scale of 5 overestimates good recovery. Universal registry and follow-up of these children are needed.

Adequate dietary vitamin D and calcium are both required to reduce bone turnover and increased bone mineral volume.

Clinical studies indicate that the combination of vitamin D and dietary calcium supplementation is more effective for reducing fracture risk than either supplement alone. Our previous dietary studies demonstrated that an adequate serum 25-hydroxyvitamin D3 (25D) of 80nmol/L or more reduces bone RANKL expression, osteoclastogenesis and maintains the optimal levels of trabecular bone volume (BV/TV%) in young rats. The important clinical question of the interaction between vitamin D status, dietary calcium intake and age remains unclear. Hence, 9 month-old female Sprague-Dawley rats (n=5-6/group) were pair-fed a semi-synthetic diet containing varying levels of vitamin D (0, 2, 12 or 20IU/day) and dietary calcium (0.1% or 1%) for 6 months. At 15 months of age, animals were killed, for biochemical and skeletal analyses. While changes to serum 25D were determined by both dietary vitamin D and calcium levels, changes to serum 1,25-dihydroxyvitamin D3 (1,25D) were consistently raised in animals fed 0.1% Ca regardless of dietary vitamin D or vitamin D status. Importantly, serum cross-laps levels were significantly increased in animals fed 0.1% Ca only when combined with 0 or 2 IUD/day of vitamin D, suggesting a contribution of both dietary calcium and vitamin D in determining bone resorption activity. Serum 25(OH)D3 levels were positively correlated with both femoral mid-diaphyseal cortical bone volume (R(2)=0.24, P<0.01) and metaphyseal BV/TV% (R(2)=0.23, P<0.01, data not shown). In multiple linear regressions, serum 1,25(OH)2D3 levels were a negative determinant of CBV (R(2)=0.24, P<0.01) and were not a determinant of metaphyseal BV/TV% levels. These data support clinical data that reduced bone resorption and increased bone volume can only be achieved with adequate 25D levels in combination with high dietary calcium and low serum 1,25D levels. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.

The role of the calcitonin receptor in protecting against induced hypercalcemia is mediated via its actions in osteoclasts to inhibit bone resorption.

Despite the therapeutic value of calcitonin in treating bone disease, a biological role of endogenous calcitonin is controversial. Having previously demonstrated that the CTR has a biological role in protecting against calcium stress using a global CTRKO mouse model, the purpose of this study was to determine whether the protection conferred by the CTR during induced hypercalcemia is mediated via CTR expression on osteoclasts. Mice were generated, in which the CTR was deleted specifically within osteoclasts (OCL-CTRKOs) and compared with mice in which the CTR was deleted globally (global CTRKOs). Significantly, peak serum calcium levels following induced hypercalcemia were >18% higher in global-CTRKOs and OCL-CTRKOs than controls (P<0.01) due to increased bone resorption (P<0.05). Peak serum calcium levels relative to controls were greater in global-CTRKO males than OCL-CTRKO males (P<0.001), which may, at least in part, be due to increased reabsorption of calcium in the kidney (P<0.01). Controls for all analyses were sex-matched littermates with normal CTR expression. In conclusion, the CTR protects against hypercalcemia predominantly via its inhibitory action on osteoclasts.

Discordant effects of vitamin D deficiency in trabecular and cortical bone architecture and strength in growing rodents.

We have previously shown that vitamin D deficiency in young male rats results in significant reduction in femoral trabecular bone volume (BV/TV). However, the effects of vitamin D deficiency and its impact on other relevant skeletal sites remain unclear. Ten week old male Sprague-Dawley rats were fed various levels of vitamin D3 (2, 4, 8, and 12 IU/day) with standard Ca (0.4%) until 30 weeks of age and achieved stable serum 25-hydroxyvitamin D3 (25D) levels between 16 and 117 nmol/L. At time of death, femora, L2 vertebrae and tibiae were processed for bone histomorphometric analyses and tibial cortical strength by 3-point mechanical testing. A significant association between serum 25D and trabecular bone occurred for both the distal femoral metaphysis (R2=0.34, P<0.05) and L2 vertebrae (R2=0.24, P<0.05). Tibia mid-shaft cortical bone was not, however, changed in terms of total volume, periosteal surface or endosteal surface as a function of vitamin D status. Furthermore, no changes to mechanical and intrinsic properties of the cortices were observed. We conclude that cortical bone is maintained under conditions of vitamin D deficiency in preference to cancellous bone in young growing rats.

DNA-binding-dependent androgen receptor signaling contributes to gender differences and has physiological actions in males and females.

We used our genomic androgen receptor (AR) knockout (ARKO) mouse model, in which the AR is unable to bind DNA to: 1) document gender differences between males and females; 2) identify the genomic (DNA-binding-dependent) AR-mediated actions in males; 3) determine the contribution of genomic AR-mediated actions to these gender differences; and 4) identify physiological genomic AR-mediated actions in females. At 9 weeks of age, control males had higher body, heart and kidney mass, lower spleen mass, and longer and larger bones compared to control females. Compared to control males, ARKO males had lower body and kidney mass, higher splenic mass, and reductions in cortical and trabecular bone. Deletion of the AR in ARKO males abolished the gender differences in heart and cortical bone. Compared with control females, ARKO females had normal body weight, but 14% lower heart mass and heart weight/body weight ratio. Relative kidney mass was also reduced, and relative spleen mass was increased. ARKO females had a significant reduction in cortical bone growth and changes in trabecular architecture, although with no net change in trabecular bone volume. In conclusion, we have shown that androgens acting via the genomic AR signaling pathway mediate, at least in part, the gender differences in body mass, heart, kidney, spleen, and bone, and play a physiological role in the regulation of cardiac, kidney and splenic size, cortical bone growth, and trabecular bone architecture in females.

Mineralization and bone resorption are regulated by the androgen receptor in male mice.

Androgens play a key role in skeletal growth and bone maintenance; however, their mechanism of action remains unclear. To address this, we selectively deleted the androgen receptor (AR) in terminally differentiated, mineralizing osteoblasts using the Cre/loxP system in mice (osteocalcin-Cre AR knockouts [mOBL-ARKOs]). Male mOBL-ARKOs had decreased femoral trabecular bone volume compared with littermate controls because of a reduction in trabecular number at 6, 12, and 24 wk of age, indicative of increased bone resorption. The effects of AR inactivation in mineralizing osteoblasts was most marked in the young mutant mice at 6 wk of age when rates of bone turnover are high, with a 35% reduction in trabecular bone volume, decreased cortical thickness, and abnormalities in the mineralization of bone matrix, characterized by increased unmineralized bone matrix and a decrease in the amount of mineralizing surface. This impairment in bone architecture in the mOBL-ARKOs persisted throughout adulthood despite an unexpected compensatory increase in osteoblast activity. Our findings show that androgens act through the AR in mineralizing osteoblasts to maintain bone by regulating bone resorption and the coordination of bone matrix synthesis and mineralization, and that this action is most important during times of bone accrual and high rates of bone remodeling.

Vitamin D depletion induces RANKL-mediated osteoclastogenesis and bone loss in a rodent model.

The association between increased risk of hip fracture and low vitamin D status has long been recognized. However, the level of vitamin D required to maintain bone strength is controversial. We used a rodent model of vitamin D depletion to quantify the 25-hydroxyvitamin D (25D) levels required for normal mineralization. Six groups of 10-wk-old male Sprague-Dawley rats (n = 42) were fed a diet containing 0.4% calcium and various levels of dietary vitamin D(3) for 4 mo to achieve stable mean serum 25D levels ranging between 10 and 115 nM. At 7 mo of age, animals were killed, and the histomorphometry of distal and proximal femora and L(2) vertebra was analyzed. Total RNA was extracted from whole femora for real-time RT-PCR analyses. In the distal femoral metaphysis, trabecular bone mineral volume (BV/TV) showed a significant positive association with circulating 25D levels (r(2) = 0.42, p < 0.01) in the animals with serum 25D levels between 20 and 115 nM. Osteoclast surface (Oc.S) levels were positively associated with RANKL:OPG mRNA ratio, higher in groups with lower serum 25D levels, and were independent of serum 1,25D levels. Serum 25D levels <80 nM gave rise to osteopenia as a result of increased osteoclastogenesis, suggesting that levels of 25D >80 nM are needed for optimal bone volume. These data indicate that serum 25D levels are a major determinant of osteoclastogenesis and bone mineral volume and are consistent with the levels of 25D recommended to reduce the risk of fracture in humans.

Calcitonin receptor plays a physiological role to protect against hypercalcemia in mice.

It is well established that calcitonin is a potent inhibitor of bone resorption; however, a physiological role for calcitonin acting through its cognate receptor, the calcitonin receptor (CTR), has not been identified. Data from previous genetically modified animal models have recognized a possible role for calcitonin and the CTR in controlling bone formation; however, interpretation of these data are complicated, in part because of their mixed genetic background. Therefore, to elucidate the physiological role of the CTR in calcium and bone metabolism, we generated a viable global CTR knockout (KO) mouse model using the Cre/loxP system, in which the CTR is globally deleted by >94% but <100%. Global CTRKOs displayed normal serum ultrafiltrable calcium levels and a mild increase in bone formation in males, showing that the CTR plays a modest physiological role in the regulation of bone and calcium homeostasis in the basal state in mice. Furthermore, the peak in serum total calcium after calcitriol [1,25(OH)(2)D(3)]-induced hypercalcemia was substantially greater in global CTRKOs compared with controls. These data provide strong evidence for a biological role of the CTR in regulating calcium homeostasis in states of calcium stress.