Background: Open spina bifida is the most complex congenital abnormality compatible with long-term survival. This report outlines the 20- to 25-year outcome for our original cohort of patients with a myelomeningocele treated in a nonselective, prospective manner. Methods: Of the initial 118 children, 71 patients were available for our most recent review. Nineteen patients have been lost to follow-up and 28 patients have died. Data were collected on: motor level, shunt status, education/employment, seizure history, mobility, bladder/bowel continence, tethered cord, scoliosis, latex allergy, posterior cervical decompression, tracheostomy and/or gastrostomy tube. Results: Mortality (24%) continues to climb into young adulthood. Eighty-six percent of the cohort have cerebrospinal fluid diversion, with 95% having undergone at least one shunt revision. Thirty-two percent have undergone a tethered cord release, with 97% having an improvement or stabilization in their preoperative symptoms. Forty-nine percent have scoliosis, with 43% eventually requiring a spinal fusion. Sixteen patients (23%) have had at least one seizure. Eighty-five percent are attending or have graduated from high school and/or college. More than 80% of young adults have social bladder continence. Approximately 1/3 of patients are allergic to latex, with 6 patients having experienced a life-threatening reaction. Conclusion: At least 75% of children born with a myelomeningocele can be expected to reach their early adult years. Late deterioration is common. One of the greatest challenges in medicine today is establishing a network of care for these adults with spina bifida.

Midline pediatric high-grade astrocytomas (pHGAs) are incurable with few treatment targets identified. Most tumors harbor K27M mutations on histone 3 variants. In 40 treatment-naïve midline pHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with H3.1 K27M, while FGFR1 mutations/fusions occur in thalamic tumors associated with H3.3 K27M. Hyper-activation of the bone morphogenetic protein (BMP)/ACVR1 developmental pathway in pHGAs harbouring ACVR1 mutations led to increased phospho-SMAD1/5/8 expression and up-regulation of BMP downstream early response genes in tumour cells. Global DNA methylation profiles were significantly associated with the K27M mutation regardless of the mutant H3 variant and irrespective of tumor location, supporting its role in driving the epigenetic phenotype. This significantly expands the potential treatment targets and further justifies pre-treatment biopsy in pHGA as a means to orient therapeutic efforts in this disease.

Calcium hydroxyapatite ceramics (CHA) are nontoxic materials, provoke little reaction from tissues, and by virtue of these properties represent a good starting point for creating bone substitutes. Although several porous CHAs have been used clinically, there have been few reports that CHA is fully replaced by newly formed bone, which may be due to its structure and the limited connectivity between pores. We recently developed a fully interconnected porous CHA (IP-CHA) by adopting a "foam-gel" technique. Structural analysis by scanning electron microscopy revealed that IP-CHA had spherical pores of uniform size that were interconnected by window-like holes. The surface of the wall structure was smooth, and hydroxyapatite particles were bound tightly to one another. Most of the interpore connections of IP-CHA ranged from 10 to 80 microm in diameter (average, 40 microm). When the cylindrical IP-CHA (diameter, 6 mm; height, 15 mm) was implanted into a rabbit femoral condyle, bone, and bone marrow with abundant vessels formed deep in the pores through the interpore connections. Within a period of 6 weeks, new bone had formed and penetrated to a distance of 3 mm from the surface of the IP-CHA implant. Furthermore, a compression test at 9 weeks revealed that the implanted IP-CHA steadily increased in strength to more than double the value of the initial test. These results indicate that the IP-CHA may have clinical utility as a superior bone substitute.

Recent clinical studies suggest that several antihypertensive drugs, especially angiotensin-converting enzyme inhibitors, reduced bone fractures. To clarify the relationship between hypertension and osteoporosis, we focused on the role of angiotensin II (Ang II) on bone metabolism. In bone marrow-derived mononuclear cells, Ang II (1x10(-6) M) significantly increased tartrate-resistant acid phosphatase (TRAP) -positive multinuclear osteoclasts. Of importance, Ang II significantly induced the expression of receptor activator of NF-kappaB ligand (RANKL) in osteoblasts, leading to the activation of osteoclasts, whereas these effects were completely blocked by an Ang II type 1 receptor blockade (olmesartan) and mitogen-activated protein kinase kinase inhibitors. In a rat ovariectomy model of estrogen deficiency, administration of Ang II (200 ng/kg/min) accelerated the increase in TRAP activity, accompanied by a significant decrease in bone density and an increase in urinary deoxypyridinoline. In hypertensive rats, treatment with olmesartan attenuated the ovariectomy-induced decrease in bone density and increase in TRAP activity and urinary deoxypyridinoline. Furthermore, in wild-type mice ovariectomy with five-sixths nephrectomy decreased bone volume by microcomputed tomography, whereas these change was not detect in Ang II type 1a receptor-deficient mice. Overall, Ang II accelerates osteoporosis by activating osteoclasts via RANKL induction. Blockade of Ang II might become a novel therapeutic approach to prevent osteoporosis in hypertensive patients.

Available literature on neurocognitive development of children with SSC is suggestive of mild but persistent neuropsychological deficits, which become more significant as cognitive demands increase at school age. Anatomical studies of children without SSC are beginning to identify particular groups of brain structures that if disrupted or malformed, may be associated with specific cognitive deficits. Controlled research investigating the relationship between persistent anatomical changes and neurocognitive functioning of school-aged children with SSC is needed.