Congenital cervical kyphosis in an infant with Ehlers-Danlos syndrome.

BACKGROUND: Ehler-Danlos syndome (EDS) refers to a group of heritable connective tissue disorders; rare manifestations of which are cervical kyphosis and clinical myelopathy. Surgical treatment is described for the deformity in the thoracolumbar spine in adolescents but not for infantile cervical spine. Internal fixation for deformity correction in the infantile cervical spine is challenging due to the diminutive size of the bony anatomy and the lack of spinal instrumentation specifically designed for young children. We describe the first case of successful surgical treatment in an infant with a high cervical kyphotic deformity in EDS. CASE PRESENTATION: A 15-month-old female with EDS presented with several months of regression in gross motor skills in all four extremities. Imaging demonstrated 45° of kyphosis from the C2-4 levels with spinal cord compression. Corrective surgery consisted of a C3 corpectomy and C2-4 anterior fusion with allograft block and anterior fixation with dual 2 × 2 hole craniofacial miniplates, supplemented by C2-4 posterior fusion using four craniofacial miniplates fixated to the lamina. Radiographs at 20 months post-surgery demonstrated solid fusion both anteriorly and posteriorly with maintenance of correction. CONCLUSIONS: Ehlers-Danlos syndrome may present in the pediatric population with congenital kyphosis from cervical deformity in addition to the more commonly seen thoracolumbar deformities.

SIRT1 knockdown promotes neural differentiation and attenuates the heat shock response.

Neurons have a limited capacity for heat shock protein (HSP) induction and are vulnerable to the pathogenic consequence of protein misfolding and aggregation as seen in age-related neurodegenerative diseases. Sirtuin 1 (SIRT1), an NAD(+) -dependent lysine deacetylase with important biological functions, has been shown to sustain the DNA-binding state of HSF1 for HSP induction. Here we show that differentiation and maturation of embryonic cortical neurons and N2a neuroprogenitor cells is associated with decreases in SIRT1 expression and heat shock-dependent induction of HSP70 protein. Tests of a pharmacological activator and an inhibitor of SIRT1 affirm the regulatory role of SIRT1 in HSP70 induction. Protein cross-linking studies show that nuclear SIRT1 and HSF1 form a co-migrating high molecular weight complex upon stress. The use of retroviral vectors to manipulate SIRT1 expression in N2a cells show that shRNA-mediated knock down of SIRT1 causes spontaneous neurite outgrowth coincident with reduced growth rate and decreased induction of hsp70-reporter gene, whereas SIRT1 over-expression blocks the induced neural differentiation of N2a cells. Our results suggest that decreased SIRT1 expression is conducive to neuronal differentiation and this decrease contributes to the attenuated induction of HSPs in neurons.

Glutamate dehydrogenase 1 and SIRT4 regulate glial development.

Congenital hyperinsulinism/hyperammonemia (HI/HA) syndrome is caused by an activation mutation of glutamate dehydrogenase 1 (GDH1), a mitochondrial enzyme responsible for the reversible interconversion between glutamate and α-ketoglutarate. The syndrome presents clinically with hyperammonemia, significant episodic hypoglycemia, seizures, and frequent incidences of developmental and learning defects. Clinical research has implicated that although some of the developmental and neurological defects may be attributed to hypoglycemia, some characteristics cannot be ascribed to low glucose and as hyperammonemia is generally mild and asymptomatic, there exists the possibility that altered GDH1 activity within the brain leads to some clinical changes. GDH1 is allosterically regulated by many factors, and has been shown to be inhibited by the ADP-ribosyltransferase sirtuin 4 (SIRT4), a mitochondrially localized sirtuin. Here we show that SIRT4 is localized to mitochondria within the brain. SIRT4 is highly expressed in glial cells, specifically astrocytes, in the postnatal brain and in radial glia during embryogenesis. Furthermore, SIRT4 protein decreases in expression during development. We show that factors known to allosterically regulate GDH1 alter gliogenesis in CTX8 cells, a novel radial glial cell line. We find that SIRT4 and GDH1 overexpression play antagonistic roles in regulating gliogenesis and that a mutant variant of GDH1 found in HI/HA patients accelerates the development of glia from cultured radial glia cells.

Loss of ephrin-A5 function disrupts lens fiber cell packing and leads to cataract.

Cell-cell interactions organize lens fiber cells into highly ordered structures to maintain transparency. However, signals regulating such interactions have not been well characterized. We report here that ephrin-A5, a ligand of the Eph receptor tyrosine kinases, plays a key role in lens fiber cell shape and cell-cell interactions. Lens fiber cells in mice lacking ephrin-A5 function appear rounded and irregular in cross-section, in contrast to their normal hexagonal appearance in WT lenses. Cataracts eventually develop in 87% of ephrin-A5 KO mice. We further demonstrate that ephrin-A5 interacts with the EphA2 receptor to regulate the adherens junction complex by enhancing recruitment of beta-catenin to N-cadherin. These results indicate that the Eph receptors and their ligands are critical regulators of lens development and maintenance.

NOS1AP regulates dendrite patterning of hippocampal neurons through a carboxypeptidase E-mediated pathway.

During neuronal development, neurons form elaborate dendritic arbors that receive signals from axons. Additional studies are needed to elucidate the factors regulating the establishment of dendritic patterns. Our work explored possible roles played by nitric oxide synthase 1 adaptor protein (NOS1AP; also known as C-terminal PDZ ligand of neuronal nitric oxide synthase or CAPON) in dendritic patterning of cultured hippocampal neurons. Here we report that the long isoform of NOS1AP (NOS1AP-L) plays a novel role in regulating dendrite outgrowth and branching. NOS1AP-L decreases dendrite number when overexpressed at any interval between day in vitro (DIV) 0 and DIV 12, and knockdown of NOS1AP-L results in increased dendrite number. In contrast, the short isoform of NOS1AP (NOS1AP-S) decreases dendrite number only when overexpressed during DIV 5-7. Using mutants of NOS1AP-L, we show that neither the PDZ-binding domain nor the PTB domain is necessary for the effects of NOS1AP-L. We have functionally narrowed the region of NOS1AP-L that mediates this effect to the middle amino acids 181-307, a region that is not present in NOS1AP-S. Furthermore, we performed a yeast two-hybrid screen and identified carboxypeptidase E (CPE) as a binding partner for the middle region of NOS1AP-L. Biochemical and cellular studies reveal that CPE mediates the effects of NOS1AP on dendrite morphology. Together, our results suggest that NOS1AP-L plays an important role in the initiation, outgrowth, and maintenance of dendrites during development.

Bilateral paraspinal muscle flap closure technique for reduction of wound complications from posterior thoracolumbar spinal fusion: results of a series of 716 patients.

OBJECTIVE: Wound complications such as surgical site infection (SSI) and dehiscence are among the most common complications of thoracolumbar spinal fusion surgery and are particularly prevalent in patients with risk factors such as obesity, diabetes, smoking, malignancy, and multilevel and/or revision procedures. A specialized wound closure technique with muscle flap mobilization, which reduces tension at the wound edges and increases the bulk of vascularized tissue in the midline, can be employed as a salvage procedure to manage wound complications. The authors evaluated the effectiveness of prophylactic muscle flap closure for reducing SSI in patients with risk factors for wound complications who undergo thoracolumbar fusion surgery. METHODS: A retrospective review of thoracolumbar fusion surgeries over a 15-year period was conducted in a group of patients at risk for wound complications to compare outcomes of patients who underwent prophylactic muscle flap closure with outcomes of patients who had conventional wound closure. Patients were selected for specialized closure based upon a protocol adopted during the study period. Patients were excluded if they had active infections or underwent tubular retractor-mediated decompression and did not have open surgery with a midline incision. RESULTS: Of 716 patients, wound closure was performed in 455 patients using conventional closure and in 261 using muscle flap closure. There were no significant differences in the ratios of male to female patients, with 251 men and 204 women with conventional closure and 133 men and 128 women with muscle flap closure, but the muscle flap patients were older than the conventional closure patients, with mean ages of 65.2 versus 62.9 years (p < 0.005). Indications for surgery in the muscle flap group and the conventional group, respectively, were metastatic disease in 44 (17%) and 32 (7%) patients; trauma in 10 (4%) and 14 (3%) patients; and degenerative disease, including spondylolisthesis, spondylolysis, and stenosis, in 207 (79%) and 409 (90%) patients, with more muscle flap patients having metastasis (p < 0.00001). Patients having muscle flaps had significantly higher rates of diabetes, smoking, and revision surgery, and a higher mean BMI and number of operative levels. The serum albumin level was slightly lower in the muscle flap group (p < 0.047). The wound infection rate was significantly lower in the muscle flap group (0.4%) compared with the conventional closure group (2.4%) (p < 0.033). CONCLUSIONS: Prophylactic muscle flap closure significantly lowers the rate of SSI in patients undergoing thoracolumbar spinal fusion who harbor risk factors for wound complications, with even fewer infections seen than in a group of patients without similar risk factors. Given the success of the technique, consideration of wider use for thoracolumbar fusion cases, even those without a high level of complexity, may be warranted.

Improved Cosmetic Outcome With Bilateral Paraspinal Muscle Flap Closure Following Cervical Laminectomy and Fusion.

BACKGROUND: Poor cosmetic results following cervical laminectomy and fusion (CLF) are rarely considered in assessing surgical complications. Atrophy from muscle denervation and posterior bone loss may result in a sunken appearance; relative tension may lead to wide, unsightly scars. Paraspinal muscle flaps are routinely employed by plastic surgeons for closure of wound infection and dehiscence. OBJECTIVE: To assess clinical and cosmetic results of CLF with/without a paraspinal muscle flap closure technique. METHODS: A retrospectively collected cohort analysis was undertaken for a 12-yr period in CLF patients. During the study period, a paraspinal muscle flap closure technique was adopted. Wounds were inspected for scar width and depth using a scale devised to categorize the posterior neck contour. Minimum follow-up was 12 mo. RESULTS: Of 159 patients, 94 wounds were evaluated of which 34 had muscle flap closure. There were no differences in age, sex, body mass index, mJOA scores, diabetes status, or number of spinal levels treated. Mean follow-up was 18.6 (12-48) and 49.8 (12-130) mo in the muscle flap and conventional closure groups respectively; contour scores were 1.20 vs 2.65 (P < .00001) and scar width was 2.8 vs 4.9 mm (P < .0001). No patient had a wound complication in the muscle flap group and 4 (7%) in the conventional closure group. CONCLUSION: Paraspinal muscle flap closure of CLF improved cosmetic appearance in terms of wound contour and scar width. Further investigation is needed to determine any effect upon wound infection and dehiscence rates.

Local manganese chloride treatment accelerates fracture healing in a rat model.

This study investigated the effects of local delivery of manganese chloride (MnCl2), an insulin-mimetic compound, upon fracture healing using a rat femoral fracture model. Mechanical testing, histomorphometry, and immunohistochemistry were performed to assess early and late parameters of fracture healing. At 4 weeks post-fracture, maximum torque to failure was 70% higher (P<0.05) and maximum torsional rigidity increased 133% (P<0.05) in animals treated with 0.125 mg/kg MnCl2 compared to saline controls. Histological analysis of the fracture callus revealed percent new mineralized tissue was 17% higher (P<0.05) at day 10. Immunohistochemical analysis of the 0.125 mg/kg MnCl2 treated group, compared to saline controls, showed a 379% increase in the density of VEGF-C+ cells. In addition, compared to saline controls, the 0.125 mg/kg MnCl2 treated group showed a 233% and 150% increase in blood vessel density in the subperiosteal region at day 10 post-fracture as assessed by detection of PECAM and smooth muscle α actin, respectively. The results suggest that local MnCl2 treatment accelerates fracture healing by increasing mechanical parameters via a potential mechanism of amplified early angiogenesis leading to increased osteogenesis. Therefore, local administration of MnCl2 is a potential therapeutic adjunct for fracture healing.

Quality of online pediatric orthopaedic education materials.

BACKGROUND: Increased availability of medical information on the Internet empowers patients to look up answers to questions about their medical conditions. However, the quality of medical information available on the Internet is highly variable. Various tools for the assessment of online medical information have been developed and used to assess the quality and accuracy of medical web sites. In this study we used the LIDA tool (Minervation) to assess the quality of pediatric patient information on the AAOS (American Academy of Orthopaedic Surgeons) and POSNA (Pediatric Orthopaedic Society of North America) web sites. METHODS: The accessibility, usability, and reliability of online medical information in the "Children" section of the AAOS web site and on the POSNA web site were assessed with use of the LIDA tool. Flesch-Kincaid (FK) and Flesch Reading Ease (FRE) values were also calculated to assess the readability of the pediatric education material. RESULTS: Patient education materials on each web site scored in the moderate range in assessments of accessibility, usability, and reliability. FK and FRE values indicated that the readability of each web site remained at a somewhat higher (more difficult) level than the recommended benchmark. CONCLUSIONS: The quality and readability of online information for children on the AAOS and POSNA web sites are acceptable but can be improved further. CLINICAL RELEVANCE: The quality of online pediatric orthopaedic patient education materials may affect communication with patients and their caregivers, and further investigation and modification of quality are needed.

ADF/cofilin-mediated actin dynamics regulate AMPA receptor trafficking during synaptic plasticity.

Dendritic spines undergo actin-based growth and shrinkage during synaptic plasticity, in which the actin depolymerizing factor (ADF)/cofilin family of actin-associated proteins are important. Elevated ADF/cofilin activities often lead to reduced spine size and immature spine morphology but can also enhance synaptic potentiation in some cases. Thus, ADF/cofilin may have distinct effects on postsynaptic structure and function. We found that ADF/cofilin-mediated actin dynamics regulated AMPA receptor (AMPAR) trafficking during synaptic potentiation, which was distinct from actin's structural role in spine morphology. Specifically, elevated ADF/cofilin activity markedly enhanced surface addition of AMPARs after chemically induced long-term potentiation (LTP), whereas inhibition of ADF/cofilin abolished AMPAR addition. We found that chemically induced LTP elicited a temporal sequence of ADF/cofilin dephosphorylation and phosphorylation that underlies AMPAR trafficking and spine enlargement. These findings suggest that temporally regulated ADF/cofilin activities function in postsynaptic modifications of receptor number and spine size during synaptic plasticity.