The Gradual Correction of Adult Severe Rigid Equinus Deformity Using Minimal Invasive U-Osteotomy With Taylor Spatial Frame.

BACKGROUND: U-osteotomy with Taylor Spatial Frame correction is a rarely reported treatment method particularly well-suited for severe rigid equinus deformity in adults. The purpose of this study was to evaluate the effectiveness and efficacy of deformity correction and clinical outcome using this technique. METHODS: We present a retrospective review of 30 feet in 26 patients who received U-osteotomy with Taylor Spatial Frame. Radiologic outcomes were measured using the anterior tibiotalar angle (TTA) with conventional weightbearing radiographs. Functional assessments included American Orthopaedic Foot & Ankle Society (AOFAS) ankle and hindfoot scores and patient satisfaction using Likert scale. RESULTS: The etiology included trauma (9), neglected or relapsed clubfoot (6), spina bifida (5), poliomyelitis (4), Charcot-Marie-Tooth disease (4), and iatrogenic (2). All patients had equinus deformity with TTA more than 140 degrees (median 157.5, 141-177). There were varus deformity in 19 feet, limb length discrepancy in 6 legs, and genu procurvatum deformity in 2 legs. The duration of gradual correction was 53.6±13.5 days (33-73 days), and the external fixation time was 147.8±25.2 days (98-203 days). At last follow-up, TTA in all patients improved significantly (P < .001) to 113.5 degrees (111.8-116.0). All patients had plantigrade feet, except for 2 cases of residual mild equinovarus deformity, 2 cases of residual mild hindfoot varus deformity, 1 case of moderate hindfoot varus recurrence. The AOFAS scores significantly improved (P < .001) from 51.0 points (29.0-66.0) to 76.0 points (69.5-88.0). Eighteen patients were very satisfied, 6 patients were somewhat satisfied, and 2 patients were somewhat dissatisfied. CONCLUSION: Using minimally invasive U-osteotomy with Taylor Spatial Frame to gradually correct the adult severe rigid equinus deformity proved to be an effective and relatively safe method associated with high patient satisfaction rates. LEVEL OF EVIDENCE: Level IV, case series.

Assessment of bone densitometry using radiography with a step-wedge phantom: a pilot study of the forearm.

Background: Radiographic absorptiometry (RA) is one of the earliest methods of bone densitometry and has been used to measure the phalanges and metacarpals where soft tissue attenuation is minimal. The aim of this study was to determine whether the technique can be adapted to correct for soft tissue attenuation and measure areal bone mineral density (aBMD) in the forearm. Methods: A total of 51 patients referred for a clinical spine and hip dual-energy X-ray absorptiometry (DXA) examination and 8 young and middle-aged volunteers were recruited to this study. The first 29 participants (20 women, 9 men, aged 61±14 years) served as the training cohort, and the remaining 30 (20 women, 10 men, aged 55±16 years) comprised the validation cohort. All participants underwent a DXA scan of their non-dominant forearm, and a digital X-ray image of the same arm was acquired with a step phantom. Identical regions of interest (ROIs) in the radius and ulna at the one-third radius site were measured on the X-ray and DXA images, and a soft tissue ROI was measured on X-ray images between the radius and ulna. The X-ray measurements in the training cohort were expressed as equivalent step phantom thickness (Eq. SPT) and used to estimate forearm aBMD using a linear equation calibrated against the DXA scans. Estimates of forearm aBMD made from the digital X-ray images acquired in the validation cohort were compared with the results of the DXA scans. Results: Digital X-ray estimates of radius and ulna aBMD at the one-third radius site in the validation cohort showed a good correlation with GE-Lunar iDXA scanner measurements (r=0.795; P<0.001). The Bland-Altman plot had a mean bias of -0.002 g/cm2 and 95% limits of agreement of -0.185 to +0.181 g/cm2. Conclusions: Digital X-ray estimates of proximal forearm aBMD corrected for soft tissue attenuation correlated with DXA measurements with correlation coefficients comparable to those seen for other peripheral bone densitometry technologies.

Correlation between tibial valgus deformity and aspect ratio of resected tibial surface in female Chinese patients undergoing total knee arthroplasty.

Background: Morphology of the resected tibial surface is the reference for tibial component design, selection, and implantation in total knee arthroplasty (TKA). This comparative study sought to answer whether valgus deformity of the tibia would affect the morphology of the resected tibial surface in TKA. Methods: Thirty-one female Chinese patients with valgus tibias were retrospectively and consecutively identified from a single-center registration database. Thirty-one patients with well-aligned tibias were matched in terms of gender, height, and weight. Weight-bearing full-length radiographs and computed tomography images of the whole lower limb were obtained for every case. Tibial resection was mimicked perpendicular to the mechanical axis of the tibia in the frontal plane with 3° of posterior slope and a cut level individualized by the actual intraoperative cut. On the resected surface, mediolateral dimension (MLD), medial anteroposterior dimensions (mAPD), and lateral anteroposterior dimensions (lAPD) were measured, and aspect ratios (AR) were calculated. We compared the AR between the two groups. Results: The aspect ratio of resected tibial surface positively correlated with tibial valgus alignment. Patients with valgus tibias had significantly smaller AR (MLD/mAPD) for the medial plateau (1.50 ± 0.06 vs. 1.54 ± 0.07, P = 0.032). However, the AR for the lateral plateau was similar between the two groups (1.63 ± 0.08 vs. 1.65 ± 0.07, P = 0.328). Conclusion: This difference in morphology of resected tibial surface between valgus and well-aligned tibias should be considered in tibial component design, as well as in the selection and placement of TKA implants for knees with valgus tibias.

Different femoral origins of valgus deformity affect aspect ratios of resected distal femurs in total knee arthroplasty.

PURPOSE: This study aimed to evaluate the anthropometry of resected distal femurs in valgus knees at the level of standard cuts during total knee arthroplasty (TKA), and to compare these measurements to neutrally aligned knees. METHODS: Anteroposterior and mediolateral measurements of the distal femur were performed on three-dimensional computed tomography reconstructions of 57 valgus knees (34 intra-articular valgus and 23 juxta-articular valgus) and 40 neutrally aligned knees. The measured dimensions and calculated aspect ratios (ARs) were subsequently compared. RESULTS: Juxta-articular valgus knees had similar ARs when compared with neutrally aligned knees (1.14 ±â€¯0.06 vs. 1.12 ±â€¯0.05, P = 0.103). However, intra-articular valgus knees had smaller ARs (1.09 ±â€¯0.07) when compared with juxta-articular valgus (P = 0.002) or neutrally aligned knees (P = 0.023). CONCLUSION: Different origins of valgus deformity in the femur can significantly affect the AR values on the resected surface of the distal femur. Pre-operative evaluation of a valgus deformity may assist in estimating the morphology of the resected distal femur during TKA.

Preemptive Analgesia with Parecoxib in Total Hip Arthroplasty: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Total hip arthroplasty (THA) is a well-accepted surgical treatment for terminal hip diseases. OBJECTIVE: To evaluate the effect of preemptive analgesia with parecoxib in patients undergoing primary unilateral THA. STUDY DESIGN: A randomized, double-blind, placebo-controlled study. SETTING: This study was conducted at Peking Union Medical College Hospital and Beijing Jishuitan Hospital in Beijing, China. METHODS: A total of 94 patients scheduled for primary unilateral THA in 2 centers (Peking Union Medical College Hospital and Beijing Jishuitan Hospital) were randomly assigned to receive 40 mg parecoxib (n = 48) or 0.9% normal saline solution (n = 46) 30 minutes before incision. All patients received standardized intravenous patient-controlled analgesia (PCA) postoperatively. Preoperative baseline data, surgery-related conditions, postoperative Visual Analog Scale (VAS) pain score, cumulative narcotic consumption of PCA, and complications were compared between the parecoxib group and the placebo group. RESULTS: There were no significant differences in postoperative VAS pain score, cumulative narcotic consumption of PCA, proportion of analgesic remedy, and complications between the 2 groups. LIMITATIONS: Only a single dose of parecoxib was used without including a dose-dependent control group. CONCLUSION: A single dose of parecoxib 30 minutes before incision did not provide effective preemptive analgesia for the management of postoperative pain after primary unilateral THA. The possible effect of preemptive analgesia with parecoxib needs further investigation. KEY WORDS: Total hip arthroplasty, pain, parecoxib, COX-2 selective inhibitor, preemptive analgesia, clinical trial, patient-controlled analgesia, analgesics.

Screw-hole clusters in acetabular cups: a morphological study of optimal positioning of screw-holes.

BACKGROUND: Rigid and safe transacetabular screw fixation in total hip arthroplasty (THA) is achieved by pursuing deeper bone stock and avoiding injuries to the neurovascular structures, but these efforts can be restricted by the distribution of screw-holes on cups by the manufacturer. We therefore tried to determine: (i) optimal screw-hole positions on cups to allow anatomical placement of screws; (ii) rationality of the basic 3-screw-hole cluster on commercial cups; and (iii) the optimum method for placing commercial cups in accordance with acetabular anatomy. METHODS: Periacetabular osseous structure of 64 hips and arterial structures of 50 hips were three-dimensionally reconstructed. Simulated transacetabular screw fixation during THA was performed in these hips with 3 different screw lengths (15, 25, and 35 mm) to define deeper and safer screw trajectories. Screw-hole locations of 7 commercially available cups were measured and matched with the periacetabular anatomy. RESULTS: When the cup was placed into the acetabulum at 45° of abduction and 20° of anteversion, the optimal locations of 2 screw-holes on the cups were at 30° and 64° of latitude, with a 35° separation angle. The inversetriangle distribution pattern was safer than the triangle pattern in basic 3-screw-hole-cluster cups. When placing the commercial cups, 5°-10° of anterior rotation can be added to allow better screw trajectories. CONCLUSIONS: Our study determined optimal screw-hole positions and their distribution pattern on cups. We describe methods to place the commercial cups that are not designed according to acetabular anatomy.

Proteolipid protein-deficient myelin promotes axonal mitochondrial dysfunction via altered metabolic coupling.

Hereditary spastic paraplegia (HSP) is a neurological syndrome characterized by degeneration of central nervous system (CNS) axons. Mutated HSP proteins include myelin proteolipid protein (PLP) and axon-enriched proteins involved in mitochondrial function, smooth endoplasmic reticulum (SER) structure, and microtubule (MT) stability/function. We characterized axonal mitochondria, SER, and MTs in rodent optic nerves where PLP is replaced by the peripheral nerve myelin protein, P0 (P0-CNS mice). Mitochondrial pathology and degeneration were prominent in juxtaparanodal axoplasm at 1 mo of age. In wild-type (WT) optic nerve axons, 25% of mitochondria-SER associations occurred on extensions of the mitochondrial outer membrane. Mitochondria-SER associations were reduced by 86% in 1-mo-old P0-CNS juxtaparanodal axoplasm. 1-mo-old P0-CNS optic nerves were more sensitive to oxygen-glucose deprivation and contained less adenosine triphosphate (ATP) than WT nerves. MT pathology and paranodal axonal ovoids were prominent at 6 mo. These data support juxtaparanodal mitochondrial degeneration, reduced mitochondria-SER associations, and reduced ATP production as causes of axonal ovoid formation and axonal degeneration.

Debridement, internal fixation, and reconstruction using titanium mesh for the surgical treatment of thoracic and lumbar spinal tuberculosis via a posterior-only approach: a 4-year follow-up of 28 patients.

BACKGROUND: The standard recommended method for surgical treatment of spinal tuberculosis is an anterior approach for debridement and fusion combined with posterior instrumentation. However, the method has its disadvantages. The aim of this study was to analyze the effectiveness and safety of treating thoracic and lumbar spinal tuberculosis with debridement, internal fixation reconstruction, and using specially formed titanium mesh cages via a posterior-only approach. METHODS: The authors retrospectively reviewed the cases of 28 patients with spinal tuberculosis treated by debridement, internal fixation, and reconstruction with a specially formed titanium mesh cage via a posterior-only approach. The levels involved were less than two contiguous vertebrae: 13 thoracic vertebrae, 5 thoracolumbar vertebrae, and 10 lumbar vertebrae. All patients suffered from back pain, and nine patients had neurologic deficits (two were class C and seven were in class D according to the American Spinal Injury Association classification). All patients were followed up every 3 months after surgery, with a minimum 48-month follow-up. The clinical efficacy was evaluated based on the visual analog scale (VAS), the Oswestry Disability Index (ODI), neurological status, kyphosis angle, and erythrocyte sedimentation rate (ESR). RESULTS: All patients obtained solid bony fusions without failure of fixation. The infections were resolved in all patients, as noted by normalization of their ESR. The average surgery time was 2 h and 15 min, with an average blood loss of 435 ml. The VAS scores dropped from a preoperative level of 6.31 ± 1.25 to the final follow-up level of 0.57 ± 0.14. The ODI scores dropped from 39.14 ± 12.38 preoperatively to 7.29 ± 3.09 at 1 year postoperatively and 6.77 ± 2.53 at final follow-up. The kyphosis Cobb's angle was corrected from 22.31° ± 4.26° preoperatively to 5.86° ± 0.57° at final follow-up. No subsidence of titanium mesh cage or posterior instrumentation failure was observed postoperatively. The neurological outcome increased by 1-2 grades in the patients with neurological deficits. CONCLUSIONS: Debridement, internal fixation, and reconstruction using specially formed titanium mesh cages via a posterior-only approach is effective and safe for treating adults with thoracic and lumbar spinal tuberculosis involving less than two contiguous levels.

Interleukin-10 is a critical regulator of white matter lesion containment following viral induced demyelination.

Neurotropic coronavirus induces an acute encephalomyelitis accompanied by focal areas of demyelination distributed randomly along the spinal column. The initial areas of demyelination increase only slightly after the control of infection. These circumscribed focal lesions are characterized by axonal sparing, myelin ingestion by macrophage/microglia, and glial scars associated with hypertrophic astrocytes, which proliferate at the lesion border. Accelerated virus control in mice lacking the anti-inflammatory cytokine IL-10 was associated with limited initial demyelination, but low viral mRNA persistence similar to WT mice and declining antiviral cellular immunity. Nevertheless, lesions exhibited sustained expansion providing a model of dysregulated white matter injury temporally remote from the acute CNS insult. Expanding lesions in the absence of IL-10 are characterized by sustained microglial activation and partial loss of macrophage/microglia exhibiting an acquired deactivation phenotype. Furthermore, IL-10 deficiency impaired astrocyte organization into mesh like structures at the lesion borders, but did not prevent astrocyte hypertrophy. The formation of discrete foci of demyelination in IL-10 sufficient mice correlated with IL-10 receptor expression exclusively on astrocytes in areas of demyelination suggesting a critical role for IL-10 signaling to astrocytes in limiting expansion of initial areas of white matter damage. GLIA 2015;63:2106-2120.

Proteolipid protein cannot replace P0 protein as the major structural protein of peripheral nervous system myelin.

The central nervous system (CNS) of terrestrial vertebrates underwent a prominent molecular change when proteolipid protein (PLP) replaced P0 protein as the most abundant protein of CNS myelin. However, PLP did not replace P0 in peripheral nervous system (PNS) myelin. To investigate the possible consequences of a PLP to P0 shift in PNS myelin, we engineered mice to express PLP instead of P0 in PNS myelin (PLP-PNS mice). PLP-PNS mice had severe neurological disabilities and died between 3 and 6 months of age. Schwann cells in sciatic nerves from PLP-PNS mice sorted axons into one-to-one relationships but failed to form myelin internodes. Mice with equal amounts of P0 and PLP had normal PNS myelination and lifespans similar to wild-type (WT) mice. When PLP was overexpressed with one copy of the P0 gene, sciatic nerves were hypomyelinated; mice displayed motor deficits, but had normal lifespans. These data support the hypothesis that while PLP can co-exist with P0 in PNS myelin, PLP cannot replace P0 as the major structural protein of PNS myelin.

Risk factors for poor hip flexion after total hip arthroplasty for the treatment of ankylosing spondylitis a multivariate analysis.

The purpose of this study is to investigate the clinical and radiographic results of total hip arthroplasty (THA) for the treatment of ankylosing spondylitis (AS) and to evaluate the effects of patient, prosthesis design, and surgical technique-related risk factors on postoperative functional results. We retrospectively reviewed the clinical and radiographic results of THA performed in 167 hips for 100 patients with AS. The average follow-up period was 54.8 months (range, 32-129 months). The hip passive-flexion arc averaged only 0 ° (0-40.0 °) before surgery, compared with 100.0 ° (85.0-110.0 °) at the most recent follow-up examination (P < 0.001). Multivariate regression demonstrated that significant variables for postoperative hip flexion were degree of preoperative flexion contracture, preoperative level of C-reactive protein, use of a 32-mm femoral head, and postoperative heterotopic ossification. In patients with AS with severe pain, limited motion and posture, as well as deformity, the overall outcomes after THA were found to be favorable with an encouraging midterm prosthetic survivorship, a low complication rate and a high level of patients' satisfaction. It seemed these patients were particularly predisposed to relative poor range of motion of the involved hips after THA which was closely related to patients' satisfaction. The surgeons should pay careful attention to all possible risk factors perioperatively and develop a comprehensive treatment regimen.

Topography of the periacetabular bone in Chinese patients - do current cages fit?

BACKGROUND: Understanding the anatomy of the periacetabular bone is critical for designing and implanting cages, as well as reconstruction of lost periacetabular bone. We aimed to study the topography of periacetabular bone and compare it with current cages to examine their fit in a Chinese population. METHODS: We performed three-dimensional measurement on computed tomography images of 105 hemipelves to delineate the topography of the periacetabular bone. We compared the bone with digital models of commercially available cages, and divided the results into three scenarios (fit, mismatch and unfit) according to absence or existence of overhang and the extent of contouring needed after implanting the cages to the pelves. RESULTS: Our measurement provided a representation of normal topography of the periacetabular bone. Only 21% of the patients studied had commercially available cages which fit their pelves, whilst there was no cage that fitted 59% of the patients even after extensive contouring. CONCLUSION: Current acetabular cages have low fit rates for the periacetabular bone in Chinese patients.

Lipopolysaccharide-induced microglial activation and neuroprotection against experimental brain injury is independent of hematogenous TLR4.

Intraperitoneal injection of the Gram-negative bacterial endotoxin lipopolysaccharide (LPS) elicits a rapid innate immune response. While this systemic inflammatory response can be destructive, tolerable low doses of LPS render the brain transiently resistant to subsequent injuries. However, the mechanism by which microglia respond to LPS stimulation and participate in subsequent neuroprotection has not been documented. In this study, we first established a novel LPS treatment paradigm where mice were injected intraperitoneally with 1.0 mg/kg LPS for four consecutive days to globally activate CNS microglia. By using a reciprocal bone marrow transplantation procedure between wild-type and Toll-like receptor 4 (TLR4) mutant mice, we demonstrated that the presence of LPS receptor (TLR4) is not required on hematogenous immune cells but is required on cells that are not replaced by bone marrow transplantation, such as vascular endothelia and microglia, to transduce microglial activation and neuroprotection. Furthermore, we showed that activated microglia physically ensheathe cortical projection neurons, which have reduced axosomatic inhibitory synapses from the neuronal perikarya. In line with previous reports that inhibitory synapse reduction protects neurons from degeneration and injury, we show here that neuronal cell death and lesion volumes are significantly reduced in LPS-treated animals following experimental brain injury. Together, our results suggest that activated microglia participate in neuroprotection and that this neuroprotection is likely achieved through reduction of inhibitory axosomatic synapses. The therapeutic significance of these findings rests not only in identifying neuroprotective functions of microglia, but also in establishing the CNS location of TLR4 activation.

Beta4 tubulin identifies a primitive cell source for oligodendrocytes in the mammalian brain.

We have identified a novel population of cells in the subventricular zone (SVZ) of the mammalian brain that expresses beta4 tubulin (betaT4) and has properties of primitive neuroectodermal cells. betaT4 cells are scattered throughout the SVZ of the lateral ventricles in adult human brain and are significantly increased in the SVZs bordering demyelinated white matter in multiple sclerosis brains. In human fetal brain, betaT4 cell densities peak during the latter stages of gliogenesis, which occurs in the SVZ of the lateral ventricles. betaT4 cells represent <2% of the cells present in neurospheres generated from postnatal rat brain but >95% of cells in neurospheres treated with the anti-mitotic agent Ara C. betaT4 cells produce oligodendrocytes, neurons, and astrocytes in vitro. We compared the myelinating potential of betaT4-positive cells with A2B5-positive oligodendrocyte progenitor cells after transplantation (25,000 cells) into postnatal day 3 (P3) myelin-deficient rat brains. At P20, the progeny of betaT4 cells myelinated up to 4 mm of the external capsule, which significantly exceeded that of transplanted A2B5-positive progenitor cells. Such extensive and rapid mature CNS cell generation by a relatively small number of transplanted cells provides in vivo support for the therapeutic potential of betaT4 cells. We propose that betaT4 cells are an endogenous cell source that can be recruited to promote neural repair in the adult telencephalon.

Glutamate receptors on myelinated spinal cord axons: II. AMPA and GluR5 receptors.

OBJECTIVE: Glutamate receptors, which play a major role in the physiology and pathology of central nervous system gray matter, are also involved in the pathophysiology of white matter. However, the cellular and molecular mechanisms responsible for excitotoxic damage to white matter elements are not fully understood. We explored the roles of AMPA and GluR5 kainate receptors in axonal Ca(2+) deregulation. METHODS: Dorsal column axons were loaded with a Ca(2+) indicator and imaged in vitro using confocal microscopy. RESULTS: Both AMPA and a GluR5 kainate receptor agonist increased intraaxonal Ca(2+) in myelinated rat dorsal column fibers. These responses were inhibited by selective antagonists of these receptors. The GluR5-mediated Ca(2+) increase was mediated by both canonical (ie, ionotropic) and noncanonical (metabotropic) signaling, dependent on a pertussis toxin-sensitive G protein/phospholipase C-dependent pathway, promoting Ca(2+) release from inositol triphosphate-dependent stores. In addition, the GluR5 response was reduced by intraaxonal NO scavengers. In contrast, GluR4 AMPA receptors operated via Ca(2+)-induced Ca(2+) release, dependent on ryanodine receptors, and unaffected by NO scavengers. Neither pathway depended on L-type Ca(2+) channels, in contrast with GluR6 kainate receptor action.1 Immunohistochemistry confirmed the presence of GluR4 and GluR5 clustered at the surface of myelinated axons; GluR5 coimmunoprecipitated with nNOS and often colocalized with neuronal nitric oxide synthase clusters on the internodal axon. INTERPRETATION: Central myelinated axons express functional AMPA and GluR5 kainate receptors, and can directly respond to glutamate receptor agonists. These glutamate receptor-dependent signaling pathways promote an increase in intraaxonal Ca(2+) levels potentially contributing to axonal degeneration.

Glutamate receptors on myelinated spinal cord axons: I. GluR6 kainate receptors.

OBJECTIVE: The deleterious effects of glutamate excitotoxicity are well described for central nervous system gray matter. Although overactivation of glutamate receptors also contributes to axonal injury, the mechanisms are poorly understood. Our goal was to elucidate the mechanisms of kainate receptor-dependent axonal Ca(2+) deregulation. METHODS: Dorsal column axons were loaded with a Ca(2+) indicator and imaged in vitro using confocal laser-scanning microscopy. RESULTS: Activation of glutamate receptor 6 (GluR6) kainate receptors promoted a substantial increase in axonal [Ca(2+)]. This Ca(2+) accumulation was due not only to influx from the extracellular space, but a significant component originated from ryanodine-dependent intracellular stores, which, in turn, depended on activation of L-type Ca(2+) channels: ryanodine, nimodipine, or nifedipine blocked the agonist-induced Ca(2+) increase. Also, GluR6 stimulation induced intraaxonal production of nitric oxide (NO), which greatly enhanced the Ca(2+) response: quenching of NO with intraaxonal (but not extracellular) scavengers, or inhibition of neuronal NO synthase with intraaxonal Nomega-nitro-L-arginine methyl ester, blocked the Ca(2+) increase. Loading axons with a peptide that mimics the C-terminal PDZ binding sequence of GluR6, thus interfering with the coupling of GluR6 to downstream effectors, greatly reduced the agonist-induced axonal Ca(2+) increase. Immunohistochemistry showed GluR6/7 clusters on the axolemma colocalized with neuronal NO synthase and Ca(v)1.2. INTERPRETATION: Myelinated spinal axons express functional GluR6-containing kainate receptors, forming part of novel signaling complexes reminiscent of postsynaptic membranes of glutamatergic synapses. The ability of such axonal "nanocomplexes" to release toxic amounts of Ca(2+) may represent a key mechanism of axonal degeneration in disorders such as multiple sclerosis where abnormal accumulation of glutamate and NO are known to occur.

Neurogenesis in the chronic lesions of multiple sclerosis.

Subcortical white matter in the adult human brain contains a population of interneurons that helps regulate cerebral blood flow. We investigated the fate of these neurons following subcortical white matter demyelination. Immunohistochemistry was used to examine neurons in normal-appearing subcortical white matter and seven acute and 59 chronic demyelinated lesions in brains from nine patients with multiple sclerosis and four controls. Seven acute and 44 of 59 chronic multiple sclerosis lesions had marked neuronal loss. Compared to surrounding normal-appearing white matter, the remaining 15 chronic multiple sclerosis lesions contained a 72% increase in mature interneuron density, increased synaptic densities and cells with phenotypic characteristics of immature neurons. Lesion areas with increased neuron densities contained a morphologically distinct population of activated microglia. Subventricular zones contiguous with demyelinated lesions also contained an increase in cells with phenotypes of neuronal precursors. These results support neurogenesis in a subpopulation of demyelinated subcortical white matter lesions in multiple sclerosis brains.

P0 protein is required for and can induce formation of schmidt-lantermann incisures in myelin internodes.

Axons in the PNS and CNS are ensheathed by multiple layers of tightly compacted myelin membranes. A series of cytoplasmic channels connect outer and inner margins of PNS, but not CNS, myelin internodes. Membranes of these Schmidt-Lantermann (S-L) incisures contain the myelin-associated glycoprotein (MAG) but not P(0) or proteolipid protein (PLP), the structural proteins of compact PNS (P(0)) and CNS (PLP) myelin. We show here that incisures are present in MAG-null and absent from P(0)-null PNS internodes. To test the possibility that P(0) regulates incisure formation, we replaced PLP with P(0) in CNS myelin. S-L incisures formed in P(0)-CNS myelin internodes. Furthermore, axoplasm ensheathed by 65% of the CNS incisures examined by electron microscopy had focal accumulations of organelles, indicating that these CNS incisures disrupt axonal transport. These data support the hypotheses that P(0) protein is required for and can induce S-L incisures and that P(0)-induced CNS incisures can be detrimental to axonal function.

Constitutively active Akt induces enhanced myelination in the CNS.

The serine/threonine kinase Akt regulates multiple cellular functions. The current studies identify a new role for Akt in CNS myelination. In earlier studies on cultured oligodendrocytes, we showed that neuregulin signals through phosphatidylinositol-3'-OH kinase and Akt to enhance survival of oligodendrocytes. However, when transgenic animals were generated that overexpressed constitutively active Akt in oligodendrocytes and their progenitor cells, no enhanced survival of oligodendrocytes or progenitors was found. No alteration in the proliferation or death of progenitors was noted. In contrast, the major impact of Akt overexpression in oligodendrocytes was enhanced myelination. Most interestingly, oligodendrocytes in these mice continued actively myelinating throughout life. Thus, expression of constitutively active Akt in oligodendrocytes and their progenitor cells generated no more oligodendrocytes, but dramatically more myelin. The increased myelination continued as these mice aged, resulting in enlarged optic nerves and white matter areas. In older animals with enlarged white matter areas, the density of oligodendrocytes was reduced, but because of the increased area, the total number of oligodendrocytes remained comparable with wild-type controls. Interestingly, in these animals, overexpression of Akt in Schwann cells did not impact myelination. Thus, in vivo, constitutively active Akt enhances CNS myelination but not PNS myelination and has no impact developmentally on oligodendrocyte number. Understanding the unique aspects of Akt signal transduction in oligodendrocytes that lead to myelination rather than uncontrolled proliferation of oligodendrocyte progenitor cells may have important implications for understanding remyelination in the adult nervous system.

Transgenic mice overexpressing reticulon 3 develop neuritic abnormalities.

Dystrophic neurites are swollen dendrites or axons recognizable near amyloid plaques as a part of important pathological feature of Alzheimer's disease (AD). We report herein that reticulon 3 (RTN3) is accumulated in a distinct population of dystrophic neurites named as RTN3 immunoreactive dystrophic neurites (RIDNs). The occurrence of RIDNs is concomitant with the formation of high-molecular-weight RTN3 aggregates in brains of AD cases and mice expressing mutant APP. Ultrastructural analysis confirms accumulation of RTN3-containing aggregates in RIDNs. It appears that the protein level of RTN3 governs the formation of RIDNs because transgenic mice expressing RTN3 will develop RIDNs, initially in the hippocampal CA1 region, and later in other hippocampal and cortical regions. Importantly, we show that the presence of dystrophic neurites in Tg-RTN3 mice causes impairments in spatial learning and memory, as well as synaptic plasticity, implying that RIDNs potentially contribute to AD cognitive dysfunction. Together, we demonstrate that aggregation of RTN3 contributes to AD pathogenesis by inducing neuritic dystrophy. Inhibition of RTN3 aggregation is likely a therapeutic approach for reducing neuritic dystrophy.