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1.  Flexibility and Symmetry of Prokaryotic Genome Rearrangement Reveal Lineage-Associated Core-Gene-Defined Genome Organizational Frameworks 
mBio  2014;5(6):e01867-14.
The prokaryotic pangenome partitions genes into core and dispensable genes. The order of core genes, albeit assumed to be stable under selection in general, is frequently interrupted by horizontal gene transfer and rearrangement, but how a core-gene-defined genome maintains its stability or flexibility remains to be investigated. Based on data from 30 species, including 425 genomes from six phyla, we grouped core genes into syntenic blocks in the context of a pangenome according to their stability across multiple isolates. A subset of the core genes, often species specific and lineage associated, formed a core-gene-defined genome organizational framework (cGOF). Such cGOFs are either single segmental (one-third of the species analyzed) or multisegmental (the rest). Multisegment cGOFs were further classified into symmetric or asymmetric according to segment orientations toward the origin-terminus axis. The cGOFs in Gram-positive species are exclusively symmetric and often reversible in orientation, as opposed to those of the Gram-negative bacteria, which are all asymmetric and irreversible. Meanwhile, all species showing strong strand-biased gene distribution contain symmetric cGOFs and often specific DnaE (α subunit of DNA polymerase III) isoforms. Furthermore, functional evaluations revealed that cGOF genes are hub associated with regard to cellular activities, and the stability of cGOF provides efficient indexes for scaffold orientation as demonstrated by assembling virtual and empirical genome drafts. cGOFs show species specificity, and the symmetry of multisegmental cGOFs is conserved among taxa and constrained by DNA polymerase-centric strand-biased gene distribution. The definition of species-specific cGOFs provides powerful guidance for genome assembly and other structure-based analysis.
Prokaryotic genomes are frequently interrupted by horizontal gene transfer (HGT) and rearrangement. To know whether there is a set of genes not only conserved in position among isolates but also functionally essential for a given species and to further evaluate the stability or flexibility of such genome structures across lineages are of importance. Based on a large number of multi-isolate pangenomic data, our analysis reveals that a subset of core genes is organized into a core-gene-defined genome organizational framework, or cGOF. Furthermore, the lineage-associated cGOFs among Gram-positive and Gram-negative bacteria behave differently: the former, composed of 2 to 4 segments, have their fragments symmetrically rearranged around the origin-terminus axis, whereas the latter show more complex segmentation and are partitioned asymmetrically into chromosomal structures. The definition of cGOFs provides new insights into prokaryotic genome organization and efficient guidance for genome assembly and analysis.
PMCID: PMC4251990  PMID: 25425232
2.  Characteristics of an extended internal fixation system for polysegmental transpedicular reduction and stabilization of the thoracic, lumbar, and lumbosacral spine 
European Spine Journal  1999;8(1):61-69.
The Kluger internal fixator, with its artificial fulcrum outside the operative site, had to be extended for multisegmental use. Three different prototypes, called Central Bar (CB), Double Bar I (DB I) and Double Bar II (DB II) were designed, which were fully compatible with the existing reduction system. To evaluate the ability of these newly developed systems to provide primary stability in a destabilized spine, their stiffness characteristics and stabilizing effects were investigated in multidirectional biomechanical stability tests and compared with those of the clinically well-known Cotrel-Dubousset (CD) system. The investigations were performed on a spine tester using freshly prepared calf spines. The model tested was that of an intact straight spine followed by a defined three-column lesion simulating the most destabilizing type of injury. Pure moments of up to 7.5 Nm were continuously applied to the top of each specimen in flexion/extension, left/right axial rotation, and left/right lateral bending. Segmental motion was measured using a three-dimensional goniometric linkage system. Range of motion and stiffness within the neutral zone were calculated from obtained load-displacement curves. The DB II attained 112.5% (P = 0.26) of the absolute stiffness of the CD system in flexion and enhanced its stability in extension by up to 144.3% (P = 0.004). In axial rotation of the completely destabilized spine, this system achieved 183.3% of the stiffness of the CD system (P < 0.001), and in lateral bending no motion was measured in the most injured specimens stabilized by the DB II. The DB I, which was the first to be designed and was considered to provide high biomechanical stability, did not attain the stiffness standard set by the CD system in either flexion/extension or axial rotation of the most injured spine. The study confirms that it is worthwhile to evaluate in vitro the biomechanical properties of a newly developed implant before its use in patients, in order to refine weak construction points and help to reduce device-related complications and to better evaluate its efficacy in stabilizing the spine.
PMCID: PMC3611130  PMID: 10190856
Key words Biomechanics; Stability; Calf spine; Spinal implants; Transpedicular fixation
3.  Outcome analysis of retrograde nailing and less invasive stabilization system in distal femoral fractures: A retrospective analysis 
Indian Journal of Orthopaedics  2011;45(3):243-250.
Two major therapeutic principles can be employed for the treatment of distal femoral fractures: retrograde intramedullary (IM) nailing (RN) or less invasive stabilization on system (LISS). Both operative stabilizing systems follow the principle of biological osteosynthesis. IM nailing protects the soft-tissue envelope due to its minimally invasive approach and closed reduction techniques better than distal femoral locked plating. The purpose of this study was to evaluate and compare outcome of distal femur fracture stabilization using RN or LISS techniques.
Materials and Methods:
In a retrospective study from 2003 to 2008, we analyzed 115 patients with distal femur fracture who had been treated by retrograde IM nailing (59 patients) or LISS plating (56 patients). In the two cohort groups, mean age was 54 years (17–89 years). Mechanism of injury was high energy impact in 57% (53% RN, 67% LISS) and low-energy injury in 43% (47% RN, 33% LISS), respectively. Fractures were classified according to AO classification: there were 52 type A fractures (RN 31, LISS 21) and 63 type C fractures (RN 28, LISS 35); 32% (RN) and 56% (LISS) were open and 68% (RN) and 44% (LISS) were closed fractures, respectively. Functional and radiological outcome was assessed.
Clinical and radiographic evaluation demonstrated osseous healing within 6 months following RN and following LISS plating in over 90% of patients. However, no statistically significant differences were found for the parameters time to osseous healing, rate of nonunion, and postoperative complications. The following complications were treated: hematoma formation (one patient RN and three patients LISS), superficial infection (one patient RN and three patients LISS), deep infection (2 patients LISS). Additional secondary bone grafting for successful healing 3 months after the primary operation was required in four patients in the RN (7% of patients) and six in the LISS group (10% of patients). Accumulative result of functional outcome using the Knee and Osteoarthritis Outcome (KOOS) score demonstrated in type A fractures a score of 263 (RN) and 260 (LISS), and in type C fractures 257 (RN) and 218 (LISS). Differences between groups for type A were statistically insignificant, statistical analysis for type C fractures between the two groups are not possible, since in type C2 and C3 fractures only LISS plating was performed.
Both retrograde IM nailing and angular stable plating are adequate treatment options for distal femur fractures. Locked plating can be used for all distal femur fractures including complex type C fractures, periprosthetic fractures, as well as osteoporotic fractures. IM nailing provides favorable stability and can be successfully implanted in bilateral or multisegmental fractures of the lower extremity as well as in extra-articular fractures. However, both systems require precise preoperative planning and advanced surgical experience to reduce the risk of revision surgery. Clinical outcome largely depends on surgical technique rather than on the choice of implant.
PMCID: PMC3087226  PMID: 21559104
Distal femoral fractures; osteosynthesis; minimally invasive techniques; retrograde intramedullary nailing; angular stable plating
4.  Severe kyphoscoliosis after primary Echinococcus granulosus infection of the spine 
European Spine Journal  2010;19(9):1415-1422.
A primary Echinococcus granulosus infection of the spine involving the vertebrae T8 and T9 of a 6-year-old child was treated elsewhere by thoracotomy, partial corporectomy, multiple laminectomies and uninstrumented fusion. Owing to inappropriate stabilization, severe deformity developed secondary to these surgeries. X-rays, CT and MRI scans of the spine revealed a severe thoracic kyphoscoliosis of more than 100° (Fig. 1) and recurrence of Echinococcus granulosus infection. The intraspinal cyst formation was located between the stretched dural sac and the vertebral bodies of the kyphotic apex causing significant compression of the cord (Figs. 2, 3, 4). A progressive neurologic deficit was reported by the patient. At the time of referral, the patient was wheelchair bound and unable to walk by herself (Frankel Grade C). Standard antiinfectious therapy of Echinococcus granulosus requires a minimum treatment period of 3 months. This should be done before any surgical intervention because in case of a rupture of an active cyst, the delivered lipoprotein antigens of the parasite may cause a potentially lethal anaphylactic shock. Owing to the critical neurological status, we decided to perform surgery without full length preoperative antiinfectious therapy. Surgical treatment consisted in posterior vertebral column resection technique with an extensive bilateral costotransversectomy over three levels, re-decompression with cyst excision around the apex and multilevel corporectomy of the apex of the deformity. Stabilisation and correction of the spinal deformity were done by insertion of a vertebral body replacement cage anteriorly and posterior shortening by compression and by a multisegmental pedicle screw construct. After the surgery, antihelminthic therapy was continued. The patients neurological deficits resolved quickly: 4 weeks after surgery, the patient had Frankel Grade D and was ambulatory without any assistance. After an 18-month follow-up, the patient is free of recurrence of infection and free of neurologically deficits (Frankel E). This case demonstrates that inappropriate treatment—partial resection of the cyst, inappropriate anterior stabilization and posterior multilevel laminectomies without posterior stabilization—may lead to severe progressive kyphoscoliotic deformity and recurrence of infection, both leading to significant neurological injury presenting as a very difficult to treat pathology.Fig. 1X-rays of the patient showing a kyhoscoliotic deformity. a ap view, b lateral viewFig. 2CT reconstruction of the whole spine showing the apex of the deformity is located in the area of the previous surgeriesFig. 3Sagittal CT-cut showing the bone bloc at the apex with a translation deformityFig. 4Sagittal T2-weighted MRI image showing the cystic formation at the apex
PMCID: PMC2989289  PMID: 20514501
Echinococcus granulosus; Infection; Thoracic spine; Kyphotic deformity; Neurologic deficit
5.  Obese elderly women exhibit low postural stability: a novel three-dimensional evaluation system 
Clinics  2012;67(5):475-481.
The aim of this study was to evaluate the multisegmental static postural balance of active eutrophic and obese elderly women using a three-dimensional system under different sensory conditions.
A cross-sectional study was conducted on 31 elderly women (16 eutrophic and 15 obese) aged 65 to 75 years. The following anthropometric measurements were obtained: weight, height, waist and hip circumference, and handgrip strength. The physical activity level was evaluated using the International Physical Activity Questionnaire. Body composition was measured using the deuterium oxide dilution technique. The Polhemus® Patriot (three-dimensional) equipment was used to measure the parameters of postural balance along the anteroposterior and laterolateral axes. The data acquisition involved one trial of 60 s to test the limit of stability and four trials of 90 s each under the following conditions: (1) eyes open, stable surface; (2) eyes closed, stable surface; (3) eyes open, unstable surface; and (4) eyes closed, unstable surface.
For the limit of stability, significant differences were observed in the maximum anteroposterior and laterolateral displacement (p<0.01) and in the parameter maximum anteroposterior displacement in the eyes closed stable surface condition (p<0.01) and maximum anteroposterior and laterolateral displacement in the eyes open unstable surface (p<0.01 and p = 0.03) and eyes closed unstable surface (p<0.01 and p<0.01) conditions.
Obese elderly women exhibited a lower stability limit (lower sway area) compared with eutrophic women, leaving them more vulnerable to falls.
PMCID: PMC3351265  PMID: 22666792
Elderly; Obesity; Postural Balance; Sensory Deprivation; Three-Dimensional System
6.  Complications of transpedicular screw fixation in the cervical spine 
European Spine Journal  2005;15(3):327-334.
Today, posterior stabilization of the cervical spine is most frequently performed by lateral mass screws or spinous process wiring. These techniques do not always provide sufficient stability, and anterior fusion procedures are added secondarily. Recently, transpedicular screw fixation of the cervical spine has been introduced to provide a one-stage stable posterior fixation. The aim of the present prospective study is to examine if cervical pedicle screw fixation can be done by low risk and to identify potential risk factors associated with this technique. All patients stabilized by cervical transpedicular screw fixation between 1999 and 2002 were included. Cervical disorders included multisegmental degenerative instability with cervical myelopathy in 16 patients, segmental instability caused by rheumatoid arthritis in three, trauma in five and instability caused by infection in two patients. In most cases additional decompression of the spinal cord and bone graft placement were performed. Pre-operative and post-operative CT-scans (2-mm cuts) and plain X-rays served to determine changes in alignment and the position of the screws. Clinical outcome was assessed in all cases. Ninety-four cervical pedicle screws were implanted in 26 patients, most frequently at the C3 (26 screws) and C4 levels (19 screws). Radiologically 66 screws (70%) were placed correctly (maximal breach 1 mm) whereas 20 screws (21%) were misplaced with reduction of mechanical strength, slight narrowing of the vertebral artery canal (<25%) or the lateral recess without compression of neural structures. However, these misplacements were asymptomatic in all cases. Another eight screws (9%) had a critical breach. Four of them showed a narrowing of the vertebral artery canal of more then 25%, in all cases without vascular problems. Three screws passed through the intervertebral foramen, causing temporary paresis in one case and a new sensory loss in another. In the latter patient revision surgery was performed. The screw was loosened and had to be corrected. The only statistically significant risk factor was the level of surgery: all critical breaches were seen from C3 to C5. Percutaneous application of the screws reduced the risk for misplacement, although this finding was not statistically significant. There was also a remarkable learning curve. Instrumentation with cervical transpedicular screws results in very stable fixation. However, with the use of new techniques like percutaneous screw application or computerized image guidance there remains a risk for damaging nerve roots or the vertebral artery. This technique should be reserved for highly selected patients with clear indications and to highly experienced spine surgeons.
PMCID: PMC3489301  PMID: 15912352
Cervical spine; Pedicle screw fixation; Complication; Posterior fusion
7.  Identification of the contribution of the ankle and hip joints to multi-segmental balance control 
Human stance involves multiple segments, including the legs and trunk, and requires coordinated actions of both. A novel method was developed that reliably estimates the contribution of the left and right leg (i.e., the ankle and hip joints) to the balance control of individual subjects.
The method was evaluated using simulations of a double-inverted pendulum model and the applicability was demonstrated with an experiment with seven healthy and one Parkinsonian participant. Model simulations indicated that two perturbations are required to reliably estimate the dynamics of a double-inverted pendulum balance control system. In the experiment, two multisine perturbation signals were applied simultaneously. The balance control system dynamic behaviour of the participants was estimated by Frequency Response Functions (FRFs), which relate ankle and hip joint angles to joint torques, using a multivariate closed-loop system identification technique.
In the model simulations, the FRFs were reliably estimated, also in the presence of realistic levels of noise. In the experiment, the participants responded consistently to the perturbations, indicated by low noise-to-signal ratios of the ankle angle (0.24), hip angle (0.28), ankle torque (0.07), and hip torque (0.33). The developed method could detect that the Parkinson patient controlled his balance asymmetrically, that is, the right ankle and hip joints produced more corrective torque.
The method allows for a reliable estimate of the multisegmental feedback mechanism that stabilizes stance, of individual participants and of separate legs.
PMCID: PMC3662596  PMID: 23433148
Balance control; Closed-loop system identification; Multivariate systems; Asymmetry
8.  Alternative option in patients with multisegmental left anterior descending coronary artery disease for providing complete myocardial revascularization 
Objectives: The basic aim of surgical interventions in patients with coronary artery disease is to complete myocardial revascularization. In such patients, however, complementary revascularization techniques may require in patients with multisegmental left anterior descending disease. Among the different procedures, we performed an alternative option in patients with multisegmental lad disease for providing complete myocardial revascularization. Methods: This study consists of retrospective analysis of consecutive eight patients between january 2008 and august 2013. In all patients, the surgical procedure consisted of standard aortic and right atrial cannulations followed by coronary artery bypass grafting with cardiopulmonary bypass. At the lesions of non-lad vessels distal anastomoses were performed with saphenous vein graft. After that lad arteriotomies were performed at the proximal and the distal segment of coronary stenosis, and a bridge was formed with a short segment valveless svg. The left internal mammary artery was anastomosed on the bridge. Results: This innovative technique was performed successfully in all the patients. There were no morbidity and in-hospital mortality. At follow-up 1 year control, all the patients have no complications. In 2 patients, control angiogram showed a patent lima to a bridge anastomosis. Conclusions: Although our series has a small group population, we advocate that this is a safe, easy, and efficient technique for providing complete revascularization in multisegmental lad disease. This technique could be performed with the good result and easy implementation. It perfuses both the proximal and the distal segments of the multisegmental lad stenoses.
PMCID: PMC3902252  PMID: 24482700
Coronary artery bypass grafting; revascularization techniques; complete myocardial revascularization
9.  Anterior cervical pedicle screw and plate fixation using fluoroscope-assisted pedicle axis view imaging: a preliminary report of a new cervical reconstruction technique 
European Spine Journal  2009;18(6):911-916.
Anterior procedures in the cervical spine are feasible in cases having anterior aetiologies such as anterior neural compression and/or severe kyphosis. Halo vests or anterior plates are used concurrently for cases with long segmental fixation. Halo vests are bothersome and anterior plate fixation is not adequately durable. We developed a new anterior pedicle screw (APS) and plate fixation procedure that can be used with fluoroscope-assisted pedicle axis view imaging. Six patients (3 men and 3 women; mean age, 54 years) with anterior multisegmental aetiology were included in this study. Their original diagnoses comprised cervical myelopathy and/or radiculopathy (n = 4), posterior longitudinal ligament ossification (n = 1) and post-traumatic kyphosis (n = 1). All patients underwent anterior decompression and strut grafting with APS and plate fixation. Mean operative time was 192 min and average blood loss was 73 ml. Patients were permitted to ambulate the next day with a cervical collar. Local sagittal alignment was characterised by 3.5° of kyphosis preoperatively, which improved to 6.8° of lordosis postoperatively and 5.2° of lordosis at final follow-up. Postoperative improvement and early bony union were observed in all cases. There was no serious complication except for two cases of dysphagia. Postoperative imaging demonstrated screw exposure in one screw, but no pedicle perforation. APS and plate fixation is useful in selected cases of multisegmental anterior reconstruction of cervical spine. However, the adequate familiarity and experience with both cervical pedicle screw fixation and the imaging technique used for visualising the pedicle during surgery are crucial for this procedure.
PMCID: PMC2899659  PMID: 19343377
Anterior pedicle screw; Cervical spine; Pedicle axis view; Fluoroscope
10.  Morbidity of en bloc resections in the spine 
European Spine Journal  2009;19(2):231-241.
The morbidity of surgical procedures for spine tumors can be expected to be worse than for other conditions. This is particularly true of en bloc resections, the most technically demanding procedures. A retrospective review of prospective data from a large series of en bloc resections may help to identify risk factors, and therefore to reduce the rate of complications and to improve outcome. A retrospective study of 1,035 patients affected by spine tumors—treated from 1990 to 2007 by the same team—identified 134 patients (53.0% males, age 44 ± 18 years) who had undergone en bloc resection for primary tumors (90) and bone metastases (44). All clinical, histological and radiological data were recorded from the beginning of the period in a specifically built database. The study was set up to correlate diagnosis, staging and treatment with the outcome. Oncological and functional results were recorded for all patients at periodic, diagnosis-related controls, until death or the latest follow-up examination (from 0 to 211 months, median 47 months, 25th–75th percentile 22–85 months). Forty-seven on the 134 patients (34.3%) suffered a total of 70 complications (0.86 events per 100 patient-years); 32 patients (68.1%) had one complication, while the rest had 2 or more. There were 41 major and 29 minor complications. Three patients (2.2%) died from complications. Of the 35 patients with a recurrent or contaminated tumor, 16 (45.7%) suffered at least one complication; by contrast, complications arose in 31 (31.3%) of the 99 patients who had had no previous treatment and who underwent the whole of their treatment in the same center (P = 0.125). The risk of major complications was seen to be more than twice as high in contaminated patients than in non-contaminated ones (OR = 2.52, 95%CI 1.01–6.30, P = 0.048). Factors significantly affecting the morbidity are multisegmental resections and operations including double contemporary approaches. A local recurrence was recorded in 21 cases (15.7%). The rate of deep infection was higher in patients who had previously undergone radiation therapy (RT), but the global incidence of complications was lower. Re-operations were mostly due to tumor recurrences, but also to hardware failures, wound dehiscence, hematomas and aortic dissection. En bloc resection is able to improve the prognosis of aggressive benign and low-grade malignant tumors in the spine; however, complications are not rare and possibly fatal. The rate of complication is higher in multisegmental resections and when double combined approach is performed, as it can be expected in more complex procedures. Re-operations display greater morbidity owing to dissection through scar/fibrosis from previous operations and possibly from RT. The treatment of recurrent cases and planned transgression to reduce surgical aggressiveness are associated with a higher rate of local recurrence, which can be considered the most severe complication. In terms of survival and quality of life, late results are worse in recurrent cases than in complicated cases. Careful treatment planning and, in the event of uncertainty, referral to a specialty center must be stressed.
PMCID: PMC2899819  PMID: 19690899
Spine; Tumor; En bloc resection; Complication; Morbidity
11.  International E-vita open registry 
Annals of Cardiothoracic Surgery  2013;2(3):296-299.
The E-vita open hybrid stent-graft enables successful one-stage repairs of complex pathologies of the ascending aorta, aortic arch, and descending aorta. To evaluate the efficacy and durability of this treatment concept, the International E-vita open registry (IEOR) was initiated in 2008. 416 patients from 10 European centers were recruited, separated into 138 (33.2%) acute dissection cases, 142 (34.1%) chronic dissection cases, and 136 (32.7%) patients with multisegmental thoracic aneurysmal disease. In-hospital mortality was 16%, 14%, and 13% for each of the three groups, respectively, and stroke and spinal cord injury rates ranged between 5-7% and 3-9%. Survival after 5 years was 79%, 86%, and 78% for acute dissection, chronic dissection, and multisegmental aneurysmal patients, with freedom from open aortic surgery after 5 years at 96%, 94% and 82%. Findings from IEOR demonstrate the importance of the registry as an important tool for developing guidelines and frameworks in the management of this complex pathology.
PMCID: PMC3741859  PMID: 23977597
E-vita open; hybrid stent-graft; IEOR; registry; aortic arch surgery
12.  Does the type of T2-weighted hyperintensity influence surgical outcome in patients with cervical spondylotic myelopathy? A review 
European Spine Journal  2012;22(1):96-106.
To review the literature on different classifications of T2-weighted (T2W) increased signal intensity (ISI) on preoperative magnetic resonance (MR) images of patients with cervical spondylotic myelopathy (CSM).
The authors searched the databases of PubMed and Cochrane for studies that used a categorization of T2W ISI to predict the functional outcome after decompressive surgery for CSM. Selected studies were analyzed for the type of ISI classification used, patient selection, methodology and results. The level of evidence provided by each study was determined.
Twenty-two studies fulfilled our search criteria. There were 11 prospective studies and a total of 1,508 patients were studied. The majority of studies classified ISI based on either the longitudinal extent (12 studies) or the qualitative features of the ISI (10 studies). Three studies used both parameters to classify T2W ISI. Other classifications were based on the position of ISI (1 study), presence of snake-eye appearance on axial MR images (1 study) and signal intensity ratio (SIR) (1 study). Poorer functional outcomes correlated with sharp, intense ISI (6 studies) and multisegmental ISI (5 studies) (Class II evidence). Five of ten studies reported that the regression of ISI postoperatively was associated with better neurological outcomes (Class II evidence).
Methodological variations in previous studies made it difficult to compare studies and results. Both multisegmental T2W ISI and sharp, intense T2W ISI are associated with poorer surgical outcome (Class II evidence). The regression of T2W ISI postoperatively correlates with better functional outcomes (Class II). Future studies on the significance of ISI should ensure use of a uniform grading system, standardized outcome measures and multivariate analyses to control for other preoperative variables.
PMCID: PMC3540309  PMID: 22926434
Cervical spondylotic myelopathy; Cervical spine surgery; T2-weighted MRI; Intramedullary; Review
13.  Multisegmental spondylitis due to Tropheryma whipplei: Case report 
We report a patient who presented with inflammatory back pain due to multisegmental spondylitis. Following a vertebral biopsy which failed to detect an infectious organism, the patient was treated with etanercept, a tumor necrosis factor (TNF)-α inhibitor, for suspected undifferentiated spondyloarthritis. The back pain worsened and the spondylitic lesions increased. Only in a vertebral rebiopsy with polymerase chain reaction (PCR) amplification of Tropheryma whipplei, the causative agent of Whipple's disease was identified. Tropheryma whipplei should be considered as a cause of spondylitis even with multisegmental involvement and in the absence of gastrointestinal symptoms. In this clinical setting, routine PCR for Tropheryma whipplei from vertebral biopsies is recommended.
PMCID: PMC2697142  PMID: 19493331
14.  Somatosensory evoked potentials after multisegmental lower limb stimulation in focal lesions of the lumbosacral spinal cord 
OBJECTIVES—Recording techniques permit the separate analysis of the response from cauda equina roots and the spinal potential that is probably generated by the activation of dorsal horn cells. To improve the functional assessment of focal lesions of the lumbosacral cord, lower limb somatosensory evoked potentials (SEPs) were measured by multisegmental stimulation.
METHODS—Common peroneal and tibial nerves SEPs were recorded in 14 patients in whom MRI demonstrated compressive cord damage ranging from T9 to L1 levels. SEPs were recorded in each patient at the lumbar level (cauda equina response), lower thoracic level (spinal response), and from the scalp (cortical response).
RESULTS—Abnormalities in spinal response occurred in 50% and 70% of tibial and common peroneal nerve SEPs respectively; these findings were well explained by the radiological compression level, involving in most of the patients lumbar rather than sacral myelomeres. The SEPs were often more effective than the clinical examination in showing the actual extension of damage.
CONCLUSIONS—The recording of spinal SEPs after multisegmental lower limb stimulation proved useful in assessing cord dysfunction and determining the cord levels mainly involved by the compression.

PMCID: PMC1737022  PMID: 10864611
15.  Biomechanics of the Double Rocker Sole Shoe: Gait Kinematics and Kinetics 
The use of footwear with contoured soles is common in treatment and care of patients with diabetes; these rocker sole shoes are designed to alleviate loading in key areas on the plantar surface of the foot, reducing pressure in key areas and alleviating pain and potential soft tissue damage. While investigations of pressure changes have been conducted, no quantitative study to date has addressed the three-dimensional kinematic and kinetic changes that result from using these shoes. Forty (40) subjects were tested wearing both unmodified and double rocker sole shoes, and the resulting motion patterns were compared to assess change caused by the rocker sole. Overall walking speed remained unchanged throughout testing; slightly increased flexion (<5°) was apparent at the hip, knee, and ankle during early and midstance. These results demonstrate the maintenance of gait function with minimal kinematic changes when using the rocker sole shoe. Investigations of multisegmental foot motion may reveal additional information about the contour effects; analysis of contour variations may also be warranted to investigate the possibility of controlling motion based on rocker sole parameters.
PMCID: PMC2211387  PMID: 17271467
Gait; Rocker sole shoe; Diabetes; Corrective footwear; Double rocker; Pedorthics
16.  Expansion of formalin-evoked Fos-immunoreactivity in rats with a spinal cord injury 
Neuroscience research  2007;58(4):386-393.
Peripheral tissue injury as well as spinal cord injury (SCI) may lead to sensitization of dorsal horn neurons and alterations in nociceptive processing. Thus, peripheral injuries experienced by SCI patients, even if not initially perceived, could result in a persistent and widespread activation of dorsal horn neurons and emerge as chronic pain with interventive repair or modest recovery from SCI. To visualize the spinal neuron response to peripheral tissue injury following complete SCI in rats, the neural transcription factor Fos was quantitated in the spinal cord. Two weeks following either a complete transection of the spinal cord at the level of T8 or a sham surgery (laminectomy), rats were injected with formalin into the left hind paw. Sham-operated rats demonstrated biphasic hind paw pain-related behavior following formalin injection, but transected rats displayed fewer behaviors in the second (tonic) phase. Stereological analysis of the sham group revealed that the extent of formalin-induced Fos expression was within the lumbar dorsal horn, with numerous Fos-like immunoreactive profiles in the ipsilateral dorsal horn and some contralateral immunoreactive profiles. In contrast, the level of Fos-like immunoreactivity in the transected group was significantly elevated and expanded in range compared to the sham group, with increases observed in the normal laminar distribution regions, as well as multisegmentally through sacral levels and increases in the contralateral dorsal horn segments. The data demonstrate that widespread activation of spinal, especially dorsal horn, neurons following peripheral insult can occur in the injured spinal cord, despite reduced pain responsiveness, and suggests that exaggerated pain may emerge as spinal recovery or repair progresses.
PMCID: PMC2211738  PMID: 17531342
central pain; spinal cord injury; dorsal horn; immediate early genes
17.  Analytic IMRT dose calculations utilizing Monte Carlo to predict MLC fluence modulation 
Medical physics  2006;33(4):828-839.
A hybrid dose-computation method is designed which accurately accounts for multileaf collimator (MLC)-induced intensity modulation in intensity modulated radiation therapy (IMRT) dose calculations. The method employs Monte Carlo (MC) modeling to determine the fluence modulation caused by the delivery of dynamic or multisegmental (step-and-shoot) MLC fields, and a conventional dose-computation algorithm to estimate the delivered dose to a phantom or a patient. Thus, it determines the IMRT fluence prediction accuracy achievable by analytic methods in the limit that the analytic method includes all details of the MLC leaf transport and scatter. The hybrid method is validated and benchmarked by comparison with in-phantom film dose measurements, as well as dose calculations from two in-house, and two commercial treatment planning system analytic fluence estimation methods. All computation methods utilize the same dose algorithm to calculate dose to a phantom, varying only in the estimation of the MLC modulation of the incident photon energy fluence. Gamma analysis, with respect to measured two-dimensional (2D) dose planes, is used to benchmark each algorithm’s performance. The analyzed fields include static and dynamic test patterns, as well as fields from ten DMLC IMRT treatment plans (79 fields) and five SMLC treatment plans (29 fields). The test fields (fully closed MLC, picket fence, sliding windows of different size, and leaf-tip profiles) cover the extremes of MLC usage during IMRT, while the patient fields represent realistic clinical conditions. Of the methods tested, the hybrid method most accurately reproduces measurements. For the hybrid method, 79 of 79 DMLC field calculations have γ ≤1 (3% /3 mm) for more than 95% of the points (per field) while for SMLC fields, 27 of 29 pass the same criteria. The analytic energy fluence estimation methods show inferior pass rates, with 76 of 79 DMLC and 24 of 29 SMLC fields having more than 95% of the test points with γ ≤1 (3% /3 mm). Paired one-way ANOVA tests of the gamma analysis results found that the hybrid method better predicts measurements in terms of both the fraction of points with γ ≤1 and the average gamma for both 2% /2 mm and 3% /3 mm criteria. These results quantify the enhancement in accuracy in IMRT dose calculations when MC is used to model the MLC field modulation.
PMCID: PMC2621101  PMID: 16696458
IMRT; MLC; dose computation; Monte Carlo simulation; fluence
18.  Glutamate Receptor Blockade in the Rostral Ventromedial Medulla Reduces the Force of Multisegmental Motor Responses to Supramaximal Noxious Stimuli 
Neuroscience letters  2007;426(3):175-180.
The rostral ventromedial medulla (RVM) has been established as part of a descending pain-modulatory pathway. While the RVM has been shown to modulate homosegmental nociceptive reflexes such as tail flick or hindpaw withdrawal, it is not known what role the RVM plays in modulating the magnitude of multisegmental, organized motor responses elicited by noxious stimuli. Using local blockade of glutamate receptors with the non-specific glutamate receptor antagonist kynurenate (known to selectively block nociceptive facilitatory ON-cells), we tested the hypothesis that the RVM facilitates the magnitude of multi-limb movements elicited by intense noxious stimuli. In male Sprague-Dawley rats, we determined the minimum alveolar concentration (MAC) of isoflurane necessary to block multilimb motor responses to noxious tail clamp. MAC was determined so that all animals were anesthetized at an equipotent isoflurane concentration (0.7 MAC). Supramaximal mechanical stimulation of the hindpaw or electrical stimulation of the tail elicited synchronous, repetitive movements in all four limbs that ceased upon, or shortly after (<5sec) termination of the stimulus. Kynurenate microinjection (2 nmol) into the RVM significantly attenuated, by 40- 60%, the peak and integrated limb forces elicited by noxious mechanical stimulation of the hindpaw (p< 0.001; two-way ANOVA; n= 8) or electrical stimulation of the tail (peak force: p<0.011, two-way ANOVA; n= 8), with significant recovery 40-60 min following injection. The results suggest that glutamatergic excitation of RVM neurons, presumably ON-cells, facilitates organized, multi-limb escape responses to intense noxious stimuli.
PMCID: PMC2675539  PMID: 17904740
nociception, pain; descending modulation; glutamate; motor reflex; rostral ventromedial medulla
19.  Fifty Years of CPGs: Two Neuroethological Papers that Shaped the Course of Neuroscience 
Half a century ago, two independent papers that described unexpected results of experiments on locomotion in insects and crayfish appeared almost simultaneously. Together these papers demonstrated that an animal's central nervous system (CNS) was organized to produce behaviorally important motor output without the need for constant sensory feedback. These results contradicted the established line of thought that was based on interpretations of reflexes and ablation experiments, and established that in these animals the CNS contained neural circuits that could produce complex, periodic, multisegmental patterns of activity. These papers stimulated a flowering of research on central pattern-generating mechanisms that displaced reflex-based thinking everywhere except in medical physiology texts. Here we review these papers and their influence on thinking in the 1960s, 1970s, and today. We follow the development of ideas about central organization and control of expression of motor patterns, the roles of sensory input to central pattern-generating circuits, and integration of continuous sensory signals into a periodic motor system. We also review recent work on limb coordination that provides detailed cellular explanations of observations and speculations contained in those original papers.
PMCID: PMC2917247  PMID: 20700502
motor pattern; central pattern-generation; flight; swimmeret; command neuron
20.  Segment-by-segment stabilization for degenerative disc disease: a hybrid technique 
European Spine Journal  2010;19(6):1010-1020.
Patients with multisegmental degenerative disc disease (DDD) resistant to conservative therapy are typically treated with either fusion or non-fusion surgical techniques. The two techniques can be applied at adjacent levels using Dynesys® (Zimmer GmbH, Winterthur, Switzerland) implants in a segment-by-segment treatment of multiple level DDD. The objective of this study was to evaluate the clinical and radiological outcome of patients treated using this segment-by-segment application of Dynesys in some levels as a non-fusion device and in other segments in combination with a PLIF as a fusion device. A consecutive case series is reported. The sample included 16 females and 15 males with a mean age of 53.6 years (range 26.3–76.4 years). Mean follow-up time was 39 months (range 24–90 months). Preoperative Oswestry disability index (ODI), back- and leg-pain scores (VAS) were compared to postoperative status. Fusion success and system failure were assessed by an independent reviewer who analyzed AP and lateral X-rays. Back pain improved from 7.3 ± 1.7 to 3.4 ± 2.7 (p < 0.000002), leg pain from 6.0 ± 2.9 to 2.3 ± 2.9 (p < 0.00006), and ODI from 51.6 ± 13.2% to 28.7 ± 18.0% (p < 0.00001). Screw loosening occurred in one of a total of 222 implanted screws (0.45%). The results indicate that segment-by-segment treatment with Dynesys® in combination with interbody fusion is technically feasible, safe, and effective for the surgical treatment of multilevel DDD.
PMCID: PMC2899972  PMID: 20130934
Hybrid stabilization; Segment-by-segment treatment; Dynesys; PLIF; Multilevel DDD treatment
21.  Takotsubo Cardiomyopathy Associated with Titration of Duloxetine 
Texas Heart Institute Journal  2011;38(5):573-576.
Takotsubo cardiomyopathy is characterized by transient multisegmental left ventricular dysfunction, dynamic electrocardiographic changes that mimic acute myocardial infarction, and the absence of obstructive coronary disease. Takotsubo cardiomyopathy has been solidly associated with antecedent emotional and physical stressors that trigger catecholamine surges, which lead to coronary vasospasm or direct myocardial injury. Some medications can also cause catecholamine surges, although this phenomenon is not as well described. Duloxetine is a combined serotonin and norepinephrine reuptake inhibitor (SNRI). The basic goal of SNRIs is to increase catecholamine levels in neuronal tissue. However, the increased catecholamine levels may also affect the cardiovascular system.
Herein, we report the case of a 59-year-old woman whose takotsubo cardiomyopathy was temporally associated with the titration of duloxetine. The duloxetine therapy was subsequently discontinued, and the patient's left ventricular function recovered completely 1 month after the index event. The purpose of this report is to alert clinicians to a possible association between SNRI medications and takotsubo cardiomyopathy.
PMCID: PMC3231522  PMID: 22163139
Adrenergic uptake inhibitors/adverse effects; cardiomyopathies/chemically induced; catecholamines/blood; chest pain/etiology; drug therapy/adverse effects; duloxetine; norepinephrine/blood; serotonin uptake inhibitors/adverse effects; takotsubo cardiomyopathy/chemically induced/physiopathology; ventricular dysfunction, left/chemically induced
22.  Vertebral growth modulation by hemicircumferential electrocoagulation: an experimental study in pigs 
European Spine Journal  2011;20(Suppl 3):367-375.
This experimental study in pigs was aimed at evaluating spinal growth disorders after partial arrest of the vertebral epiphyseal plates (EP) and neurocentral cartilages (NCC). Unilateral and multisegmental single or combined lesions of the physeal structures were performed by electrocogulation throughout a video-assisted thoracoscopical approach.
Materials and methods
Thirty 4-week-old domestic pigs (mean weight 16 kg) were included in the experiments. The superior and inferior epiphyseal plates of T5 to T9 vertebra were damaged in ten animals by hemicircumferential electrocoagulation (group I). In other ten pigs (group II), right NCC at the same T5–T9 levels were damaged. Ten other animals underwent combined lesions of the ipsilateral hemiepiphyseal plates and NCC at the T5–T9 levels. A total of 26 animals could be evaluated after 12 weeks of follow-up using conventional X-rays, CT scans and histology.
The pigs with hemicircumferential EP damage developed very slight concave non-structured scoliotic deformities without vertebral rotation.(mean 12° Cobb; range10–16°). Some of the damaged vertebra showed a marked wedgening with unilateral development alteration of the vertebral body, including the adjacent discs The animals with damage of the NCC developed mild scoliotic curves (mean 19° Cobb; range 16–24°) with convexity opposite to the damaged side and loss of physiological kyphosis. The injured segments showed an asymmetric growth with hypoplasia of the pedicle and costovertebral joints at the damaged side. The pigs undergoing combined EP and NCC lesions developed minimal non-structured curves, ranging from 10 to 12° Cobb. In these animals there was a lack of growth of a vertebral hemibody and disc hypoplasia at the damaged segments. Both damage of the NCC and the EP affect the height of the vertebral body. No spinal stenosis was found in any case. In most cases, the adjacent superior and inferior vertebral EP to damaged segments had a compensatory growth that maintained the straight spinal shape.
In summary, unilateral direct lesion of the EP by hemicircumferential thoracoscopic electrocoagulation modifies vertebral growth, but is not able to induce true scoliostic curves in pigs. Only animals with damaged NCC developed mild scoliotic curves of lordotic type. This work rediscovers and emphasizes the decisive role of the neurocentral cartilage in the ethiopatogeny of idiopathic scoliosis.
PMCID: PMC3175833  PMID: 21779856
Experimental scoliosis; Epiphyseal vertebral plate; Neurocentral cartilage; Spinal growth
23.  Titanium mesh cages (TMC) in spine surgery 
European Spine Journal  2004;14(3):211-221.
The introduction of the titanium mesh cage (TMC) in spinal surgery has opened up a variety of applications that are realizable as a result of the versatility of the implant. Differing applications of TMCs in the whole spine are described in a series of 150 patients. Replacement and reinforcement of the anterior column represent the classic use of cylindrical TMCs. The TMC as a multisegmental concave support in kyphotic deformities and as a posterior interlaminar spacer or lamina replacement after wide laminectomy are additional applications. Implant subsidence, pseudarthrosis and implant loosening are the complications typically encountered with use of TMCs. The versatility of the implant permits its use in unusual surgical situations.
PMCID: PMC3476740  PMID: 15340827
Titanium mesh cages; Spinal surgery; Anterior column support; Kyphotic deformity; Lamina replacement
24.  Characteristics of sensory DRG neurons innervating the lumbar facet joints in rats 
European Spine Journal  2005;14(6):559-564.
The rat L5/6 facet joint, from which low-back pain can originate, is multisegmentally innervated from the L1 to L5 dorsal root ganglions (DRGs). Sensory fibers from the L1 and L2 DRGs are reported to non-segmentally innervate the paravertebral sympathetic trunks, whilst those from the L3 to L5 DRGs segmentally innervate the L5/6 facet joint. In the current study, characteristics of sensory DRG neurons innervating the L5/6 facet joint were investigated in rats, using a retrograde neurotransport method, lectin affinity- and immuno-histochemistry. We used four markers: (1) calcitonin gene-related peptide (CGRP) as a marker of small peptide containing neurons, (2) the glycoprotein binding the isolectin from Griffonia simplicifolia (IB4) or (3 the purinergic P2X3 receptor for small, non-peptide containing neurons, and (4) neurofilament 200 (NF200) for small and large myelinated fibers. IB4-binding and CGRP and P2X3 receptor containing neurons are typically involved in pain sensation, whereas NF200 is associated with pain and proprioception. Neurons innervating the L5/6 facet joints, retrogradely-labeled with fluoro-gold (FG), were distributed throughout DRGs from L1 to L5. Of FG-labeled neurons, the ratios of NF200 immunoreactive (IR) neurons and CGRP-IR neurons were 37% and 35% respectively. The ratio of IB4-binding and P2X3 receptor-IR neurons was 10%, significantly less than the ratio of CGRP-IR neurons to FG-labeled neurons. The ratios of IB4-binding and P2X3 receptor-IR neurons were significantly higher, and that of CGRP-IR neurons was significantly less in L1 and L2 DRGs than those in L3, L4 or L5 DRGs. Under physiological conditions in rats, DRG neurons transmit several types of sensations, such as proprioception or nociception of the facet joint. Most neurons transmitting pain are CGRP-IR peptide-containing neurons. They may have a more significant role in pain sensation in the facets via peptidergic DRG neurons.
PMCID: PMC3489236  PMID: 15690212
Sensory innervation; Lumbar facet joint; Calcitonin gene-related peptide; Isolectin B4; Dorsal root ganglion; Low back pain
25.  Lumbar spinal angiolipoma: case report and review of the literature 
European Spine Journal  2005;15(6):1025-1028.
Spinal angiolipomas are extremely rare benign tumors composed of mature lipomatous and angiomatous elements. Most are symptomatic due to progressive spinal cord or root compression. This article describes the case of a 60-year-old woman who presented with a 6-month history of low back pain radiating to her right leg. The pain was multisegmental. The condition had worsened with time. Lumbar magnetic resonance imaging revealed a dorsal epidural mass at L5 and erosion of the lamina of the L5 vertebra. Laminectomy was performed, and an extradural tumor was totally excised. Neuropathologic examination identified it as a lumbar spinal angiolipoma. There was no evidence of recurrence in follow-up 12 months later. This rare clinical entity must be considered in the differential diagnosis for any spinal epidural lesion.
PMCID: PMC3489428  PMID: 16172903
Angiolipoma; Spinal tumor

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