James M. Mok

Bone Morphogenetic Protein (BMP) signaling in development and human diseases.

Bone Morphogenetic Proteins (BMPs) are a group of signaling molecules that belongs to the Transforming Growth Factor-β (TGF-β) superfamily of proteins. Initially discovered for their ability to induce bone formation, BMPs are now known to play crucial roles in all organ systems. BMPs are important in embryogenesis and development, and also in maintenance of adult tissue homeostasis. Mouse knockout models of various components of the BMP signaling pathway result in embryonic lethality or marked defects, highlighting the essential functions of BMPs. In this review, we first outline the basic aspects of BMP signaling and then focus on genetically manipulated mouse knockout models that have helped elucidate the role of BMPs in development. A significant portion of this review is devoted to the prominent human pathologies associated with dysregulated BMP signaling.

The versatile functions of Sox9 in development, stem cells, and human diseases

The transcription factor Sox9 was first discovered in patients with campomelic dysplasia, a haploinsufficiency disorder with skeletal deformities caused by dysregulation of Sox9 expression during chondrogenesis. Since then, its role as a cell fate determiner during embryonic development has been well characterized; Sox9 expression differentiates cells derived from all three germ layers into a large variety of specialized tissues and organs. However, recent data has shown that ectoderm- and endoderm-derived tissues continue to express Sox9 in mature organs and stem cell pools, suggesting its role in cell maintenance and specification during adult life. The versatility of Sox9 may be explained by a combination of post-transcriptional modifications, binding partners, and the tissue type in which it is expressed. Considering its importance during both development and adult life, it follows that dysregulation of Sox9 has been implicated in various congenital and acquired diseases, including fibrosis and cancer. This review provides a summary of the various roles of Sox9 in cell fate specification, stem cell biology, and related human diseases. Ultimately, understanding the mechanisms that regulate Sox9 will be crucial for developing effective therapies to treat disease caused by stem cell dysregulation or even reverse organ damage.

Lumbar Plexus Anatomy within the Psoas Muscle: Implications for the Transpsoas Lateral Approach to the L4-L5 Disc

BACKGROUND The transpsoas lateral surgical approach has been advocated as an alternative to direct anterior approaches for less invasive or minimally invasive access to the spine. Postoperative thigh pain, paresthesia, and/or weakness have been described after the use of this surgical approach. The purpose of this cadaveric anatomic study is to provide a description of the lumbar plexus as it relates to the transpsoas lateral surgical approach. METHODS Dissection of the lumbar plexus was performed in eighteen cadaveric specimens. Needle markers were placed in the L2-L3, L3-L4, and L4-L5 discs in the midcoronal plane. The anatomic structures were surveyed, and the proximity of the needle to the neural structures was observed. RESULTS In thirteen of the eighteen specimens, the femoral nerve received its contributions from the L2 to L4 nerve roots and was formed at the L4-L5 disc space. In all specimens, the femoral nerve passed dorsal to or directly at the midpoint of the disc. In three specimens, the needle displaced or was immediately adjacent to the femoral nerve. The femoral nerve was found between the needle and the posterior aspect of the L4-L5 disc space in thirteen of the eighteen specimens. CONCLUSIONS Because of the proximity of the neural elements, in particular the femoral nerve, to the center of the disc space, the transpsoas lateral surgical approach to the L4-L5 disc space will likely cause intraoperative displacement of neural structures from their anatomic course during retractor dilation. Careful attention should be paid to retractor placement and dilation time during transpsoas lateral access surgery, particularly at the L4-L5 disc.

Effect of vacuum spine board immobilization on incidence of pressure ulcers during evacuation of military casualties from theater.

BACKGROUND CONTEXT In the summer of 2009, the vacuum spine board (VSB) was designated by the US Air Force as the preferred method of external spinal immobilization during aeromedical transport of patients with suspected unstable thoracolumbar spine fractures. One purported advantage of the VSB is that, by distributing weight over a larger surface area, it decreases the risk of skin pressure ulceration. PURPOSE To examine whether the rate of pressure ulcers has changed since the introduction of the VSB. STUDY DESIGN Retrospective cohorts. PATIENT SAMPLE Injured US service members undergoing spinal immobilization during evacuation from the Iraq and Afghanistan theaters to Landstuhl, Germany. OUTCOME MEASURES Presence and stage of pressure ulceration, and deterioration in neurologic status. METHODS Records of the initial 60 patients medically evacuated on the VSB to Landstuhl Regional Medical Center were retrospectively analyzed for patient demographics, injury characteristics, and incidence of pressure injury. The incidence of pressure ulcers after the use of VSB was compared with that in a historical control consisting of 30 patients with unstable spinal injuries evacuated before the introduction of the VSB. No sources of external funding were used for this investigation. RESULTS The combined cohort had a mean age of 28.8 years and mean Injury Severity Score (ISS) of 20.63 and comprised 96% men. Most injury mechanisms were blunt (58%). The rate of neurological injury was 19%. There were no cases of progressive neurological deficit or deformity in either cohort. In the VSB group, using a broad definition of pressure ulcer, incidence was 13 of 60 patients (22%). Using a strict definition, incidence was eight of 60 (13%): five Stage I and three Stage II. In the non-VSB group, incidence of pressure ulcers was three of 30 (10%), using either definition, all Stage II. Difference in incidence between the groups was not statistically significant. Intubated patients had a significantly higher incidence of pressure ulcers. CONCLUSION Both the VSB and historic means (non-VSB) of spinal immobilization appear to be safe and produce only transient morbidity despite an average of 9 to 10 hours of transport. Intubated status was identified as the most important risk factor for the development of a pressure ulcer.

Direct Measurement of Tissue Oxygenation as a Method of Diagnosis of Acute Compartment Syndrome.

Objective: The aim of this study was to investigate the utility of direct measurement of tissue oxygenation during compartment syndrome (CS) and tourniquet-induced ischemia in a large animal model. We hypothesize that as compartment pressure (CP) rises, circulation within the compartment will decrease resulting in a decreased level of oxygen in the muscle. Methods: This study used a dog model of both CS- and tourniquet-based ischemia. In 15 animals, CS was induced in 1 hind limb with varying degrees of severity using an infusion model. Tourniquet ischemia was induced in the contralateral hind limb for varying durations. The partial pressure of oxygen (PmO2) was continuously monitored using a polarographic oxygen probe in the muscle of both hind limbs. CP was monitored in the CS limb. PmO2 and CP were analyzed after fasciotomy, performed after approximately 7 hours of warm ischemia, or release of tourniquet. Results: With the application of tourniquet ischemia, PmO2 fell from 38.40 to 1.30 mm Hg (P < 0.001) and subsequently rose after release of the tourniquet to 39.81 mm Hg (P < 0.001). Elevated CP induced by infusion was relieved by fasciotomy (52.04–11.37 mm Hg postfasciotomy, P < 0.001). PmO2 readings in the infusion model were significantly higher in pre-CS than during CS (31.77 mm Hg vs. 3.88 mm Hg, P < 0.001) and rebounded after fasciotomy (50.24 mm Hg, P < 0.001), consistent with hyperemic response. Conclusions: Increased CP caused an observable decrease in PmO2 that was reversed by fasciotomy. PmO2 can be directly measured in real time with a polarographic tissue pO2 probe. This study is the first step of evaluating an alternative method for diagnosing acute CS.

Evaluation of immediate postoperative complications and outcomes among military personnel treated for spinal trauma in Afghanistan: a cohort-control study of 50 cases.

Study Design: Retrospective case-control study. Objective: The objective of the study was to compare neurological outcomes and complication rates between a series of combat-injured patients treated in Afghanistan (AFG) and those treated at Landstuhl Regional Medical Center (LRMC). Summary of Background Data: At present, no studies have addressed the ideal timing and setting for surgical stabilization in combat-injured soldiers who sustain spinal trauma. Methods: Soldiers who sustained spine injuries while deployed to Afghanistan and who underwent surgery in theater or at LRMC between 2010 and 2011 were identified. Demographic information, injury-specific data, neurological status, type of surgical intervention, postoperative complications, and need for additional surgery were abstracted for all patients. Neurological improvement was the primary dependent variable. Secondary variables included the risk of developing complications and the need for additional surgery. Statistical analysis was performed using t tests, and the Fisher exact test was used for categorical variables. Results: Between 2010 and 2011, 30 individuals were treated in AFG, and 20 received surgery at LRMC. Neurological improvement occurred in 10% of AFG patients and 5% of those treated at LRMC. Complications occurred in 40% of AFG patients and in 20% of the LRMC group. Twenty-three percent of AFG patients required additional spine surgery after leaving Afghanistan. There was no statistical difference in neurological improvement between the AFG and LRMC groups (P=0.64). Soldiers who received surgery in AFG were at significantly increased risk of requiring additional procedures (P=0.03). Conclusions: Soldiers treated in theater did not have statistically higher rates of neurological improvement as compared with those treated at LRMC. Patients treated in-theater were at elevated risk for the need for additional surgery. This study is among the first to evaluate clinical outcomes after surgical intervention for war-related spinal trauma. Level of Evidence: Level III (case-control).

Is the lateral jack-knife position responsible for cases of transient neurapraxia?

OBJECTIVE The lateral jack-knife position is often used during transpsoas surgery to improve access to the spine. Postoperative neurological signs and symptoms are very common after such procedures, and the mechanism is not adequately understood. The objective of this study is to assess if the lateral jack-knife position alone can cause neurapraxia. This study compares neurological status at baseline and after positioning in the 25° right lateral jack-knife (RLJK) and the right lateral decubitus (RLD) position. METHODS Fifty healthy volunteers, ages 21 to 35, were randomly assigned to one of 2 groups: Group A (RLD) and Group B (RLJK). Motor and sensory testing was performed prior to positioning. Subjects were placed in the RLD or RLJK position, according to group assignment, for 60 minutes. Motor testing was performed immediately after this 60-minute period and again 60 minutes thereafter. Sensory testing was performed immediately after the 60-minute period and every 15 minutes thereafter, for a total of 5 times. Motor testing was performed by a physical therapist who was blinded to group assignment. A follow-up call was made 7 days after the positioning sessions. RESULTS Motor deficits were observed in the nondependent lower limb in 100% of the subjects in Group B, and no motor deficits were seen in Group A. Statistically significant differences (p < 0.05) were found between the 2 groups with respect to the performance on the 10-repetition maximum test immediately immediately and 60 minutes after positioning. Subjects in Group B had a 10%-70% (average 34.8%) decrease in knee extension strength and 20%-80% (average 43%) decrease in hip flexion strength in the nondependent limb. Sensory abnormalities were observed in the nondependent lower limb in 98% of the subjects in Group B. Thirty-six percent of the Group B subjects still exhibited sensory deficits after the 60-minute recovery period. No symptoms were reported by any subject during the follow-up calls 7 days after positioning. CONCLUSIONS Twenty-five degrees of right lateral jack-knife positioning for 60 minutes results in neurapraxia of the nondependent lower extremity. Our results support the hypothesis that jack-knife positioning alone can cause postoperative neurological symptoms.

Diagnosis of Acute Compartment Syndrome: Direct Measurement of Tissue Oxygenation

We present a technique and feasibility study of continuous measurement of intramuscular tissue oxygenation as a potential novel approach to the diagnosis of acute extremity compartment syndrome. Polarographic probes were inserted percutaneously into the anterior compartment of the leg to measure the partial pressure of oxygen (PmO2). Five patients underwent open reduction internal fixation of ankle fracture under a thigh tourniquet. With application of the tourniquet, the mean PmO2 decreased rapidly from 26.62 to 0.52 mm Hg (range, 0.1 to 1.4 mm Hg). Eleven patients underwent monitoring of tissue oxygenation after intramedullary nailing for an isolated closed tibia fracture. No compartment syndrome occurred. In the absence of compartment syndrome, 1.35% of PmO2 measurements spanning 424 hours fulfilled the predefined warning criterion of PmO2<10 mm Hg. Our data establish the feasibility of measuring tissue oxygenation and its responsiveness to ischemia. In contrast to compartment pressure, PmO2 measurements after tibia fracture rarely fulfilled the warning criterion in the absence of compartment syndrome. A floor PmO2 value of nearly zero was established in live ischemic muscle. Tissue oxygenation may represent a minimally invasive, physiologic, and specific method for diagnosing compartment syndrome.

Impact of a Bundled Payment System on Resource Utilization During Spine Surgery.

Background In a bundled payment system, a single payment covers all costs associated with a single episode of care. Spine surgery may be well suited for bundled payments because of clearly defined episodes of care, but the impact on current practice has not been studied. We sought to examine how a theoretical bundled payment strategy with financial disincentives to resource utilization would impact practice patterns. Methods A multiple-choice survey was administered to spine surgeons describing eight clinical scenarios. Respondents were asked about their current practice, and then their practice in a hypothetical bundled payment system. Respondents could choose from multiple types of implants, bone grafts, and other resources utilized at the surgeons discretion. Results Forty-three respondents completed the survey. Within each scenario, 24%-49% of respondents changed at least one aspect of management. The proportion of cases performed without implants was unchanged for four scenarios and increased in four by an average of 8%. Use of autologous iliac crest bone graft increased across all scenarios by an average of 18%. Use of neuromonitoring decreased in all scenarios by an average of 21%. Differences in costs were not statistically significant. Conclusions Financial disincentives to resource utilization may result in some changes to surgeons’ practices but these appear limited to items with less clear benefits to patients. Choices of implants, which account for the majority of intra-operative costs, did not change meaningfully. A bundling strategy targeting peri-operative costs solely related to surgical practice may not yield substantive savings while rationing potentially beneficial treatments to patient care. Level of Evidence: 5.

Comparison of tissue oxygenation and compartment pressure following tibia fracture

OBJECTIVE We investigated the ability of direct continuous measurement of intramuscular tissue oxygenation (PmO(2)) to detect acute ischaemia in the leg in patients at risk for acute extremity compartment syndrome. Following tibia fracture treated by intramedullary nailing, we compared the proportions of PmO(2) and compartment pressure (CP) measurements that met the warning criteria for compartment syndrome. METHODS Participants included 10 patients sustaining acute isolated closed tibia shaft fractures treated by intramedullary nailing. A tissue oxygenation probe and a CP probe were percutaneously placed into the anterior compartment of the leg. PmO(2) and CP in the anterior compartment were measured in the injured leg for 48 h postoperatively. Measurements meeting the warning criteria were defined as PmO(2) < 10 mmHg, CP > 30 mmHg and perfusion pressure ΔP < 30 mmHg. RESULTS None of the patients developed compartment syndrome. Comparison of CP and PmO(2) showed a CP > 30 mmHg in 50.39% of CP measurements in all patients and a PmO(2) < 10 mmHg in 0.75% of PmO(2) measurements in two patients (P = 0.005). Comparison of ΔP and PmO(2) showed a ΔP < 30 mmHg in 31.01% of ΔP measurements in nine patients and a PmO(2) < 10 mmHg in 0.76% of PmO(2) measurements in one patient (P = 0.01). CONCLUSION In the absence of compartment syndrome, pressure measurements following tibia fracture treated with intramedullary nailing often met the warning criteria, whereas PmO(2) did not, suggesting that measurement of intramuscular tissue oxygenation may represent a potential method for the identification of acute compartment syndrome that deserves continued investigation.