The Safety and Efficacy of Stand-Alone Lateral Lumbar Interbody Fusion for Adjacent Segment Disease in a Cohort of 44 Patients.

BACKGROUND: A mainstay of treatment for symptomatic adjacent segment disease (ASD) has consisted of revision with posterior decompression and fusion. This carries significant morbidity and can be technically difficult. An alternative is stand-alone lateral lumbar interbody fusion (LLIF), which may avoid complications associated with revision surgery. We describe the largest cohort of patients treated with LLIF for ASD to our knowledge. METHODS: We conducted a retrospective cohort study on all patients who underwent transpsoas LLIF for ASD at a single academic center between 2012 and 2019. Postoperative improvement was measured using the Visual Analog Scale (VAS) and the Oswestry Disability Index (ODI). RESULTS: Forty-four patients who underwent LLIF for ASD were identified. Median age was 65 years. Median time from index surgery to ASD development was 78 months. Median levels fused via LLIF was 1. Our median follow-up was 358 days. At follow-up, the median VAS back pain score was 0 (mean, 0.884), median VAS leg pain score was 1 (mean, 0.953), and median ODI was 8. The median improvement for VAS back pain was 8, for VAS leg pain was 6, and for ODI was 40. No patients suffered new neurologic symptoms postoperatively. Of the 17 patients who initially presented with non-pain neurologic symptoms, 8 (47.1%) experienced complete resolution of symptoms, and 5 (29.4%) experienced only some improvement. CONCLUSIONS: To our knowledge, this is the largest cohort study of patients to date evaluating stand-alone LLIF for ASD. Our patient outcomes show it is safe and effective with low risk of morbidity.

Moisture affinity of HDPE/phase-change material composites for thermal energy storage applications.

Moisture adsoprtion can degrade the structural integrity of thermal energy storage devices and can negatively impact the capacity and charging/discharging behaviour. Steady-state and transient experiments are conducted at various operating temperatures to evaluate the moisture affinity of organic phase-change material (PCM) shape stabilized with high-density polyethylene (HDPE).

Simultaneous Sacroiliac Joint Fusion in Patients with Long Lumbosacral Constructs: Case Report and Operative Technique.

BACKGROUND: Literature data on the frequency and pathogenesis of sacroiliac joint (SIJ) pain and arthropathy following lumbosacral fusion with long constructs combined with sacroiliac fixation remains scarce. From clinical experience, we noticed that many patients undergoing these surgeries develop SIJ disease postoperatively. CASE DESCRIPTION: We report a clinical observation of no occurrence or remission of SIJ pain following simultaneous SIJ fusion in cases of long-construct lumbosacral fusion and sacropelvic fixation with S2-alar-iliac screws. An illustrative case and description of the simultaneous SIJ fusion technique are discussed as well. CONCLUSIONS: Based on our experience, we believe that fusing the SIJ simultaneously during sacropelvic fixation in the context of a long lumbosacral fusion surgery may lead to a decline in the incidence of SIJ disease, as well as remission of SIJ pain in patients requiring revision surgeries. Future, multicenter prospective studies are needed to test and validate this observation.

Influence of Lumbar Stenosis Surgery on Sacroiliac Joint Pain-Long-Term Results.

OBJECTIVE: To investigate whether sacroiliac join (SIJ) pain can be secondary to walking with a flexed posture resulting from stenosis with neurogenic claudication, and resolves spontaneously after lumbar decompression. METHODS: A review of charts from January 1, 2014, through March 3, 2019, was performed to identify consecutive cases of adults 35 years of age or older with surgical spinal stenosis with neurogenic claudication as well as concomitant severe SIJ pain. Posture was considered flexed during walking if self-reported, confirmed by a close companion, or observed directly. SIJ pain was diagnosed clinically ± confirmatory injection. A 10-point visual analog scale was used to assess SIJ pain. The primary endpoint was SIJ pain improvement at a minimum of 24 months' follow-up. SIJ pain improvement at 3 months was used to assess the rate of improvement as a secondary endpoint. RESULTS: Ten patients (3 female) met entry criteria: 4 were treated with decompression alone; 6 with decompression and spinal fusion. Mean SIJ visual analog scale pain score improved by 6.9 ± 2.4 (8.7 ± 1.6-1.8 ± 2.2; P < 0.0005). Results were similar for 20 patients at the secondary endpoint of 3 months. CONCLUSIONS: Sacroiliac joint pain shows robust, rapid, reliable, and durable improvement following lumbar decompressive surgery. The addition of a spinal fusion also leads to a similar improvement in SIJ pain. This study demonstrates the importance of evaluating the specific source of low back pain in patients with stenosis, claudication, and SIJ pain so as to more effectively plan appropriate surgery.

Presence of tau pathology within foetal neural allografts in patients with Huntington's and Parkinson's disease.

Cell replacement has been explored as a therapeutic strategy to repair the brain in patients with Huntington's and Parkinson's disease. Post-mortem evaluations of healthy grafted tissue in such cases have revealed the development of Huntington- or Parkinson-like pathology including mutant huntingtin aggregates and Lewy bodies. An outstanding question remains if tau pathology can also be seen in patients with Huntington's and Parkinson's disease who had received foetal neural allografts. This was addressed by immunohistochemical/immunofluorescent stainings performed on grafted tissue of two Huntington's disease patients, who came to autopsy 9 and 12 years post-transplantation, and two patients with Parkinson's disease who came to autopsy 18 months and 16 years post-transplantation. We show that grafts also contain tau pathology in both types of transplanted patients. In two patients with Huntington's disease, the grafted tissue showed the presence of hyperphosphorylated tau [both AT8 (phospho-tau Ser202 and Thr205) and CP13 (pSer202) immunohistochemical stainings] pathological inclusions, neurofibrillary tangles and neuropil threads. In patients with Parkinson's disease, the grafted tissue was characterized by hyperphosphorylated tau (AT8; immunofluorescent staining) pathological inclusions, neurofibrillary tangles and neuropil threads but only in the patient who came to autopsy 16 years post-transplantation. Abundant tau-related pathology was observed in the cortex and striatum of all cases studied. While the striatum of the grafted Huntington's disease patient revealed an equal amount of 3-repeat and 4-repeat isoforms of tau, the grafted tissue showed elevated 4-repeat isoforms by western blot. This suggests that transplants may have acquired tau pathology from the host brain, although another possibility is that this was due to acceleration of ageing. This finding not only adds to the recent reports that tau pathology is a feature of these neurodegenerative diseases, but also that tau pathology can manifest in healthy neural tissue transplanted into the brains of patients with two distinct neurodegenerative disorders.

Robust graft survival and normalized dopaminergic innervation do not obligate recovery in a Parkinson disease patient.

OBJECTIVE: The main goal of dopamine cell replacement therapy in Parkinson disease (PD) is to provide clinical benefit mediated by graft survival with nigrostriatal reinnervation. We report a dichotomy between graft structure and clinical function in a patient dying 16 years following fetal nigral grafting. METHODS: A 55-year-old levodopa-responsive woman with PD received bilateral putaminal fetal mesencephalic grafts as part of an NIH-sponsored double-blind sham-controlled trial. The patient never experienced clinical benefit, and her course was complicated by the development of graft-related dyskinesias. Fluorodopa positron emission tomography demonstrated significant increases postgrafting bilaterally. She experienced worsening of parkinsonism with severe dyskinesias, and underwent subthalamic nucleus deep brain stimulation 8 years after grafting. She died 16 years after transplantation. RESULTS: Postmortem analyses confirmed the diagnosis of PD and demonstrated >300,000 tyrosine hydroxylase (TH)-positive grafted cells per side with normalized striatal TH-immunoreactive fiber innervation and bidirectional synaptic connectivity. Twenty-seven percent and 17% of grafted neurons were serine 129-phosphorylated α-synuclein positive in the left and right putamen, respectively. INTERPRETATION: These findings represent the largest number of surviving dopamine neurons and the densest and most widespread graft-mediated striatal dopamine reinnervation following a transplant procedure reported to date. Despite this, clinical recovery was not observed. Furthermore, the grafts were associated with a form of dyskinesias that resembled diphasic dyskinesia and persisted in the off-medication state. We hypothesize that the grafted cells produced a low level of dopamine sufficient to cause a levodopa-independent continuous form of diphasic dyskinesias, but insufficient to provide an antiparkinsonian benefit. ANN NEUROL 2017;81:46-57.

Bone marrow-derived stem cell therapy for metastatic brain cancers.

We propose that stem cell therapy may be a potent treatment for metastatic melanoma in the brain. Here we discuss the key role of a leaky blood-brain barrier (BBB) that accompanies the development of brain metastases. We review the need to characterize the immunological and inflammatory responses associated with tumor-derived BBB damage in order to reveal the contribution of this brain pathological alteration to the formation and growth of brain metastatic cancers. Next, we discuss the potential repair of the BBB and attenuation of brain metastasis through transplantation of bone marrow-derived mesenchymal stem cells with the endothelial progenitor cell phenotype. In particular, we review the need for evaluation of the efficacy of stem cell therapy in repairing a disrupted BBB in an effort to reduce neuroinflammation, eventually attenuating brain metastatic cancers. The demonstration of BBB repair through augmented angiogenesis and vasculogenesis will be critical to establishing the potential of stem cell therapy for the treatment/prevention of metastatic brain tumors. The overarching hypothesis we advanced here is that BBB breakdown is closely associated with brain metastatic cancers of melanoma, exacerbating the inflammatory response of the brain during metastasis, and ultimately worsening the outcome of metastatic brain cancers. Abrogating this leaky BBB-mediated inflammation via stem cell therapy represents a paradigm-shifting approach to treating brain cancer. This review article discusses the pros and cons of cell therapy for melanoma brain metastases.

Mutant huntingtin is present in neuronal grafts in Huntington disease patients.

OBJECTIVE: Huntington disease (HD) is caused by a genetically encoded pathological protein (mutant huntingtin [mHtt]), which is thought to exert its effects in a cell-autonomous manner. Here, we tested the hypothesis that mHtt is capable of spreading within cerebral tissue by examining genetically unrelated fetal neural allografts within the brains of patients with advancing HD. METHODS: The presence of mHtt aggregates within the grafted tissue was confirmed using 3 different types of microscopy (bright-field, fluorescence, and electron), 2 additional techniques consisting of Western immunoblotting and infrared spectroscopy, and 4 distinct antibodies targeting different epitopes of mHtt aggregates. RESULTS: We describe the presence of mHtt aggregates within intracerebral allografts of striatal tissue in 3 HD patients who received their transplants approximately 1 decade earlier and then died secondary to the progression of their disease. The mHtt(+) aggregates were observed in the extracellular matrix of the transplanted tissue, whereas in the host brain they were seen in neurons, neuropil, extracellular matrix, and blood vessels. INTERPRETATION: This is the first demonstration of the presence of mHtt in genetically normal and unrelated allografted neural tissue transplanted into the brain of affected HD patients. These observations raise questions on protein spread in monogenic neurodegenerative disorders of the central nervous system characterized by the formation of mutant protein oligomers/aggregates.

Striatal allografts in patients with Huntington's disease: impact of diminished astrocytes and vascularization on graft viability.

Neuronal transplantation has been proposed as a potential therapy to replace lost neurons in Huntington's disease. Transplant vascularization and trophic support are important for graft survival. However, very few studies have specifically addressed graft vascularization in patients with neurological disorders. In the present study, we analysed the vasculature of the host putamen and solid grafts of foetal striatal tissue transplanted into patients with Huntington's disease 9 and 12 years previously. Grafts were characterized by a significantly reduced number of large calibre blood vessels in comparison with the host brain. There were also significantly fewer astrocytes and gap junctions, suggesting a lack of functional blood-brain barrier components within the grafted tissue. Additionally, grafts demonstrated a nearly complete absence of pericytes (compared with the striatum) that are considered important for vascular stabilization and angiogenesis. Finally, the host striatum had a marked increase in atrophic astrocytes in comparison with controls and grafts. The extent to which the lower number of large calibre vessels and astrocytes within the transplants contributed to suboptimal graft survival is unknown. The marked increase in atrophic astrocytes in the host brain surrounding the grafts suggests that reduced host trophic support may also contribute to poor graft survival in Huntington's disease. A better understanding of the way in which these components support allografted tissue is critical to the future development of cell-based therapies for the treatment of Huntington's disease.

Sham neurosurgical procedures in clinical trials for neurodegenerative diseases: scientific and ethical considerations.

There have been several recent scientific advances in gene-based and cell-based therapies that might translate into novel therapeutic approaches for neurodegenerative disorders. Such therapies might need to be directly delivered into the CNS, and complex scientific and ethical assessment will be needed to determine whether a sham neurosurgical arm should be included in clinical trials assessing these agents. We have developed a framework of points for investigators to consider when designing trials that involve direct delivery of a therapeutic agent to the CNS. The inclusion of a sham neurosurgical arm will be guided in part by the objectives of the clinical study (preliminary safety, optimisation, and feasibility vs preliminary efficacy vs confirmatory efficacy) and the need to minimise bias and confounds. Throughout the clinical development process, the perspectives of researchers, ethicists, and patients must be considered, and risks should be minimised whenever possible in a manner that is consistent with good trial design.

The great migration of bone marrow-derived stem cells toward the ischemic brain: therapeutic implications for stroke and other neurological disorders.

Accumulating laboratory studies have implicated the mobilization of bone marrow (BM)-derived stem cells in brain plasticity and stroke therapy. This mobilization of bone cells to the brain is an essential concept in regenerative medicine. Over the past ten years, mounting data have shown the ability of bone marrow-derived stem cells to mobilize from BM to the peripheral blood (PB) and eventually enter the injured brain. This homing action is exemplified in BM stem cell mobilization following ischemic brain injury. Various BM-derived cells, such as hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs) and very small embryonic-like cells (VSELs) have been demonstrated to exert therapeutic benefits in stroke. Here, we discuss the current status of these BM-derived stem cells in stroke therapy, with emphasis on possible cellular and molecular mechanisms of action that mediate the cells' beneficial effects in the ischemic brain. When possible, we also discuss the relevance of this therapeutic regimen in other central nervous system (CNS) disorders.

Neuronal degeneration in striatal transplants and Huntington's disease: potential mechanisms and clinical implications.

Cell therapy offers the possibility of replacing degenerated neurons thereby improving the symptoms of neurodegenerative disorders such as Huntington's disease. However, clinical benefits in patients with Huntington's disease, if any, have been transient and modest. Grafts survived well at 18 months in one patient with Huntington's disease, but graft survival was markedly attenuated by 10 years in three other patients from this transplantation cohort. It is critical to delineate the causes of graft degeneration if such therapies will be utilized in patients with a goal of achieving meaningful clinical benefit. Similar challenges may also accrue to future stem cell therapies. Here we discuss the potential causes of suboptimal long-term graft survival in patients with Huntington's disease, including allograft immunoreactivity, microglial responses targeted to grafted cells and cell-to-cell neurotoxicity. We also discuss similar challenges and unique differences comparing neuronal grafts in patients with Parkinson's and Huntington's diseases.

Technique to minimize paraspinal muscle atrophy after posterior cervical fusion.

OBJECTIVE: Paraspinal muscle atrophy (PMA) after posterior cervical fusion is a known complication that causes considerable morbidity. It has been shown in the lumbar spine that preservation of the posterior ramus of the spinal nerve is important in minimizing paraspinal muscle atrophy. During posterior cervical spine fusions, we modified the exposure of the dorsal cervical spine by exposing only the medial two-thirds of the lateral mass utilizing a low electrocautery setting. In a retrospective analysis, we compared the incidence of paraspinal muscle atrophy using this modified technique with historical cohorts who underwent posterior cervical fusion using the standard technique of exposure of the entire lateral mass. MATERIALS AND METHODS: All patients who underwent posterior cervical fusion and internal fixation between 1999 and 2007 were included. Patients operated from 1999 to 2003 who underwent the standard exposure of the lateral mass formed Group 1 (n=31). Group 2 (n=32) included patients whose lateral masses were exposed using the modified technique of limiting the exposure only to the medial two-thirds of the lateral mass with the cautery on a low setting. All patients were assessed for PMA at six months after surgery. Atrophy was graded as no atrophy, mild atrophy (minimal midline atrophy), moderate atrophy (muscle lost without palpable hardware) and severe atrophy (hardware palpable). Before initiating the study, no atrophy and mild atrophy were grouped together as a non-significant atrophy and moderate atrophy and severe atrophy were grouped together as significant atrophy. RESULTS: We found a statistically lower incidence of paraspinal atrophy using this modified exposure of the lateral mass (p<0.03). CONCLUSIONS: This modified technique of cervical spine exposure is associated with lower paraspinal muscle atrophy secondary to the preservation of the innervation of the paraspinal musculature.

Postnatal PPARdelta activation and myostatin inhibition exert distinct yet complimentary effects on the metabolic profile of obese insulin-resistant mice.

BACKGROUND: Interventions for T2DM have in part aimed to mimic exercise. Here, we have compared the independent and combined effects of a PPARdelta agonist and endurance training mimetic (GW501516) and a myostatin antibody and resistance training mimetic (PF-879) on metabolic and performance outcomes in obese insulin resistant mice. METHODOLOGY/PRINCIPAL FINDINGS: Male ob/ob mice were treated for 6 weeks with vehicle, GW501516, PF-879, or GW501516 in combination with PF-879. The effects of the interventions on body composition, glucose homeostasis, glucose tolerance, energy expenditure, exercise capacity and metabolic gene expression were compared at the end of study. GW501516 attenuated body weight and fat mass accumulation and increased the expression of genes of oxidative metabolism. In contrast, PF-879 increased body weight by driving muscle growth and altered the expression of genes involved in insulin signaling and glucose metabolism. Despite their differences, both interventions alone improved glucose homeostasis. Moreover, GW501516 more effectively improved serum lipids, and PF-879 uniquely increased energy expenditure, exercise capacity and adiponectin levels. When combined the robust effects of GW501516 and/or PF-879 on body weight, adiposity, muscle mass, glycemia, serum lipids, energy expenditure and exercise capacity were highly conserved. CONCLUSIONS/SIGNIFICANCE: The data, for the first time, demonstrate postnatal inhibition of myostatin not only promotes gains in muscle mass similar to resistance training,but improves metabolic homeostasis. In several instances, these effects were either distinct from or complimentary to those of GW501516. The data further suggest that strategies to increase muscle mass, and not necessarily oxidative capacity, may effectively counter insulin resistance and T2DM.

Otolaryngologic management of delayed pharyngoesophageal perforation following anterior cervical spine surgery.

Delayed pharyngoesophageal perforation is a rare complication following anterior cervical spine surgery. Patients usually present weeks to years after surgery with vague symptoms, such as dysphagia and neck pain. We report five cases of delayed pharyngoesophageal perforation following anterior cervical spine surgery with hardware fixation. Successful surgical management of these patients required removal of hardware and closure of the defect supported with a vascularized flap.

Transplanted dopaminergic neurons develop PD pathologic changes: a second case report.

This report describes pathological changes within the grafted neurons of another patient with Parkinson's disease (PD) who died 14 years posttransplantation. Although numerous healthy appearing grafted neurons were present at this long-term time point, some displayed Lewy bodies as evidenced by alpha-synuclein, ubiquitin, and thioflavin-S staining. Additionally, there was a general loss of dopamine transporter-immunoreactivity in grafted neurons. Some grafted cell displayed a loss of tyrosine hydroxylase. These data support the emerging concept that PD-like pathology is seen in young grafted neurons when they survive long term.

Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease.

Fourteen years after transplantation into the striatum of an individual with Parkinson's disease, grafted nigral neurons were found to have Lewy body-like inclusions that stained positively for alpha-synuclein and ubiquitin and to have reduced immunostaining for dopamine transporter. These pathological changes suggest that Parkinson's disease is an ongoing process that can affect grafted cells in the striatum in a manner similar to host dopamine neurons in the substantia nigra. These findings have implications for cell-based therapies and for understanding the cause of Parkinson's disease.

Torsion-induced pressure distribution changes in human intervertebral discs: an in vitro study.

STUDY DESIGN: Biomechanical testing of human cadaveric lumbar specimens was performed to evaluate the effects of torsional torque on intradiscal pressure and disc height. OBJECTIVE: Evaluate the effects of small torsion torques on intradiscal pressure and disc height in human lumbar specimens. SUMMARY OF BACKGROUND DATA: Nuclear depressurization in addition to an instantaneous disc height increase were found in previous porcine research when small (<2 degrees) axial vertebral rotations were applied. If applicable to human spines, this phenomenon may support spinal manipulation for the relief of low back pain. METHODS: Six human lumbar cadaveric functional spine units (FSU) were loaded in the neutral position with 600 N axial compression. Intranuclear pressure measurements were then obtained at 0, 0.5, 1.0, and 2.0 Nm of torsion. Posterior elements were removed and measurements were repeated for the disc body unit (DBU). RESULTS: There was no statistically significant difference in nuclear pressure or intervertebral disc height with different torsion torques among or between the FSUs and DBUs. However, a disc height increase ranging from 0.13 mm to 0.16 mm occurred with the insertion of a 1.85-mm diameter pressure probe cannula. CONCLUSIONS: Small torsion torques showed no significant difference in intradiscal pressures or disc heights. This is an unlikely mechanism for the perceived benefits of spinal manipulation.

Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules.

Cholesteryl ester transfer protein (CETP) shuttles various lipids between lipoproteins, resulting in the net transfer of cholesteryl esters from atheroprotective, high-density lipoproteins (HDL) to atherogenic, lower-density species. Inhibition of CETP raises HDL cholesterol and may potentially be used to treat cardiovascular disease. Here we describe the structure of CETP at 2.2-A resolution, revealing a 60-A-long tunnel filled with two hydrophobic cholesteryl esters and plugged by an amphiphilic phosphatidylcholine at each end. The two tunnel openings are large enough to allow lipid access, which is aided by a flexible helix and possibly also by a mobile flap. The curvature of the concave surface of CETP matches the radius of curvature of HDL particles, and potential conformational changes may occur to accommodate larger lipoprotein particles. Point mutations blocking the middle of the tunnel abolish lipid-transfer activities, suggesting that neutral lipids pass through this continuous tunnel.