Target Engagement of a Phosphodiesterase 2A Inhibitor Affecting Long-Term Memory in the Rat.

Inhibition of phosphodiesterase 2A (PDE2A) has been proposed as a potential approach to enhance cognitive functioning and memory through boosting intracellular cGMP/cAMP and enhancing neuroplasticity in memory-related neural circuitry. Previous preclinical studies demonstrated that PDE2A inhibitors could reverse N-methyl-D-aspartate receptor antagonist (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine or ketamine-induced memory deficit. Here, we report that the potent and selective PDE2A inhibitor 4-(1-azetidinyl)-7-methyl-5-[1-methyl-5-[5-(trifluoromethyl)-2-pyridinyl]-1H-pyrazol-4-yl]-imidazo[5,1-f][1,2,4]triazine (PF-05180999) enhances long-term memory in a contextual fear conditioning model in the rat at the oral dose of 0.3 mg/kg. Target engagement at this efficacious dose was explored using in vivo autoradiography. Converse to the results of a decrease of PDE2A binding (target occupancy) by the PDE2A inhibitor, a paradoxical increase (up to 40%) in PDE2A binding was detected. However, a typical target occupancy curve could be generated by PF-05180999 at much higher doses. In vitro experiments using recombinant PDE2A protein or rat brain homogenate that contains native PDE2A protein demonstrated that increased cGMP after initial PDE2A inhibition could be responsible for the activation of PDE2A enzyme via allosteric binding to the GAF-B domain, leading to positive cooperativity of the dormant PDE2A enzymes. Our results suggest that when evaluating target engagement of PDE2A inhibitors for memory disorder in clinical setting with occupancy assays, the efficacious dose may not fall on the typical receptor/target curve. On the contrary, an increase in PDE2A tracer binding is likely seen. Our results also suggest that when evaluating target occupancy of enzymes, potential regulation of enzyme activities should be considered.

A Retrieval Analysis of Impingement in Dual-Mobility Liners.

BACKGROUND: Implant-related impingement is likely a major causative factor of total hip arthroplasty (THA) instability. Dual-mobility (DM) cups can theoretically improve stability in THA, but impingement rates with DM cups are not well studied. We examined retrieved DM THA liners to determine if less evidence existed for prosthetic impingement between the neck and the polyethylene liner than historical studies from our institution on fixed-bearing THAs. METHODS: DM components from 93 THAs were identified from 164 THAs whose DM components were revised between 2008 and 2015 through our institutional review board-approved implant retrieval program. The mean age was 63 ± 11 years, mean body mass index was 30 ± 7 kg/m2, and mean length of implantation was 2.08 ± 1.89 years. Two independent graders scored each liner for the presence and severity of impingement. Radiographs were evaluated for inclination, anteversion, change in leg length, and combined offset. RESULTS: Only 21.5% (20/93) of DM cups showed evidence of impingement compared to 77% (75/97) of fixed-bearing cups found in a previous study performed at our institution (P < .001). Of the revision components, 35.2% (5/14) demonstrated evidence of impingement compared to 19.7% (14/71) implanted in primary surgery (P = .189). In the cohort revised for instability, the rate of impingement was 35.3% (6/17); for the implants revised for any other reason, the impingement rate was 18.4% (14/77) (P = .126). CONCLUSION: This study demonstrates that DM liners significantly reduce the rate of impingement (21.5%) when compared to fixed-bearing liners (77%).

Polished, Collarless, Tapered, Cemented Stems for Primary Hip Arthroplasty May Exhibit High Rate of Periprosthetic Fracture at Short-Term Follow-Up.

BACKGROUND: Cemented stems are designed to follow 1 of 2 principles of fixation: composite beams or slide taper. Stems in the latter category have a collarless, polished, tapered (CPT) design and subside into the cement mantle, creating hoop stresses. We compared the rate of periprosthetic fracture (PPF) of stem designed with these 2 principles of fixation. In addition, we examined radiographic factors that may predispose to the development of PPF. METHODS: We retrospectively reviewed all patients who underwent primary THA by a single surgeon using highly polished cemented stems. PPF rates were compared between CPT stems (follow-up, 21 months; standard deviation [SD], 22) and composite beam stems (follow-up, 21.7 months; SD, 26). Demographic data were compared between patients with and without a PPF. Three preoperative radiographic parameters (canal bone ratio [CBR], canal-calcar ratio, and canal flare index), stem alignment, and cement mantle were compared in match-paired patients with and without a PPF (1:34). RESULTS: Seven of 1460 THA patients developed a PPF (0.479%); 4 hips of 185 with a CPT stem (2.2%); and 3 of 1275 hips with a composite beam stem (0.23%; P = .0064). Three of the 4 PPFs in the CPT group and none in the composite beam group were classified as Vancouver B2. The CBR in patients with a PPF was 0.50 (SD, 0.07) and 0.43 (SD, 0.07) in the match cohort of hips without PPF (P = .013). CONCLUSION: CPT stems may be associated with a higher risk of PPF that often require reoperation. An increased CBR may be a risk factor for postoperative PPF.

The evaluation of cervical spine mobility without significant spondylosis by kMRI.

STUDY DESIGN: Retrospective analysis of kinetic magnetic resonance images (kMRI). OBJECTIVE: To analyse the kinematics of cervical spine inpatients without significant spondylosis and to understand the normal movement of the cervical spine as reference for future comparison. SUMMARY OF BACKGROUND DATA: Although some studies have been conducted to describe the normal mobility of the cervical spine, prior studies did not establish a relationship between the kinematics of cervical spine and disc degeneration. Only a few studies of the kinematics of the non-degenerated cervical spine have been reported; however, they focused on single level and not all the levels of cervical spine. METHODS: 468 symptomatic patients underwent upright cervical kMRI, and cervical disc degeneration was evaluated with a new grading system. This grading system consists of four grades (0-III), and the cervical spines with grade 0 and grade I discs were included in this study. Finally, 61 symptomatic patients were studied 34 male and 27 female with an average age of 41.9 years. kMRI was used to define the normal mobility of the cervical spine by calculating the translation motion, angular variation and percentage angular contribution to the total cervical spine. RESULTS: The translation motion of the cervical spine at each level was 0.85 ± 1.22 mm at C2/3, 1.05 ± 1.19 mm at C3/4, 0.63 ± 1.19 mm at C4/5, 0.57 ± 0.91 mm at C5/6, 0.16 ± 0.86 mm at C6/7 and -0.11 ± 0.81 at C7/T1. In general, the translation motion decreased from proximal segment to distal segment. The angular variation of the cervical spine at each level was 5.58 ± 3.86° at C2/3, 8.26 ± 4.81° at C3/4, 9.11 ± 4.87° at C4/5, 10.05 ± 5.26° at C5/6, 8.31 ± 4.30° at C6/7 and 4.87 ± 3.28° at C7/T1. The angular variation at C2/3 and C7/T1 was significantly lower compared to other levels (P < 0.05). The contribution of each cervical level to the total angular mobility of cervical spine was the greatest at C5/6 (21.68 ± 10.31%) and least at C7/T1 (11.11 ± 7.60%) (P < 0.05). CONCLUSION: This study demonstrates the normal cervical segmental mobility for the entire cervical spine using kMRI. These results will be helpful to understand the normal mobility of the cervical spine and for understanding the relationship between kinematics of the cervical spine and disc degeneration for future comparisons.

Missed cervical disc bulges diagnosed with kinematic magnetic resonance imaging.

PURPOSE: To determine if adding flexion and extension MRI studies to the traditional neutral views would be beneficial in the diagnosis of cervical disc bulges. METHODS: Five hundred patients underwent MRI in neutral, flexion and extension positions. The images were analyzed using computer software to objectively quantify the amount of disc bulge. RESULTS: Compared to the neutral position, cervical disc bulges were significantly increased in the extension position (P < 0.05), but on flexion position, there was no significant difference (P > 0.05). For patients without or <3 mm of disc bulge in neutral, 2.97% demonstrated an increase in bulge to ≥3 mm bulge in flexion, and 16.41% demonstrated an increase to ≥3 mm bulge in extension. For patients in the neutral view that had a baseline disc bulge of 3-5 mm, 3.73% had increased bulges to ≥5 mm in flexion and 11.57% had increased bulges to ≥5 mm in extension. CONCLUSION: A significant increase in the degree of cervical disc bulge was found by examining extension views when compared with neutral views alone. Kinematic MRI views provide valuable added information, especially in situations where symptomatic radiculopathy is present without any abnormalities demonstrated on traditional neutral MRI.

Non-native earthworms increase the abundance and diet quality of a common woodland salamander in its northern range.

Non-native earthworms found in Eastern Canada substantially affect soil properties and plant diversity, but less is known about their impacts on higher faunal species. We investigated the effects of non-native earthworms on populations of Plethodon cinereus, a common woodland salamander. We hypothesized that earthworms could adversely affect P. cinereus by consuming the forest floor, thereby decreasing soil moisture and the abundance of native preys. Conversely, earthworms could positively affect P. cinereus by providing refuge in their abandoned burrows and by being a novel prey. We installed 25 coverboards in 38 mature sugar maple (Acer saccharum) forests, 24 of which were earthworm-free. Over the next two years, we monitored earthworm and salamander populations using hot mustard extractions and visible implant elastomers, respectively. At a subset of four sites, two with and two without earthworms, we determined salamander diets in the spring (May-June), summer (July-August) and fall (September-October) seasons, using gastric lavage techniques. Forest floor depth decreased, whereas population density, body size and total prey volume of P. cinereus increased, with earthworm abundance. Earthworms, which are soft-bodied and nutritious prey, composed most of the salamander diet at sites with earthworms, volumetrically accounting for > 50% of total prey volume. Despite this, we found fewer prey items in the stomach of salamanders at earthworm-invaded sites, indicating that salamanders are getting a higher caloric intake per feeding while expending less energy. We conclude that non-native earthworms have a net beneficial effect on P. cinereus populations in Eastern Canada, mainly by improving diet quality. Supplementary Information: The online version contains supplementary material available at 10.1007/s10530-023-03168-3.

Regional anesthesia for breast cancer surgery: which block is best? A review of the current literature.

Breast cancer is the most common type of cancer worldwide. Fortunately, continual advances in diagnosis and treatment are resulting in increased survival rates. Earlier detection and treatment, to include surgical resection, can greatly improve patients outcomes. However, due to the complex innervation of the breast, management of postoperative pain has proven difficult in the past. Approximately, half of all women who undergo breast cancer surgery report postoperative pain syndrome. The paravertebral block has long been the anesthesiologist's choice for mitigating pain during and after the procedure. Newer techniques such as the pectoral nerve block and erector spinae plane block may prove to have some additional benefits. This literature review compares the risks, benefits and specific uses of these three regional nerve blocks in women undergoing breast cancer surgery. It aims to better inform anesthesiologists when they are choosing which technique is best for their patients.

Breast cancer is the most common type of cancer worldwide with 2 million new cases each year. Approximately 12% of women are diagnosed with breast cancer at some point in their lives. Part of breast cancer treatment often involves surgery to remove a mass. This can cause pain in both the short and long term. There are multiple different kinds of procedures a person can have done that may decrease the pain, they have from that surgery. These procedures are called nerve blocks. This article examines how well different nerve blocks decrease pain from breast cancer surgery. The nerve blocks we review in this article are called paravertebral blocks, pectoral nerve blocks and erector spinae plane blocks. They all block pain from breast surgery in slightly different ways. The decision of which block is best rests on the person performing the block.

Patterns of Lumbar Disc Degeneration: Magnetic Resonance Imaging Analysis in Symptomatic Subjects.

STUDY DESIGN: Cross-sectional study. PURPOSE: To evaluate lumbar disc degeneration (LDD) on magnetic resonance imaging (MRI) in symptomatic subjects to accumulate baseline data on the pattern of degeneration. OVERVIEW OF LITERATURE: LDD plays an important role in the diagnosis and treatment of low-back pain in patients. Few studies have focused on the pattern of LDD to understand how the lumbar spine ages. METHODS: This study included 1,095 patients (mean age, 44.29 years; range, 16-85 years) who underwent upright lumbar MRI. LDD was graded into five categories (I-V). Positive LDD was defined as grade III or greater. The prevalence and pattern of LDD were analyzed, and the correlations between age and total grade of LDD were evaluated. RESULTS: The average number of LDD levels and the total grade of LDD increased with age. LDD moved cephalad with age. The rate of LDD increased rapidly during the decade before the prevalence of LDD and became >50%. In the single-level LDD group, the levels L5-S1 were the most common levels (60.3%). In the two-level group, L4-L5 and L5-S1 were the most common levels (53.5%). In the three-level group, L3-L4, L4-L5, and L5-S1 were the most common levels (55.7%). In the multilevel LDD group, contiguous multilevel disc degeneration (CMDD) was more common than the skipped level disc degeneration (SLDD). The levels L4-L5 were the most common levels in the CMDD group, and L5-S1 were the most common levels among SLDD. CONCLUSIONS: LDD was found to correlate with age, and the specific patterns and rates of LDD depended on lumbar disc level and age. These LDD pattern data can be used before spinal procedures to predict the probability of natural LDD progression with age.

Rapid identification of a novel phosphodiesterase 7B tracer for receptor occupancy studies using LC─MS/MS.

Phosphodiesterase 7B (PDE7B) inhibition has been considered as a therapeutic target for the treatment of several neurological disorders. Currently, there are no radio-labeled tracers available to determine receptor occupancy (RO) of this target. Developing such a tracer could greatly facilitate the identification of viable PDE7B inhibitors. In the current study, a liquid chromatography tandem mass spectrometry (LC─MS/MS) method was utilized to evaluate the brain distribution of unlabeled tracer candidates following intravenous micro-dosing. This novel approach resulted in an accelerated identification of a potential novel RO tracer for PDE7B. The identified molecule, Compound 30, showed reasonable target-tissue specificity (striatum/cerebellum ratio of 2.2) and suitable uptake (0.25% of the injected dose/g brain tissue) as demonstrated in rats dosed with the unlabeled compound. Compound 30 was subsequently labeled with tritium (3H). In vitro characterization of 3H-Compound 30 demonstrated that this compound possessed a high target affinity with a subnanomolar Kd (0.8 nM) and a Bmax of 58 fmol/mg of protein using rat brain homogenate. Intravenous microdosing of 3H-Compound 30 showed preferential binding in the rat striatum, consistent with the mRNA distribution of PDE7B. In vitro displacement study with other structurally distinct PDE7B target-specific inhibitors using rat brain homogenate indicated that 3H-Compound 30 is an ideal tracer for Ki analysis. This is the first report of a preclinical tracer for PDE7B. With further characterization, Compound 30 may ultimately show the appropriate properties required to be further developed as a PDE7B PET ligand for clinical studies.

Improving maraviroc oral bioavailability by formation of solid drug nanoparticles.

Oral drug administration remains the preferred approach for treatment of HIV in most patients. Maraviroc (MVC) is the first in class co-receptor antagonist, which blocks HIV entry into host cells. MVC has an oral bioavailability of approximately 33%, which is limited by poor permeability as well as affinity for CYP3A and several drug transporters. While once-daily doses are now the favoured option for HIV therapy, dose-limiting postural hypotension has been of theoretical concern when administering doses high enough to achieve this for MVC (particularly during coadministration of enzyme inhibitors). To overcome low bioavailability and modify the pharmacokinetic profile, a series of 70 wt% MVC solid drug nanoparticle (SDN) formulations (containing 30 wt% of various polymer/surfactant excipients) were generated using emulsion templated freeze-drying. The lead formulation contained PVA and AOT excipients (MVCSDNPVA/AOT), and was demonstrated to be fully water-dispersible to release drug nanoparticles with z-average diameter of 728 nm and polydispersity index of 0.3. In vitro and in vivo studies of MVCSDNPVA/AOT showed increased apparent permeability of MVC, compared to a conventional MVC preparation, with in vivo studies in rats showing a 2.5-fold increase in AUC (145.33 vs. 58.71 ng h ml-1). MVC tissue distribution was similar or slightly increased in tissues examined compared to the conventional MVC preparation, with the exception of the liver, spleen and kidneys, which showed statistically significant increases in MVC for MVCSDNPVA/AOT. These data support a novel oral format with the potential for dose reduction while maintaining therapeutic MVC exposure and potentially enabling a once-daily fixed dose combination product.

Towards a Maraviroc long-acting injectable nanoformulation.

Suboptimal adherence to antiretroviral (ARV) therapy can lead to insufficient drug exposure leading to viral rebound and increased likelihood of resistance. This has driven the development of long-acting injectable (LAI) formulations which may mitigate some of these problems. Maraviroc (MVC) is an orally dosed CCR5 antagonist approved for use in patients infected with CCR5-trophic HIV-1. MVC prevents viral entry into host cells, is readily distributed to biologically relevant tissues and has an alternative resistance profile compared to more commonly used therapies. This makes a MVC LAI formulation particularly appealing for implementation in Pre-Exposure Prophylaxis (PrEP). A 70 wt% MVC-loaded nanodispersion stabilised with polyvinyl alcohol (PVA) and sodium 1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate (AOT) was prepared using emulsion-templated freeze-drying. In vitro release rate studies revealed over a 22% decrease in MVC release rate constant across a size selective membrane compared with an aqueous solution of MVC (<5% DMSO). Pharmacokinetic studies in rats were subsequently carried out following intramuscular injection of either the nanodispersion or an aqueous MVC preparation (<5% DMSO). Results demonstrated over a 3.4-fold increase in AUC0-∞ (1959.71 vs 567.17 ng.h ml), over a 2.6-fold increase in MVCs terminal half-life (t½) (140.69 vs 53.23 h) and MVC concentrations present up to 10-days. These data support development of a MVC LAI formulation with potential application in HIV therapy or prevention.

Patterns of Cervical Disc Degeneration: Analysis of Magnetic Resonance Imaging of Over 1000 Symptomatic Subjects.

STUDY DESIGN: Cross-sectional study. OBJECTIVES: The aim of this study was to evaluate cervical disc degeneration on magnetic resonance imaging (MRI) in a large population of symptomatic patients and to provide baseline data on the pattern of degeneration in order to understand how the cervical spine ages. METHODS: We performed a cross-sectional study of 1059 patients who underwent upright cervical MRI for neck pain with and without neurological symptoms. A total of 6354 cervical discs from C2/3 to C7/T1 were evaluated. Cervical disc degeneration was evaluated on T2-weighted MRI and graded into 4 categories (Grades 0-III). Positive degeneration was defined as greater than Grade II. The correlation between age and total grade of degeneration of each patient was evaluated, as well as the prevalence and pattern of degeneration. RESULTS: The average number of degenerated disc levels and the total grade of cervical disc degeneration significantly increase with age. In the patient group with 1-level degeneration, C5/6 was the most common degenerated level followed by C4/5 and C6/7. In the group with 2-level degeneration, C5/6 & C6/7 was most common followed by C4/5 & C5/6 and C3/4 & C4/5. Skip level degeneration was significantly rarer than contiguous level degeneration, and C7/T1 and C2/3 were the most unlikely to degenerate in multilevel degeneration. CONCLUSION: Disc degeneration is most common in the middle cervical spine (C5/6) and progresses to contiguous levels, except for C7/T1 and C2/3. This pattern may play a role in adjacent-level disc degeneration associated with spinal fusion.

Magnetic Resonance Classification System of Cervical Intervertebral Disk Degeneration: Its Validity and Meaning.

STUDY DESIGN: Retrospective analysis of kinetic magnetic resonance images (kMRIs). OBJECTIVE: (1) To analyze the changes seen on MRI related to disk degeneration and to develop a new grading system for cervical disk degeneration. (2) To evaluate the reliability and validity of the grading system. SUMMARY OF BACKGROUND DATA: Few have studied the relationship between changes seen on MRI with cervical disk degeneration and the chronological order of disk degeneration. A few grading systems for cervical disk degeneration have been reported; however, there have been problems related to subjectivity and lack of a clear, reliable algorithm. METHODS: A total of 300 cervical intervertebral disks were graded for nucleus color, structure, disk bulge, and disk height. On the basis of the analysis, a new grading system consisting of 4 grades (grade 0-III) and algorithm were developed. Intraobserver and interobserver reliabilities were assessed. A total of 2802 intervertebral disks were then evaluated using the grading system to correlate disk degeneration grades with patient age and function and to evaluate the validity of the new system. RESULTS: On the basis of cross-table analysis, disk degeneration presents in the following order: (1) decrease and/or change of nucleus intensity; (2) loss of distinction between nucleus and annulus; (3) positive disk bulge; and (4) disk height decrease. The κ-coefficients for intraobserver and interobserver agreements were 0.96 and 0.90, respectively. Severe disk degeneration is most common at C5/C6 followed by C6/C7 and C4/C5, and total disk degeneration grade is correlated with age (R=0.467). There was a decrease of angular motion in grades I-III and an increase in translational motion and decrease of space available for the cord in grades II-III. CONCLUSIONS: We developed a new classification system of cervical disk degeneration based on analysis of the changes seen on MRI. Reliability tests indicated high reproducibility of this system, and further analysis confirmed its validity and clinical significance.

Dynamic Evaluation of the Cervical Spine and the Spinal Cord of Symptomatic Patients Using a Kinetic Magnetic Resonance Imaging Technique.

PURPOSE: The purpose of this study was to examine the movement of the spinal cord and its relationship to the spinal canal in patients with mild spondylosis using kinetic magnetic resonance imaging (kMRI). METHODS: Weight-bearing, multiposition kMRI was performed on symptomatic patients through a full range of flexion-extension. A total of 52 study patients were selected based on the C2-C7 Cobb angle of sagittal alignment: lordotic (from 30 to 45 degrees). We evaluated dynamic changes in different parameters from flexion-extension: spinal canal diameter (CD), spinal cord diameter (SCD), space available for the cord, anterior space available for the cord (ASAC), posterior space available for the cord (PSAC), average distance between the anterior canal and the cord (d-value), and global angle for the spinal canal and cord. RESULTS: The CD tended to decrease from flexion to extension from C3/C4 to C6/C7, however, there were no significant differences at the proximal and distal levels, C2/C3 and C7/T1. There were no significant differences of SCD between different postures. The SCD tended to decrease from C2/C3 to C7/T1. The ASAC followed the same pattern as CD-values. The ASAC was narrowest at C4/C5 and C5/C6. The PSAC tended to increase from C2/C3 to C7/T1. The spinal cord shifted anteriorly with extension and posteriorly with flexion. In addition, the spinal cord maintained its curve with the movement. CONCLUSIONS: The kinematics of spinal cord motion may be associated with the pathogenesis of cervical spondylotic myelopathy. However, the spinal cord maintains its curve with position changes. Consequently, different motions of the cervical spine may affect spinal cord migration and cause changes in ASAC and PSAC.

Once-daily abacavir/lamivudine/zidovudine plus tenofovir for the treatment of HIV-1 infection in antiretroviral-naïve subjects: a 48-week pilot study.

PURPOSE: To assess the safety and efficacy of a 4-drug, 3-tablet, once-daily (qd) regimen consisting of abacavir/lamivudine/zidovudine (ABC/3TC/ZDV; 2 tablets) and tenofovir (TDF) in antiretroviral-naïve patients with plasma HIV-1 RNA 30,000 copies/mL at 48 weeks. METHOD: All participants received ABC/3TC/ZDV (300/150/300 mg) and TDF (300 mg) qd in this pilot, open-label, multicenter study. Intent-to-treat (ITT) analyses were conducted to evaluate virologic and immunologic efficacy. RESULTS: Of the 123 participants enrolled, 52 (42%) prematurely discontinued study for adverse events (14), were lost to follow-up (13), had virologic nonresponse (12), and withdrew for other reasons (13). At week 48, by ITT missing=failure analysis, 41% (51/123) and 51% (63/123) of participants had plasma HIV-1 RNA <50 copies/mL and <400 copies/mL, respectively; by ITT-observed analysis, 75% (51/68) and 93% (63/68) had plasma HIV-1 RNA <50 copies/mL and <400 copies/mL, respectively; 11% (14/123) met virologic nonresponse criteria. Median week 48 change in CD4+ cell count from baseline was +127 cells/mm3. Median week 48 changes from baseline for fasting lipids were as follows: cholesterol (-9 mg/dL), HDL (+1 mg/dL), LDL (-9 mg/dL), and triglycerides (-4 mg/dL). CONCLUSION: A high rate of premature discontinuations contributed to the overall suboptimal virologic response to ABC/3TC/ZDV+TDF qd; however, the regimen was not associated with high rates of virologic failure previously observed with TDF+ABC/3TC.

The Compensatory Relationship of Upper and Subaxial Cervical Motion in the Presence of Cervical Spondylosis.

STUDY DESIGN: This study was an in vivo kinematic magnetic resonance imaging analysis of cervical spinal motion in human subjects. OBJECTIVE: The objective of the study was to identify associations between disk degeneration in the subaxial cervical spine and upper cervical spinal motion in patients with general age-related cervical spondylosis. SUMMARY OF BACKGROUND DATA: The kinematic relationship between the occipital-atlantoaxial complex and subaxial cervical spine in patients with cervical spondylosis and decreased cervical motion is not well understood. METHODS: A total of 446 symptomatic patients who had neck pain with and without neurogenic symptoms were included in this study. Kinematic magnetic resonance imaging was performed with dynamic motion of the cervical spine in upright, weight-bearing neutral, flexion, and extension positions. Intervertebral disk degeneration for each segment from C2-3 to C7-T1 and sagittal angular motion between flexion and extension for each segment from Oc-C1 to C7-T1 was evaluated. Depending on the amount of sagittal subaxial angular motion, the patients were classified into 3 groups by sagittal angular motion using cutoff points based on tertile (<36-degree group: 149 cases; 36-47-degree group: 148 cases; and >47-degree group: 149 cases). RESULTS: A significant correlation was found between subaxial angular motion and intervertebral disk degeneration, indicating that the subaxial motion decreases according to the degree of disk degeneration. Mean angular motion of the occipital-atlantoaxial complex, especially of Oc-C1, was significantly higher in the <36-degree and 36-47-degree group than in the >47-degree group, whereas no significant difference was found at C1-C2. CONCLUSIONS: Our study demonstrates that decreased subaxial cervical spinal motion is associated with intervertebral disk degeneration in a symptomatic population. This decrease in mobility at the subaxial cervical spine is compensated for by an increase in angular mobility of the upper cervical spine at the occipital-atlantoaxial complex, especially at Oc-C1.

A comparison of commercially available demineralized bone matrices with and without human mesenchymal stem cells in a rodent spinal fusion model.

OBJECTIVE The efficacy of some demineralized bone matrix (DBM) substances has been demonstrated in the spinal fusion of rats; however, no previous comparative study has reported the efficacy of DBM with human mesenchymal stem cells (hMSCs). There is an added cost to the products with stem cells, which should be justified by improved osteogenic potential. The purpose of this study is to prospectively compare the fusion rates of 3 different commercially available DBM substances, both with and without hMSCs. METHODS Posterolateral fusion was performed in 32 mature athymic nude rats. Three groups of 8 rats were implanted with 1 of 3 DBMs: Trinity Evolution (DBM with stem cells), Grafton (DBM without stem cells), or DBX (DBM without stem cells). A fourth group with no implanted material was used as a control group. Radiographs were obtained at 2, 4, and 8 weeks. The rats were euthanized at 8 weeks. Overall fusion was determined by manual palpation and micro-CT. RESULTS The fusion rates at 8 weeks on the radiographs for Trinity Evolution, Grafton, and DBX were 8 of 8 rats, 3 of 8 rats, and 5 of 8 rats, respectively. A significant difference was found between Trinity Evolution and Grafton (p = 0.01). The overall fusion rates as determined by micro-CT and manual palpation for Trinity Evolution, Grafton, and DBX were 4 of 8 rats, 3 of 8 rats, and 3 of 8 rats, respectively. The Trinity Evolution substance had the highest overall fusion rate, however no significant difference was found between groups. CONCLUSIONS The efficacies of these DBM substances are demonstrated; however, the advantage of DBM with hMSCs could not be found in terms of posterolateral fusion. When evaluating spinal fusion using DBM substances, CT analysis is necessary in order to not overestimate fusion.

Growth-Factor Nanocapsules That Enable Tunable Controlled Release for Bone Regeneration.

Growth factors are of great potential in regenerative medicine. However, their clinical applications are largely limited by the short in vivo half-lives and the narrow therapeutic window. Thus, a robust controlled release system remains an unmet medical need for growth-factor-based therapies. In this research, a nanoscale controlled release system (degradable protein nanocapsule) is established via in situ polymerization on growth factor. The release rate can be finely tuned by engineering the surface polymer composition. Improved therapeutic outcomes can be achieved with growth factor nanocapsules, as illustrated in spinal cord fusion mediated by bone morphogenetic protein-2 nanocapsules.

Combining fosamprenavir with lopinavir/ritonavir substantially reduces amprenavir and lopinavir exposure: ACTG protocol A5143 results.

OBJECTIVE: To evaluate fosamprenavir/lopinavir (LPV)/ritonavir (RTV), fosamprenavir/RTV, or LPV/RTV in antiretroviral treatment-experienced patients. Lack of drug interaction data prompted a pharmacokinetic substudy to minimize subject risk. DESIGN: Multi-center, open-label, selectively randomized, steady-state pharmacokinetic study in HIV-infected subjects. METHODS: A planned independent interim review occurred after at least eight subjects were randomized to each arm. Subjects received twice daily LPV/RTV 400/100 mg (arm A; n = 8); fosamprenavir/RTV 700/100 mg (arm B; n = 8) or LPV/RTV/fosamprenavir 400/100/700 mg (arm C; n = 17). Plasma samples were collected over 12 h between study weeks 2 and 4. Pharmacokinetic parameters were compared based on a one-sided t-test on log-transformed data with a Peto stopping boundary (P < 0.001). RESULTS: Amprenavir mean area under the curve over 12 h (AUC0-12 h) and concentration at 12 h (C12 h) (microg/ml) were, respectively, 42.7 microg x h/ml (range, 33.1-55.1) and 2.4 microg/ml (range, 1.4-3.2) in arm B and 17.4 microg x h/ml (range, 4.6-41.3) and 0.9 microg/ml (range, 0.2-2.7) in arm C: geometric mean ratio (GMR) arm C:B was 0.36 [99.9% upper confidence boundary (UCB), 0.64] and 0.31 (99.9% h UCB, 0.61), respectively (P < or = 0.0001). Lopinavir AUC0-12 h and C12 h were, respectively, 95.3 microg x h/ml (range, 60.3-119.3) and 6.3 microg/ml (range, 2.2-9.2) in arm A and 54.4 microg x h/ml (range, 23.5-112.2) and 3.0 microg/ml (range, 0.4-7.9) in arm C: GMR arm C:A of 0.52 (99.9% UCB, 0.89) and 0.39 (99.9% UCB, 0.98), respectively (P < or = 0.0008). Ritonavir exposure was not significantly different between arms. CONCLUSION: APV and LPV exposures are significantly reduced using LPV/RTV/fosamprenavir, possibly increasing the risk of virologic failure. Consequently, A5143 was closed to enrollment.

Kinematic analysis of diseased and adjacent segments in degenerative lumbar spondylolisthesis.

BACKGROUND CONTEXT: Degenerative spondylolisthesis is a common pathologic condition that leads to lumbar instability and significant clinical symptoms. The effect of this pathology on adjacent lumbar motion segments, however, has not yet been studied. PURPOSE: To characterize the motion characteristics of lumbar degenerative spondylolisthesis at both the diseased and adjacent levels in patients with low-grade, single-level lumbar degenerative spondylolisthesis using kinetic magnetic resonance imaging (kMRI). STUDY DESIGN: Retrospective study of patient kMRIs. PATIENT SAMPLE: One-hundred twelve patient MRIs with low-grade, single-level lumbar spondylolisthesis were included. OUTCOME MEASURES: Angular and translational motion. METHODS: This study compared 112 patients diagnosed with low-grade (Grade 1 or 2), single-level lumbar degenerative spondylolisthesis at L3-L4, L4-L5, or L5-S1 with 296 control patients without spondylolisthesis. Angular and translational motion were measured using patient kMRIs. The level of slip was graded according to the Meyerding classification system, and disc degeneration was classified according to the Pfirrmann system. Instability was defined as translational motion greater than 4 mm. RESULTS: Lumbar hypomobility was often present regardless of the level of degenerative spondylolisthesis. A slip at L3-L4 resulted in the largest decrease in lumbar range of motion. Instability at the diseased level was most common at L3-L4 (36%), followed by L5-S1 (31%) and L4-L5 (30%). Instability at the adjacent segments was most frequent at L4-L5 (49%), followed by L5-S1 (34%) and L3-L4 (23%). Patients with stable spondylolisthesis generally had decreased angular motion at all lumbar levels. Translational motion at the diseased level was consistently increased. Disc degeneration was significantly greater at the level of slip for the L3-L4 and L4-L5 spondylolisthesis groups and equal to the control group in the L5-S1 group. There was no significant difference in disc degeneration at adjacent segments in L3-L4 and L4-L5 degenerative spondylolisthesis patients, but there was a significant decrease with an L5-S1 slip. CONCLUSIONS: There were a similar percentage of patients in each degenerative spondylolisthesis group with lumbar instability. Angular motion decreased at the diseased level with L3-L4 and L5-S1 spondylolisthesis, but increased with L4-L5 spondylolisthesis. Translational motion, however, increased at the diseased level in all three groups. There was compensatory hypermobility at adjacent levels in patients with unstable spondylolisthesis at L3-L4 and L4-L5, but not at L5-S1.