T1rho MR properties of human patellar cartilage: correlation with indentation stiffness and biochemical contents.

OBJECTIVE: Cartilage degeneration involves structural, compositional, and biomechanical alterations that may be detected non-invasively using quantitative MRI. The goal of this study was to determine if topographical variation in T1rho values correlates with indentation stiffness and biochemical contents of human patellar cartilage. DESIGN: Cadaveric patellae from unilateral knees of 5 donors with moderate degeneration were imaged at 3-Telsa with spiral chopped magnetization preparation T1rho sequence. Indentation testing was performed, followed by biochemical analyses to determine water and sulfated glycosaminoglycan contents. T1rho values were compared to indentation stiffness, using semi-circular regions of interest (ROIs) of varying sizes at each indentation site. ROIs matching the resected tissues were analyzed, and univariate and multivariate regression analyses were performed to compare T1rho values to biochemical contents. RESULTS: Grossly, superficial degenerative change of the cartilage (i.e., roughened texture and erosion) corresponded with regions of high T1rho values. High T1rho values correlated with low indentation stiffness, and the strength of correlation varied slightly with the ROI size. Spatial variations in T1rho values correlated positively with that of the water content (R2 = 0.10, p < 0.05) and negatively with the variations in the GAG content (R2 = 0.13, p < 0.01). Multivariate correlation (R2 = 0.23, p < 0.01) was stronger than either of the univariate correlations. CONCLUSION: These results demonstrate the sensitivity of T1rho values to spatially varying function and composition of cartilage and that the strength of correlation depends on the method of data analysis and consideration of multiple variables.

Ultrashort time-to-echo MR morphology of cartilaginous endplate correlates with disc degeneration in the lumbar spine.

PURPOSE: Using ultrashort echo time (UTE) MRI, we determined prevalence of abnormal cartilaginous endplate (CEP), and the relationship between CEP and disc degeneration in human lumbar spines. MATERIALS AND METHODS: Lumbar spines from 71 cadavers (age 14-74 years) were imaged at 3 T using sagittal UTE and spin echo T2 map sequences. On UTE images, CEP morphology was defined as "normal" with linear high signal intensity or "abnormal" with focal signal loss and/or irregularity. On spin echo images, disc grade and T2 values of the nucleus pulposus (NP) and annulus fibrosus (AF) were determined. 547 CEPs and 284 discs were analysed. Effects of age, sex, and level on CEP morphology, disc grade, and T2 values were determined. Effects of CEP abnormality on disc grade, T2 of NP, and T2 of AF were also determined. RESULTS: Overall prevalence of CEP abnormality was 33% and it tended to increase with older ages (p = 0.08) and at lower spinal levels of L5 than L2 or L3 (p = 0.001). Disc grades were higher and T2 values of the NP were lower in older spines (p < 0.001) and at lower disc level of L4-5 (p < 0.05). We found significant association between CEP and disc degeneration; discs adjacent to abnormal CEPs had high grades (p < 0.01) and lower T2 values of the NP (p < 0.05). CONCLUSION: These results suggest that abnormal CEPs are frequently found, and it associates significantly with disc degeneration, suggesting an insight into pathoetiology of disc degeneration.

Cytokine Inhibitors Upregulate Extracellular Matrix Anabolism of Human Intervertebral Discs under Alginate Beads and Alginate-Embedded Explant Cultures.

We investigated the effects of the cytokine inhibitors IL-1 receptor antagonist (IL-1Ra) and soluble tumor necrosis factor receptor-1 (sTNFR1) on the extracellular matrix metabolism of human intervertebral discs (IVDs) and the roles of IL-1ß and TNF in the homeostasis of IVD cells. The 1.2% alginate beads and the explants obtained from 35 human lumbar discs were treated with cytokine inhibitors. Extracellular matrix metabolism was evaluated by proteoglycan (PG) and collagen syntheses and IL-1ß, TNF, and IL-6 expressions after three days of culture in the presence or absence of IL-1Ra, sTNFR1, and cycloheximide. Simultaneous treatment with IL-1Ra and sTNFR1 stimulated PG and collagen syntheses in the NP and AF cells and explants. The IL-1ß concentration was significantly correlated to the relative increase in PG synthesis in AF explants after simultaneous cytokine inhibitor treatment. The relative increase in PG synthesis induced by simultaneous cytokine treatment was significantly higher in an advanced grade of MRI. Expressions of IL-1ß and TNF were upregulated by each cytokine inhibitor, and simultaneous treatment suppressed IL-1ß and TNF productions. In conclusion, IL-1Ra and sTNFR1 have the potential to increase PG and collagen synthesis in IVDs. IL-1ß and TNF have a feedback pathway to maintain optimal expression, resulting in the control of homeostasis in IVD explants.

Prevalence of radiographic hip dysplasia in Japanese population-based study.

OBJECTIVES: The purpose of this study was to measure the indices of radiographic developmental dysplasia of the hip (DDH) in a cross-sectional study of an elderly Japanese population. METHODS: Hip radiographs of 427 informed, voluntary Japanese community-dwelling individuals (279 female and 148 male) aged 50-96 years-old were obtained from Miyagawa village in Japan through a health screening. The hip radiographs were measured by a custom-written, semi-automated MATLAB program. The center edge (CE) angle, acetabular roof obliquity (ARO), acetabular head index (AHI), and minimum joint space width (mJSW) were measured. We examined the associations between gender, side-of-hip, and age group on radiographic DDH and hip osteoarthritis (OA). RESULTS: The mean CE angle was 31.0°. The mean ARO was 5.8°. The mean AHI was 88.2%. The mean mJSW was 4.0 mm. Of the total population, 29.9% had DDH and 4.0% had hip OA. Of those who had hip OA, 41.2% were secondary OA, and 58.8% were primary OA. The relationship between DDH and OA was not significant. CONCLUSION: DDH is unlikely to be an important cause of hip OA in the present population-based study.

High-contrast osteochondral junction imaging using a 3D dual adiabatic inversion recovery-prepared ultrashort echo time cones sequence.

While conventional MRI sequences cannot visualize tissues from the osteochondral junction (OCJ) due to these tissues' short transverse T2 /T2 * relaxations, ultrashort echo time (UTE) sequences can overcome this limitation. A 2D UTE sequence with a dual adiabatic inversion recovery preparation (DIR-UTE) for selective imaging of short T2 tissues with high contrast has previously been developed, but high sensitivity to eddy currents and aliased out-of-slice excitation make it difficult to image the thin layer of the OCJ in vivo. Here, we combine the DIR scheme with a 3D UTE cones sequence for volumetric imaging of OCJ tissues in vivo, aiming to generate higher OCJ contrast compared with a recently developed single IR-prepared UTE sequence with a fat saturation module (IR-FS-UTE). All sequences were implemented on a 3-T clinical scanner. The DIR-UTE cones sequence combined a 3D UTE cones sequence with two narrow-band adiabatic IR preparation pulses centered on water and fat spectrum frequencies, respectively. The 3D DIR-UTE cones sequence was first applied to a phantom, then to the knees of four healthy volunteers and four patients diagnosed with osteoarthritis and compared with the IR-FS-UTE sequence. In both phantom and volunteer studies, the proposed DIR-UTE cones sequence showed much higher contrast for OCJ imaging than the IR-FS-UTE sequence did. The 3D DIR-UTE cones sequence showed a significantly higher contrast-to-noise ratio between the OCJ and subchondral bone fat (mean, standard deviation [SD]: 25.7 ± 2.3) and between the OCJ and superficial layers of cartilage (mean, SD: 22.2 ± 3.5) compared with the IR-FS-UTE sequence (mean, SD: 10.8 ± 2.5 and 16.3 ± 2.6, respectively). The 3D DIR-UTE cones sequence is feasible for imaging of the OCJ region of the knee in vivo and produces both high resolution and high contrast.

High contrast cartilaginous endplate imaging using a 3D adiabatic inversion-recovery-prepared fat-saturated ultrashort echo time (3D IR-FS-UTE) sequence.

Ultrashort echo time (UTE) sequences can image tissues with transverse T 2 /T 2 * relaxations too short to be efficiently observed on routine clinical MRI sequences, such as the vertebral body cartilaginous endplate (CEP). Here, we describe a 3D adiabatic inversion-recovery-prepared fat-saturated ultrashort echo time (3D IR-FS-UTE) sequence to highlight the CEP of vertebral bodies in comparison to the intervertebral disc (IVD) and bone marrow fat (BF) at 3 T. The IR-FS-UTE sequence used a 3D UTE sequence combined with an adiabatic IR preparation pulse centered in the middle of the water and fat peaks, while a fat saturation module was used to suppress the signal from fat. A slab-selective half pulse was used for signal excitation, and a 3D center-out cones trajectory was used for more efficient data sampling. The 3D IR-FS-UTE sequence was applied to an ex vivo human spine sample, as well as the spines of six healthy volunteers and of three patients with back pain. Bright continuous lines representing signal from CEP were found in healthy IVDs. The measured contrast-to-noise ratio was 18.5 ± 4.9 between the CEP and BF, and 20.3 ± 4.15 between the CEP and IVD for the six volunteers. Abnormal IVDs showed CEP discontinuity or irregularity in the sample and patient studies. In conclusion, the proposed 3D IR-FS-UTE sequence is feasible for imaging the vertebral body's CEP in vivo with high contrast.

Three-dimensional computed tomographic evaluation of lateral lumbar interbody fusion: morphometric change of intervertebral structure.

PURPOSE: Two-dimensional (2D) analyses of intervertebral disc (IVD) height and foramen measurements following lateral lumbar interbody fusion (LLIF) have been reported. However, three-dimensional (3D) morphometric analysis of intervertebral structure using 3D computed tomography (3D CT) provides increased precision for measuring morphological changes. The purpose of this study was to evaluate 3D changes of lumbar IVD height and foramen diameter in degenerative lumbar disease patients following LLIF. METHODS: Subject-based 3D CT lumbar models were created for 26 patients before and following LLIF. IVD height (whole and five anatomical zones) and foramen diameter (minimum and maximum) were measured based on the model using custom software. The sagittal placement of cages (SPC) and cross-sectional area of the thecal sac (CSA) were measured. Changes in these parameters by LLIF were quantified and statistically analysed. RESULTS: Following LLIF, disc height increased by an average of 2.9 mm (P < 0.01). Post-operative measurements of both minimum and maximum diameters of the foramen were significantly increased by 1.0 mm and 1.9 mm, respectively (P < 0.01). Change in maximum foramen diameter was significantly correlated with change in disc height (P < 0.05). The SPC was significantly correlated with the changes in disc height and foraminal diameters (P < 0.05, respectively). No significant change between the change in disc height and CSA was found. CONCLUSION: This preliminary study quantifies disc height and foramen diameter changes in 3D following LLIF. The presented data provide baseline intervertebral changes for future comparisons with follow-up studies and clinical outcomes. LEVEL OF EVIDENCE I: Diagnostic: individual cross-sectional studies with the consistently applied reference standard and blinding.

Correction to: ISSLS PRIZE IN BASIC SCIENCE 2018: Growth differentiation factor-6 attenuated pro-inflammatory molecular changes in the rabbit anular-puncture model and degenerated disc-induced pain generation in the rat xenograft radiculopathy model.

The author "Ashish D. Diwan" receives educational consultant fees from Nuvasive Inc.

Efficacy of Hyaluronic Acid/Carboxymethyl Cellulose-Based Bioresorbable Membranes in Reducing Perihepatic Adhesion Formation: A Prospective Cohort Study.

BACKGROUND: Perihepatic adhesions induced by hepatectomy make the subsequent repeat hepatectomy technically demanding. The aim of this study was to verify the effect of hyaluronic acid/carboxymethyl cellulose-based bioresorbable membrane (HA membrane) in preventing posthepatectomy adhesion formation by focusing on the ease of the adhesiolysis in subsequent hepatectomy for recurrent tumors. METHODS: A total of 201 patients who underwent hepatectomy using HA membrane were prospectively followed-up for 3 years. Thirty of the 201 patients underwent a repeat hepatectomy for recurrence. The operative data of 85 cases of repeat hepatectomy, the primary hepatectomy of which had been performed without the use of HA membrane, served as the historical control data. The primary endpoint was the time interval between the skin incision and the start of hepatic parenchymal transection (the preparation time) including adhesiolysis. Secondary endpoints were blood loss during the operation, incidence of postoperative complications, and the biochemical data. RESULTS: The median preparation time (183 vs. 228 min; p = 0.027) and total operation time (374 vs. 439 min; p = 0.041) were significantly shorter in the HA membrane group than in the control group. CONCLUSION: Use of HA membranes during hepatectomy enabled significant shortening of the adhesiolysis time during the sequential hepatectomy performed for recurrent tumors.

ISSLS PRIZE IN BASIC SCIENCE 2018: Growth differentiation factor-6 attenuated pro-inflammatory molecular changes in the rabbit anular-puncture model and degenerated disc-induced pain generation in the rat xenograft radiculopathy model.

PURPOSE: To elucidate the effects of growth differentiation factor-6 (GDF6) on: (i) gene expression of inflammatory/pain-related molecules and structural integrity in the rabbit intervertebral disc (IVD) degeneration model, and (ii) sensory dysfunction and changes in pain-marker expression in dorsal nerve ganglia (DRGs) in the rat xenograft radiculopathy model. METHODS: Forty-six adolescent rabbits received anular-puncture in two non-consecutive lumbar IVDs. Four weeks later, phosphate-buffered saline (PBS) or GDF6 (1, 10 or 100 µg) was injected into the nucleus pulposus (NP) of punctured discs and followed for 4 weeks for gene expression analysis and 12 weeks for structural analyses. For pain assessment, eight rabbits were sacrificed at 4 weeks post-injection and NP tissues of injected discs were transplanted onto L5 DRGs of 16 nude rats to examine mechanical allodynia. The rat DRGs were analyzed immunohistochemically. RESULTS: In GDF6-treated rabbit NPs, gene expressions of interleukin-6, tumor necrosis factor-α, vascular endothelial growth factor, prostaglandin-endoperoxide synthase 2, and nerve growth factor were significantly lower than those in the PBS group. GDF6 injections resulted in partial restoration of disc height and improvement of MRI disc degeneration grades with statistical significance in rabbit structural analyses. Allodynia induced by xenograft transplantation of rabbit degenerated NPs onto rat DRGs was significantly reduced by GDF6 injection. Staining intensities for ionized calcium-binding adaptor molecule-1 and calcitonin gene-related peptide in rat DRGs of the GDF6 group were significantly lower than those of the PBS group. CONCLUSION: GDF6 injection may change the pathological status of degenerative discs and attenuate degenerated IVD-induced pain.

Morphology of intervertebral disc ruptures evaluated by vacuum phenomenon using multi-detector computed tomography: association with lumbar disc degeneration and canal stenosis.

BACKGROUND: The progression of intervertebral disc (IVD) degeneration leads to rupture within IVD tissues. The location and appearance of areas of gaseous radiolucency in the IVD, known as vacuum phenomena (VPs), are considered to indirectly indicate the position and extent of IVD rupture. The clinical significance of VPs in degenerated IVDs is not fully understood. The purpose of this study is to assess and classify the morphology of IVD ruptures by the presence of intradiscal VPs, and to examine the association between morphological VP-positive IVD ruptures and degenerative lumbar diseases. METHODS: IVD rupture was evaluated by the presence of VPs using computed tomography (CT) imaging. VP shape (spot, linear, island) was classified using sagittal imaging, and VP distribution (A-N: anterior AF-NP; N: NP only; N-P: NP-posterior AF; A-N-P: anterior and posterior AF-NP) was classified using axial imaging. The disc height index (DHI) was calculated from lateral radiographs. Disc degeneration and lumbar spinal stenosis were evaluated by MRI grade. RESULTS: In the VP shape analysis, the island type was the most common, followed by linear and spot types. In the VP distribution analysis, A-N was the most common group, followed by N, N-P and A-N-P. Intra- and inter-observer reliabilities were statistically sufficient to classify different rupture shapes and distributions. The DHI tended to be lower in discs that contained VPs, especially in the anterior AF area. The shape and distribution of intradiscal VPs were significantly associated with the degree of disc degeneration and lumbar spinal stenosis graded by MRI. Discs with VPs extending from the NP into the anterior and/or posterior AF had a significantly higher proportion of advanced disc degeneration (Pfirrmann's classification: grades IV and V). CONCLUSIONS: This is the first study to analyze the morphology of IVD rupture evaluated by the presence of intradiscal VPs using CT imaging. This classification can comprehensively present the shape and axial distribution of VPs within IVDs. Intradiscal VPs are associated with the progression of disc degeneration and lumbar spinal stenosis.

Diagnostic accuracy of indocyanine green fluorescence imaging and multidetector row computed tomography for identifying hepatocellular carcinoma with liver explant correlation.

AIM: Indocyanine green (ICG)-fluorescence imaging is useful for detecting hepatocellular carcinoma (HCC) during surgery, but its accuracy has not been compared to that of multidetector row computed tomography (MDCT) with liver explant correlation. The aim of the present study was to clarify the precise diagnostic accuracy of ICG-fluorescence imaging for detecting HCC in a whole explant liver survey. METHODS: Thirty-three patients with end-stage liver disease (mean age, 53 years) were prospectively enrolled in the present study. The mean Model for End-stage Liver Disease score was 14.6. One month before and 1 week prior to living donor liver transplantation, all patients underwent MDCT and administration of ICG. Following whole liver resection, the explanted liver was sliced. Gross examination and ICG-fluorescence imaging of both sides of the cut specimen was carried out and all focal liver lesions were recorded. RESULTS: Pathologic examination diagnosed 18 of 84 focal liver lesions as HCC. Of those, MDCT and ICG-fluorescence imaging diagnosed 12 and 13 HCCs, respectively. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of MDCT were 66.7%, 92.4%, 70.6%, 91.0%, and 86.9%, respectively, compared with those of ICG-fluorescence imaging at 72.2%, 31.8%, 22.4%, 80.8%, and 40.5%, respectively. CONCLUSION: The sensitivity of ICG-fluorescence imaging for detecting HCC with liver explant correlation was similar to that of MDCT. However, ICG-fluorescence imaging had low specificity in the setting of decompensated cirrhotic explant liver correlation.

Three-dimensional micro-computed tomography analysis for spinal instability after lumbar facetectomy in the rat.

PURPOSE: Intervertebral disc degeneration is thought to contribute to low back pain. However, the pathophysiological mechanisms remain controversial. In a previous study, we developed an animal model that showed delayed gait disturbance after lumbar facetectomy in the rat. We believe that this gait disturbance was caused by low back pain, although the mechanisms of this gait abnormality remain unknown. The purpose of this study was to evaluate structural changes of the lumbar spine after facetectomy in the rat utilizing three-dimensional micro-computed tomography (3DµCT) compared to histology. METHODS: Thirty male SD rats were divided into three groups. In the Sham group (n = 13), only exposure of bilateral facet joints at the L4-5 level was performed. In the Experimental group (n = 13), complete resection of bilateral L4-5 facet joints was achieved. Naïve rats (n = 4) were used for controls. At 7-week postoperative, 3DµCT and histological analyses were performed. RESULTS: On 3DµCT images, increased disc height and endplate irregularities at the L4-5 segment and decreased disc height at adjacent segments were observed in the Experimental group. Histological scores were also higher in the Experimental group than the Sham Group. CONCLUSIONS: Degenerative changes were observed at the facetectomy level. These may correspond with the previously reported delayed gait disturbance after facetectomy. This animal model may be useful to create mechanically induced disc degeneration without direct tissue damage to the disc.

Evaluation of the disco-vertebral junction using ultrashort time-to-echo magnetic resonance imaging: inter-reader agreement and association with vertebral endplate lesions.

OBJECTIVE: To evaluate ultrashort time to echo (UTE) magnetic resonance (MR) morphology of the cartilaginous endplates (CEP) in cadaveric lumbar spines with bony vertebral endplate (VEP) lesions, to determine inter-reader agreement as well as associations between the CEP morphology and VEP lesions as well as other abnormalities. MATERIALS AND METHODS: MR imaging of cadaveric lumbar spines from 10 donors was performed at 3T using a UTE MR sequence. Two musculoskeletal radiologists identified the location of vertebral endplate lesions in consensus. The morphology of the CEP overlying the lesions and in the adjacent normal regions was assessed individually. A total of 55 vertebral lesions and 55 normal regions were assessed. The presence of osteophytosis, morphological changes of the anterior and posterior longitudinal ligament, and intervertebral disc signal and morphology was also assessed. Agreement between observers was determined using Cohen's kappa analysis, and association between CEP and vertebral endplate lesions was determined using the chi square test. RESULTS: Fifty-five vertebral endplate lesions were identified and the morphology of CEP evaluated by two readers was in substantial agreement with Cohen's kappa of 0.78. The presence of vertebral endplate abnormality was associated with the presence of osteophytes (39 out of 55 levels), altered morphology and signal of the anterior longitudinal ligament (23 out of 55 levels) and intervertebral discs (30 out of 55 levels). CONCLUSION: UTE MRI enables evaluation of the CEP with substantial inter-reader agreement. Abnormal changes of the CEP may facilitate formation of lesions of vertebral endplate over time and are associated with degenerative changes of the lumbar spine.

Mesenchymal stem cells reduce intervertebral disc fibrosis and facilitate repair.

Intervertebral disc degeneration is associated with back pain and radiculopathy which, being a leading cause of disability, seriously affects the quality of life and presents a hefty burden to society. There is no effective intervention for the disease and the etiology remains unclear. Here, we show that disc degeneration exhibits features of fibrosis in humans and confirmed this in a puncture-induced disc degeneration (PDD) model in rabbit. Implantation of bone marrow-derived mesenchymal stem cells (MSCs) to PDD discs can inhibit fibrosis in the nucleus pulposus with effective preservation of mechanical properties and overall spinal function. We showed that the presence of MSCs can suppress abnormal deposition of collagen I in the nucleus pulposus, modulating profibrotic mediators MMP12 and HSP47, thus reducing collagen aggregation and maintaining proper fibrillar properties and function. As collagen fibrils can regulate progenitor cell activities, our finding provides new insight to the limited self-repair capability of the intervertebral disc and importantly the mechanism by which MSCs may potentiate tissue regeneration through regulating collagen fibrillogenesis in the context of fibrotic diseases.

Mechanistic background and clinical applications of indocyanine green fluorescence imaging of hepatocellular carcinoma.

BACKGROUND: Although clinical applications of intraoperative fluorescence imaging of liver cancer using indocyanine green (ICG) have begun, the mechanistic background of ICG accumulation in the cancerous tissues remains unclear. METHODS: In 170 patients with hepatocellular carcinoma cells (HCC), the liver surfaces and resected specimens were intraoperatively examined by using a near-infrared fluorescence imaging system after preoperative administration of ICG (0.5 mg/kg i.v.). Microscopic examinations, gene expression profile analysis, and immunohistochemical staining were performed for HCCs, which showed ICG fluorescence in the cancerous tissues (cancerous-type fluorescence), and HCCs showed fluorescence only in the surrounding non-cancerous liver parenchyma (rim-type fluorescence). RESULTS: ICG fluorescence imaging enabled identification of 273 of 276 (99%) HCCs in the resected specimens. HCCs showed that cancerous-type fluorescence was associated with higher cancer cell differentiation as compared with rim-type HCCs (P < 0.001). Fluorescence microscopy identified the presence of ICG in the canalicular side of the cancer cell cytoplasm, and pseudoglands of the HCCs showed a cancerous-type fluorescence pattern. The ratio of the gene and protein expression levels in the cancerous to non-cancerous tissues for Na(+)/taurocholate cotransporting polypeptide (NTCP) and organic anion-transporting polypeptide 8 (OATP8), which are associated with portal uptake of ICG by hepatocytes that tended to be higher in the HCCs that showed cancerous-type fluorescence than in those that showed rim-type fluorescence. CONCLUSIONS: Preserved portal uptake of ICG in differentiated HCC cells by NTCP and OATP8 with concomitant biliary excretion disorders causes accumulation of ICG in the cancerous tissues after preoperative intravenous administration. This enables highly sensitive identification of HCC by intraoperative ICG fluorescence imaging.

Nuclear Factor-κB Decoy Oligodeoxynucleotide Attenuates Cartilage Resorption In Vitro.

BACKGROUND: Cartilage harvest and transplantation is a common surgery using costal, auricular, and septal cartilage for craniofacial reconstruction. However, absorption and warping of the cartilage grafts can occur due to inflammatory factors associated with wound healing. Transcription factor nuclear factor-κB (NF-κB) is activated by the various stimulation such as interleukin-1 (IL-1), and plays a central role in the transactivation of this inflammatory cytokine gene. Inhibition of NF-κB may have anti-inflammatory effects. The aim of this study was to explore the potential of an NF-κB decoy oligodeoxynucleotide (Decoy) as a chondroprotective agent. MATERIALS AND METHODS: Safe and efficacious concentrations of Decoy were assessed using rabbit nasal septal chondrocytes (rNSChs) and assays for cytotoxicity, proteoglycan (PG) synthesis, and PG turnover were carried out. The efficacious concentration of Decoy determined from the rNSChs was then applied to human nasal septal cartilage (hNSC) in vitro and analyzed for PG turnover, the levels of inflammatory markers, and catabolic enzymes in explant-conditioned culture medium. RESULTS: Over the range of Decoy conditions and concentrations, no inhibition of PG synthesis or cytotoxicity was observed. Decoy at 10 µM effectively inhibited PG degradation in the hNSC explant, prolonging PG half-life by 63% and decreasing matrix metalloprotease 3 (MMP-3) by 70.7% (p = 0.027). CONCLUSIONS: Decoy may be considered a novel chondroprotective therapeutic agent in cartilage transplantation due to its ability to inhibit cartilage degradation due to inflammation cytokines.

Chest Wall to Heart Distance Reproducibility in Postoperative Deep Inspiration Breath-Hold Radiotherapy for Left-Sided Breast Cancer Using an Anzai Laser Sensor With Visual Feedback.

Background Left-sided breast cancer radiotherapy may increase the risk of cardiovascular death due to possible heart irradiation. The reproducibility of the chest wall to heart distance in deep inspiration breath-hold (DIBH) was studied using a laser sensor with visual feedback. Methodology A total of 10 consecutive postoperative left-sided breast cancer cases receiving DIBH radiotherapy between December 2022 and September 2023 were retrospectively investigated. The prescribed dose was 50 Gy in 25 fractions. An Anzai respiratory gating system, AZ-733VI (Anzai, Tokyo, Japan), was employed that has a laser displacement sensor and a visual feedback device. An Elekta linac with a cone-beam CT unit, Axesse (Elekta AB, Stockholm, Sweden), was used in this study. The interfractional changes in the chest wall to heart distance among 25 fractions were analyzed for each of the 10 patients in each coordinate axis. In addition, the median with the 95% confidence interval (CI) and interquartile range (IQR) for all 250 fractions were calculated in each axis to assess the reproducibility of our DIBH technique. Results The medians of the interfractional changes in the chest wall to heart distance in each of the 10 patients ranged from -2 mm to 3 mm, -1 mm to 3 mm, and -2 mm to 1 mm in the lateral (X), superior-inferior (Y), and anterior-posterior (Z) directions, respectively. For all 10 cases, the medians were 1 mm (95% CI = 0.72 to 1.28 mm) in X, 1 mm (95% CI = 0.76 to 1.24 mm) in Y, and 0 mm (95% CI = -0.20 to 0.20 mm) in Z directions, whereas the IQRs were 4 mm in X, 2 mm in Y and 2 mm in Z directions. The measured IQRs were two to three times smaller than those shown in a previous report without visual feedback, suggesting a clinical advantage of the visual feedback in DIBH for left-sided breast cancer radiotherapy. The DIBH solution shown in this study required approximately 10 minutes from room-in to room-out, thereby not reducing the daily number of patients. Conclusions Our DIBH approach with visual feedback achieved better distance reproducibility between the chest wall and heart by a factor of two to three in terms of IQR compared to the previously reported data without visual feedback. Patient throughput was also favorable. To our knowledge, this is the first report demonstrating the chest wall to heart distance reproducibility in DIBH with visual feedback.

Pharmacokinetics, Fecal Output, and Grimace Scores in Rabbits Given Long-acting Buprenorphine or Fentanyl for Postsurgical Analgesia.

The New Zealand white rabbit (Oryctolagus cuniculus) is a frequently used surgical model. Pain management after surgery is a critical aspect of animal welfare. Recently, a long-acting buprenorphine formulation (Ethiqa XR; EXR) was approved for use in rats and mice but has not yet been investigated in rabbits. The current study aimed to determine whether a single subcutaneous dose of 0.15mg/kg of EXR could achieve and maintain therapeutic buprenorphine plasma concentrations (0.1ng/mL) for 72h in male and female rabbits. We also evaluated the safety profiles of EXR and the fentanyl patch (FP) by assessing fecal output after surgery, because opioids are known to decrease intestinal motility. Behavior and pain scores were compared for rabbits that received either EXR or the FP after undergoing an annulus puncture procedure to induce osteoarthritis. EXR at 0.15mg/kg SC provided a shorter time to onset and sustained analgesia for 72h in male and female rabbits, whereas the FP provided suboptimal analgesia after 48h. Both EXR and FP reduced fecal output after surgery. Output returned to baseline levels within 72h for the EXR group and remained slightly below baseline at 96h after surgery for the fentanyl group. Grimace pain scores revealed no significant difference between treatment groups. These results suggest that EXR is a safe and effective option for postoperative pain management in rabbits.

Portal uptake function in veno-occlusive regions evaluated by real-time fluorescent imaging using indocyanine green.

BACKGROUND & AIMS: Although recent advances in preoperative imaging have enabled accurate estimation of the regional liver volume with venous occlusion, the extent of functional decrease in such regions remains unclear. In this study, the portal uptake function in postoperative veno-occlusive regions and non-veno-occlusive regions was evaluated by intraoperative fluorescent imaging after intravenous injection of indocyanine green (ICG). METHODS: In 22 liver resection patients and 23 recipients and 18 donors of liver transplantation, fluorescent intensity on the remnant liver or the liver graft was evaluated in real time following intravenous injection of ICG (0.0025 mg per 1 ml of remnant liver volume). RESULTS: Plateau ICG concentrations were significantly lower in the veno-occlusive regions (C(VO)) than in the non-veno-occlusive regions (C(Non)) in liver resection patients (median [range], 0.75 [0.29-2.0]µg/ml vs. 3.0 [0.46-6.4]µg/ml, p<0.001), donors (0.69 [0.29-1.9]µg/ml vs. 2.4 [0.46-6.4]µg/ml, p<0.001), and recipients (0.75 [0.34-1.8]µg/ml vs. 1.8 [0.54-6.4]µg/ml, p<0.001). Distributions of the C(VO)/C(Non) and the ratio of the hepatic uptake rate constant in the veno-occlusive regions to that in non-veno-occlusive regions were both around 40% (mean ± standard deviation, 0.36 ± 0.17 and 0.42 ± 0.16, respectively). When the functional remnant liver volume was calculated as a sum of non-veno-occlusive regions and veno-occlusive regions multiplied by C(VO)/C(Non), its ratio to the total liver volume was correlated with the improved postoperative/preoperative ratio of prothrombin time. CONCLUSIONS: Portal uptake function in veno-occlusive regions is approximately 40% of that in non-veno-occlusive regions. Intraoperative ICG-fluorescent imaging enables real-time evaluation of the extent of the functional decrease in veno-occlusive regions, enhancing accurate estimation of the hepatic functional reserve for determining the surgical indications and procedures.